Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury.
Willis Gareth R,Fernandez-Gonzalez Angeles,Reis Monica,Yeung Vincent,Liu Xianlan,Ericsson Maria,Andrews Nick A,Mitsialis S Alex,Kourembanas Stella
Journal of extracellular vesicles
Early administration of mesenchymal stromal cell (MSC)-derived small extracellular vesicles (MEx) has shown considerable promise in experimental models of bronchopulmonary dysplasia (BPD). However, the ability of MEx to reverse the long-term pulmonary complications associated with established BPD remains unknown. In this study, MEx were isolated from media conditioned by human Wharton's Jelly-derived MSC cultures. Newborn mice (FVB strain) were exposed to hyperoxia (HYRX (75% O2)) before returning to room air at postnatal day 14 (PN14). Following prolonged HYRX-exposure, animals received a single MEx dose at PN18 or serial MEx treatments at PN18-39 ("late" intervention). This group was compared to animals that received an early single MEx dose at PN4 ("early" intervention). Animals were harvested at PN28 or 60 for assessment of pulmonary parameters. We found that early and late MEx interventions effectively ameliorated core features of HYRX-induced neonatal lung injury, improving alveolar simplification, pulmonary fibrosis, vascular remodelling and blood vessel loss. Exercise capacity testing and assessment of pulmonary hypertension (PH) showed functional improvements following both early and late MEx interventions. In conclusion, delivery of MEx following prolonged HYRX-exposure improves core features of experimental BPD, restoring lung architecture, decreasing pulmonary fibrosis and vascular muscularization, ameliorating PH and improving exercise capacity. Taken together, delivery of MEx may not only be effective in the immediate neonatal period to prevent the development of BPD but may provide beneficial effects for the management and potentially the reversal of cardiorespiratory complications in infants and children with established BPD.
10.1080/20013078.2020.1790874
Pulmonary gas exchange in relation to exercise pulmonary hypertension in patients with heart failure with preserved ejection fraction.
The European respiratory journal
BACKGROUND:Exercise pulmonary hypertension (ePH), defined as a mean pulmonary artery pressure (mPAP)/cardiac output (Qc) slope >3 WU during exercise, is common in patients with heart failure with preserved ejection fraction (HFpEF). However, the pulmonary gas exchange-related effects of an exaggerated ePH (EePH) response are not well-defined, especially in relation to dyspnea on exertion (DOE) and exercise intolerance. METHODS:48 HFpEF patients underwent invasive (pulmonary and radial artery catheters) constant-load (20W) and maximal incremental cycle testing. Hemodynamic measurements (mPAP and Qc), arterial blood and expired gases, and ratings of breathlessness (RPB, Borg 0-10) were obtained. The mPAP/Qc slope was calculated from rest-to-20W. Those with a mPAP/Qc slope >4.2 (median) were classified as HFpEF+EePH (n=24) and those with a mPAP/Qc slope <4.2 were classified as HFpEF (without EePH) (n=24). The A-aDO, V/V (Bohr equation), and the V/VCO slope (from rest-to-20W) were calculated. RESULTS:PaO was lower (p=0.03), and V/V was higher (p=0.03) at peak exercise in HFpEF+EePH compared with HFpEF. A-aDO was similar at peak exercise between groups (p=0.14); however, HFpEF+EePH achieved the peak A-aDO at a lower peak work rate (p<0.01). The V/VCO slope was higher in HFpEF+EePH compared with HFpEF (p=0.01). RPB was ≥1-unit higher at 20W and VO was lower (p<0.01) in HFpEF+EePH compared with HFpEF. CONCLUSIONS:These data suggest that EePH contributes to pulmonary gas exchange impairments during exercise by causing a V/Q mismatch that provokes both ventilatory inefficiency and hypoxemia, both of which seem to contribute to DOE and exercise intolerance in patients with HFpEF.
10.1183/13993003.00722-2024
Deep phenotype characterization of hypertensive response to exercise: implications on functional capacity and prognosis across the heart failure spectrum.
European journal of heart failure
AIMS:Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE. METHODS AND RESULTS:We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A-B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36-0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30-0.63) was similar to controls (0.43, 0.35-0.57) but significantly lower than Stages A-B (0.61, 0.47-0.75) and HFpEF (0.63, 0.42-0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF. CONCLUSION:A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A-B and HFpEF.
10.1002/ejhf.2827
High soluble transferrin receptor in patients with heart failure: a measure of iron deficiency and a strong predictor of mortality.
European journal of heart failure
AIMS:Iron deficiency (ID) is frequent in heart failure (HF), linked with exercise intolerance and poor prognosis. Intravenous iron repletion improves clinical status in HF patients with left ventricular ejection fraction (LVEF) ≤45%. However, uncertainty exists about the accuracy of serum biomarkers in diagnosing ID. The aims of this study were (i) to identify the iron biomarker with the greatest accuracy for the diagnosis of ID in bone marrow in patients with ischaemic HF, and (ii) to establish the prevalence of ID using this biomarker and its prognostic value in HF patients. METHODS AND RESULTS:Bone marrow was stained for iron in 30 patients with ischaemic HF with LVEF ≤45% and 10 healthy controls, and ID was diagnosed for 0-1 grades (Gale scale). A total of 791 patients with HF with LVEF ≤45% were prospectively followed up for 3 years. Serum ferritin, transferrin saturation, soluble transferrin receptor (sTfR) were assessed as iron biomarkers. Most patients with HF (n = 25, 83%) had ID in bone marrow, but none of the controls (P < 0.001). Serum sTfR had the best accuracy in predicting ID in bone marrow (area under the curve 0.920, 95% confidence interval 0.761-0.987, for cut-off 1.25 mg/L sensitivity 84%, specificity 100%). Serum sTfR was ≥1.25 mg/L in 47% of HF patients, in 56% and 46% of anaemics and non-anaemics, respectively (P < 0.05). The reclassification methods revealed that serum sTfR significantly added the prognostic value to the baseline prognostic model, and to the greater extent than plasma N-terminal pro B-type natriuretic peptide. Based on internal derivation and validation procedures, serum sTfR ≥1.41 mg/L was the optimal threshold for predicting 3-year mortality, independent of other established variables. CONCLUSIONS:High serum sTfR accurately reflects depleted iron stores in bone marrow in patients with HF, and identifies those with a high 3-year mortality.
10.1002/ejhf.2036
A prospective STudy using invAsive haemodynamic measurements foLLowing catheter ablation for AF and early HFpEF: STALL AF-HFpEF.
Sugumar Hariharan,Nanayakkara Shane,Vizi Donna,Wright Leah,Chieng David,Leet Angeline,Mariani Justin A,Voskoboinik Aleksandr,Prabhu Sandeep,Taylor Andrew J,Kalman Jonathan M,Kistler Peter M,Kaye David M,Ling Liang-Han
European journal of heart failure
AIMS:The impact of atrial fibrillation (AF) ablation in early heart failure with preserved ejection fraction (HFpEF) is unknown. Our aim was to determine the impact of AF ablation on symptoms and exercise haemodynamic parameters of early HFpEF. METHODS AND RESULTS:Symptomatic AF patients referred for index AF ablation with ejection fraction ≥50% underwent baseline quality of life questionnaires, echocardiography, cardiac magnetic resonance imaging, exercise right heart catheterisation (exRHC), and brain natriuretic peptide (BNP) testing. HFpEF was defined by resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or peak exercise PCWP ≥25 mmHg. Patients with HFpEF were offered AF ablation and follow-up exRHC ≥6 months post-ablation. Of 54 patients undergoing baseline evaluation, 35 (65%) had HFpEF identified by exRHC. HFpEF patients were older (64 ± 10 vs. 54 ± 13 years, P < 0.01), and more frequently female (54% vs. 16%, P < 0.01), hypertensive (63% vs. 16%, P < 0.001), and suffering persistent AF (66% vs. 11%, P < 0.001), compared to those without HFpEF. Twenty HFpEF patients underwent AF ablation and follow-up exRHC 12 ± 6 months post-ablation. Nine (45%) patients no longer fulfilled exRHC criteria for HFpEF at follow-up. Patients remaining arrhythmia free (n = 9, 45%) showed significant improvements in peak exercise PCWP (29 ± 4 to 23 ± 2 mmHg, P < 0.01) and Minnesota Living with Heart Failure (MLHF) score (55 ± 30 to 22 ± 30, P < 0.01) while the remainder did not (PCWP 31 ± 5 to 30.0 ± 4 mmHg, P = NS; MLHF score 55 ± 23 to 25 ± 20, P = NS). CONCLUSION:Heart failure with preserved ejection fraction frequently coexists in patients with symptomatic AF and preserved ejection fraction. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improves haemodynamic parameters, BNP and symptoms associated with HFpEF.
10.1002/ejhf.2122
Risk of subsequent disabling or fatal stroke in patients with transient ischaemic attack or minor ischaemic stroke: an international, prospective cohort study.
The Lancet. Neurology
BACKGROUND:Patients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability. METHODS:We analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0-1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence, categorised as disabling (mRS score of >1, including death) or non-disabling (mRS score of 0-1), at 5 years after baseline, were associated with poor functional outcome (defined as an mRS score of >1). We used multivariable generalised equation models for factors associated with poor functional outcome at 5 years and multivariable cause-specific Cox hazard regression models in case of stroke recurrence. FINDINGS:Between May 30, 2009, and Dec 30, 2011, 3847 eligible patients were included in the study, 3105 (80·7%) of whom had an mRS evaluation at 5 years of follow-up. Median follow-up duration was 5·00 years (IQR 4·78-5·00). 710 (22·9%) of 3105 patients had an mRS score greater than 1 at 5 years. Factors associated with poor functional outcome at 5 years were older age (per 10-year increase, odds ratio [OR] 2·18, 95% CI 1·93-2·46; p<0·0001), diabetes of any type (1·45, 1·18-1·78; p=0·0001), history of stroke or transient ischaemic attack before the qualifying event (1·74, 1·37-2·22; p<0·0001), hypertension (1·38, 1·00-1·92; p=0·050), atrial fibrillation or flutter (1·52, 1·04-1·94; p=0·030), congestive heart failure (1·73, 1·22-2·46; p=0·0024), valvular disease (2·47, 1·70-3·58; p<0·0001), stroke as qualifying event (1·31, 1·09-1·57; p=0·0037), history of peripheral artery disease (1·98, 1·28-3·07; p=0·0023), history of coronary artery disease (1·32, 1·00-1·74; p=0·049), intracranial haemorrhage during follow up (4·94, 1·91-12·78; p=0·0013), and living alone (1·32, 1·10-1·59; p=0·0031). Regular physical activity before the index event was associated with reduced risk of poor functional outcome (OR 0·52, 95% CI 0·42-0·66; p<0·0001). 345 recurrent strokes had occurred at 5 years of follow-up, 141 (40·9%) of which were disabling or fatal. Stroke recurrence increased the risk of having a disability at 5 years (OR 3·52, 95% CI 2·37-5·22; p<0·0001). Recurrent disabling or fatal strokes were independently associated with older age (per 10-year increase, hazard ratio [HR] 1·61, 95% CI 1·35-1·92; p<0·0001), diabetes of any type (2·23, 1·56-3·17; p<0·0001), National Institutes of Health Stroke Scale score of greater than 5 at discharge (5·11, 2·15-12·13; p=0·0013), history of coronary artery disease (1·76, 1·17-2·65; p=0·0063), history of stroke or transient ischaemic attack before the qualifying event (1·54, 1·03-2·29; p=0·035), congestive heart failure (1·86, 1·01-3·47; p=0·044), stroke as qualifying event (1·73, 1·22-2·45; p=0·0024), mRS score of greater than 1 at discharge (2·48, 1·27-4·87; p=0·0083), and intracranial haemorrhage during follow-up (17·15, 9·95-27·43; p<0·0001). Regular physical activity before the index event was associated with reduced risk of recurrent disabling stroke at 5 years (HR 0·56, 95% CI 0·31-0·99; p=0·046), and 5-year disability without recurrent stroke (0·61, 0·47-0·79; p=0·0001). INTERPRETATION:We found a substantial burden of disability (mRS score of >1) at 5 years after transient ischaemic attack or minor ischemic stroke, and most predictors of this disability were modifiable risk factors. Patients who did regular physical exercise before the index event had a significantly reduced risk of disability at 5 years compared with patients who did no exercise. FUNDING:AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.
10.1016/S1474-4422(22)00302-7
IMPROvE-CED Trial: Intracoronary Autologous CD34+ Cell Therapy for Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Arteries.
Corban Michel T,Toya Takumi,Albers Diana,Sebaali Faten,Lewis Bradley R,Bois John,Gulati Rajiv,Prasad Abhiram,Best Patricia J M,Bell Malcolm R,Rihal Charanjit S,Prasad Megha,Ahmad Ali,Lerman Lilach O,Solseth Mary L,Winters Jeffrey L,Dietz Allan B,Lerman Amir
Circulation research
BACKGROUND:Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. METHODS:Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×10 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. RESULTS:Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [-18.0 to 32.4] to 57.6 [16.3-98.3]%; =0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, =0.00018), and sublingual nitroglycerin use/day (1 [0.4-3.5] to 0 [0-1], Wilcoxon signed-rank test, =0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. CONCLUSIONS:A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03471611.
10.1161/CIRCRESAHA.121.319644
Long-Distance Skiing and Incidence of Hypertension: A Cohort Study of 206 889 Participants in a Long-Distance Cross-Country Skiing Event.
Andersen Kasper,Hållmarker Ulf,James Stefan,Sundström Johan
Circulation
BACKGROUND:Hypertension is the leading risk factor for death worldwide, and high levels of physical activity are associated with a lower incidence of hypertension. The associations of excessive levels of exercise and incidence of hypertension are less well known. We aim to compare the incidence of hypertension among 206 889 participants in a long-distance cross-country skiing event and 505 542 people randomly sampled from the general population (matched to the skiers on age, sex, and place of residence). METHODS:Skiers' best performance (in percent of winning time) and number of completed races during the study period were associated with incidence of hypertension after participation in Vasaloppet. Hypertension was defined as prescription of blood pressure-lowering drugs as obtained from the national drug registry. Models were adjusted for sex, age, education, and income (total effect). RESULTS:During a median time of risk of 8.3 years, skiers had a lower incidence of hypertension compared with nonskiers (hazard ratio [HR], 0.59 [95% CI, 0.58-0.60]). Among the skiers, better performance (in percent of winning time) in Vasaloppet was strongly associated with a lower incidence of hypertension (fastest fifth: HR, 0.41 [95% CI, 0.39-0.42]; slowest fifth: HR, 0.78 [95% CI, 0.75-0.81]). The association was nearly linear and did not differ between sexes. Among the skiers, a weaker association was seen between the number of completed races during the study period and the incidence of hypertension (1 race: HR, 0.63 [95% CI, 0.62-0.65]; >5 races: HR, 0.51 [95% CI, 0.50-0.53]). A subanalysis of 10 804 participants including adjustment for lifestyle factors showed similar results. CONCLUSIONS:Participation in a long-distance skiing event was associated with a 41% lower incidence of hypertension over the next 8 years compared with nonparticipation. A near linear association between performance and incidence of hypertension was observed. This adds to the list of beneficial effects of intensive training, because hypertension is the leading risk factor of premature death globally.
10.1161/CIRCULATIONAHA.119.042208
Global, regional, and national burden of stroke and its risk factors, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
The Lancet. Neurology
BACKGROUND:Up-to-date estimates of stroke burden and attributable risks and their trends at global, regional, and national levels are essential for evidence-based health care, prevention, and resource allocation planning. We aimed to provide such estimates for the period 1990-2021. METHODS:We estimated incidence, prevalence, death, and disability-adjusted life-year (DALY) counts and age-standardised rates per 100 000 people per year for overall stroke, ischaemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage, for 204 countries and territories from 1990 to 2021. We also calculated burden of stroke attributable to 23 risk factors and six risk clusters (air pollution, tobacco smoking, behavioural, dietary, environmental, and metabolic risks) at the global and regional levels (21 GBD regions and Socio-demographic Index [SDI] quintiles), using the standard GBD methodology. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. FINDINGS:In 2021, stroke was the third most common GBD level 3 cause of death (7·3 million [95% UI 6·6-7·8] deaths; 10·7% [9·8-11·3] of all deaths) after ischaemic heart disease and COVID-19, and the fourth most common cause of DALYs (160·5 million [147·8-171·6] DALYs; 5·6% [5·0-6·1] of all DALYs). In 2021, there were 93·8 million (89·0-99·3) prevalent and 11·9 million (10·7-13·2) incident strokes. We found disparities in stroke burden and risk factors by GBD region, country or territory, and SDI, as well as a stagnation in the reduction of incidence from 2015 onwards, and even some increases in the stroke incidence, death, prevalence, and DALY rates in southeast Asia, east Asia, and Oceania, countries with lower SDI, and people younger than 70 years. Globally, ischaemic stroke constituted 65·3% (62·4-67·7), intracerebral haemorrhage constituted 28·8% (28·3-28·8), and subarachnoid haemorrhage constituted 5·8% (5·7-6·0) of incident strokes. There were substantial increases in DALYs attributable to high BMI (88·2% [53·4-117·7]), high ambient temperature (72·4% [51·1 to 179·5]), high fasting plasma glucose (32·1% [26·7-38·1]), diet high in sugar-sweetened beverages (23·4% [12·7-35·7]), low physical activity (11·3% [1·8-34·9]), high systolic blood pressure (6·7% [2·5-11·6]), lead exposure (6·5% [4·5-11·2]), and diet low in omega-6 polyunsaturated fatty acids (5·3% [0·5-10·5]). INTERPRETATION:Stroke burden has increased from 1990 to 2021, and the contribution of several risk factors has also increased. Effective, accessible, and affordable measures to improve stroke surveillance, prevention (with the emphasis on blood pressure, lifestyle, and environmental factors), acute care, and rehabilitation need to be urgently implemented across all countries to reduce stroke burden. FUNDING:Bill & Melinda Gates Foundation.
10.1016/S1474-4422(24)00369-7
Left atrial enlargement is associated with pulmonary vascular disease in heart failure with preserved ejection fraction.
European journal of heart failure
AIMS:Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. METHODS AND RESULTS:Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m , >34 to ≤45 ml/m , >45 ml/m ). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (p <0.001), higher resting mean pulmonary artery pressure (p = 0.003), with similar wedge pressure (p = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (p <0.001). Larger LA volumes featured reduced LA strain (p <0.001), with reduced strain associated with reduced PVR-compliance time (0.34 [0.28-0.40] vs. 0.38 [0.33-0.43], p = 0.03). CONCLUSION:Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR-compliance relationship, further augmenting impaired pulmonary haemodynamics.
10.1002/ejhf.2805
Efficacy of supermarket and web-based interventions for improving dietary quality: a randomized, controlled trial.
Nature medicine
Dietary interventions may best be delivered at supermarkets, which offer convenience, accessibility, full food inventories and, increasingly, in-store registered dietitians, online shopping and delivery services. In collaboration with a large retail supermarket chain, we conducted a multisite supermarket and web-based intervention targeting nutrition trial (no. NCT03895580), randomizing participants (n = 247 (139 women and 108 men)) 2:2:1 to two levels of dietary education (Strategy 1 and Strategy 2) or an enhanced control group that included educational components beyond the routine standard of care. Both Strategies 1 and 2 included individualized, in-person, dietitian-led, purchasing data-guided interventions. Strategy 2 also included online tools for shopping, home delivery, selection of healthier purchases, meal planning and healthy recipes. The primary endpoint was change in dietary approaches to stop hypertension (DASH) score (a measure of adherence to the DASH diet) from baseline to 3 months. The primary endpoint was met because, at 3 months, the DASH score increased by 4.7 more for the combined Strategy 1 and Strategy 2 groups than for the control group (95% confidence interval (CI) (0.9, 8.5), P = 0.02). In a prespecified hierarchical test, at 3 months, DASH score increased by 3.8 more for the Strategy 2 group than for the Strategy 1 group (95% CI (0.8, 6.)9, P = 0.01). This trial demonstrates the efficacy of data-guided, supermarket-based, dietary interventions and modern online shopping tools in improving dietary quality in a free-living, community-based population. The trial also demonstrates the opportunity for academic investigators to collaborate with retailers to design and rigorously test comprehensive healthcare interventions.
10.1038/s41591-022-02077-7
Non-arterial line cardiac output calculation misclassifies exercise pulmonary hypertension and increases risk of data loss particularly in black, scleroderma and Raynaud's patients during invasive exercise testing.
The European respiratory journal
BACKGROUND:The direct Fick principle is the standard for calculating cardiac output (CO) to detect CO-dependent conditions like exercise pulmonary hypertension (ePH). Fick CO incorporates arterial haemoglobin (Hb) and oxygen saturation ( ) with oxygen consumption from exercise testing, while Fick CO substitutes mixed venous haemoglobin (Hb) and peripheral oxygen saturation ( ) in the absence of an arterial line. The decision to employ an arterial catheter for exercise testing varies, and discrepancies in oxygen saturation and haemoglobin between arterial and non-arterial methods may lead to differences in Fick CO, potentially affecting ePH classification. METHODS:We performed a retrospective analysis of 296 consecutive invasive cardiopulmonary exercise testing (iCPET) studies comparing oxygen saturation from pulse oximetry ( ) and radial arterial ( ), Hb and Hb, and CO calculated with arterial (CO) and non-arterial (CO) values. We assessed the risk of misclassification of pre- and post-capillary ePH and data loss due to inaccurate . RESULTS:When considering all stages from rest to peak exercise, Hb and Hb demonstrated high correlation, while and as well as CO and CO demonstrated low correlation. Data loss was significantly higher across all stages of exercise for (n=346/1926 (18%)) compared to (n=17/1923 (0.88%)). We found that pre- and post-capillary ePH were misclassified as CO data (n=7/41 (17.1%) and n=2/23 (8.7%), respectively). Patients with scleroderma and/or Raynaud's (n=11/33 (33.3%)) and black patients (n=6/19 (31.6%)) had more data loss. CONCLUSION:Reliance upon during invasive exercise testing results in the misclassification of pre- and post-capillary ePH, and unmeasurable for black, scleroderma and Raynaud's patients can preclude accurate exercise calculations, thus limiting the diagnostic and prognostic value of invasive exercise testing without an arterial line.
10.1183/13993003.02232-2023
Haemodynamic and metabolic phenotyping of hypertensive patients with and without heart failure by combining cardiopulmonary and echocardiographic stress test.
Pugliese Nicola R,Mazzola Matteo,Fabiani Iacopo,Gargani Luna,De Biase Nicolò,Pedrinelli Roberto,Natali Andrea,Dini Frank L
European journal of heart failure
AIM:We combined cardiopulmonary exercise test (CPET) and exercise stress echocardiography (ESE) to identify early haemodynamic and metabolic alterations in patients with hypertension (HT) with and without heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS:Fifty stable HFpEF-HT outpatients (mean age 68 ± 14 years) on optimal medical therapy, 63 well-controlled HT subjects (mean age 63 ± 11 years) and 32 age and sex-matched healthy controls (mean age 59 ± 15 years) underwent a symptom-limited graded ramp bicycle CPET-ESE. The acquisition protocol included left ventricular cardiac output, global longitudinal strain, E/e', peak oxygen consumption (VO ), non-invasive arterial-venous oxygen content difference (AVO diff) and lung ultrasound B-lines. There was a decline in peak VO from controls (24.4 ± 3 mL/min/kg) to HFpEF-HT (15.2 ± 2 mL/min/kg), passing through HT (18.7 ± 2 mL/min/kg; P < 0.0001). HFpEF-HT displayed a lower peak cardiac output (9.8 ± 0.9 L/min) compared to HT (12.6 ± 1.0 L/min; P = 0.02) and controls (13.3 ± 1.0 L/min; P = 0.01). Peak AVO diff was reduced in HFpEF-HT and HT (13.3 ± 2 and 13.5 ± 2 mL/dL vs. controls: 16.9 ± 2 mL/dL; P < 0.0001). A different left ventricular contractility was observed among groups, expressed as low-load global longitudinal strain (-16.8 ± 5% in HFpEF-HT, -18.2 ± 3% in HT, and 20.9 ± 3% in controls; P < 0.0001), and distribution of E/e' and B-lines [HFpEF-HT: 13.7 ± 3 and 16, interquartile range (IQR) 10-22; HT: 9.5 ± 2 and 8, IQR 4-10; controls: 6.2 ± 2 and 0, IQR 0-2; P < 0.0001]. CONCLUSIONS:Reduced peak VO values in HT with and without HFpEF may be the result of decreased AVO diff. CPET-ESE can also identify mild signs of left ventricular systo-diastolic dysfunction and pulmonary congestion, promoting advances in personalized therapy.
10.1002/ejhf.1739
Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort.
Journal of the American College of Cardiology
BACKGROUND:Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear. OBJECTIVES:This study sought to investigate the association of exPH with clinical determinants and outcomes. METHODS:The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality. RESULTS:Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both). CONCLUSIONS:Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.
10.1016/j.jacc.2019.10.048
Behavioral Counseling to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults With Cardiovascular Risk Factors: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
O'Connor Elizabeth A,Evans Corinne V,Rushkin Megan C,Redmond Nadia,Lin Jennifer S
JAMA
Importance:Cardiovascular disease is the leading cause of death in the US, and poor diet and lack of physical activity are major factors contributing to cardiovascular morbidity and mortality. Objective:To review the benefits and harms of behavioral counseling interventions to improve diet and physical activity in adults with cardiovascular risk factors. Data Sources:MEDLINE, PubMed, PsycINFO, and the Cochrane Central Register of Controlled Trials through September 2019; literature surveillance through July 24, 2020. Study Selection:English-language randomized clinical trials (RCTs) of behavioral counseling interventions to help people with elevated blood pressure or lipid levels improve their diet and increase physical activity. Data Extraction and Synthesis:Data were extracted from studies by one reviewer and checked by a second. Random-effects meta-analysis and qualitative synthesis were used. Main Outcomes and Measures:Cardiovascular events, mortality, subjective well-being, cardiovascular risk factors, diet and physical activity measures (eg, minutes of physical activity, meeting physical activity recommendations), and harms. Interventions were categorized according to estimated contact time as low (≤30 minutes), medium (31-360 minutes), and high (>360 minutes). Results:Ninety-four RCTs were included (N = 52 174). Behavioral counseling interventions involved a median of 6 contact hours and 12 sessions over the course of 12 months and varied in format and dietary recommendations; only 5% addressed physical activity alone. Interventions were associated with a lower risk of cardiovascular events (pooled relative risk, 0.80 [95% CI, 0.73-0.87]; 9 RCTs [n = 12 551]; I2 = 0%). Event rates were variable; in the largest trial (Prevención con Dieta Mediterránea [PREDIMED]), 3.6% in the intervention groups experienced a cardiovascular event, compared with 4.4% in the control group. Behavioral counseling interventions were associated with small, statistically significant reductions in continuous measures of blood pressure, low-density lipoprotein cholesterol levels, fasting glucose levels, and adiposity at 12 to 24 months' follow-up. Measurement of diet and physical activity was heterogeneous, and evidence suggested small improvements in diet consistent with the intervention recommendation targets but mixed findings and a more limited evidence base for physical activity. Adverse events were rare, with generally no group differences in serious adverse events, any adverse events, hospitalizations, musculoskeletal injuries, or withdrawals due to adverse events. Conclusions and Relevance:Medium- and high-contact multisession behavioral counseling interventions to improve diet and increase physical activity for people with elevated blood pressure and lipid levels were effective in reducing cardiovascular events, blood pressure, low-density lipoproteins, and adiposity-related outcomes, with little to no risk of serious harm.
10.1001/jama.2020.17108
Noninvasive evaluation of pulmonary artery pressure during exercise: the importance of right atrial hypertension.
Obokata Masaru,Kane Garvan C,Sorimachi Hidemi,Reddy Yogesh N V,Olson Thomas P,Egbe Alexander C,Melenovsky Vojtech,Borlaug Barry A
The European respiratory journal
INTRODUCTION:Identification of elevated pulmonary artery pressures during exercise has important diagnostic, prognostic and therapeutic implications. Stress echocardiography is frequently used to estimate pulmonary artery pressures during exercise testing, but data supporting this practice are limited. This study examined the accuracy of Doppler echocardiography for the estimation of pulmonary artery pressures at rest and during exercise. METHODS:Simultaneous cardiac catheterisation-echocardiographic studies were performed at rest and during exercise in 97 subjects with dyspnoea. Echocardiography-estimated pulmonary artery systolic pressure (ePASP) was calculated from the right ventricular (RV) to right atrial (RA) pressure gradient and estimated RA pressure (eRAP), and then compared with directly measured PASP and RAP. RESULTS:Estimated PASP was obtainable in 57% of subjects at rest, but feasibility decreased to 15-16% during exercise, due mainly to an inability to obtain eRAP during stress. Estimated PASP correlated well with direct PASP at rest (r=0.76, p<0.0001; bias -1 mmHg) and during exercise (r=0.76, p=0.001; bias +3 mmHg). When assuming eRAP of 10 mmHg, ePASP correlated with direct PASP (r=0.70, p<0.0001), but substantially underestimated true values (bias +9 mmHg), with the greatest underestimation among patients with severe exercise-induced pulmonary hypertension (EIPH). Estimation of eRAP during exercise from resting eRAP improved discrimination of patients with or without EIPH (area under the curve 0.81), with minimal bias (5 mmHg), but wide limits of agreement (-14-25 mmHg). CONCLUSIONS:The RV-RA pressure gradient can be estimated with reasonable accuracy during exercise when measurable. However, RA hypertension frequently develops in patients with EIPH, and the inability to noninvasively account for this leads to substantial underestimation of exercise pulmonary artery pressures.
10.1183/13993003.01617-2019
Coronary microvascular dysfunction is associated with exertional haemodynamic abnormalities in patients with heart failure with preserved ejection fraction.
Ahmad Ali,Corban Michel T,Toya Takumi,Verbrugge Frederik H,Sara Jaskanwal D,Lerman Lilach O,Borlaug Barry A,Lerman Amir
European journal of heart failure
AIMS:This study uniquely explored the relationship between coronary microvascular function and exercise haemodynamics using concurrent invasive testing. METHODS AND RESULTS:Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease and normal left ventricular ejection fraction (>50%) underwent haemodynamic exercise assessment and concurrent coronary reactivity testing. Heart failure with preserved ejection fraction (HFpEF) was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg at rest and/or ≥25 mmHg at peak exercise. Endothelium-independent coronary microvascular dysfunction (CMD) was defined as a coronary flow reserve (CFR) ≤2.5, while endothelium-dependent CMD was defined as ≤50% increase in coronary blood flow (CBF) in response to intracoronary acetylcholine infusions. Patients with HFpEF (n = 22) had significantly lower CFR (2.5 ± 0.6 vs. 3.2 ± 0.7; P = 0.0003) and median %CBF increase in response to intracoronary acetylcholine [1 (-35; 34) vs. 64 (-4; 133); P = 0.002] compared to patients without HFpEF (n = 29). PAWP was significantly higher in patients with endothelium-independent CMD compared to controls during both rest and exercise. This significant elevation was only present during exercise in patients with endothelium-dependent CMD compared to controls. CFR had significant inverse correlations with PAWP at rest (r = -0.31; P = 0.03) and peak exercise (r = -0.47, P = 0.001). CFR also had positive correlations with maximal exercise capacity (in W/kg) (r = 0.33, P = 0.02). CONCLUSIONS:Coronary microvascular function is inversely associated with filling pressures, particularly during exercise. Both types of CMD are associated with higher filling pressures at peak exercise. These findings underscore the potential mechanism and therapeutic target for CMD and HFpEF.
10.1002/ejhf.2010
Screening for pulmonary arterial hypertension in adults carrying a mutation.
The European respiratory journal
BACKGROUND:Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. METHODS:Asymptomatic mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. RESULTS:55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. CONCLUSIONS:Asymptomatic mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.
10.1183/13993003.04229-2020
Screening for Hypertension in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
Gartlehner Gerald,Vander Schaaf Emily B,Orr Colin,Kennedy Sara M,Clark Rachel,Viswanathan Meera
JAMA
Importance:Childhood hypertension can result in adverse outcomes during adulthood; identifying and treating primary and secondary childhood hypertension may reduce such risks. Objective:To update the evidence on screening and treatment of hypertension in childhood and adolescence for the US Preventive Services Task Force. Data Sources:PubMed, Cochrane Library, International Pharmaceutical Abstracts, EMBASE, and trial registries through September 3, 2019; bibliographies from retrieved articles, experts, and surveillance of the literature through October 6, 2020. Study Selection:Fair- or good-quality English-language studies evaluating diagnostic accuracy of blood pressure screening; cohort studies assessing the association of hypertension in childhood and adolescence with blood pressure or other intermediate outcomes in adulthood; randomized clinical trials (RCTs) or meta-analyses of pharmacological and lifestyle interventions. Data Extraction and Synthesis:Two reviewers independently assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; the evidence was synthesized qualitatively. Main Outcomes and Measures:Sensitivity, specificity, and measures of association between childhood and adulthood blood pressure; reduction of childhood blood pressure; adverse effects of treatments. Results:Forty-two studies from 43 publications were included (N>12 400). No studies evaluated the benefits or harms of screening and the effect of treating childhood hypertension on outcomes in adulthood. One study reported a sensitivity of 0.82 and a specificity of 0.70 for 2 office-based blood pressure measurements. Twenty observational studies suggested a significant association between childhood hypertension and abnormal blood pressure in adulthood (odds ratios, 1.1-4.5; risk ratios, 1.45-3.60; hazard ratios, 2.8-3.2). Thirteen placebo-controlled RCTs and 1 meta-analysis assessed reductions in systolic (SBP) and diastolic blood pressure from pharmacological treatments. Pooled reductions of SBP were -4.38 mm Hg (95% CI, -7.27 to -2.16) for angiotensin-converting enzyme inhibitors and -3.07 mm Hg (95% CI, -4.99 to -1.44) for angiotensin receptor blockers. Candesartan reduced SBP by -6.56 mm Hg (P < .001; n = 240). β-Blockers, calcium channel blockers, and mineralocorticoid receptor antagonists did not achieve significant reductions over 2 to 4 weeks. SBP was significantly reduced by exercise over 8 months (-4.9 mm Hg, P ≤ .05; n = 69), by dietary approaches to stop hypertension over 3 months (-2.2 mm Hg, P < .01; n = 57), and by a combination of drug treatment and lifestyle interventions over 6 months (-7.6 mm Hg; P < .001; n = 95). Low-salt diet did not achieve reductions of blood pressure. Conclusions and Relevance:Observational studies indicate an association between hypertension in childhood and hypertension in adulthood. However, the evidence is inconclusive whether the diagnostic accuracy of blood pressure measurements is adequate for screening asymptomatic children and adolescents in primary care.
10.1001/jama.2020.11119
Poor cardiac output reserve in pulmonary arterial hypertension is associated with right ventricular stiffness and impaired interventricular dependence.
The European respiratory journal
BACKGROUND:Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (-) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS:RV - loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance ( )) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. RESULTS:Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 49 mL·m; p=0.0001), with higher associated exercise afterload (effective arterial elastance ( ) 1.76 0.90 mmHg·mL; p<0.0001), RV stiffness ( 0.68 0.26 mmHg·mL; p=0.003) and right-sided pressures (right atrial pressure 14 8 mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 3.2 mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS:Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.
10.1183/13993003.00420-2024
Persistent exercise intolerance after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.
Ruigrok Dieuwertje,Meijboom Lilian J,Nossent Esther J,Boonstra Anco,Braams Natalia J,van Wezenbeek Jessie,de Man Frances S,Marcus J Tim,Vonk Noordegraaf Anton,Symersky Petr,Bogaard Harm-Jan
The European respiratory journal
AIM:Haemodynamic normalisation is the ultimate goal of pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH). However, whether normalisation of haemodynamics translates into normalisation of exercise capacity is unknown. The incidence, determinants and clinical implications of exercise intolerance after PEA are unknown. We performed a prospective analysis to determine the incidence of exercise intolerance after PEA, assess the relationship between exercise capacity and (resting) haemodynamics and search for preoperative predictors of exercise intolerance after PEA. METHODS:According to clinical protocol all patients underwent cardiopulmonary exercise testing (CPET), right heart catheterisation and cardiac magnetic resonance (CMR) imaging before and 6 months after PEA. Exercise intolerance was defined as a peak oxygen consumption (' ) <80% predicted. CPET parameters were judged to determine the cause of exercise limitation. Relationships were analysed between exercise intolerance and resting haemodynamics and CMR-derived right ventricular function. Potential preoperative predictors of exercise intolerance were analysed using logistic regression analysis. RESULTS:68 patients were included in the final analysis. 45 (66%) patients had exercise intolerance 6 months after PEA; in 20 patients this was primarily caused by a cardiovascular limitation. The incidence of residual pulmonary hypertension was significantly higher in patients with persistent exercise intolerance (p=0.001). However, 27 out of 45 patients with persistent exercise intolerance had no residual pulmonary hypertension. In the multivariate analysis, preoperative transfer factor of the lung for carbon monoxide ( ) was the only predictor of exercise intolerance after PEA. CONCLUSIONS:The majority of CTEPH patients have exercise intolerance after PEA, often despite normalisation of resting haemodynamics. Not all exercise intolerance after PEA is explained by the presence of residual pulmonary hypertension, and lower preoperative was a strong predictor of exercise intolerance 6 months after PEA.
10.1183/13993003.00109-2020
Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in the COPDGene Study.
American journal of respiratory and critical care medicine
Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.
10.1164/rccm.202312-2342OC
Exercise-Induced Ventricular Ectopy and Cardiovascular Mortality in Asymptomatic Individuals.
Refaat Marwan M,Gharios Charbel,Moorthy M Vinayaga,Abdulhai Farah,Blumenthal Roger S,Jaffa Miran A,Mora Samia
Journal of the American College of Cardiology
BACKGROUND:The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES:This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS:A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS:Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS:High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.
10.1016/j.jacc.2021.09.1366
Prognostic relevance of exercise pulmonary hypertension: results of the multicentre PEX-NET Clinical Research Collaboration.
The European respiratory journal
BACKGROUND:Exercise pulmonary hypertension (PH) was defined by a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope >3 mmHg·min·L between rest and exercise in the 2022 European Society of Cardiology/European Respiratory Society PH guidelines. However, large, multicentre studies on the prognostic relevance of exercise haemodynamics and its added value to resting haemodynamics are missing. PATIENTS AND METHODS:The PEX-NET (Pulmonary Haemodynamics during Exercise Network) registry enrolled patients who underwent clinically indicated right heart catheterisations both at rest and ergometer exercise from 23 PH centres worldwide. In this retrospective analysis we included subjects with resting mPAP <25 mmHg and complete haemodynamic data at rest and exercise in the same body position. Mixed effects Cox proportional hazard models with random effect centre were applied to identify independent markers of prognosis among the haemodynamic parameters. RESULTS:We included 764 patients (64% females; median (interquartile range) age 59 (46-69) years and mPAP 17 (14-20) mmHg). Median (range) observation time was 6.8 (0.1-15.9) years and 87 patients (11%) died during follow-up. After adjustment for age, sex, haemoglobin level and resting haemodynamics, CO (hazard ratio (HR) 0.85, 95% CI 0.77-0.93; p=0.001) and transpulmonary gradient (HR 1.04, 95% CI 1.00-1.08; p=0.044) at peak exercise and the mPAP/CO slope (HR 1.12, 95% CI 1.06-1.18; p<0.001) were the only independent predictors of prognosis. Patients with a mPAP/CO slope >3 mmHg·min·L had significantly worse survival compared to those with a mPAP/CO slope ≤3 mmHg·min·L (HR 2.04, 95% CI 1.16-3.58; p=0.013). CONCLUSION:The mPAP/CO slope is a robust and independent predictor of prognosis in patients with normal or mildly elevated resting PAP that provides prognostic information beyond resting haemodynamics and appears suitable to define exercise PH.
10.1183/13993003.00698-2024
Exercise intolerance in chronic thromboembolic pulmonary hypertension after pulmonary angioplasty.
Kikuchi Hanako,Goda Ayumi,Takeuchi Kaori,Inami Takumi,Kohno Takashi,Sakata Konomi,Soejima Kyoko,Satoh Toru
The European respiratory journal
INTRODUCTION:Exercise pulmonary hypertension is common in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who experience shortness of breath during exercise and reduced exercise capacity despite normalised pulmonary arterial pressure (PAP) at rest; however, the relationship between exercise pulmonary hypertension and exercise capacity remains unclear. Here we aimed to determine whether exercise pulmonary hypertension is related to exercise capacity and ventilatory efficiency in CTEPH patients with normalised resting haemodynamics after pulmonary balloon angioplasty (BPA). PATIENTS AND METHODS:In total, 249 patients with CTEPH treated with BPA (mean±sd age 63±14 years; male:female 62:187) with normal mean PAP (mPAP) (<25 mmHg) and pulmonary arterial wedge pressure (≤15 mmHg) at rest underwent cardiopulmonary exercise testing with right heart catheterisation. mPAP-cardiac output (CO) during exercise was plotted using multipoint plots. Exercise pulmonary hypertension was defined by a mPAP-CO slope >3.0. RESULTS:At rest, pulmonary vascular resistance was significantly higher in the exercise pulmonary hypertension group (n=116) than in the non-exercise pulmonary hypertension group (n=133). Lower peak oxygen consumption (13.5±3.8 16.6±4.7 mL·min·kg; p<0.001) was observed in the former group. The mPAP-CO slope was negatively correlated with peak oxygen consumption (r= -0.45, p<0.001) and positively correlated with the minute ventilation carbon dioxide output slope (r=0.39, p<0.001). CONCLUSIONS:Impaired exercise capacity and ventilatory efficiency were observed in patients with CTEPH who had normalised PAP at rest but exercise pulmonary hypertension.
10.1183/13993003.01982-2019
Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction.
European journal of heart failure
AIMS:Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnoea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF. METHODS AND RESULTS:Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non-heart failure controls (non-cardiac dyspnoea [NCD]) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA-PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle-tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (area under the curve 0.87, p < 0.0001), with a superior diagnostic ability to exercise E/e' ratio (DeLong p = 0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ 212.4 vs. 166.2, p < 0.0001). These findings were confirmed in Protocol 2. CONCLUSION:Left atrial compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnoea.
10.1002/ejhf.2862
Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial.
Udelson James E,Lewis Gregory D,Shah Sanjiv J,Zile Michael R,Redfield Margaret M,Burnett John,Parker John,Seferovic Jelena P,Wilson Phebe,Mittleman Robert S,Profy Albert T,Konstam Marvin A
JAMA
Importance:Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. Objective:To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. Design, Setting, and Participants:CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Interventions:Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). Main Outcomes and Measures:The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Results:Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). Conclusions and Relevance:Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. Trial Registration:ClinicalTrials.gov Identifier: NCT03254485.
10.1001/jama.2020.16641
Disproportionate exercise-induced pulmonary hypertension in relation to cardiac output in heart failure with preserved ejection fraction: a non-invasive echocardiographic study.
European journal of heart failure
AIMS:Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non-invasively by the mean pulmonary artery pressure-cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise-induced PH in relation to CO (DEi-PH) and its prognostic impact in patients with HFpEF. METHODS AND RESULTS:A total of 345 patients (166 HFpEF and 179 controls) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. DEi-PH was defined as the mPAP/CO slope >5.2 mmHg/L/min (median value). At rest, there were no differences in right ventricular (RV) function and severity of PH between HFpEF patients with and without DEi-PH. Compared with controls (n = 179) and HFpEF without DEi-PH (n = 83), HFpEF with DEi-PH (n = 83) demonstrated worse exercise capacity (lower peak oxygen consumption), depressed RV systolic function, impaired RV-pulmonary artery coupling, limitation in CO augmentation, more right-sided congestion, and worse ventilatory efficiency (higher minute ventilation vs. carbon dioxide volume) during peak exercise. Kaplan-Meier analyses showed that HFpEF patients with DEi-PH had higher rates of composite outcomes of all-cause mortality or heart failure events than those without (log-rank p = 0.0002). CONCLUSION:Patients with HFpEF and DEi-PH demonstrated distinct pathophysiologic features that become apparent only during exercise. These data suggest that DEi-PH is a pathophysiologic phenotype of HFpEF and reinforce the importance of exercise stress echocardiography for detailed characterization of HFpEF.
10.1002/ejhf.2821
Effects of Exercise and Weight Loss on Proximal Aortic Stiffness in Older Adults With Obesity.
Circulation
BACKGROUND:Obesity may accelerate age-related increases in aortic stiffness. Although aerobic exercise training generally has favorable effects on aortic structure and function, exercise alone may not be sufficient to improve aortic stiffness in older adults with obesity. We determined the effects of aerobic exercise training with and without moderate- to high-caloric restriction (CR) on the structure and function of the proximal aorta in 160 older (65-79 years) men and women with obesity (body mass index=30-45 kg/m). METHODS:Participants were randomly assigned to 1 of 3 groups: aerobic exercise training only (treadmill 4 days/week for 30 minutes at 65% to 70% of heart rate reserve; n=56), aerobic exercise training plus moderate CR (n=55), or aerobic exercise training plus more intensive CR (n=49) for 20 weeks. Aortic pulse wave velocity, aortic distensibility, and other measures of aortic structure and function were assessed by cardiovascular magnetic resonance imaging. Pearson correlation coefficients were examined to assess associations between changes in proximal aortic stiffness and changes in fitness, fatness, and other potential confounders. RESULTS:Weight loss in the aerobic exercise training plus moderate CR (-8.0 kg [95% CI, -9.17 to -6.87]) and aerobic exercise training plus more intensive CR (-8.98 kg [95% CI, -10.23 to -7.73) groups was significantly greater compared with the aerobic exercise training-only group (-1.66 kg [95% CI, -2.94 to -0.38]; <0.017 for both). There were significant treatment effects for descending aorta distensibility (=0.008) and strain (=0.004) and aortic arch pulse wave velocity (=0.01) with the aerobic exercise training plus moderate CR group having a 21% increase in distensibility (=0.016) and an 8% decrease in pulse wave velocity (=0.058). None of the aortic stiffness measures changed significantly in the aerobic exercise training-only or aerobic exercise training plus more intensive CR groups, and there were no significant changes in any other measure of aortic structure or function in these groups. Overall, increases in aortic distensibility were correlated with improvements in body weight and body fat distribution, but these associations were not statistically significant after adjustment for multiple comparisons. CONCLUSIONS:In older adults with obesity, combining aerobic exercise with moderate CR leads to greater improvements in proximal aortic stiffness than exercise alone. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01048736.
10.1161/CIRCULATIONAHA.120.051943
Oxygen Pathway Limitations in Patients With Chronic Thromboembolic Pulmonary Hypertension.
Howden Erin J,Ruiz-Carmona Sergio,Claeys Mathias,De Bosscher Ruben,Willems Rik,Meyns Bart,Verbelen Tom,Maleux Geert,Godinas Laurent,Belge Catharina,Bogaert Jan,Claus Piet,La Gerche Andre,Delcroix Marion,Claessen Guido
Circulation
BACKGROUND:Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis has been attributed to central factors, including ventilation/perfusion mismatch, increased pulmonary vascular resistance, and right heart dysfunction and uncoupling. Pulmonary endarterectomy and balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention. METHODS:Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (n=10). Furthermore, we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10). RESULTS:Peak Vo (oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted; <0.0001). The difference was attributable to impairments in multiple steps of the O cascade, including O delivery (product of cardiac output and arterial O content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O extracted in the periphery (ie, ΔAVo [arteriovenous O content difference]) was not different. After pulmonary vascular intervention, peak Vo increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min]; =0.036) but remained below age-predicted levels (70±11%). The O delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo was unchanged, as was skeletal muscle diffusion capacity. CONCLUSIONS:We demonstrated that patients with CTEPH have significant impairment of all steps in the O use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo by partly correcting O delivery but had no effect on abnormalities in peripheral O extraction. This suggests that current interventions only partially address patients' limitations and that additional therapies may improve functional capacity.
10.1161/CIRCULATIONAHA.120.052899
Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): a randomized placebo-controlled multicentre trial.
European journal of heart failure
AIMS:Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT. The aim of this study was to determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT. METHODS AND RESULTS:The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomized, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-min walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (interquartile range [IQR] 62-74) years, median left ventricular ejection fraction 29% (IQR 24-35), median PASP 45 (IQR 42-55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%). CONCLUSION:Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.
10.1002/ejhf.2527
Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.
Circulation
BACKGROUND:In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS:REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS:Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; =0.004). CONCLUSIONS:In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.
10.1161/CIRCULATIONAHA.122.059486
Sequencing and titrating approach of therapy in heart failure with reduced ejection fraction following the 2021 European Society of Cardiology guidelines: an international cardiology survey.
European journal of heart failure
AIMS:In symptomatic patients with heart failure and reduced ejection fraction (HFrEF), recent international guidelines recommend initiating four major therapeutic classes rather than sequential initiation. It remains unclear how this change in guidelines is perceived by practicing cardiologists versus heart failure (HF) specialists. METHODS AND RESULTS:An independent academic web-based survey was designed by a group of HF specialists and posted by email and through various social networks to a broad community of cardiologists worldwide 1 year after the publication of the latest European HF guidelines. Overall, 615 cardiologists (38 [32-47] years old, 63% male) completed the survey, of which 58% were working in a university hospital and 26% were HF specialists. The threshold to define HFrEF was ≤40% for 61% of the physicians. Preferred drug prescription for the sequential approach was angiotensin-converting enzyme inhibitors or angiotensin receptor-neprilysin inhibitors first (74%), beta-blockers second (55%), mineralocorticoid receptor antagonists third (52%), and sodium-glucose cotransporter 2 inhibitors (53%) fourth. Eighty-four percent of participants felt that starting all four classes was feasible within the initial hospitalization, and 58% felt that titration is less important than introducing a new class. Age, status in training, and specialization in HF field were the principal characteristics that significantly impacted the answers. CONCLUSION:In a broad international cardiology community, the 'historical approach' to HFrEF therapies remains the preferred sequencing approach. However, accelerated introduction and uptitration are also major treatment goals. Strategy trials in treatment guidance are needed to further change practices.
10.1002/ejhf.2743
Independent and Opposing Associations of Habitual Exercise and Chronic PM Exposures on Hypertension Incidence.
Guo Cui,Zeng Yiqian,Chang Ly-Yun,Yu Zengli,Bo Yacong,Lin Changqing,Lau Alexis Kh,Tam Tony,Lao Xiang Qian
Circulation
BACKGROUND:We investigated the joint associations of habitual physical activity (PA) and long-term exposure to fine particulate matter (PM) with the development of hypertension in a longitudinal cohort in Taiwan. METHODS:We selected 140 072 adults (≥18 years of age) without hypertension who joined a standard medical screening program with 360 905 medical examinations between 2001 and 2016. PM exposure was estimated at each participant's address using a satellite data-based spatiotemporal model with 1 km resolution. Information on habitual PA and a wide range of covariates was collected using a standard self-administered questionnaire. We used the Cox regression model with time-dependent covariates to examine the joint associations. RESULTS:The mean age of all observations was 41.7 years, and 48.8% were male. The mean value for systolic and diastolic blood pressure was 112.5 and 68.7mm Hg, respectively. Approximately 34.2% of all observations were inactive (0 metabolic equivalence values-hours), 29.8% had moderate-PA (median [interquartile range]; 3.75 [3.38 to 4.38] metabolic equivalence values-hours), and 36.0% had high-PA (15.7 [10.3 to 24.8] metabolic equivalence values-hours). The mean±SD of PM was 26.1±7.3 μg/m. The prevalence of cardiovascular disease, diabetes mellitus, and cancer was 2.1%, 2.9%, and 1.5%, respectively. After adjusting for a wide range of covariates (including a mutual adjustment for PA or PM), a higher PA level was associated with a lower risk of hypertension (hazard ratio [HR] for the moderate- and high-PA was 0.93 [95% CI, 0.89-0.97] and 0.92 [95% CI, 0.88-0.96], respectively, as compared with the inactive-PA), whereas a higher level of PM was associated with a higher risk of hypertension (HR for the moderate- and high-PM was 1.37 [95% CI, 1.32-1.43] and 1.92 [95% CI, 1.81-2.04], respectively, as compared with the low-PM group]. No significant interaction was observed between PA and PM (HR 1.01 [95% CI, 1.00-1.02]). CONCLUSIONS:A high-PA and low PM exposure were associated with a lower risk of hypertension. The negative association between PA and hypertension remained stable in people exposed to various levels of PM, and the positive association between PM and hypertension was not modified by PA. Our results indicated that PA is a suitable hypertension prevention strategy for people residing in relatively polluted regions.
10.1161/CIRCULATIONAHA.120.045915
Aerobic Exercise Training Response in Preterm-Born Young Adults with Elevated Blood Pressure and Stage 1 Hypertension: A Randomized Clinical Trial.
American journal of respiratory and critical care medicine
Premature birth is an independent predictor of long-term cardiovascular risk. Individuals affected are reported to have a lower rate of [Formula: see text]o at peak exercise intensity ([Formula: see text]o) and at the ventilatory anaerobic threshold ([Formula: see text]o), but little is known about their response to exercise training. The primary objective was to determine whether the [Formula: see text]o response to exercise training differed between preterm-born and term-born individuals; the secondary objective was to quantify group differences in [Formula: see text]o response. Fifty-two preterm-born and 151 term-born participants were randomly assigned (1:1) to 16 weeks of aerobic exercise training ( = 102) or a control group ( = 101). Cardiopulmonary exercise tests were conducted before and after the intervention to measure [Formula: see text]o and the [Formula: see text]o. A prespecified subgroup analysis was conducted by fitting an interaction term for preterm and term birth histories and exercise group allocation. For term-born participants, [Formula: see text]o increased by 3.1 ml/kg/min (95% confidence interval [CI], 1.7 to 4.4), and the [Formula: see text]o increased by 2.3 ml/kg/min (95% CI, 0.7 to 3.8) in the intervention group versus controls. For preterm-born participants, [Formula: see text]o increased by 1.8 ml/kg/min (95% CI, -0.4 to 3.9), and the [Formula: see text]o increased by 4.6 ml/kg/min (95% CI, 2.1 to 7.0) in the intervention group versus controls. No significant interaction was observed with birth history for [Formula: see text]o ( = 0.32) or the [Formula: see text]o ( = 0.12). The training intervention led to significant improvements in [Formula: see text]o and [Formula: see text]o, with no evidence of a statistically different response based on birth history. Clinical trial registered with www.clinicaltrials.gov (NCT02723552).
10.1164/rccm.202205-0858OC
Treatment of chronic kidney disease in older populations.
Nature reviews. Nephrology
As the world population ages, an expected increase in the prevalence of chronic kidney disease (CKD) among older individuals will pose a considerable challenge for health care systems in terms of resource allocation for disease management. Treatment strategies for older patients with CKD should ideally align with those applied to the general population, focusing on minimizing cardiovascular events and reducing the risk of progression to kidney failure. Emerging therapies, such as SGLT-2 inhibitors and GLP-1 receptor agonists, hold promise for the effective management of CKD in older individuals. In addition, non-pharmacological interventions such as nutritional and exercise therapies have a crucial role. These interventions enhance the effects of pharmacotherapy and, importantly, contribute to the maintenance of cognitive function and overall quality of life. Various factors beyond age and cognitive function must be taken into account when considering kidney replacement therapy for patients with kidney failure. Importantly, all treatment options, including dialysis, transplantation and conservative management approaches, should be tailored to the individual through patient-centred decision-making. The dynamic integration of digital technologies into medical practice has the potential to transform the management of CKD in the aging population.
10.1038/s41581-024-00854-w
Non-invasive prediction of pulmonary vascular disease-related exercise intolerance and survival in non-group 1 pulmonary hypertension.
European journal of heart failure
AIMS:The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. METHODS AND RESULTS:We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all). CONCLUSIONS:Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.
10.1002/ejhf.3396
Incorporating fatty liver disease in multidisciplinary care and novel clinical trial designs for patients with metabolic diseases.
Eslam Mohammed,Ahmed Aijaz,Després Jean-Pierre,Jha Vivekanand,Halford Jason C G,Wei Chieh Jack Tan,Harris David C H,Nangaku Masaomi,Colagiuri Stephen,Targher Giovanni,Joshi Shashank,Byrne Christopher D,Khunti Kamlesh,Nguyen Mindie H,Gish Robert G,George Jacob
The lancet. Gastroenterology & hepatology
With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.
10.1016/S2468-1253(21)00132-1
Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications.
European heart journal
AIMS:Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS:Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION:The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.
10.1093/eurheartj/ehad149
Heart failure with preserved ejection fraction: relevance of a dedicated dyspnoea clinic.
European heart journal
BACKGROUND AND AIMS:Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. This study provides an in-;depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic. METHODS AND RESULTS:Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H2FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation-perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were performed (median of 3 modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure. CONCLUSION:Holistic workup of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases.
10.1093/eurheartj/ehad141
The effect of high altitude (2500 m) on incremental cycling exercise in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a randomised controlled crossover trial.
The European respiratory journal
BACKGROUND:Our objective was to investigate the effect of a day-long exposure to high altitude on peak exercise capacity and safety in stable patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS:In a randomised controlled crossover trial, stable patients with PAH or distal CTEPH without resting hypoxaemia at low altitude performed two incremental exercise tests to exhaustion: one after 3-5 h at high altitude (2500 m) and one at low altitude (470 m). RESULTS:In 27 patients with PAH/CTEPH (44% females, mean±sd age 62±14 years), maximal work rate was 110±64 W at 2500 m and 123±64 W at 470 m (-11%, 95% CI -16- -11%; p<0.001). Oxygen saturation measured by pulse oximetry and arterial oxygen tension at end-exercise were 83±6% 91±6% and 6.1±1.9 8.6±1.9 kPa (-8% and -29%; both p<0.001) at 2500 470 m, respectively. Maximal oxygen uptake was 17.8±7.5 L·min·kg at high altitude 20±7.4 L·min·kg at low altitude (-11%; p<0.001). At end-exercise, the ventilatory equivalent for carbon dioxide was 43±9 at 2500 m 39±9 at 470 m (9%, 95% CI 2-6%; p=0.002). No adverse events occurred during or after exercise. CONCLUSIONS:Among predominantly low-risk patients with stable PAH/CTEPH, cycling exercise during the first day at 2500 m was well tolerated, but peak exercise capacity, blood oxygenation and ventilatory efficiency were lower compared with 470 m.
10.1183/13993003.01001-2023
Counseling and Behavioral Interventions for Healthy Weight and Weight Gain in Pregnancy: Evidence Report and Systematic Review for the US Preventive Services Task Force.
Cantor Amy G,Jungbauer Rebecca M,McDonagh Marian,Blazina Ian,Marshall Nicole E,Weeks Chandler,Fu Rongwei,LeBlanc Erin S,Chou Roger
JAMA
Importance:Counseling and active behavioral interventions to limit excess gestational weight gain (GWG) during pregnancy may improve health outcomes for women and infants. The 2009 National Academy of Medicine (NAM; formerly the Institute of Medicine) recommendations for healthy GWG vary according to prepregnancy weight category. Objective:To review and synthesize the evidence on benefits and harms of behavioral interventions to promote healthy weight gain during pregnancy to inform the US Preventive Services Task Force recommendation. Data Sources:Ovid MEDLINE and the Cochrane Library to March 2020, with surveillance through February 2021. Study Selection:Randomized clinical trials and nonrandomized controlled intervention studies focused on diet, exercise, and/or behavioral counseling interventions on GWG. Data Extraction and Synthesis:Independent data abstraction and study quality rating with dual review. Main Outcomes and Measures:Gestational weight-related outcomes; maternal and infant morbidity and mortality; harms. Results:Sixty-eight studies (N = 25 789) were included. Sixty-seven studies evaluated interventions during pregnancy, and 1 evaluated an intervention prior to pregnancy. GWG interventions were associated with reductions in risk of gestational diabetes (43 trials, n = 19 752; relative risk [RR], 0.87 [95% CI, 0.79 to 0.95]; absolute risk difference [ARD], -1.6%) and emergency cesarean delivery (14 trials, n = 7520; RR, 0.85 [95% CI, 0.74 to 0.96]; ARD, -2.4%). There was no significant association between GWG interventions and risk of gestational hypertension, cesarean delivery, or preeclampsia. GWG interventions were associated with decreased risk of macrosomia (25 trials, n = 13 990; RR, 0.77 [95% CI, 0.65 to 0.92]; ARD, -1.9%) and large for gestational age (26 trials, n = 13 000; RR, 0.89 [95% CI, 0.80 to 0.99]; ARD, -1.3%) but were not associated with preterm birth. Intervention participants experienced reduced weight gain across all prepregnancy weight categories (55 trials, n = 20 090; pooled mean difference, -1.02 kg [95% CI, -1.30 to -0.75]) and demonstrated lower likelihood of GWG in excess of NAM recommendations (39 trials, n = 14 271; RR, 0.83 [95% CI, 0.77 to 0.89]; ARD, -7.6%). GWG interventions were associated with reduced postpartum weight retention at 12 months (10 trials, n = 3957; mean difference, -0.63 kg [95% CI, -1.44 to -0.01]). Data on harms were limited. Conclusions and Relevance:Counseling and active behavioral interventions to limit GWG were associated with decreased risk of gestational diabetes, emergency cesarean delivery, macrosomia, and large for gestational age. GWG interventions were also associated with modest reductions in mean GWG and decreased likelihood of exceeding NAM recommendations for GWG.
10.1001/jama.2021.4230
Impact of hepatopulmonary syndrome in liver transplantation candidates and the role of angiogenesis.
The European respiratory journal
BACKGROUND:Hepatopulmonary syndrome affects 10-30% of patients with cirrhosis and portal hypertension. We evaluated the serum angiogenic profile of hepatopulmonary syndrome and assessed the clinical impact of hepatopulmonary syndrome in patients evaluated for liver transplantation. METHODS:The Pulmonary Vascular Complications of Liver Disease 2 study was a multicentre, prospective cohort study of adults undergoing their first liver transplantation evaluation. Hepatopulmonary syndrome was defined as an alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >64 years), positive contrast-enhanced transthoracic echocardiography and absence of lung disease. RESULTS:We included 85 patients with hepatopulmonary syndrome and 146 patients without hepatopulmonary syndrome. Patients with hepatopulmonary syndrome had more complications of portal hypertension and slightly higher Model for End-Stage Liver Disease-Na score compared to those without hepatopulmonary syndrome (median (interquartile range) 15 (12-19) 14 (10-17), p=0.006). Hepatopulmonary syndrome patients had significantly lower 6-min walk distance and worse functional class. Hepatopulmonary syndrome patients had higher circulating angiopoietin 2, Tie2, tenascin C, tyrosine protein kinase Kit (c-Kit), vascular cell adhesion molecule 1 and von Willebrand factor levels, and lower E-selectin levels. Patients with hepatopulmonary syndrome had an increased risk of death (hazard ratio 1.80, 95% CI 1.03-3.16, p=0.04), which persisted despite adjustment for covariates (hazard ratio 1.79, 95% CI 1.02-3.15, p=0.04). This association did not vary based on levels of oxygenation, reflecting the severity of hepatopulmonary syndrome. CONCLUSION:Hepatopulmonary syndrome was associated with a profile of abnormal systemic angiogenesis, worse exercise and functional capacity, and an overall increased risk of death.
10.1183/13993003.02304-2021
Effects of Sedentary Behavior Reduction on Blood Pressure in Desk Workers: Results From the RESET-BP Randomized Clinical Trial.
Circulation
BACKGROUND:Sedentary behavior (SB) is observationally associated with cardiovascular disease risk. However, randomized clinical trials testing causation are limited. We hypothesized that reducing SB would decrease blood pressure (BP) and pulse wave velocity (PWV) in sedentary adults. METHODS:This parallel-arm, 3-month randomized clinical trial recruited desk workers, age 18 to 65 years, with systolic BP 120 to 159 or diastolic BP (DBP) 80 to 99 mm Hg, off antihypertensive medications, and reporting <150 min/wk of moderate to vigorous intensity physical activity. Participants were randomized to a SB reduction intervention or a no-contact control group. The intervention sought to replace 2 to 4 h/d of SB with standing and stepping through coaching, a wrist-worn activity prompter, and a sit-stand desk. SB and physical activity were measured with a thigh-worn accelerometer and quantified during all waking hours and separately during work and nonwork times. Clinic-based resting systolic BP (primary outcome) and DBP, 24-hour ambulatory BP, and PWV were assessed by blinded technicians at baseline and 3 months. RESULTS:Participants (n=271) had a mean age of 45 years and systolic BP/DBP 129/83 mm Hg. Compared with controls, intervention participants reduced SB (-1.15±0.17 h/d), increased standing (0.94±0.14 h/d), and increased stepping (5.4±2.4 min/d; all <0.05). SB and activity changes mainly occurred during work time and were below the goal. The intervention did not reduce BP or PWV in the intervention group compared with controls. Between-group differences in resting systolic BP and DBP changes were -0.22±0.90 (=0.808) and 0.13±0.61 mm Hg (=0.827), respectively. The findings were similarly null for ambulatory BP and PWV. Decreases in work-time SB were associated with favorable reductions in resting DBP (r=0.15, =0.017). Contrary to our hypotheses, reductions in work-time SB (r=-0.19, =0.006) and increases in work-time standing (r=0.17, =0.011) were associated with unfavorable increases in carotid-femoral PWV. As expected, increases in nonwork-time standing were favorably associated with carotid-femoral PWV (r=-0.14, =0.038). CONCLUSIONS:A 3-month intervention that decreased SB and increased standing by ≈1 hour during the work day was not effective for reducing BP. Future directions include examining effects of interventions reducing SB through activity other than work-time standing and clarifying association between standing and PWV in opposite directions for work and nonwork time. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03307343.
10.1161/CIRCULATIONAHA.123.068564
Excess ventilation and exertional dyspnoea in heart failure and pulmonary hypertension.
The European respiratory journal
Increased ventilation relative to metabolic demands, indicating alveolar hyperventilation and/or increased physiological dead space (excess ventilation), is a key cause of exertional dyspnoea. Excess ventilation has assumed a prominent role in the functional assessment of patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction, pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). We herein provide the key pieces of information to the caring physician to 1) gain unique insights into the seeds of patients' shortness of breath and 2) develop a rationale for therapeutically lessening excess ventilation to mitigate this distressing symptom. Reduced bulk oxygen transfer induced by cardiac output limitation and/or right ventricle-pulmonary arterial uncoupling increase neurochemical afferent stimulation and (largely chemo-) receptor sensitivity, leading to alveolar hyperventilation in HFrEF, PAH and small-vessel, distal CTEPH. As such, interventions geared to improve central haemodynamics and/or reduce chemosensitivity have been particularly effective in lessening their excess ventilation. In contrast, 1) high filling pressures in HFpEF and 2) impaired lung perfusion leading to ventilation/perfusion mismatch in proximal CTEPH conspire to increase physiological dead space. Accordingly, 1) decreasing pulmonary capillary pressures and 2) mechanically unclogging larger pulmonary vessels (pulmonary endarterectomy and balloon pulmonary angioplasty) have been associated with larger decrements in excess ventilation. Exercise training has a strong beneficial effect across diseases. Addressing some major unanswered questions on the link of excess ventilation with exertional dyspnoea under the modulating influence of pharmacological and nonpharmacological interventions might prove instrumental to alleviate the devastating consequences of these prevalent diseases.
10.1183/13993003.00144-2022
Minimal Clinically Important Difference in the 6-minute-walk Distance for Patients with Pulmonary Arterial Hypertension.
American journal of respiratory and critical care medicine
The 6-minute-walk distance (6MWD) is an important clinical and research metric in pulmonary arterial hypertension (PAH); however, there is no consensus about what minimal change in 6MWD is clinically significant. We aimed to determine the minimal clinically important difference in the 6MWD. We performed a meta-analysis using individual participant data from eight randomized clinical trials of therapy for PAH submitted to the U.S. Food and Drug Administration to derive minimal clinically important differences in the 6MWD. The estimates were externally validated using the Pulmonary Hypertension Association Registry. We anchored the change in 6MWD to the change in the Medical Outcomes Survey Short Form physical component score. The derivation (clinical trial) and validation (Pulmonary Hypertension Association Registry) samples were comprised of 2,404 and 537 adult patients with PAH, respectively. The mean ± standard deviation age of the derivation sample was 50.5 ± 15.2 years, and 1,849 (77%) were female, similar to the validation sample. The minimal clinically important difference in the derivation sample was 33 meters (95% confidence interval, 27-38), which was almost identical to that in the validation sample (36 m [95% confidence interval, 29-43]). The minimal clinically important difference did not differ by age, sex, race, pulmonary hypertension etiology, body mass index, use of background therapy, or World Health Organization functional class. We estimated a 6MWD minimal clinically important difference of approximately 33 meters for adults with PAH. Our findings can be applied to the design of clinical trials of therapies for PAH.
10.1164/rccm.202208-1547OC
Exercise catheterization in adults post-Fontan with normal and abnormal haemodynamic criteria: Insights into normal Fontan physiology.
European journal of heart failure
AIM:The normal (i.e. expected) haemodynamics in adults post-Fontan remain poorly delineated. Moreover, the definitions of elevated exercise pulmonary artery (PA) and PA wedge pressure (PAWP) for this population have not been described. METHODS AND RESULTS:Seventy-two adults post-Fontan undergoing exercise catheterization were categorized into abnormal (Group I, n = 59; defined as resting mean PA ≥14 mmHg and/or PAWP ≥12 mmHg, ΔPAWP/Δsystemic flow [Qs] >2 mmHg/L/min, and/or ΔPA/Δpulmonary flow >3 mmHg/L/min) and normal (Group II, n = 13) haemodynamics. Thirty-nine patients with non-cardiac dyspnoea (NCD) were included as controls. There was no difference in exercise arterial oxygen saturation (87% [81-92] vs. 89% [85-93], p = 0.29), while exercise PA pressure (27 [23-31] vs. 16 [14.5-19.5] mmHg, p < 0.001) and PAWP were higher (21 [18-28] vs. 12 [8-14] mmHg, p < 0.001) in Group I. At peak exercise, Group I had lower heart rate (97 [81-120] vs. 133 [112.5-147.5] bpm, p < 0.001) and Qs response (67.3 [43.8-93.1] vs. 105.9 (82-118.5) % predicted, p < 0.001) than Group II. Exercise superior vena cava pressures were higher (16 [14-22.5] vs. 5.5 [3-7.3] mmHg, p < 0.001) and arterial oxygen saturation lower (89% [85-93] vs. 97% [96-98], p < 0.001) in Group II compared to NCD, while no differences in PAWP, stroke volume index, heart rate, or Qs response were seen. If defined as two standard deviations above mean values for Group II, elevated PAWP and mean PA pressure post-Fontan would correspond to 20.6 mmHg and 25.8 mmHg, respectively. CONCLUSION:PAWP >20 mmHg and mean PA pressure >25 mmHg could be used to define elevated values during exercise in adults post-Fontan. The major discrepancy in exercise haemodynamics among Group II compared to controls appears to be the degree of systemic venous hypertension and arterial desaturation.
10.1002/ejhf.3119
Cardiovascular manifestations of sickle cell disease.
Hammoudi Nadjib,Lionnet François,Redheuil Alban,Montalescot Gilles
European heart journal
Sickle cell disease (SCD) is the most frequent genetic haemoglobinopathy worldwide. Early childhood mortality has dramatically decreased in high-income countries, and most patients now survive beyond the 5th decade. However, in the aging SCD population, the morbidity related to chronic organ damage, especially kidney and heart, has become a major concern. While pulmonary hypertension has attracted most attention, it appears that this condition is frequently linked to left heart failure (HF). Accordingly, SCD-associated cardiomyopathy is emerging as a major cause of reduced quality of life and early mortality in these patients. The diagnosis of this particular phenotype of high-output HF is challenging. Exercise intolerance and dyspnoea in SCD patients are linked to multiple causes including chronic anaemia. Moreover, echocardiographic features are unusual and can be misinterpreted. The classical diagnosis algorithm for HF is generally not suitable in SCD patients, and HF is poorly recognized and mostly diagnosed at a late congestive stage in routine practice. Such patients need to be identified at an earlier stage of myocardial dysfunction via improved phenotyping. This constitutes the first step towards further investigations in SCD needed to improve the prognosis and the quality of life. This article provides an updated review of the recent advances in the pathophysiology and diagnosis, and in addition, perspectives of new therapeutic approaches in SCD-related cardiac manifestations.
10.1093/eurheartj/ehz217
Portopulmonary hypertension in the current era of pulmonary hypertension management.
Savale Laurent,Guimas Manuel,Ebstein Nathan,Fertin Marie,Jevnikar Mitja,Renard Sébastien,Horeau-Langlard Delphine,Tromeur Cécile,Chabanne Céline,Prevot Grégoire,Chaouat Ari,Moceri Pamela,Artaud-Macari Élise,Degano Bruno,Tresorier Romain,Boissin Clément,Bouvaist Hélène,Simon Anne-Claire,Riou Marianne,Favrolt Nicolas,Palat Sylvain,Bourlier Delphine,Magro Pascal,Cottin Vincent,Bergot Emmanuel,Lamblin Nicolas,Jaïs Xavier,Coilly Audrey,Durand François,Francoz Claire,Conti Filomena,Hervé Philippe,Simonneau Gérald,Montani David,Duclos-Vallée Jean-Charles,Samuel Didier,Humbert Marc,De Groote Pascal,Sitbon Olivier
Journal of hepatology
BACKGROUND & AIMS:Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. METHODS:Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS:Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). CONCLUSION:Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. LAY SUMMARY:Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation.
10.1016/j.jhep.2020.02.021
Behavioral Counseling Interventions to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Cardiovascular Disease Risk Factors: US Preventive Services Task Force Recommendation Statement.
JAMA
Importance:Cardiovascular disease (CVD), which includes heart disease, myocardial infarction, and stroke, is the leading cause of death in the US. A large proportion of CVD cases can be prevented by addressing modifiable risk factors, including smoking, obesity, diabetes, elevated blood pressure or hypertension, dyslipidemia, lack of physical activity, and unhealthy diet. Adults who adhere to national guidelines for a healthy diet and physical activity have lower rates of cardiovascular morbidity and mortality than those who do not; however, most US adults do not consume healthy diets or engage in physical activity at recommended levels. Objective:To update its 2017 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a review of the evidence on the benefits and harms of behavioral counseling interventions to promote healthy behaviors in adults without CVD risk factors. Population:Adults 18 years or older without known CVD risk factors, which include hypertension or elevated blood pressure, dyslipidemia, impaired fasting glucose or glucose tolerance, or mixed or multiple risk factors such as metabolic syndrome or an estimated 10-year CVD risk of 7.5% or greater. Evidence Assessment:The USPSTF concludes with moderate certainty that behavioral counseling interventions have a small net benefit on CVD risk in adults without CVD risk factors. Recommendation:The USPSTF recommends that clinicians individualize the decision to offer or refer adults without CVD risk factors to behavioral counseling interventions to promote a healthy diet and physical activity. (C recommendation).
10.1001/jama.2022.10951
Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.
European heart journal
AIMS:This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS:For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group. CONCLUSION:This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.
10.1093/eurheartj/ehaa696
Pulmonary hypertension across the spectrum of left heart and lung disease.
European journal of heart failure
AIMS:Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized. METHODS AND RESULTS:Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86). CONCLUSIONS:Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT02980887.
10.1002/ejhf.3302
Bariatric Surgery as a Long-Term Treatment for Type 2 Diabetes/Metabolic Syndrome.
Hanipah Zubaidah Nor,Schauer Philip R
Annual review of medicine
Metabolic surgery is increasingly becoming recognized as a more effective treatment for patients with type 2 diabetes (T2D) and obesity as compared to lifestyle modification and medical management alone. Both observational studies and clinical trials have shown metabolic surgery to result in sustained weight loss (20-30%), T2D remission rates ranging from 23% to 60%, and improvement in cardiovascular risk factors such as hypertension and dyslipidemia. Metabolic surgery is cost-effective and relatively safe, with perioperative risks and mortality comparable to low-risk procedures such as cholecystectomy, hysterectomy, and appendectomy. International diabetes and medical organizations have endorsed metabolic surgery as a standard treatment for T2D with obesity.
10.1146/annurev-med-053117-123246
Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop.
Nature reviews. Cardiology
The accessibility of the retina with the use of non-invasive and relatively low-cost ophthalmic imaging techniques and analytics provides a unique opportunity to improve the detection, diagnosis and monitoring of systemic diseases. The National Heart, Lung, and Blood Institute conducted a workshop in October 2022 to examine this concept. On the basis of the discussions at that workshop, this Roadmap describes current knowledge gaps and new research opportunities to evaluate the relationships between the eye (in particular, retinal biomarkers) and the risk of cardiovascular diseases, including coronary artery disease, heart failure, stroke, hypertension and vascular dementia. Identified gaps include the need to simplify and standardize the capture of high-quality images of the eye by non-ophthalmic health workers and to conduct longitudinal studies using multidisciplinary networks of diverse at-risk populations with improved implementation and methods to protect participant and dataset privacy. Other gaps include improving the measurement of structural and functional retinal biomarkers, determining the relationship between microvascular and macrovascular risk factors, improving multimodal imaging 'pipelines', and integrating advanced imaging with 'omics', lifestyle factors, primary care data and radiological reports, by using artificial intelligence technology to improve the identification of individual-level risk. Future research on retinal microvascular disease and retinal biomarkers might additionally provide insights into the temporal development of microvascular disease across other systemic vascular beds.
10.1038/s41569-024-01060-8
Prevention and rehabilitation after heart transplantation: A clinical consensus statement of the European Association of Preventive Cardiology, Heart Failure Association of the ESC, and the European Cardio Thoracic Transplant Association, a section of ESOT.
European journal of heart failure
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
10.1002/ejhf.3185
Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.
Circulation research
BACKGROUND:Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. METHODS:Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. RESULTS:Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; =0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; =0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. CONCLUSIONS:Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.
10.1161/CIRCRESAHA.124.324272
mPAP/CO Slope and Oxygen Uptake Add Prognostic Value in Aortic Stenosis.
Circulation
BACKGROUND:Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L·min. A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown. METHODS:In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141). RESULTS:One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; =0.036), indexed left atrial volume (OR per SD, 2.15; =0.001), E/e' at rest (OR per SD, 1.61; =0.012), mPAP/CO slope (OR per SD, 2.01; =0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; =0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; =0.219). Peak Vo (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area (<0.001). These results were confirmed in the validation cohort. CONCLUSIONS:In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo and mPAP/CO slope cumulatively improved risk stratification.
10.1161/CIRCULATIONAHA.123.067130
Clinical Implications of Pretest Probability of HFpEF on Outcomes in Precapillary Pulmonary Hypertension.
Journal of the American College of Cardiology
BACKGROUND:Patients with group 1 pulmonary hypertension (PH) and risk factors for heart failure with preserved ejection fraction (HFpEF) demonstrate worse response to pulmonary vasodilator therapy. The mechanisms and optimal diagnostic approach to identify such patients remain unclear. OBJECTIVES:The purpose of this study was to compare exercise capacity, cardiac function, and hemodynamic responses to provocative maneuvers among patients with group 1 PH based upon pretest probability of HFpEF. METHODS:Pretest probability for HFpEF was determined using the validated HFpEF-ABA algorithm based on age, body mass index, and history of atrial fibrillation among group 1 PH patients recruited to the multicenter PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) study. Functional capacity, quality of life, and dynamic pulmonary capillary wedge pressure (PCWP) responses were compared between those with low (<25%), intermediate (25%-74%), and high (≥75%) ABA score-based HFpEF probability. RESULTS:Among 424 patients with group 1 PH, 54% (n = 228) had intermediate HFpEF probability and 15% (n = 64) had high HFpEF probability. Resting PCWP increased progressively with higher HFpEF probability (P < 0.0001), and patients with group 1 PH and high HFpEF probability had the greatest increases in PCWP with nitric oxide, fluid challenge, and exercise (P < 0.001 for all), changes that were comparable to patients with HFpEF with no pulmonary vascular disease (n = 194), but lower than those with HFpEF and combined precapillary and postcapillary PH. Left ventricular/atrial size, diastolic function, quality of life, 6-minute walk distance, and peak VO were most abnormal in patients with group 1 PH and high HFpEF probability compared with those with low or intermediate HFpEF probability (P < 0.0001 for all). Increasing HFpEF probability in group 1 PH was associated with greater risk of death (HR per decile of HFpEF probability 1.09; 95% CI: 1.05-1.13; P < 0.0001). CONCLUSIONS:Quantifying pretest probability for HFpEF in patients with group 1 PH identifies a subset of patients with worse dynamic PCWP response indicative of subclinical left heart disease, with poorer functional status, quality of life, and survival. Further study in this group 1 PH subgroup is indicated to determine whether PH therapies are effective and safe, and also whether HFpEF-specific therapies can improve functional status and outcomes.
10.1016/j.jacc.2024.08.061
Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.
The European respiratory journal
BACKGROUND:Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS:Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS:Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS:In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.
10.1183/13993003.00846-2023
Sex Differences in Peripheral Artery Disease.
Circulation research
Peripheral artery disease (PAD) is a prevalent condition that confers substantial morbidity and mortality and remains underdiagnosed as well as undertreated in the overall population. Although PAD prevalence is similar or higher in women compared with men, associations of traditional and nontraditional risk factors with PAD and clinical manifestations of PAD differ by sex and may contribute to delayed or lack of diagnosis in women. Such sex-based differences in the manifestation of PAD may arise from sexual dimorphism in the vascular substrate in health as well as sex variation in the responses to vascular stressors. Despite the availability of proven therapies for improving symptoms and reducing risk of ischemic cardiovascular and limb events among patients with diagnosed PAD, important sex differences in treatment and outcomes have been observed. We provide an overview of current knowledge regarding sex differences in the epidemiology, pathophysiology, clinical presentation, and management of PAD.
10.1161/CIRCRESAHA.121.320702
Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.
European heart journal
BACKGROUND AND AIMS:In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS:In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS:At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% confidence interval (CI) -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24-.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P < .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P < .001 for both) from baseline to 52 weeks. CONCLUSIONS:In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICAL TRIAL REGISTRATION:NCT04788511 and NCT04916470.
10.1093/eurheartj/ehae322
Worldwide CTEPH Registry: Long-Term Outcomes With Pulmonary Endarterectomy, Balloon Pulmonary Angioplasty, and Medical Therapy.
Circulation
BACKGROUND:The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context. METHODS:Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019. RESULTS:Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm. During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention (<0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants (=0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention. CONCLUSIONS:This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02656238.
10.1161/CIRCULATIONAHA.124.068610
Diet and Exercise in Cancer Metabolism.
Cancer discovery
Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for patients with cancer. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this perspective, I propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, I will discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.
10.1158/2159-8290.CD-22-0096
The association of eicosanoids and eicosanoid-related metabolites with pulmonary hypertension.
The European respiratory journal
BACKGROUND:Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), yet their role remains incompletely understood. METHODS:We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients. RESULTS:Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11β-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13()-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH. CONCLUSIONS:Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.
10.1183/13993003.00561-2023
Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.
The European respiratory journal
Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.
10.1183/13993003.01205-2024
Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.
Journal of the American College of Cardiology
BACKGROUND:Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. OBJECTIVES:In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. METHODS:Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. RESULTS:Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm; 95% CI: -3.60 to -0.38 cm; P = 0.016; EMD in RV end-systolic area: -1.41 cm; 95% CI: -2.42 to -0.40] cm; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (P = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area. CONCLUSIONS:In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).
10.1016/j.jacc.2024.08.021
Deep phenotyping of unaffected carriers of pathogenic variants screened for pulmonary arterial hypertension.
The European respiratory journal
INTRODUCTION:Pathogenic variants in the gene encoding for are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension. METHODS:28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic rat model was employed to validate findings from humans. RESULTS:Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m 62.7±15.3 mL·m; p=0.001), end-systolic (34.2±10.5 mL·m 27.1±8.3 mL·m; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m 58.5±10.7 mL·m; p=0.007) volumes than control subjects. rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06 0.27±0.08 mmHg·mL; p<0.001) and end-systolic elastance (0.28±0.07 0.35±0.10 mmHg·mL; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis. CONCLUSION:Unaffected mutation carriers have an altered cardiac phenotype mimicked in transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.
10.1183/13993003.00442-2024
Behavioral Counseling Interventions to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults With Cardiovascular Risk Factors: US Preventive Services Task Force Recommendation Statement.
,Krist Alex H,Davidson Karina W,Mangione Carol M,Barry Michael J,Cabana Michael,Caughey Aaron B,Donahue Katrina,Doubeni Chyke A,Epling John W,Kubik Martha,Landefeld Seth,Ogedegbe Gbenga,Pbert Lori,Silverstein Michael,Simon Melissa A,Tseng Chien-Wen,Wong John B
JAMA
Importance:Cardiovascular disease (CVD) is a leading cause of death in the US. Known modifiable risk factors for CVD include smoking, overweight and obesity, diabetes, elevated blood pressure or hypertension, dyslipidemia, lack of physical activity, and unhealthy diet. Adults who adhere to national guidelines for a healthy diet and physical activity have lower cardiovascular morbidity and mortality than those who do not. All persons, regardless of their CVD risk status, benefit from healthy eating behaviors and appropriate physical activity. Objective:To update its 2014 recommendation, the USPSTF commissioned a review of the evidence on behavioral counseling to promote a healthy diet and physical activity for CVD prevention in adults with cardiovascular risk factors. Population:This recommendation statement applies to adults 18 years or older with known hypertension or elevated blood pressure, those with dyslipidemia, or those who have mixed or multiple risk factors such as metabolic syndrome or an estimated 10-year CVD risk of 7.5% or greater. Adults with other known modifiable cardiovascular risk factors such as abnormal blood glucose levels, obesity, and smoking are not included in this recommendation. Evidence Assessment:The USPSTF concludes with moderate certainty that behavioral counseling interventions have a moderate net benefit on CVD risk in adults at increased risk for CVD. Recommendation:The USPSTF recommends offering or referring adults with CVD risk factors to behavioral counseling interventions to promote a healthy diet and physical activity. (B recommendation).
10.1001/jama.2020.21749
Effect of a Salt Substitute on Incidence of Hypertension and Hypotension Among Normotensive Adults.
Journal of the American College of Cardiology
BACKGROUND:Reports on the effects of salt substitution among individuals with normal blood pressure are scarce and controversial. OBJECTIVES:This study sought to assess the effects of a salt substitute (62.5% NaCl, 25% KCl, and 12.5% flavorings) on incidence of hypertension and hypotension among older adults with normal blood pressure. METHOD:A post hoc analysis was conducted among older adults with normal blood pressure participating in DECIDE-Salt, a large, multicenter, cluster-randomized trial in 48 elderly care facilities for 2 years. We used the frailty survival model to compare risk of incident hypertension and the generalized linear mixed model to compare risk of hypotension episodes. RESULTS:Compared with usual salt group (n = 298), the salt substitute group (n = 313) had a lower hypertension incidence (11.7 vs 24.3 per 100 person-years; adjusted HR: 0.60; 95% CI: 0.39 to 0.92; P = 0.02) but did not increase incidence of hypotension episodes (9.0 vs 9.7 per 100 person-years; P = 0.76). Mean systolic/diastolic blood pressure did not increase from the baseline to the end of intervention in the salt substitute group (mean changes: -0.3 ± 11.9/0.2 ± 7.1 mm Hg) but increased in the usual salt group (7.0 ± 14.3/2.1 ± 7.5 mm Hg), resulting in a net reduction of -8.0 mm Hg (95% CI: -12.4 to -3.7 mm Hg) in systolic and -2.0 mm Hg (95% CI: -4.1 to 0.1 mm Hg) in diastolic blood pressure between intervention groups. CONCLUSIONS:In Chinese older adults with normal blood pressure, replacing usual salt with a salt substitute may reduce the incidence of hypertension without increasing hypotension episodes. This suggests a desirable strategy for population-wide prevention and control of hypertension and cardiovascular disease, deserving further consideration in future studies. (Diet Exercise and Cardiovascular Health [DECIDE]-Salt Reduction Strategies for the Elderly in Nursing Homes in China [DECIDE-Salt]; NCT03290716).
10.1016/j.jacc.2023.12.013
Effects of a Workplace Wellness Program on Employee Health, Health Beliefs, and Medical Use: A Randomized Clinical Trial.
Reif Julian,Chan David,Jones Damon,Payne Laura,Molitor David
JAMA internal medicine
Importance:Many employers use workplace wellness programs to improve employee health and reduce medical costs, but randomized evaluations of their efficacy are rare. Objective:To evaluate the effect of a comprehensive workplace wellness program on employee health, health beliefs, and medical use after 12 and 24 months. Design, Setting, and Participants:This randomized clinical trial of 4834 employees of the University of Illinois at Urbana-Champaign was conducted from August 9, 2016, to April 26, 2018. Members of the treatment group (n = 3300) received incentives to participate in the workplace wellness program. Members of the control group (n = 1534) did not participate in the wellness program. Statistical analysis was performed on April 9, 2020. Interventions:The 2-year workplace wellness program included financial incentives and paid time off for annual on-site biometric screenings, annual health risk assessments, and ongoing wellness activities (eg, physical activity, smoking cessation, and disease management). Main Outcomes and Measures:Measures taken at 12 and 24 months included clinician-collected biometrics (16 outcomes), administrative claims related to medical diagnoses (diabetes, hypertension, and hyperlipidemia) and medical use (office visits, inpatient visits, and emergency department visits), and self-reported health behaviors and health beliefs (14 outcomes). Results:Among the 4834 participants (2770 women; mean [SD] age, 43.9 [11.3] years), no significant effects of the program on biometrics, medical diagnoses, or medical use were seen after 12 or 24 months. A significantly higher proportion of employees in the treatment group than in the control group reported having a primary care physician after 24 months (1106 of 1200 [92.2%] vs 477 of 554 [86.1%]; adjusted P = .002). The intervention significantly improved a set of employee health beliefs on average: participant beliefs about their chance of having a body mass index greater than 30, high cholesterol, high blood pressure, and impaired glucose level jointly decreased by 0.07 SDs (95% CI, -0.12 to -0.01 SDs; P = .02); however, effects on individual belief measures were not significant. Conclusions and Relevance:This randomized clinical trial showed that a comprehensive workplace wellness program had no significant effects on measured physical health outcomes, rates of medical diagnoses, or the use of health care services after 24 months, but it increased the proportion of employees reporting that they have a primary care physician and improved employee beliefs about their own health. Trial Registration:American Economic Association Randomized Controlled Trial Registry number: AEARCTR-0001368.
10.1001/jamainternmed.2020.1321
Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.
The Lancet. Respiratory medicine
BACKGROUND:INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest. METHODS:In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316. FINDINGS:Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea. INTERPRETATION:In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study. FUNDING:United Therapeutics Corporation.
10.1016/S2213-2600(21)00165-X
Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury.
Science translational medicine
Acute kidney injury (AKI) is a major risk factor for long-term adverse outcomes, including chronic kidney disease. In mouse models of AKI, maladaptive repair of the injured proximal tubule (PT) prevents complete tissue recovery. However, evidence for PT maladaptation and its etiological relationship with complications of AKI is lacking in humans. We performed single-nucleus RNA sequencing of 120,985 nuclei in kidneys from 17 participants with AKI and seven healthy controls from the Kidney Precision Medicine Project. Maladaptive PT cells, which exhibited transcriptomic features of dedifferentiation and enrichment in pro-inflammatory and profibrotic pathways, were present in participants with AKI of diverse etiologies. To develop plasma markers of PT maladaptation, we analyzed the plasma proteome in two independent cohorts of patients undergoing cardiac surgery and a cohort of marathon runners, linked it to the transcriptomic signatures associated with maladaptive PT, and identified nine proteins whose genes were specifically up- or down-regulated by maladaptive PT. After cardiac surgery, both cohorts of patients had increased transforming growth factor-β2 (TGFB2), collagen type XXIII-α1 (COL23A1), and X-linked neuroligin 4 (NLGN4X) and had decreased plasminogen (PLG), ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6), and protein C (PROC). Similar changes were observed in marathon runners with exercise-associated kidney injury. Postoperative changes in these markers were associated with AKI progression in adults after cardiac surgery and post-AKI kidney atrophy in mouse models of ischemia-reperfusion injury and toxic injury. Our results demonstrate the feasibility of a multiomics approach to discovering noninvasive markers and associating PT maladaptation with adverse clinical outcomes.
10.1126/scitranslmed.ade7287
Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.
Circulation
BACKGROUND:Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. METHODS:We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. RESULTS:Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. CONCLUSIONS:In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.
10.1161/CIRCULATIONAHA.121.053889
Wearable device-measured moderate to vigorous physical activity and risk of degenerative aortic valve stenosis.
European heart journal
BACKGROUND AND AIMS:Physical activity has proven effective in preventing atherosclerotic cardiovascular disease, but its role in preventing degenerative valvular heart disease (VHD) remains uncertain. This study aimed to explore the dose-response association between moderate to vigorous physical activity (MVPA) volume and the risk of degenerative VHD among middle-aged adults. METHODS:A full week of accelerometer-derived MVPA data from 87 248 UK Biobank participants (median age 63.3, female: 56.9%) between 2013 and 2015 were used for primary analysis. Questionnaire-derived MVPA data from 361 681 UK Biobank participants (median age 57.7, female: 52.7%) between 2006 and 2010 were used for secondary analysis. The primary outcome was the diagnosis of incident degenerative VHD, including aortic valve stenosis (AS), aortic valve regurgitation (AR), and mitral valve regurgitation (MR). The secondary outcome was VHD-related intervention or mortality. RESULTS:In the accelerometer-derived MVPA cohort, 555 incident AS, 201 incident AR, and 655 incident MR occurred during a median follow-up of 8.11 years. Increased MVPA volume showed a steady decline in AS risk and subsequent AS-related intervention or mortality risk, levelling off beyond approximately 300 min/week. In contrast, its association with AR or MR incidence was less apparent. The adjusted rates of AS incidence (95% confidence interval) across MVPA quartiles (Q1-Q4) were 11.60 (10.20, 13.20), 7.82 (6.63, 9.23), 5.74 (4.67, 7.08), and 5.91 (4.73, 7.39) per 10 000 person-years. The corresponding adjusted rates of AS-related intervention or mortality were 4.37 (3.52, 5.43), 2.81 (2.13, 3.71), 1.93 (1.36, 2.75), and 2.14 (1.50, 3.06) per 10 000 person-years, respectively. Aortic valve stenosis risk reduction was also observed with questionnaire-based MVPA data [adjusted absolute difference Q4 vs. Q1: AS incidence, -1.41 (-.67, -2.14) per 10 000 person-years; AS-related intervention or mortality, -.38 (-.04, -.88) per 10 000 person-years]. The beneficial association remained consistent in high-risk populations for AS, including patients with hypertension, obesity, dyslipidaemia, and chronic kidney disease. CONCLUSIONS:Higher MVPA volume was associated with a lower risk of developing AS and subsequent AS-related intervention or mortality. Future research needs to validate these findings in diverse populations with longer durations and repeated periods of activity monitoring.
10.1093/eurheartj/ehae406
Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.
White R James,Jerjes-Sanchez Carlos,Bohns Meyer Gisela Martina,Pulido Tomas,Sepulveda Pablo,Wang Kuo Yang,Grünig Ekkehard,Hiremath Shirish,Yu Zaixin,Gangcheng Zhang,Yip Wei Luen James,Zhang Shuyang,Khan Akram,Deng C Q,Grover Rob,Tapson Victor F,
American journal of respiratory and critical care medicine
Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).
10.1164/rccm.201908-1640OC
Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain.
Gastroenterology
BACKGROUND & AIMS:We evaluated the efficacy and safety of diet-modulated autologous fecal microbiota transplantation (aFMT) for treatment of weight regain after the weight-loss phase. METHODS:In the DIRECT PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols-Unprocessed) weight-loss trial (May 2017 through July 2018), abdominally obese or dyslipidemic participants in Israel were randomly assigned to healthy dietary guidelines, Mediterranean diet, and green-Mediterranean diet weight-loss groups. All groups received free gym membership and physical activity guidelines. Both isocaloric Mediterranean groups consumed 28 g/d walnuts (+440 mg/d polyphenols provided). The green-Mediterranean dieters also consumed green tea (3-4 cups/d) and a Wolffia globosa (Mankai strain, 100 g/d) green shake (+800 mg/d polyphenols provided). After 6 months (weight-loss phase), 90 eligible participants (mean age, 52 years; mean weight loss, 8.3 kg) provided a fecal sample that was processed into aFMT by frozen, opaque, and odorless capsules. The participants were then randomly assigned to groups that received 100 capsules containing their own fecal microbiota or placebo until month 14. The primary outcome was regain of the lost weight over the expected weight-regain phase (months 6-14). Secondary outcomes were gastrointestinal symptoms, waist circumference, glycemic status, and changes in the gut microbiome, as measured by metagenomic sequencing and 16s ribosomal RNA. We validated the results in a parallel in vivo study of mice specifically fed with Mankai compared with control chow diet. RESULTS:Of the 90 participants in the aFMT trial, 96% ingested at least 80 of 100 oral aFMT or placebo frozen capsules during the transplantation period. No aFMT-related adverse events or symptoms were observed. For the primary outcome, although no significant differences in weight regain were observed among the participants in the different lifestyle interventions during months 6-14 (aFMT, 30.4% vs placebo, 40.6%; P = .28), aFMT significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02), but not in the dietary guidelines (P = .57) or Mediterranean diet (P = .64) groups (P for the interaction = .03). Accordingly, aFMT attenuated waist circumference gain (aFMT, 1.89 cm vs placebo, 5.05 cm; P = .01) and insulin rebound (aFMT, -1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) in the green-Mediterranean group but not in the dietary guidelines or Mediterranean diet (P for the interaction = .04 and .03, respectively). The green-Mediterranean diet was the only intervention to induce a significant change in microbiome composition during the weight-loss phase, and to prompt preservation of weight-loss-associated specific bacteria and microbial metabolic pathways (mainly microbial sugar transport) after the aFMT. In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet-induced regain phase (all, P < .05). CONCLUSIONS:Autologous FMT, collected during the weight-loss phase and administrated in the regain phase, might preserve weight loss and glycemic control, and is associated with specific microbiome signatures. A high-polyphenols, green plant-based or Mankai diet better optimizes the microbiome for an aFMT procedure. ClinicalTrials.gov number, NCT03020186.
10.1053/j.gastro.2020.08.041
Associations of "Weekend Warrior" Physical Activity With Incident Disease and Cardiometabolic Health.
Circulation
BACKGROUND:Achievement of guideline-recommended levels of physical activity (≥150 minutes of moderate-to-vigorous physical activity per week) is associated with lower risk of adverse cardiovascular events and represents an important public health priority. Although physical activity commonly follows a "weekend warrior" pattern, in which most moderate-to-vigorous physical activity is concentrated in 1 or 2 days rather than spread more evenly across the week (regular), the effects of physical activity pattern across a range of incident diseases, including cardiometabolic conditions, are unknown. METHODS:We tested associations between physical activity pattern and incidence of 678 conditions in 89 573 participants (62±8 years of age; 56% women) of the UK Biobank prospective cohort study who wore an accelerometer for 1 week between June 2013 and December 2015. Models were adjusted for multiple baseline clinical factors, and value thresholds were corrected for multiplicity. RESULTS:When compared to inactive (<150 minutes moderate-to-vigorous physical activity/week), both weekend warrior (267 total associations; 264 [99%] with lower disease risk; hazard ratio [HR] range, 0.35-0.89) and regular activity (209 associations; 205 [98%] with lower disease risk; HR range, 0.41-0.88) were broadly associated with lower risk of incident disease. The strongest associations were observed for cardiometabolic conditions such as incident hypertension (weekend warrior: HR, 0.77 [95% CI, 0.73-0.80]; =1.2×10; regular: HR, 0.72 [95% CI, 0.68-0.77]; =4.5×10), diabetes (weekend warrior: HR, 0.57 [95% CI, 0.51-0.62]; =3.9×10; regular: HR, 0.54 [95% CI, 0.48-0.60]; =8.7×10), obesity (weekend warrior: HR, 0.55 [95% CI, 0.50-0.60]; =2.4×10, regular: HR, 0.44 [95% CI, 0.40-0.50]; =9.6×10), and sleep apnea (weekend warrior: HR, 0.57 [95% CI, 0.48-0.69]; =1.6×10; regular: HR, 0.49 [95% CI, 0.39-0.62]; =7.4×10). When weekend warrior and regular activity were compared directly, there were no conditions for which effects differed significantly. Observations were similar when activity was thresholded at the sample median (≥230.4 minutes of moderate-to-vigorous physical activity/week). CONCLUSIONS:Achievement of measured physical activity volumes consistent with guideline recommendations is associated with lower risk for >200 diseases, with prominent effects on cardiometabolic conditions. Associations appear similar whether physical activity follows a weekend warrior pattern or is spread more evenly throughout the week.
10.1161/CIRCULATIONAHA.124.068669
2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.
Journal of the American College of Cardiology
AIM:The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS:A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE:This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.
10.1016/j.jacc.2023.04.003
3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study.
Wu Xiaojun,Liu Xiaofan,Zhou Yilu,Yu Hongying,Li Ruiyun,Zhan Qingyuan,Ni Fang,Fang Si,Lu Yang,Ding Xuhong,Liu Hailing,Ewing Rob M,Jones Mark G,Hu Yi,Nie Hanxiang,Wang Yihua
The Lancet. Respiratory medicine
BACKGROUND:The consequences of COVID-19 in those who recover from acute infection requiring hospitalisation have yet to be clearly defined. We aimed to describe the temporal trends in respiratory outcomes over 12 months in patients hospitalised for severe COVID-19 and to investigate the associated risk factors. METHODS:In this prospective, longitudinal, cohort study, patients admitted to hospital for severe COVID-19 who did not require mechanical ventilation were prospectively followed up at 3 months, 6 months, 9 months, and 12 months after discharge from Renmin Hospital of Wuhan University, Wuhan, China. Patients with a history of hypertension; diabetes; cardiovascular disease; cancer; and chronic lung disease, including asthma or chronic obstructive pulmonary disease; or a history of smoking documented at time of hospital admission were excluded at time of electronic case-note review. Patients who required intubation and mechanical ventilation were excluded given the potential for the consequences of mechanical ventilation itself to influence the factors under investigation. During the follow-up visits, patients were interviewed and underwent physical examination, routine blood test, pulmonary function tests (ie, diffusing capacity of the lungs for carbon monoxide [DLCO]; forced expiratory flow between 25% and 75% of forced vital capacity [FVC]; functional residual capacity; FVC; FEV; residual volume; total lung capacity; and vital capacity), chest high-resolution CT (HRCT), and 6-min walk distance test, as well as assessment using a modified Medical Research Council dyspnoea scale (mMRC). FINDINGS:Between Feb 1, and March 31, 2020, of 135 eligible patients, 83 (61%) patients participated in this study. The median age of participants was 60 years (IQR 52-66). Temporal improvement in pulmonary physiology and exercise capacity was observed in most patients; however, persistent physiological and radiographic abnormalities remained in some patients with COVID-19 at 12 months after discharge. We found a significant reduction in DLCO over the study period, with a median of 77% of predicted (IQR 67-87) at 3 months, 76% of predicted (68-90) at 6 months, and 88% of predicted (78-101) at 12 months after discharge. At 12 months after discharge, radiological changes persisted in 20 (24%) patients. Multivariate logistic regression showed increasing odds of impaired DLCO associated with female sex (odds ratio 8·61 [95% CI 2·83-26·2; p=0·0002) and radiological abnormalities were associated with peak HRCT pneumonia scores during hospitalisation (1·36 [1·13-1·62]; p=0·0009). INTERPRETATION:In most patients who recovered from severe COVID-19, dyspnoea scores and exercise capacity improved over time; however, in a subgroup of patients at 12 months we found evidence of persistent physiological and radiographic change. A unified pathway for the respiratory follow-up of patients with COVID-19 is required. FUNDING:National Natural Science Foundation of China, UK Medical Research Council, and National Institute for Health Research Southampton Biomedical Research Centre. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.
10.1016/S2213-2600(21)00174-0
Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications.
European heart journal
AIMS:Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. METHODS AND RESULTS:Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV-PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch. CONCLUSIONS:Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV-PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.
10.1093/eurheartj/ehac184
Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.
Nature genetics
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
10.1038/s41588-020-00713-x
Selexipag for the treatment of chronic thromboembolic pulmonary hypertension.
The European respiratory journal
BACKGROUND:Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH. METHODS:In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide. RESULTS:The change in PVR was -98.2±111.3 dyn·s·cm and -4.6±163.6 dyn·s·cm in the selexipag and placebo groups, respectively (mean difference -93.5 dyn·s·cm; 95% CI -156.8 to -30.3; p=0.006). The changes in cardiac index (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue. CONCLUSION:Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.
10.1183/13993003.01694-2021
Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans.
Nature biomedical engineering
The mechanisms by which physical exercise benefits brain functions are not fully understood. Here, we show that vertically oscillating head motions mimicking mechanical accelerations experienced during fast walking, light jogging or treadmill running at a moderate velocity reduce the blood pressure of rats and human adults with hypertension. In hypertensive rats, shear stresses of less than 1 Pa resulting from interstitial-fluid flow induced by such passive head motions reduced the expression of the angiotensin II type-1 receptor in astrocytes in the rostral ventrolateral medulla, and the resulting antihypertensive effects were abrogated by hydrogel introduction that inhibited interstitial-fluid movement in the medulla. Our findings suggest that oscillatory mechanical interventions could be used to elicit antihypertensive effects.
10.1038/s41551-023-01061-x
AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review.
Gastroenterology
DESCRIPTION:Nonalcoholic fatty liver disease (NAFLD) is well recognized as a leading etiology for chronic liver disease, affecting >25% of the US and global populations. Up to 1 in 4 individuals with NAFLD have nonalcoholic steatohepatitis, which is associated with significant morbidity and mortality due to complications of liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although NAFLD is observed predominantly in persons with obesity and/or type 2 diabetes mellitus, an estimated 7%-20% of individuals with NAFLD have lean body habitus. Limited guidance is available to clinicians on appropriate clinical evaluation in lean individuals with NAFLD, such as for inherited/genetic disorders, lipodystrophy, drug-induced NAFLD, and inflammatory disorders. Emerging data now provide more robust evidence to define the epidemiology, natural history, prognosis, and mortality of lean individuals with NAFLD. Multiple studies have found that NAFLD among lean individuals is associated with increased cardiovascular, liver, and all-cause mortality relative to those without NAFLD. This American Gastroenterological Association Clinical Practice Update provides Best Practice Advice to assist clinicians in evidence-based approaches to the diagnosis, staging, and management of NAFLD in lean individuals. METHODS:This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Lean NAFLD should be diagnosed in individuals with NAFLD and body mass index <25 kg/m (non-Asian race) or body mass index <23 kg/m (Asian race). BEST PRACTICE ADVICE 2: Lean individuals with NAFLD should be evaluated routinely for comorbid conditions, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. BEST PRACTICE ADVICE 3: Lean individuals with NAFLD should be risk stratified for hepatic fibrosis to identify those with advanced fibrosis or cirrhosis. BEST PRACTICE ADVICE 4: Lean individuals in the general population should not undergo routine screening for NAFLD; however, screening should be considered for individuals older than 40 years with type 2 diabetes mellitus. BEST PRACTICE ADVICE 5: NAFLD should be considered in lean individuals with metabolic diseases (such as type 2 diabetes mellitus, dyslipidemia, and hypertension), elevated liver biochemical tests, or incidentally noted hepatic steatosis. BEST PRACTICE ADVICE 6: Clinicians should query patients routinely regarding alcohol consumption patterns in all patients with lean NAFLD. BEST PRACTICE ADVICE 7: In patients with lean NAFLD, other causes of liver disease should be ruled out, including other causes of fatty liver, such as HIV, lipodystrophy, lysosomal acid lipase deficiency, familial hypobetalipoproteinemia, and medication-induced hepatic steatosis (methotrexate, amiodarone, tamoxifen, and steroids). BEST PRACTICE ADVICE 8: Current evidence is inadequate to support routine testing for genetic variants in patients with lean NAFLD. BEST PRACTICE ADVICE 9: Liver biopsy, as the reference standard, should be considered if there is uncertainty regarding contributing causes of liver injury and/or the stage of liver fibrosis. BEST PRACTICE ADVICE 10: Serum indices (NAFLD fibrosis score and Fibrosis-4 score) and imaging techniques (transient elastography and magnetic resonance elastography) may be used as alternatives to liver biopsy for fibrosis staging and patient follow-up. These tests can be performed at the time of diagnosis and repeated at intervals of 6 months to 2 years, depending on fibrosis stage and the patient's response to intervention. BEST PRACTICE ADVICE 11: If noninvasive tests (eg, Fibrosis-4 and NAFLD fibrosis score) are indeterminate, a second noninvasive test (eg, transient elastography or magnetic resonance elastography) should be performed to confirm the stage and prognosis of NAFLD. BEST PRACTICE ADVICE 12: In lean patients with NAFLD, lifestyle intervention, including exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to target a modest weight loss of 3%-5% is suggested. BEST PRACTICE ADVICE 13: Administration of vitamin E may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis, but without type 2 diabetes mellitus or cirrhosis. Oral pioglitazone 30 mg daily may be considered in lean persons with biopsy-confirmed nonalcoholic steatohepatitis without cirrhosis. BEST PRACTICE ADVICE 14: The therapeutic role of glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors in the management of lean NAFLD is not fully defined and requires further investigation. BEST PRACTICE ADVICE 15: Hepatocellular carcinoma surveillance with abdominal ultrasound with or without serum α-fetoprotein twice per year is suggested in patients with lean NAFLD and clinical markers compatible with liver cirrhosis.
10.1053/j.gastro.2022.06.023
Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation.
Journal of the American College of Cardiology
BACKGROUND:Exercise echocardiography is used for assessment of pulmonary circulation and right ventricular function, but limits of normal and disease-specific changes remain insufficiently established. OBJECTIVES:The objective of this study was to explore the physiological vs pathologic response of the right ventricle and pulmonary circulation to exercise. METHODS:A total of 2,228 subjects were enrolled: 375 healthy controls, 40 athletes, 516 patients with cardiovascular risk factors, 17 with pulmonary arterial hypertension, 872 with connective tissue diseases without overt pulmonary hypertension, 113 with left-sided heart disease, 30 with lung disease, and 265 with chronic exposure to high altitude. All subjects underwent resting and exercise echocardiography on a semirecumbent cycle ergometer. All-cause mortality was recorded at follow-up. RESULTS:The 5th and 95th percentile of the mean pulmonary artery pressure-cardiac output relationships were 0.2 to 3.5 mm Hg.min/L in healthy subjects without cardiovascular risk factors, and were increased in all patient categories and in high altitude residents. The 5th and 95th percentile of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio at rest were 0.7 to 2.0 mm/mm Hg at rest and 0.5 to 1.5 mm/mm Hg at peak exercise, and were decreased at rest and exercise in all disease categories and in high-altitude residents. An increased all-cause mortality was predicted by a resting tricuspid annular plane systolic excursion to systolic pulmonary artery pressure <0.7 mm/mm Hg and mean pulmonary artery pressure-cardiac output >5 mm Hg.min/L. CONCLUSIONS:Exercise echocardiography of the pulmonary circulation and the right ventricle discloses prognostically relevant differences between healthy subjects, athletes, high-altitude residents, and patients with various cardio-respiratory conditions. (Right Heart International NETwork During Exercise in Different Clinical Conditions; NCT03041337).
10.1016/j.jacc.2023.09.807
Racial and Ethnic Disparities in Peripheral Artery Disease.
Hackler Eddie L,Hamburg Naomi M,White Solaru Khendi T
Circulation research
Peripheral artery disease is an obstructive, atherosclerotic disease of the lower extremities causing significant morbidity and mortality. Black Americans are disproportionately affected by this disease while they are also less likely to be diagnosed and promptly treated. The consequences of this disparity can be grim as Black Americans bear the burden of lower extremity amputation resulting from severe peripheral artery disease. The risk factors of peripheral artery disease and how they differentially affect certain groups are discussed in addition to a review of pharmacological and nonpharmacological treatment modalities. The purpose of this review is to highlight health care inequities and provide a review and resource of available recommendations for clinical management of all patients with peripheral artery disease.
10.1161/CIRCRESAHA.121.318243
Exercise Regulates MicroRNAs to Preserve Coronary and Cardiac Function in the Diabetic Heart.
Lew Jason Kar-Sheng,Pearson James T,Saw Eugene,Tsuchimochi Hirotsugu,Wei Melanie,Ghosh Nilanjan,Du Cheng-Kun,Zhan Dong-Yun,Jin Meihua,Umetani Keiji,Shirai Mikiyasu,Katare Rajesh,Schwenke Daryl O
Circulation research
RATIONALE:Diabetic heart disease (DHD) is a debilitating manifestation of type 2 diabetes mellitus. Exercise has been proposed as a potential therapy for DHD, although the effectiveness of exercise in preventing or reversing the progression of DHD remains controversial. Cardiac function is critically dependent on the preservation of coronary vascular function. OBJECTIVE:We aimed to elucidate the effectiveness and mechanisms by which exercise facilitates coronary and cardiac-protection during the onset and progression of DHD. METHODS AND RESULTS:Diabetic db/db and nondiabetic mice, with or without underlying cardiac dysfunction (16 and 8 weeks old, respectively) were subjected to either moderate-intensity exercise or high-intensity exercise for 8 weeks. Subsequently, synchrotron microangiography, immunohistochemistry, Western blot, and real-time polymerase chain reaction were used to assess time-dependent changes in cardiac and coronary structure and function associated with diabetes mellitus and exercise and determine whether these changes reflect the observed changes in cardiac-enriched and vascular-enriched microRNAs (miRNAs). We show that, if exercise is initiated from 8 weeks of age, both moderate-intensity exercise and high-intensity exercise prevented the onset of coronary and cardiac dysfunction, apoptosis, fibrosis, microvascular rarefaction, and disruption of miRNA signaling, as seen in the nonexercised diabetic mice. Conversely, the cardiovascular benefits of moderate-intensity exercise were absent if the exercise was initiated after the diabetic mice had already established cardiac dysfunction (ie, from 16 weeks of age). The experimental silencing or upregulation of miRNA-126 activity suggests the mechanism underpinning the cardiovascular benefits of exercise were mediated, at least in part, through tissue-specific miRNAs. CONCLUSIONS:Our findings provide the first experimental evidence for the critical importance of early exercise intervention in ameliorating the onset and progression of DHD. Our results also suggest that the beneficial effects of exercise are mediated through the normalization of cardiovascular-enriched miRNAs, which are dysregulated in DHD.
10.1161/CIRCRESAHA.120.317604
Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review.
Kim Jae Han,Kim Jong Yeob,Lee Jinhee,Jeong Gwang Hun,Lee Eun,Lee San,Lee Keum Hwa,Kronbichler Andreas,Stubbs Brendon,Solmi Marco,Koyanagi Ai,Hong Sung Hwi,Dragioti Elena,Jacob Louis,Brunoni Andre R,Carvalho Andre F,Radua Joaquim,Thompson Trevor,Smith Lee,Oh Hans,Yang Lin,Grabovac Igor,Schuch Felipe,Fornaro Michele,Stickley Andrew,Rais Theodor B,Salazar de Pablo Gonzalo,Shin Jae Il,Fusar-Poli Paolo
The lancet. Psychiatry
BACKGROUND:Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD. METHODS:In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta-analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032. FINDINGS:We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51). INTERPRETATION:Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality. FUNDING:None.
10.1016/S2215-0366(20)30312-6
EULAR recommendations for the treatment of systemic sclerosis: 2023 update.
Annals of the rheumatic diseases
OBJECTIVES:To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. METHODS:An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. RESULTS:The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. CONCLUSION:These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.
10.1136/ard-2024-226430
Cardiopulmonary Hemodynamics in Pulmonary Hypertension and Heart Failure: JACC Review Topic of the Week.
Maron Bradley A,Kovacs Gabor,Vaidya Anjali,Bhatt Deepak L,Nishimura Rick A,Mak Susanna,Guazzi Marco,Tedford Ryan J
Journal of the American College of Cardiology
Pulmonary hypertension (PH) is an independent risk factor for adverse clinical outcome, particularly in left heart disease (LHD) patients. Recent advances have clarified the mean pulmonary artery pressure (mPAP) range that is above normal and is associated with clinical events, including mortality. This progress has for the first time resulted in a new clinical definition of PH that is evidenced-based, is inclusive of mPAP >20 mm Hg, and emphasizes early diagnosis. Additionally, pulmonary vascular resistance (PVR) 2.2 to 3.0 WU, considered previously to be normal, appears to associate with elevated clinical risk. A revised approach to classifying PH patients as pre-capillary, isolated post-capillary, or combined pre-/post-capillary PH now guides point-of-care diagnosis, risk stratification, and treatment. Exercise hemodynamic or confrontational fluid challenge studies may also aid decision-making for patients with PH-LHD or otherwise unexplained dyspnea. This collective progress in pulmonary vascular and heart failure medicine reinforces the critical importance of accurate hemodynamic assessment.
10.1016/j.jacc.2020.10.007
MED1 Regulates BMP/TGF-β in Endothelium: Implication for Pulmonary Hypertension.
Circulation research
BACKGROUND:Dysregulated BMP (bone morphogenetic protein) or TGF-β (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-β axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-β axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (), and TGFBR2 (TGF-β receptor 2) and their involvement in the PH. METHODS:High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-) were used to study the PH-protective effect of MED1. RESULTS:Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents. CONCLUSIONS:A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-β signaling is implicated in the disease progression of PAH in humans and PH in rodent models.
10.1161/CIRCRESAHA.122.321532
Lifestyle and Risk Factor Modification for Reduction of Atrial Fibrillation: A Scientific Statement From the American Heart Association.
Chung Mina K,Eckhardt Lee L,Chen Lin Y,Ahmed Haitham M,Gopinathannair Rakesh,Joglar José A,Noseworthy Peter A,Pack Quinn R,Sanders Prashanthan,Trulock Kevin M,
Circulation
Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with substantial morbidity, mortality, and healthcare use. Great strides have been made in stroke prevention and rhythm control strategies, yet reducing the incidence of AF has been slowed by the increasing incidence and prevalence of AF risk factors, including obesity, physical inactivity, sleep apnea, diabetes mellitus, hypertension, and other modifiable lifestyle-related factors. Fortunately, many of these AF drivers are potentially reversible, and emerging evidence supports that addressing these modifiable risks may be effective for primary and secondary AF prevention. A structured, protocol-driven multidisciplinary approach to integrate lifestyle and risk factor management as an integral part of AF management may help in the prevention and treatment of AF. However, this aspect of AF management is currently underrecognized, underused, and understudied. The purpose of this American Heart Association scientific statement is to review the association of modifiable risk factors with AF and the effects of risk factor intervention. Implementation strategies, care pathways, and educational links for achieving impactful weight reduction, increased physical activity, and risk factor modification are included. Implications for clinical practice, gaps in knowledge, and future directions for the research community are highlighted.
10.1161/CIR.0000000000000748
Association of Antenatal Diet and Physical Activity-Based Interventions With Gestational Weight Gain and Pregnancy Outcomes: A Systematic Review and Meta-analysis.
JAMA internal medicine
IMPORTANCE:Excessive gestational weight gain (GWG) is common and associated with adverse pregnancy outcomes. Antenatal lifestyle interventions limit GWG; yet benefits of different intervention types and specific maternal and neonatal outcomes are unclear. OBJECTIVE:To evaluate the association of different types of diet and physical activity-based antenatal lifestyle interventions with GWG and maternal and neonatal outcomes. DATA SOURCES:A 2-stage systematic literature search of MEDLINE, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Health Technology Assessment Database was conducted from February 1, 2017, to May 31, 2020. Search results from the present study were integrated with those from a previous systematic review from 1990 to February 2017. STUDY SELECTION:Randomized trials reporting GWG and maternal and neonatal outcomes. DATA EXTRACTION AND SYNTHESIS:Data were extracted for random-effects meta-analyses to calculate the summary effect estimates and 95% CIs. MAIN OUTCOMES AND MEASURES:Outcomes were clinically prioritized, with mean GWG as the primary outcome. Secondary outcomes included gestational diabetes, hypertensive disorders of pregnancy, cesarean section, preterm delivery, large or small for gestational age neonates, neonatal intensive care unit admission, or fetal death. RESULTS:A total of 117 randomized clinical trials of antenatal lifestyle interventions (involving 34 546 women) were included. Overall lifestyle intervention was associated with reduced GWG (-1.15 kg; 95% CI, -1.40 to -0.91), risk of gestational diabetes (odds ratio [OR], 0.79; 95% CI, 0.70-0.89), and total adverse maternal outcomes (OR, 0.89; 95% CI, 0.84-0.94) vs routine care. Compared with routine care, diet was associated with less GWG (-2.63 kg; 95% CI, -3.87 to -1.40) than physical activity (-1.04 kg; 95% CI, -1.33 to -0.74) or mixed interventions (eg, unstructured lifestyle support, written information with weight monitoring, or behavioral support alone) (-0.74 kg; 95% CI, -1.06 to -0.43). Diet was associated with reduced risk of gestational diabetes (OR, 0.61; 95% CI, 0.45-0.82), preterm delivery (OR, 0.43; 95% CI, 0.22-0.84), large for gestational age neonate (OR, 0.19; 95% CI, 0.08-0.47), neonatal intensive care admission (OR, 0.68; 95% CI, 0.48-0.95), and total adverse maternal (OR, 0.75; 95% CI, 0.61-0.92) and neonatal outcomes (OR, 0.44; 95% CI, 0.26-0.72). Physical activity was associated with reduced GWG and reduced risk of gestational diabetes (OR, 0.60; 95% CI, 0.47-0.75), hypertensive disorders (OR, 0.66; 95% CI, 0.48-0.90), cesarean section (OR, 0.85; 95% CI, 0.75-0.95), and total adverse maternal outcomes (OR, 0.78; 95% CI, 0.71-0.86). Diet with physical activity was associated with reduced GWG (-1.35 kg; 95% CI, -1.95 to -0.75) and reduced risk of gestational diabetes (OR, 0.72; 95% CI, 0.54-0.96) and total adverse maternal outcomes (OR, 0.81; 95% CI, 0.69-0.95). Mixed interventions were associated with reduced GWG only. CONCLUSIONS AND RELEVANCE:This systematic review and meta-analysis found level 1 evidence that antenatal structured diet and physical activity-based lifestyle interventions were associated with reduced GWG and lower risk of adverse maternal and neonatal outcomes. The findings support the implementation of such interventions in routine antenatal care and policy around the world.
10.1001/jamainternmed.2021.6373
Hypertension in Low- and Middle-Income Countries.
Circulation research
In recent decades low- and middle-income countries (LMICs) have been witnessing a significant shift toward raised blood pressure; yet in LMICs, only 1 in 3 are aware of their hypertension status, and ≈8% have their blood pressure controlled. This rising burden widens the inequality gap, contributes to massive economic hardships of patients and carers, and increases costs to the health system, facing challenges such as low physician-to-patient ratios and lack of access to medicines. Established risk factors include unhealthy diet (high salt and low fruit and vegetable intake), physical inactivity, tobacco and alcohol use, and obesity. Emerging risk factors include pollution (air, water, noise, and light), urbanization, and a loss of green space. Risk factors that require further in-depth research are low birth weight and social and commercial determinants of health. Global actions include the HEARTS technical package and the push for universal health care. Promising research efforts highlight that successful interventions are feasible in LMICs. These include creation of health-promoting environments by introducing salt-reduction policies and sugar and alcohol tax; implementing cost-effective screening and simplified treatment protocols to mitigate treatment inertia; pooled procurement of low-cost single-pill combination therapy to improve adherence; increasing access to telehealth and mHealth (mobile health); and training health care staff, including community health workers, to strengthen team-based care. As the blood pressure trajectory continues creeping upward in LMICs, contextual research on effective, safe, and cost-effective interventions is urgent. New emergent risk factors require novel solutions. Lowering blood pressure in LMICs requires urgent global political and scientific priority and action.
10.1161/CIRCRESAHA.120.318729
Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease.
Waxman Aaron,Restrepo-Jaramillo Ricardo,Thenappan Thenappan,Ravichandran Ashwin,Engel Peter,Bajwa Abubakr,Allen Roblee,Feldman Jeremy,Argula Rahul,Smith Peter,Rollins Kristan,Deng Chunqin,Peterson Leigh,Bell Heidi,Tapson Victor,Nathan Steven D
The New England journal of medicine
BACKGROUND:No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS:We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS:A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS:In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).
10.1056/NEJMoa2008470
Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial.
JAMA
Importance:The benefits of vitamin D, omega-3 fatty acids, and exercise in disease prevention remain unclear. Objective:To test whether vitamin D, omega-3s, and a strength-training exercise program, alone or in combination, improved 6 health outcomes among older adults. Design, Setting, and Participants:Double-blind, placebo-controlled, 2 × 2 × 2 factorial randomized clinical trial among 2157 adults aged 70 years or older who had no major health events in the 5 years prior to enrollment and had sufficient mobility and good cognitive status. Patients were recruited between December 2012 and November 2014, and final follow-up was in November 2017. Interventions:Participants were randomized to 3 years of intervention in 1 of the following 8 groups: 2000 IU/d of vitamin D3, 1 g/d of omega-3s, and a strength-training exercise program (n = 264); vitamin D3 and omega-3s (n = 265); vitamin D3 and exercise (n = 275); vitamin D3 alone (n = 272); omega-3s and exercise (n = 275); omega-3s alone (n = 269); exercise alone (n = 267); or placebo (n = 270). Main Outcomes and Measures:The 6 primary outcomes were change in systolic and diastolic blood pressure (BP), Short Physical Performance Battery (SPPB), Montreal Cognitive Assessment (MoCA), and incidence rates (IRs) of nonvertebral fractures and infections over 3 years. Based on multiple comparisons of 6 primary end points, 99% confidence intervals are presented and P < .01 was required for statistical significance. Results:Among 2157 randomized participants (mean age, 74.9 years; 61.7% women), 1900 (88%) completed the study. Median follow-up was 2.99 years. Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years. For instance, the differences in mean change in systolic BP with vitamin D vs no vitamin D and with omega-3s vs no omega-3s were both -0.8 (99% CI, -2.1 to 0.5) mm Hg, with P < .13 and P < .11, respectively; the difference in mean change in diastolic BP with omega-3s vs no omega-3s was -0.5 (99% CI, -1.2 to 0.2) mm Hg; P = .06); and the difference in mean change in IR of infections with omega-3s vs no omega-3s was -0.13 (99% CI, -0.23 to -0.03), with an IR ratio of 0.89 (99% CI, 0.78-1.01; P = .02). No effects were found on the outcomes of SPPB, MoCA, and incidence of nonvertebral fractures). A total of 25 deaths were reported, with similar numbers in all treatment groups. Conclusions and Relevance:Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT01745263.
10.1001/jama.2020.16909
Sleep Disordered Breathing and Cardiovascular Disease: JACC State-of-the-Art Review.
Cowie Martin R,Linz Dominik,Redline Susan,Somers Virend K,Simonds Anita K
Journal of the American College of Cardiology
Sleep disordered breathing causes repetitive episodes of nocturnal hypoxemia, sympathetic nervous activation, and cortical arousal, often associated with excessive daytime sleepiness. Sleep disordered breathing is common in people with, or at risk of, cardiovascular (CV) disease including those who are obese or have hypertension, coronary disease, heart failure, or atrial fibrillation. Current therapy of obstructive sleep apnea includes weight loss (if obese), exercise, and positive airway pressure (PAP) therapy. This improves daytime sleepiness. Obstructive sleep apnea is associated with increased CV risk, but treatment with PAP in randomized trials has not been shown to improve CV outcome. Central sleep apnea (CSA) is not usually associated with daytime sleepiness in heart failure or atrial fibrillation and is a marker of increased CV risk, but PAP has been shown to be harmful in 1 randomized trial. The benefits of better phenotyping, targeting of higher-risk patients, and a more personalized approach to therapy are being explored in ongoing trials.
10.1016/j.jacc.2021.05.048
Sex Differences in Cardiac Rehabilitation Outcomes.
Circulation research
Cardiovascular disease is a leading cause of morbidity and mortality in males and females in the United States and globally. Cardiac rehabilitation (CR) is recommended by the American Heart Association/American College of Cardiology for secondary prevention for patients with cardiovascular disease. CR participation is associated with improved cardiovascular disease risk factor management, quality of life, and exercise capacity as well as reductions in hospital admissions and mortality. Despite these advantageous clinical outcomes, significant sex disparities exist in outpatient phase II CR programming. This article reviews sex differences that are present in the spectrum of care provided by outpatient phase II CR programming (ie, from referral to clinical management). We first review CR participation by detailing the sex disparities in the rates of CR referral, enrollment, and completion. In doing so, we discuss patient, health care provider, and social/environmental level barriers to CR participation with a particular emphasis on those barriers that majorly impact females. We also evaluate sex differences in the core components incorporated into CR programming (eg, patient assessment, exercise training, hypertension management). Next, we review strategies to mitigate these sex differences in CR participation with a focus on automatic CR referral, female-only CR programming, and hybrid CR. Finally, we outline knowledge gaps and areas of future research to minimize and prevent sex differences in CR programming.
10.1161/CIRCRESAHA.121.319894
Effects of Lifestyle Modification on Patients With Resistant Hypertension: Results of the TRIUMPH Randomized Clinical Trial.
Circulation
BACKGROUND:Although lifestyle modifications generally are effective in lowering blood pressure (BP) among patients with unmedicated hypertension and in those treated with 1 or 2 antihypertensive agents, the value of exercise and diet for lowering BP in patients with resistant hypertension is unknown. METHODS:One hundred forty patients with resistant hypertension (mean age, 63 years; 48% female; 59% Black; 31% with diabetes; 21% with chronic kidney disease) were randomly assigned to a 4-month program of lifestyle modification (C-LIFE [Center-Based Lifestyle Intervention]) including dietary counseling, behavioral weight management, and exercise, or a single counseling session providing SEPA (Standardized Education and Physician Advice). The primary end point was clinic systolic BP; secondary end points included 24-hour ambulatory BP and select cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of the baroreflex on heart rate, high-frequency heart rate variability to assess vagally mediated modulation of heart rate, flow-mediated dilation to evaluate endothelial function, pulse wave velocity to assess arterial stiffness, and left ventricular mass to characterize left ventricular structure. RESULTS:Between-group comparisons revealed that the reduction in clinic systolic BP was greater in C-LIFE (-12.5 [95% CI, -14.9 to -10.2] mm Hg) compared with SEPA(-7.1 [-95% CI, 10.4 to -3.7] mm Hg) (=0.005); 24-hour ambulatory systolic BP also was reduced in C-LIFE (-7.0 [95% CI, -8.5 to -4.0] mm Hg), with no change in SEPA (-0.3 [95% CI, -4.0 to 3.4] mm Hg) (=0.001). Compared with SEPA, C-LIFE resulted in greater improvements in resting baroreflex sensitivity (2.3 ms/mm Hg [95% CI, 1.3 to 3.3] versus -1.1 ms/mm Hg [95% CI, -2.5 to 0.3]; <0.001), high-frequency heart rate variability (0.4 ln ms [95% CI, 0.2 to 0.6] versus -0.2 ln ms [95% CI, -0.5 to 0.1]; <0.001), and flow-mediated dilation (0.3% [95% CI, -0.3 to 1.0] versus -1.4% [95% CI, -2.5 to -0.3]; =0.022). There were no between-group differences in pulse wave velocity (=0.958) or left ventricular mass (=0.596). CONCLUSIONS:Diet and exercise can lower BP in patients with resistant hypertension. A 4-month structured program of diet and exercise as adjunctive therapy delivered in a cardiac rehabilitation setting results in significant reductions in clinic and ambulatory BP and improvement in selected cardiovascular disease biomarkers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02342808.
10.1161/CIRCULATIONAHA.121.055329
Obesity in Adolescents: A Review.
JAMA
Importance:Obesity affects approximately 21% of US adolescents and is associated with insulin resistance, hypertension, dyslipidemia, sleep disorders, depression, and musculoskeletal problems. Obesity during adolescence has also been associated with an increased risk of mortality from cardiovascular disease and type 2 diabetes in adulthood. Observations:Obesity in adolescents aged 12 to younger than 18 years is commonly defined as a body mass index (BMI) at the 95th or greater age- and sex-adjusted percentile. Comprehensive treatment in adolescents includes lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Lifestyle modification therapy, which includes dietary, physical activity, and behavioral counseling, is first-line treatment; as monotherapy, lifestyle modification requires more than 26 contact hours over 1 year to elicit approximately 3% mean BMI reduction. Newer antiobesity medications, such as liraglutide, semaglutide, and phentermine/topiramate, in combination with lifestyle modification therapy, can reduce mean BMI by approximately 5% to 17% at 1 year of treatment. Adverse effects vary, but severe adverse events from these newer antiobesity medications are rare. Surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy) for severe adolescent obesity (BMI ≥120% of the 95th percentile) reduces mean BMI by approximately 30% at 1 year. Minor and major perioperative complications, such as reoperation and hospital readmission for dehydration, are experienced by approximately 15% and 8% of patients, respectively. Determining the long-term durability of all obesity treatments warrants future research. Conclusions and Relevance:The prevalence of adolescent obesity is approximately 21% in the US. Treatment options for adolescents with obesity include lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Intensive lifestyle modification therapy reduces BMI by approximately 3% while pharmacotherapy added to lifestyle modification therapy can attain BMI reductions ranging from 5% to 17%. Surgery is the most effective intervention for adolescents with severe obesity and has been shown to achieve BMI reduction of approximately 30%.
10.1001/jama.2024.11809
Lifestyle interventions for the prevention and treatment of hypertension.
Valenzuela Pedro L,Carrera-Bastos Pedro,Gálvez Beatriz G,Ruiz-Hurtado Gema,Ordovas José M,Ruilope Luis M,Lucia Alejandro
Nature reviews. Cardiology
Hypertension affects approximately one third of the world's adult population and is a major cause of premature death despite considerable advances in pharmacological treatments. Growing evidence supports the use of lifestyle interventions for the prevention and adjuvant treatment of hypertension. In this Review, we provide a summary of the epidemiological research supporting the preventive and antihypertensive effects of major lifestyle interventions (regular physical exercise, body weight management and healthy dietary patterns), as well as other less traditional recommendations such as stress management and the promotion of adequate sleep patterns coupled with circadian entrainment. We also discuss the physiological mechanisms underlying the beneficial effects of these lifestyle interventions on hypertension, which include not only the prevention of traditional risk factors (such as obesity and insulin resistance) and improvements in vascular health through an improved redox and inflammatory status, but also reduced sympathetic overactivation and non-traditional mechanisms such as increased secretion of myokines.
10.1038/s41569-020-00437-9
Ten-Hour Time-Restricted Eating Reduces Weight, Blood Pressure, and Atherogenic Lipids in Patients with Metabolic Syndrome.
Wilkinson Michael J,Manoogian Emily N C,Zadourian Adena,Lo Hannah,Fakhouri Savannah,Shoghi Azarin,Wang Xinran,Fleischer Jason G,Navlakha Saket,Panda Satchidananda,Taub Pam R
Cell metabolism
In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of ≥14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 h of TRE (all dietary intake within a consistent self-selected 10 h window) for 12 weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome. VIDEO ABSTRACT.
10.1016/j.cmet.2019.11.004
Update on the pathophysiology and medical treatment of peripheral artery disease.
Nature reviews. Cardiology
Approximately 6% of adults worldwide have atherosclerosis and thrombosis of the lower limb arteries (peripheral artery disease (PAD)) and the prevalence is rising. PAD causes leg pain, impaired health-related quality of life, immobility, tissue loss and a high risk of major adverse events, including myocardial infarction, stroke, revascularization, amputation and death. In this Review, I describe the pathophysiology, presentation, outcome, preclinical research and medical management of PAD. Established treatments for PAD include antithrombotic drugs, such as aspirin and clopidogrel, and medications to treat dyslipidaemia, hypertension and diabetes mellitus. Randomized controlled trials have demonstrated that these treatments reduce the risk of major adverse events. The drug cilostazol, exercise therapy and revascularization are the current treatment options for the limb symptoms of PAD, but each has limitations. Novel therapies to promote collateral and new capillary growth and treat PAD-related myopathy are under investigation. Methods to improve the implementation of evidence-based medical management, novel drug therapies and rehabilitation programmes for PAD-related pain, functional impairment and ischaemic foot disease are important areas for future research.
10.1038/s41569-021-00663-9
Sotatercept for the Treatment of Pulmonary Arterial Hypertension.
Humbert Marc,McLaughlin Vallerie,Gibbs J Simon R,Gomberg-Maitland Mardi,Hoeper Marius M,Preston Ioana R,Souza Rogerio,Waxman Aaron,Escribano Subias Pilar,Feldman Jeremy,Meyer Gisela,Montani David,Olsson Karen M,Manimaran Solaiappan,Barnes Jennifer,Linde Peter G,de Oliveira Pena Janethe,Badesch David B,
The New England journal of medicine
BACKGROUND:Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS:In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS:Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS:Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).
10.1056/NEJMoa2024277
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Journal of the American College of Cardiology
AIM:The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS:A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE:Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
10.1016/j.jacc.2023.08.017
Hypertension in children and adolescents.
European heart journal
Definition and management of arterial hypertension in children and adolescents are uncertain, due to different positions of current guidelines. The European Society of Cardiology task-force, constituted by Associations and Councils with interest in arterial hypertension, has reviewed current literature and evidence, to produce a Consensus Document focused on aspects of hypertension in the age range of 6-16 years, including definition, methods of measurement of blood pressure, clinical evaluation, assessment of hypertension-mediated target organ damage, evaluation of possible vascular, renal and hormonal causes, assessment and management of concomitant risk factors with specific attention for obesity, and anti-hypertensive strategies, especially focused on life-style modifications. The Consensus Panel also suggests aspects that should be studied with high priority, including generation of multi-ethnic sex, age and height specific European normative tables, implementation of randomized clinical trials on different diagnostic and therapeutic aspects, and long-term cohort studies to link with adult cardiovascular risk. Finally, suggestions for the successful implementation of the contents of the present Consensus document are also given.
10.1093/eurheartj/ehac328
The trans-ancestral genomic architecture of glycemic traits.
Nature genetics
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
10.1038/s41588-021-00852-9
Altitude illnesses.
Nature reviews. Disease primers
Millions of people visit high-altitude regions annually and more than 80 million live permanently above 2,500 m. Acute high-altitude exposure can trigger high-altitude illnesses (HAIs), including acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE). Chronic mountain sickness (CMS) can affect high-altitude resident populations worldwide. The prevalence of acute HAIs varies according to acclimatization status, rate of ascent and individual susceptibility. AMS, characterized by headache, nausea, dizziness and fatigue, is usually benign and self-limiting, and has been linked to hypoxia-induced cerebral blood volume increases, inflammation and related trigeminovascular system activation. Disruption of the blood-brain barrier leads to HACE, characterized by altered mental status and ataxia, and increased pulmonary capillary pressure, and related stress failure induces HAPE, characterized by dyspnoea, cough and exercise intolerance. Both conditions are progressive and life-threatening, requiring immediate medical intervention. Treatment includes supplemental oxygen and descent with appropriate pharmacological therapy. Preventive measures include slow ascent, pre-acclimatization and, in some instances, medications. CMS is characterized by excessive erythrocytosis and related clinical symptoms. In severe CMS, temporary or permanent relocation to low altitude is recommended. Future research should focus on more objective diagnostic tools to enable prompt treatment, improved identification of individual susceptibilities and effective acclimatization and prevention options.
10.1038/s41572-024-00526-w
Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension.
The New England journal of medicine
BACKGROUND:Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS:We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS:A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS:In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
10.1056/NEJMoa2213558
2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.
Circulation
AIM:The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS:A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE:This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.
10.1161/CIR.0000000000001168
Diagnosis and Management of Obstructive Sleep Apnea: A Review.
Gottlieb Daniel J,Punjabi Naresh M
JAMA
Importance:Obstructive sleep apnea (OSA) affects 17% of women and 34% of men in the US and has a similar prevalence in other countries. This review provides an update on the diagnosis and treatment of OSA. Observations:The most common presenting symptom of OSA is excessive sleepiness, although this symptom is reported by as few as 15% to 50% of people with OSA in the general population. OSA is associated with a 2- to 3-fold increased risk of cardiovascular and metabolic disease. In many patients, OSA can be diagnosed with home sleep apnea testing, which has a sensitivity of approximately 80%. Effective treatments include weight loss and exercise, positive airway pressure, oral appliances that hold the jaw forward during sleep, and surgical modification of the pharyngeal soft tissues or facial skeleton to enlarge the upper airway. Hypoglossal nerve stimulation is effective in select patients with a body mass index less than 32. There are currently no effective pharmacological therapies. Treatment with positive airway pressure lowers blood pressure, especially in patients with resistant hypertension; however, randomized clinical trials of OSA treatment have not demonstrated significant benefit on rates of cardiovascular or cerebrovascular events. Conclusions and Relevance:OSA is common and the prevalence is increasing with the increased prevalence of obesity. Daytime sleepiness is among the most common symptoms, but many patients with OSA are asymptomatic. Patients with OSA who are asymptomatic, or whose symptoms are minimally bothersome and pose no apparent risk to driving safety, can be treated with behavioral measures, such as weight loss and exercise. Interventions such as positive airway pressure are recommended for those with excessive sleepiness and resistant hypertension. Managing asymptomatic OSA to reduce cardiovascular and cerebrovascular events is not currently supported by high-quality evidence.
10.1001/jama.2020.3514
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Circulation
AIM:The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS:A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE:Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.
10.1161/CIR.0000000000001193