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Background: Elevated remnant cholesterol causes ischemic heart disease.Objectives: We tested the hypothesis that the inclusion of elevated remnant cholesterol will lead to appropriate reclassification of individuals who later experience myocardial infarction and ischemic heart disease.Methods: For >10 years we followed up 41,928 white Danish individuals from the Copenhagen General Population Study without a history of ischemic cardiovascular disease, diabetes, and statin use. Using predefined cut points for elevated remnant cholesterol, we calculated net reclassification index (NRI) from below to above 5%, 7.5%, and/or 10% 10-year occurrence of myocardial infarction and ischemic heart disease defined as a composite of death from ischemic heart disease, myocardial infarction, and coronary revascularization.Results: For individuals with remnant cholesterol levels ≥95th percentile (≥1.6 mmol/L, 61 mg/dL), 23% (P < 0.001) of myocardial infarction and 21% (P < 0.001) of ischemic heart disease were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Consequently, the addition of remnant cholesterol levels yielded NRI of 10% (95% CI: 1%-20%) for myocardial infarction and 5% (95% CI: -3% to 13%) for ischemic heart disease. Correspondingly, when reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% (P < 0.001) of individuals with myocardial infarction and 41% (P < 0.001) with ischemic heart disease were reclassified appropriately, leading to NRI of respectively 20% (95% CI: 9%-31%) and 11% (95% CI: 2%-21%).Conclusions: Elevated remnant cholesterol levels considerably improve myocardial infarction and ischemic heart disease risk prediction. [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]