Dataset Information

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

ABSTRACT: Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P<0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; P<0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P=0.11) or in the reverse direction (β=-0.012; P=0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; P<0.001), but the reverse direction was not significant (P=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (P=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; P<0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

SUBMITTER: Liu X

PROVIDER: S-EPMC10757530 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Liu Xue X Sun Xianbang X Zhang Yuankai Y Jiang Wenqing W Lai Meng M Wiggins Kerri L KL Raffield Laura M LM Bielak Lawrence F LF Zhao Wei W Pitsillides Achilleas A Haessler Jeffrey J Zheng Yinan Y Blackwell Thomas W TW Yao Jie J Guo Xiuqing X Qian Yong Y Thyagarajan Bharat B Pankratz Nathan N Rich Stephen S SS Taylor Kent D KD Peyser Patricia A PA Heckbert Susan R SR Seshadri Sudha S Boerwinkle Eric E Grove Megan L ML Larson Nicholas B NB Smith Jennifer A JA Vasan Ramachandran S RS Fitzpatrick Annette L AL Fornage Myriam M Ding Jun J Carson April P AP Abecasis Goncalo G Dupuis Josée J Reiner Alexander A Kooperberg Charles C Hou Lifang L Psaty Bruce M BM Wilson James G JG Levy Daniel D Rotter Jerome I JI Bis Joshua C JC Satizabal Claudia L CL Arking Dan E DE Liu Chunyu C

Journal of the American Heart Association 20231007 20

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and card ...[more]

PMID: 37804200

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Project description:Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-Ccorr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-Ccorr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-Ccorr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions "LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

Project description:Background Epidemiological studies show that women are generally at lower risk for cardiovascular disease than men. Here, we investigated the sex-specific differential effect of genetically increased low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) and other lipid-associated diseases. Methods and Results This is a 2-sample Mendelian randomization study that uses individual participant data from 425 043 participants from the UK Biobank, including 229 279 female participants. An 80-variant LDL-C weighted genetic score was generated. Linear and logistic regression models with interactions were used to identify differences between sex-specific LDL-C effects on lipids, carotid-intima media thickness, and multiple cardiovascular outcomes such as CVD, ischemic heart disease, peripheral artery disease, heart failure, aortic valve disease, type 2 diabetes, atrial fibrillation, and aortic aneurysm and dissection. After correction for multiple testing, we observed that the genetically increased LDL-C effect on CVD events was sex specific: per SD genetically increased LDL-C, female participants had a higher LDL-C increase but an attenuated CVD risk increase compared with male participants (LDL-C: female participants 0.71 mmol/L, 95% CI, 0.70-0.72 and male participants 0.57 mmol/L, 95% CI, 0.56-0.59. P for interaction: 5.03×10-60; CVD: female participants: odds ratio [OR], 1.32; 95% CI 1.24-1.40 and male participants: OR, 1.52; 95% CI, 1.46-1.58. P for interaction: 9.88×10-5). We also observed attenuated risks for ischemic heart disease and (nominally for) heart failure in female participants, and genetically increased LDL-C results in higher risk for aortic valve disease in female participants compared with male participants. Genetically increased LDL-C was also associated with an attenuated carotid-intima media thickness increase in female participants. We did not observe other significant attenuations. Sensitivity analyses with an unweighted genetic score and sex-specific weighted genetic scores showed similar results. Conclusions We found that genetically increased LDL-C has a sex-specific differential effect on the risk for cardiovascular disease, ischemic heart disease, heart failure, and aortic valve stenosis. Our observations provide evidence that LDL-C might be a less important determinant of CVD in women compared with men, suggesting that male patients might benefit more from LDL-C targeted therapies for CVD management than female patients and warranting investigations into the sex-specific relative contribution of risk factors for CVD.

Project description:ImportanceLimited evidence supports the association between low-density lipoprotein cholesterol (LDL-C) and mortality across different atherosclerotic cardiovascular disease (ASCVD) risk stratifications.ObjectiveTo explore the associations between LDL-C levels and mortality and to identify the optimal ranges of LDL-C with the lowest risk of mortality in populations with diverse ASCVD risk profiles.Design, setting, and participantsThe ChinaHEART project is a prospective cohort study that recruited residents aged 35 to 75 years from 31 provinces in mainland China between November 2014 and December 2022. Participants were categorized into low-risk, primary prevention, and secondary prevention cohorts on the basis of their medical history and ASCVD risk. Data analysis was performed from December 2022 to October 2023.Main outcomes and measuresThe primary end point was all-cause mortality, and secondary end points included cause-specific mortality. Mortality data were collected from the National Mortality Surveillance System and Vital Registration. The association between LDL-C levels and mortality was assessed by using Cox proportional hazard regression models with various adjusted variables.ResultsA total of 4 379 252 individuals were recruited, and 3 789 025 (2 271 699 women [60.0%]; mean [SD] age, 56.1 [10.0] years) were included in the current study. The median (IQR) LDL-C concentration was 93.1 (70.9-117.3) mg/dL overall at baseline. During a median (IQR) follow-up of 4.6 (3.1-5.8) years, 92 888 deaths were recorded, including 38 627 cardiovascular deaths. The association between LDL-C concentration and all-cause or cardiovascular disease (CVD) mortality was U-shaped in both the low-risk cohort (2 838 354 participants) and the primary prevention cohort (829 567 participants), whereas it was J-shaped in the secondary prevention cohort (121 104 participants). The LDL-C levels corresponding to the lowest CVD mortality were 117.8 mg/dL in the low-risk group, 106.0 mg/dL in the primary prevention cohort, and 55.8 mg/dL in the secondary prevention cohort. The LDL-C concentration associated with the lowest all-cause mortality (90.9 mg/dL vs 117.0 mg/dL) and CVD mortality (87 mg/dL vs 114.6 mg/dL) were both lower in individuals with diabetes than in individuals without diabetes in the overall cohort.Conclusions and relevanceThis study found that the association between LDL-C and mortality varied among different ASCVD risk cohorts, suggesting that stricter lipid control targets may be needed for individuals with higher ASCVD risk and those with diabetes.

Project description:Levels of LDL (low-density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid-related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low-density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo-allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non-high-density lipoprotein cholesterol, and triglycerides, but not LDL-c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On-statin levels of the smallest VLDL particle subclass were associated with a 68% per-SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk-this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C-index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein-related risk were observed. Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Project description:Purpose of reviewThe primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on optimizing cardiovascular health and appropriate pharmacotherapy, a mainstay of which is low-density lipoprotein-cholesterol (LDL-C) lowering. Typically, statin therapy remains the first line approach. Advances in technology and understanding of lipid metabolism have facilitated the development of several novel therapeutic targets and medications within the last decade. This review focuses on medications recently approved by the U.S. Food and Drug Administration (FDA) for the reduction of LDL-C and ASCVD risk, as well as new therapies in the pipeline.Recent findingsNovel lipid therapies aim to lower risk of ASCVD by targeting reduction of atherogenic compounds, such as LDL, lipoprotein(a) (Lp(a)), and triglyceride-rich lipoproteins. Evolocumab and alirocumab, monoclonal antibody proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors which lower LDL-C by approximately 60%, have emerged as important therapies for use in patients with ASCVD as well as familial hypercholesterolemia (FH). Bempedoic acid, an ATP citrate lyase inhibitor, is an oral medication recently approved that can lower LDL-C by approximately 18% alone and 38% when combined with ezetimibe. Inclisiran, a small-interfering RNA (siRNA) molecule which inhibits the translation of PCSK9, is the most recently FDA-approved LDL-C lowering medication, and can reduce LDL-C by approximately 50% with twice yearly subcutaneous dosing. The cardiovascular outcome trials for bempedoic acid and inclisiran are still on-going. Evinacumab, a monoclonal antibody which targets angiopoietin-like protein 3 (ANGPTL3), has been approved for use in patients with homozygous FH. SiRNAs and anti-sense oligonucleotides (ASO) facilitating selective inhibition of the production of targeted proteins including Lp(a) and ANGLPTL3 are active areas of clinical investigation.SummaryRecently several novel LDL-C lowering medications have been approved. New therapeutic targets have been identified and present additional means of lowering LDL-C and other atherogenic compounds for patients who remain at high ASCVD risk.

Dataset Information

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Publications

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

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