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This article discusses the results of six randomized trials that examined the effects of fibrates and gemfibrozil on the prevention of atherosclerotic cardiovascular disease (ASCVD). The trials showed inconsistent results, and the authors sought to understand these discrepancies by examining the effects of mass changes in remnant cholesterol and LDL cholesterol. Using the Copenhagen General Population Study (CGPS) to mimic the study population of these trials, the authors compared estimated changes in ASCVD risk through mass changes in cholesterol with the observed changes in the original trials. The results suggest that mass changes in total atherogenic cholesterol can explain the results of these trials, regardless of whether statins were used or not. The authors conclude that to reduce ASCVD, cholesterol-lowering agents should aim to reduce the total mass of atherogenic cholesterol. [Extracted from the article]

The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal. We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal. Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00–1.26) for stroke to 1.27 (1.11–1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08–1.52) for AF, 1.35 (1.06–1.71) for MI, 1.06 (0.89–1.26) for stroke, 1.19 (0.94–1.52) for HF, 1.53 (1.03–2.26) for AVS, and 1.09 (0.97–1.23) for MACE. In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways. [Display omitted] • We tested the hypothesis that TSH was associated with cardiovascular disease (CVD). • 105,224 individuals from the general population were followed for a median of 7 years. • Observationally, TSH below the median was associated with increased risk of CVD. • Genetically, Mendelian randomization suggested possible causal associations. [ABSTRACT FROM AUTHOR]

The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm. [Display omitted] • Absolute mass changes in remnant cholesterol, LDL cholesterol, and apo B can explain results of the PROMINENT trial. • To reduce ASCVD lipid lowering drugs, total atherogenic cholesterol and total number of atherogenic particles need to be reduced. • Understanding the potential for causing ASCVD, lipoproteins should be judged by their absolute mass of cholesterol content. [ABSTRACT FROM AUTHOR]

Background: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.Methods: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.Results: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.Conclusions: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.) [ABSTRACT FROM AUTHOR]

Abstract: Objective: Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the hypothesis that a common variant in ZNF202, A154V, predicts risk of ischemic heart disease (IHD), myocardial infarction (MI), and ischemic cerebrovascular disease (ICVD). Methods and results: We conducted a prospective study of more than 9000 individuals from the general population with 24 years follow-up. In women, age-adjusted hazard ratios in heterozygotes and homozygotes versus non-carriers were 1.2 (95% CI: 1.0–1.5, P =0.04) and 1.5 (1.1–2.1, P =0.007) for IHD, 1.5 (1.1–2.1; P =0.01) and 1.7 (1.1–2.8, P =0.02) for MI, and 1.3 (1.0–1.8, P =0.07) and 1.3 (0.8–2.1; P =0.33) for ICVD. Adjustments for lipids and lipoproteins did not alter these hazard ratios substantially. Genotype did not predict risk in men. Finally, results for IHD were borderline significant (P =0.06) in an independent case–control study including 933 patients and 8068 controls. Conclusion: This is the first study to suggest that ZNF202 could be a new candidate gene for IHD and MI in the general population. [Copyright &y& Elsevier]

Background: Randomised control trials and genetic analyses have demonstrated that vitamin D or 25-hydroxyvitamin D (25[OH]D) levels may not play a causal role in the development of cardiovascular disease. However, it is unclear if 25(OH)D is causally associated with cause-specific vascular disease and lipids. Therefore, we examined the causal association of 25(OH)D with myocardial infarction, stroke, ischaemic heart disease, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and lipid levels among both Chinese and Europeans.Methods: We used a Mendelian randomisation (MR) design in the China Kadoorie Biobank, the Copenhagen City Heart Study, and the Copenhagen General Population Study. The 25(OH)D-related genetic variants in the CYP2R1 and DCHR7 genes were genotyped in 99,012 Chinese adults and 106,911 Danish adults.Results: In Chinese adults, plasma 25(OH)D levels were not significantly associated with cause-specific vascular disease or mortality, with the exception of intracerebral haemorrhage (HR, 1.09 [95% CI, 1.01,1.18] per 25 nmol/L higher plasma 25(OH)D). In Europeans, plasma 25(OH)D levels were inversely associated with all types of vascular diseases and mortality. However, MR analysis did not demonstrate causal associations of genetically increased 25(OH)D levels with cause-specific vascular diseases, or mortality in both Chinese and European adults. In addition, each 25 nmol/L higher 25(OH)D was observationally associated with lower total cholesterol and low-density lipoprotein cholesterol levels, but higher high-density lipoprotein cholesterol levels. Likewise, MR analysis showed that 25(OH)D levels were not causally associated with lipids in both Chinese and European adults after Bonferroni correction.Conclusions: We found no evidence to support that genetically increased 25(OH)D was associated with a lower risk of ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and lipid levels in both Chinese and European adults. These results suggest that the inverse associations of vitamin D with vascular disease could be the result of confounding. [ABSTRACT FROM AUTHOR]