BACKGROUNDExperimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODSWe performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTSA total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONSAmong patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.

The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca 2؉ -independent and that within the zymogen autocatalytic processing site SSVFAQ2SIP Val at P4 and Pro at P3 are critical. The S127R and D374Y mutations result in ϳ50 -60% and >98% decrease in zymogen processing, respectively. In contrast, the double [D374Y ؉ N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mM ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal ϳ9-fold increase in circulating LDL cholesterol, while in LDLR(؊/؊) mice a delayed ϳ2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion.The mammalian proprotein convertases constitute a family of 9 serine proteinases related to bacterial subtilisin. These include the 7 basic amino acid-specific convertases known as PC1/PC3, PC2, furin, PC4, PACE4, PC5/PC6, PC7/LPS (1, 2) and the two enzymes cleaving at nonbasic residues SKI-1/S1P (3, 4) and NARC-1/PCSK9 (5). These proteases are implicated in the limited proteolysis of precursors of secretory proteins that regulate a variety of cellular functions, including cellular growth, adhesion, differentiation, cell to cell communications, and endocrine/paracrine functions (6, 7). Published gene knockout analyses (reviewed in Ref. 8) revealed that only furin (9) and SKI-1/S1P (10) are embryonic lethal. So far, nothing is known about the phenotype consequences of NARC-1 1 knockout in mice. The cDNA of the enzyme NARC-1 was cloned during pharmaceutical screening of mRNAs up-regulated following induction of neural apoptosis by serum withdrawal, and the encoded protein was called "neural apoptosis regulated convertase 1" (NARC-1) (11). We characterized this enzyme, and we showed that it is highly expressed in liver and small intestine and that specific mutations in the prosegment of NARC-1 completely abrogated its autocatalytic processing (5). We further showed that overexpression of NARC-1 enhances neurogenesis of progenitor brain telencephalic cells. The sustained expression of NARC-1 in liver and small intestine and its transient expression in telencephalon, kidney, and cerebellum beg for the identification of its physiological substrates, which are still unknown.Human genetic point mutations resulting in pathology have been rep...

F amilial hypercholesterolemia (FH) is a relatively common disorder, previously thought to have a monogenic basis. 1 The paradigmatic heterozygous form of FH (HeFH) is characterized by lifelong elevations in plasma low-density lipoprotein (LDL) cholesterol, typically >5.0 mmol/L (194 mg/dL), sometimes occurring with characteristic physical signs and frequently with a personal or family history of early cardiovascular disease (CVD).1 Recent populationbased surveys, including screening with DNA sequencing, suggest that HeFH has a prevalence of ≈1 in 217 individuals in Northern Europe.2 Large-scale whole-exome sequencing efforts indicate that ≈4% of individuals with early coronary heart disease have HeFH resulting from one of several lossof-function mutations in the LDLR gene encoding the LDL receptor.3 Other large-scale sequencing efforts indicate that within subgroups of individuals with severe hypercholesterolemia, defined as untreated LDL cholesterol >5.0 mmol/L (>194 mg/dL), only ≈2% had a pathogenic mutation in an autosomal dominant FH gene. Objective-Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects. Here, we examined the contributions of monogenic and polygenic factors in patients with severe hypercholesterolemia referred to a specialty clinic. Approach and Results-We applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol >5.0 mmol/L (>194 mg/dL). We found that (1) monogenic familial hypercholesterolemia-causing mutations detected by targeted next-generation sequencing were present in 47.3% of individuals; (2) the percentage of individuals with monogenic mutations increased to 53.7% when copy number variations were included; (3) the percentage further increased to 67.1% when individuals with extreme polygenic scores were included; and (4) the percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL). Conclusions-In a clinically ascertained sample with severe hypercholesterolemia, we found that most patients had a discrete genetic basis detected using a comprehensive screening approach that includes targeted next-generation sequencing, an assay for copy number variations, and polygenic trait scores.