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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]

Aims We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein. Methods and results In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n  = 5684; ASCVD = 852) and STRENGTH (n  = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93–0.99] mimicking REDUCE-IT and 0.94 (0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04–1.10) and 0.99 (0.98–0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84–0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68–0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93–0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90–1.09) in STRENGTH. Conclusion The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil. [ABSTRACT FROM AUTHOR]

Introduction: Low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) have been recognized as causative genes of heterozygous familial hypercholesterolemia (HeFH) which exhibited a marked elevation of LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). Recent study reported the presence of both mutations was infrequently observed in HeFH subjects. It remains to be fully elucidated whether this double-heterozygous mutation in LDLR and PCSK9 gene (LDLR/PCSK9) affects clinical demographics and cardiac outcome in HeFH patients. Methods: 377 clinically diagnosed HeFH probands were retrospectively analyzed. Clinical characteristics and the occurrence of MACE were compared among subjects stratified according to genotypes (LDLR/PCSK9 career, LDLR alone, and PCSK9 alone). Results: The frequency of probands with LDLR/PCSK9 , LDLR and PCSK9 gain-of-function mutation was 4, 48 and 9%, respectively. Probands with LDLR/PCSK9 were more likely to exhibit a higher LDL-C level at baseline (Table) and receive high-intensity statin (43, 16 and 6%, respectively, p=0.01 for trend). During follow-up period, probands with LDLR/PCSK9 demonstrated a lower on-treatment LDL-C level (p=0.02) and its greater percent reduction were observed under lipid-lowering therapy, although the latter comparison did not meet statistical significance (Table, p=0.08). However, probands with LDLR/PCSK9 were associated with 3.0 and 8.2-fold likelihood of experiencing cardiovascular events compared to LDLR and PCSK9 , respectively (Figure). Even after adjusting covariates, the presence of LDLR/PCSK9 was still an independent predictor for MACE (p=0.01 vs. LDLR ; p=0.007 vs. PCSK9). Conclusions: The presence of double-heterozygous mutation in the LDLR and PCSK9 gene predicted cardiac events in patients with HeFH. These findings underscore precise medicine to identify patients with double-heterozygous mutation who require more stringent management. [ABSTRACT FROM AUTHOR]

Background: The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH., Methods and Results: This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; P =0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P =0.71; high-intensity statin, P =0.81; ezetimibe, P =0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P =0.39; low-density lipoprotein apheresis, P =0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; P =0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P =0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; P =0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; P =0.002)., Conclusions: A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.

Aim: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction., Methods: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated., Results: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ., Conclusion: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.