An update on lipid oxidation and inflammation in cardiovascular diseases. Zhong Shanshan,Li Luxiao,Shen Xia,Li Qiujing,Xu Wenxin,Wang Xiaoping,Tao Yongzhen,Yin Huiyong Free radical biology & medicine Cardiovascular diseases (CVD), including ischemic heart diseases and cerebrovascular diseases, are the leading causes of morbidity and mortality worldwide. Atherosclerosis is the major underlying factor for most CVD. It is well-established that oxidative stress and inflammation are two major mechanisms leading to atherosclerosis. Under oxidative stress, polyunsaturated fatty acids (PUFA)-containing phospholipids and cholesterol esters in cellular membrane and lipoproteins can be readily oxidized through a free radical-induced lipid peroxidation (LPO) process to form a complex mixture of oxidation products. Overwhelming evidence demonstrates that these oxidized lipids are actively involved in the inflammatory responses in atherosclerosis by interacting with immune cells (such as macrophages) and endothelial cells. In addition to lipid lowering in the prevention and treatment of atherosclerotic CVD, targeting chronic inflammation has been entering the medical realm. Clinical trials are under way to lower the lipoprotein (a) (Lp(a)) and its associated oxidized phospholipids, which will provide clinical evidence that targeting inflammation caused by oxidized lipids is a viable approach for CVD. In this review, we aim to give an update on our understanding of the free radical oxidation of LPO, analytical technique to analyze the oxidation products, especially the oxidized phospholipids and cholesterol esters in low density lipoproteins (LDL), and focusing on the experimental and clinical evidence on the role of lipid oxidation in the inflammatory responses associated with CVD, including myocardial infarction and calcific aortic valve stenosis. The challenges and future directions in understanding the role of LPO in CVD will also be discussed. 10.1016/j.freeradbiomed.2019.03.036

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study. European heart journal AIMS:Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS:A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION:Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies. 10.1093/eurheartj/ehad142

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. European heart journal This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis. 10.1093/eurheartj/ehac361