Residual cardiovascular risk: When should we treat it?
European journal of internal medicine
Cardiovascular disease (CVD) still being the most common cause of death in worldwide. In spite of development of new lipid-lowering therapies which optimize low-density lipoprotein cholesterol (LDL-c) levels, recurrence of CVD events implies addressing factors related with residual cardiovascular (CV) risk. The key determinants of residual CV risk include triglyceride-rich lipoproteins (TRLs) and remnant cholesterol (RC), lipoprotein(a) [Lp(a)] and inflammation including its biochemical markers such as high sensitivity C reactive protein (hs-CRP). On the other hand, unhealthy lifestyle habits, environmental pollution, residual thrombotic risk and the residual metabolic risk determined by obesity and type 2 diabetes (T2D) have a specific weight in the residual CV risk. New pharmacologic therapies and pathways are being explored such as inhibition of apolipoprotein C-III (apoC-III) and angiopoietin-related protein 3 (ANGPTL3) in order to explore if a reduction in TRLs and RC reduce CVD events. Therapeutic target of inflammation plays an attractive way to reduce the atherosclerotic process and to date, approved therapies as colchicine plays a beneficial effect in chronic inflammation and residual CV risk. Lp(a) constitutes one of the most residual CV risk factor due to linkage with CVD and aortic valve stenosis. New and hopeful treatments including antisense oligonucleotides (ASO) and small-interfering ribonucleic acid (siRNA) which interfere in LP(a) codification have been developed to achieve an adequate control in Lp(a) levels. This review points out the paradigms of residual CV risk, discus how we should manage their features and summarize the different therapies targeting each residual CV risk factor.
10.1016/j.ejim.2023.10.013
Lipoprotein(a): cardiovascular risk and emerging therapies.
Expert review of cardiovascular therapy
INTRODUCTION:There is abundant evidence that elevated lipoprotein(a) [LP(a)] associates with cardiovascular risk. Most lipid modifying therapies don't reduce Lp(a), but new technologies are emerging that act upstream, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) that inhibit the translation of mRNA for proteins specifically involved in lipid metabolism. AREAS COVERED:Despite the benefit of therapies for the prevention of atherosclerotic cardiovascular disease (ASCVD), Lp(a) is one of the 'residual risks,' established by observational and Mendelian randomization studies. Although current established lipid modifying therapies targeting low-density-lipoprotein cholesterol, such as statins and ezetimibe, do not lower Lp(a), ASOs and siRNAs demonstrated significant reduction of Lp(a) by -98 to -101% in recent clinical trials. However, we still don't know if specifically lowering Lp(a) reduced cardiovascular events, how much Lp(a) lowering is required to produce clinical benefit, and whether diabetes and inflammation have any impact. This review summarizes Lp(a), the knowns and unknowns about Lp(a), and focus emerging treatments. EXPERT OPINION:New Lp(a) lowering therapies have the potential to contribute to the personalized prevention of ASCVD.
10.1080/14779072.2023.2197593
Targeting Inflammation to Reduce Residual Cardiovascular Risk.
Ajala Oluremi N,Everett Brendan M
Current atherosclerosis reports
PURPOSE OF REVIEW:Patients with established cardiovascular disease are at high risk for recurrent myocardial infarction, stroke, and cardiovascular death. The term residual risk refers to this risk that persists, even after optimal treatment. Considerable progress has been made to understand the biological basis of residual risk and to devise therapies that can safely and effectively reduce risk. The presence of ongoing subclinical vascular inflammation is known to be a marker of elevated residual risk, and reductions in measures of vascular inflammation predict improved outcome in these patients. RECENT FINDINGS:Recent trials of anti-inflammatory agents have specifically tested the hypothesis that inflammation reduction reduces residual cardiovascular risk. Most prominent among these are the CANTOS, COLCOT, and CIRT trials. CANTOS enrolled patients with prior myocardial infarction (MI) and a high-sensitivity C-reactive protein ≥ 2 mg/L and reported a 15% reduction in major adverse cardiovascular events (MACE; HR 0.85, 95% CI 0.74-0.98) with the interleukin-1β inhibitor canakinumab. In COLCOT, colchicine 0.5 mg daily led to a 23% relative risk reduction (HR 0.77, 95% CI 0.61-0.96) in major vascular events in patients with recent acute coronary syndrome. By contrast, CIRT was stopped early for lack of benefit of low-dose methotrexate in preventing MACE in patients with coronary artery disease and either type 2 diabetes or the metabolic syndrome. Ongoing subclinical inflammation is an important marker of risk in patients with established cardiovascular disease, and novel therapies targeted at specific inflammatory pathways now demonstrate efficacy for the prevention of major adverse cardiovascular events.
10.1007/s11883-020-00883-3
Inflammatory Links Between Hypertriglyceridemia and Atherogenesis.
Current atherosclerosis reports
PURPOSE OF REVIEW:Recent studies indicate an association between hypertriglyceridemia (HTG) and atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to discuss the potential mechanism connecting HTG and ASCVD risk and the potential efficacy of HTG-targeting therapies in ASCVD prevention. RECENT FINDINGS:HTG, with elevations in triglyceride-rich lipoproteins (TGRL) and their remnants, are causal ASCVD risk factors. The mechanisms whereby HTG increases ASCVD risk are not well understood but may include multiple factors. Inflammation plays a crucial role in atherosclerosis. TGRL compared to low-density lipoproteins (LDL) correlate better with inflammation. TGRL remnants can penetrate endothelium and interact with macrophages leading to foam cell formation and inflammation in arterial walls, thereby contributing to atherogenesis. In addition, circulating monocytes can take up TGRL and become lipid-laden foamy monocytes, which infiltrate the arterial wall and may also contribute to atherogenesis. Novel therapies targeting HTG or inflammation are in development and have potential of reducing residual ASCVD risk associated with HTG. Clinical and preclinical studies show a causal role of HTG in promoting ASCVD, in which inflammation plays a vital role. Novel therapies targeting HTG or inflammation have potential of reducing residual ASCVD risk.
10.1007/s11883-022-01006-w
Triglyceride-glucose index variability and incident cardiovascular disease: a prospective cohort study.
Cardiovascular diabetology
BACKGROUND:Recent studies have suggested that triglyceride-glucose (TyG) index is an independent predictor of cardiovascular disease (CVD). However, the impact of long-term visit-to-visit variability in TyG index on the risk of CVD is not known. We aimed to investigate the longitudinal association between baseline and mean TyG index as well as TyG index variability and incident CVD in a Chinese population. METHODS:We included 49,579 participants without previous history of CVD in the Kailuan study who underwent three health examinations (2006, 2008, and 2010) and were followed up for clinical events until 2019. TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. We measured TyG index variability as the SD of the residuals obtained from a linear regression on the three TyG index measurements for each individual. Multivariate-adjusted Cox models were used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) with incident CVD. RESULTS:During a median follow-up time of 9.0 years, 2404 developed CVD. The highest tertile (T3) of baseline and mean TyG index were each associated with higher CVD incidence as compared with the lowest tertile (T1): aHR, 1.25; 95% CI 1.11-1.42; and aHR 1.40; 95% CI 1.24-1.58, respectively. Tertile 3 of TyG index variability was associated with increased CVD incidence compared to T1 group (aHR, 1.12; 95% CI 1.01-1.24). Similar findings were observed in a series of sensitivity analyses. CONCLUSION:Higher TyG index level and greater TyGindex variability were each independently associated with a higher incidence of CVD.
10.1186/s12933-022-01541-5
Biosafety risk assessment and risk control of clinical laboratory in designated hospitals for treating COVID-19 in Chongqing, China.
American journal of infection control
BACKGROUND:If a nucleic acid preservation solution containing viral inactivators is used, the biosafety risk in the process of detecting the nucleic acid of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will be low. Patients infected with SARS-CoV-2 are sent to designated hospitals for treatment in China, except for detecting nucleic acid of SARS-CoV-2, other laboratory tests such as bacterial culture may also be carried out while the patients are being treated. However, in addition to nucleic acid testing, biosafety risks in the testing of these items for patients with coronavirus disease 2019 (COVID-19) might be ignored. Therefore, we identified and evaluated risks in these detection processes and formulated appropriate, but not excessive control measures for biosafety risk, to improve the work efficiency and prevent biosafety accidents. METHODS:Biosafety risks in all laboratory tests for COVID-19 patients were identified and evaluated according to the risk severity and occurrence probability. Subsequently, the corresponding control measures for biosafety risk were formulated according to the identified risk. Hereafter, risk monitoring was carried out. RESULTS:More than 32 risks in the entire laboratory testing process were identified and evaluated, and the residual risk after the implementation of the control measures was acceptable. CONCLUSIONS:The biosafety risk assessment of laboratories in designated hospitals for treating COVID-19 should be re-implemented before testing specimens for COVID-19 patients. Risk management by risk monitoring is even more important, as it can prevent the occurrence of biosafety incidents and can continuously improve risk management.
10.1016/j.ajic.2022.05.028
Unexplained Residual Risk In Type 2 Diabetes: How Big Is The Problem?
Current cardiology reports
PURPOSE OF REVIEW:What is new? Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D) individuals. Of the major risk factors for CVD, less than 10% of T2D people meet the American Diabetes Association/American Heart Association recommended goals of therapy. The present review examines how much of the absolute cardiovascular (CV) risk in type 2 diabetes patients can be explained by major CV intervention trials. RECENT FINDINGS:Multiple long-term cardiovascular (CV) intervention trials have examined the effect of specific target-directed therapies on the MACE endpoint. Only one prospective study, STENO-2, has employed a multifactorial intervention comparing intensified versus conventional treatment of modifiable risk factors in T2D patients, and demonstrated a 20% absolute CV risk reduction. If the absolute CV risk reduction in these trials is added to that in the only prospective multifactorial intervention trial (STENO-2), the unexplained CV risk is 44.1%. What are the clinical implications? Potential explanations for the unaccounted-for reduction in absolute CV risk in type 2 diabetes (T2D) patients are discussed. HYPOTHESIS:failure to take into account synergistic interactions between major cardiovascular risk factors is responsible for the unexplained CV risk in T2D patients. Simultaneous treatment of all major CV risk factors to recommended AHA/ADA guideline goals is required to achieve the maximum reduction in CV risk.
10.1007/s11886-024-02055-0
Residual Risk of Trimethylamine-N-Oxide and Choline for Stroke Recurrence in Patients With Intensive Secondary Therapy.
Journal of the American Heart Association
Background Trimethylamine N-oxide (TMAO) contributes to cardiovascular disease through its prothrombotic, proatherothrombotic, and proinflammatory effects. We aimed to evaluate whether residual risk of recurrent stroke of TMAO and its precursor choline remain among patients who received dual-antiplatelet therapy and intensive lipid-lowering therapy and with a low inflammation level (high-sensitivity C-reactive protein <2 mg/L on admission). Methods and Results Patients with ischemic stroke or transient ischemic attack were enrolled from the CNSR-III (Third China National Stroke Registry) in China. Plasma TMAO and choline concentrations at baseline were measured in 9793 participants using liquid chromatography-mass spectrometry. The primary outcome was a new stroke within 1 year. Multivariable-adjusted hazard ratios were calculated using Cox regression models to investigate the associations of TMAO and choline with stroke recurrence. Among all patients, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke (adjusted hazard ratios, 1.28 [95% CI, 1.12-1.45]; and 1.50 [95% CI, 1.32-1.71], respectively). Moreover, elevated TMAO and choline levels were associated with an increased risk of recurrent stroke among patients who received dual-antiplatelet therapy (1.65 [95% CI, 1.28-2.13]; and 1.70 [95% CI, 1.32-2.19], respectively), intensive lipid-lowering therapy (1.49 [95% CI, 1.15-1.94]; and 1.49 [95% CI, 1.15-1.92], respectively), with high-sensitivity C-reactive protein <2 mg/L (1.39 [95% CI, 1.14-1.69]; and 1.88 [95% CI, 1.53-2.30], respectively), and concurrently received dual-antiplatelet therapy, intensive lipid-lowering therapy and with high-sensitivity C-reactive protein <2 mg/L (3.57 [95% CI, 1.73-7.38]; and 2.19 [95% CI, 1.16-4.16], respectively). Conclusions TMAO and choline were risk factors for recurrent stroke independent of dual-antiplatelet therapy, intensive lipid-lowering therapy at discharge, and low inflammation on admission.
10.1161/JAHA.122.027265
Effect of dual residual risk of cholesterol and inflammation on all-cause mortality in patients with cardiovascular disease.
Cardiovascular diabetology
BACKGROUND:Randomized controlled trials confirm that risks of residual cholesterol and residual inflammation remains in patients with cardiovascular disease (CVD) even after lipid-lowering therapy. This study aims to investigate the association between dual residual risk of cholesterol and inflammation and all-cause mortality in a real-world population with CVD. METHODS:Patients with a CVD history who first took statins between 1 January 2010 and 31 December 2017 in the Kailuan Study were selected as study participants. According to low-density lipoprotein cholesterol (LDL-C) and hypersensitive C-reactive protein levels, patients were divided into those with no residual risk, residual inflammatory risk (RIR), residual cholesterol risk (RCR), and residual cholesterol and inflammatory risk (RCIR). Cox proportional hazard model was conducted to determine hazard ratio (HR) of all-cause mortality for RIR, RCR, and RCIR. Stratified analysis was conducted according to good medication adherence and 75% of the percentage LDL-C decline, high SMART 2 risk score, and blood pressure and blood glucose at standard levels. RESULTS:After 6.10 years of follow-up, 377 all-cause deaths occurred in 3509 participants (mean age 63.69 ± 8.41 years, 86.78% men). After adjusting for related risk factors, the HR and (95% confidence interval [CI]) of all-cause mortality in the RIR, RCR, and RCIR was 1.63 (1.05, 2.52), 1.37 (0.98, 1.90), and 1.75 (1.25, 2.46), compared with no residual risk. Similar associations were observed in participants with moderate or low statin compliance, a lower percentage of LDL-C decline, high SMART 2 risk score, uncontrolled blood pressure, and uncontrolled blood glucose, in the RCIR had a 1.66-fold, 2.08-fold, 1.69-fold, 2.04-fold, and 2.05-fold higher risk of all-cause mortality, respectively, than the reference. CONCLUSION:Risks of residual cholesterol and residual inflammation remain in patients with CVD after receiving statins, and their combined effect significantly increases the risk of all-cause mortality. Here, this increased risk was dependent on statin compliance, LDL-C reduction, SMART 2 risk score, and blood pressure and blood glucose control.
10.1186/s12933-023-01826-3
Bibliometric analysis of residual cardiovascular risk: trends and frontiers.
Journal of health, population, and nutrition
BACKGROUND:The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. METHODS:The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. RESULT:A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. CONCLUSION:In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.
10.1186/s41043-023-00478-z
Evaluation and management of residual cardiovascular risk in patients with diabetes.
Gimeno Orna José Antonio,Ortez Toro José Jorge,Peteiro Miranda Carlos Miguel
Endocrinologia, diabetes y nutricion
Presence of diabetes (types 1 and 2) increases the risk of atherosclerotic cardiovascular disease. Despite adequate metabolic control and treatment of vascular risk factors until the goals recommended by the clinical practice guidelines are achieved, residual cardiovascular risk may be very high in some patients with diabetes. Stratifying the vascular risk for each patient as precisely as possible is therefore necessary. Consolidated strategies to improve patient prognosis include aggressive reduction of LDL cholesterol, blood pressure control, achievement of the best HbA1c control possible without inducing hypoglycemia, use of hypoglycemic drugs shown to have cardiovascular benefits, and use of platelet aggregation inhibitors in patients with greater initial risk. Emerging strategies for patients with very high or extreme risk would include use of drugs intended to decrease triglyceride-rich lipoproteins and inflammation.
10.1016/j.endinu.2019.05.004
Residual risks and evolving atherosclerotic plaques.
Molecular and cellular biochemistry
Atherosclerotic disease of the coronary and carotid arteries is the primary global cause of significant mortality and morbidity. The chronic occlusive diseases have changed the epidemiological landscape of health problems both in developed and the developing countries. Despite the enormous benefit of advanced revascularization techniques, use of statins, and successful attempts of targeting modifiable risk factors, like smoking and exercise in the last four decades, there is still a definite "residual risk" in the population, as evidenced by many prevalent and new cases every year. Here, we highlight the burden of the atherosclerotic diseases and provide substantial clinical evidence of the residual risks in these diseases despite advanced management settings, with emphasis on strokes and cardiovascular risks. We critically discussed the concepts and potential underlying mechanisms of the evolving atherosclerotic plaques in the coronary and carotid arteries. This has changed our understanding of the plaque biology, the progression of unstable vs stable plaques, and the evolution of plaque prior to the occurrence of a major adverse atherothrombotic event. This has been facilitated using intravascular ultrasound, optical coherence tomography, and near-infrared spectroscopy in the clinical settings to achieve surrogate end points. These techniques are now providing exquisite information on plaque size, composition, lipid volume, fibrous cap thickness and other features that were previously not possible with conventional angiography.
10.1007/s11010-023-04689-0