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Measurement of low-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and lipoprotein(a) predicted the 30-year cardiovascular disease risk among women enrolled in the Women’s Health Study.

Inflammation is associated with adverse cardiovascular events. Data from recent trials suggest that colchicine reduces the risk of cardiovascular events. In this multicenter trial with a 2-by-2 factorial design, we randomly assigned patients who had myocardial infarction to receive either colchicine or placebo and either spironolactone or placebo. The results of the colchicine trial are reported here. The primary efficacy outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization, evaluated in a time-to-event analysis. C-reactive protein was measured at 3 months in a subgroup of patients, and safety was also assessed. A total of 7062 patients at 104 centers in 14 countries underwent randomization; at the time of analysis, the vital status was unknown for 45 patients (0.6%), and this information was most likely missing at random. A primary-outcome event occurred in 322 of 3528 patients (9.1%) in the colchicine group and 327 of 3534 patients (9.3%) in the placebo group over a median follow-up period of 3 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.16; P = 0.93). The incidence of individual components of the primary outcome appeared to be similar in the two groups. The least-squares mean difference in C-reactive protein levels between the colchicine group and the placebo group at 3 months, adjusted according to the baseline values, was -1.28 mg per liter (95% CI, -1.81 to -0.75). Diarrhea occurred in a higher percentage of patients with colchicine than with placebo (10.2% vs. 6.6%; P<0.001), but the incidence of serious infections did not differ between groups. Among patients who had myocardial infarction, treatment with colchicine, when started soon after myocardial infarction and continued for a median of 3 years, did not reduce the incidence of the composite primary outcome (death from cardiovascular causes, recurrent myocardial infarction, stroke, or unplanned ischemia-driven coronary revascularization). (Funded by the Canadian Institutes of Health Research and others; CLEAR ClinicalTrials.gov number, NCT03048825.).

Lipoprotein(a), abbreviated Lp(a), consists of apolipoprotein B-100 covalently bound to apolipoprotein(a), and represents an independent, genetically-determined, causal risk factor for atherosclerotic cardiovascular disease (CVD) and calcific aortic stenosis. More than 20% of the world CVD population has elevated Lp(a). Currently there are no approved pharmacologic treatments to lower Lp(a) levels, and no randomized trials have demonstrated that lowering Lp(a) reduces CVD risk. Lp(a) HORIZON is a phase 3, randomized, placebo-controlled, double-blind, parallel-group, multinational trial in 8,323 patients with established CVD and elevated Lp(a) levels of ≥70 mg/dL (approximately 149 nmol/L), testing the effect of pelacarsen, an antisense oligonucleotide (ASO) on the incidence of major adverse cardiovascular events (MACE). Established CVD is defined as history of myocardial infarction (MI), ischemic stroke or symptomatic peripheral artery disease. The minimum follow-up is required to be 2.5 years. The study will end when 993 CEC confirmed primary CV events have accumulated. Based on the current event accrual trend, the overal study duration is anticipated to be approximately 6 years. Patients were randomized in a 1:1 ratio to receive either monthly subcutaneous (SQ) injections of pelacarsen 80 mg or matching placebo on a background of optimized standard of care therapy for CVD. The primary endpoint is a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. This endpoint will be evaluated in the overall population and in a subpopulation of Lp(a) ≥90 mg/dL (approximately 192 nmol/L) at screening, with multiplicity control designed to test the primary endpoint in both the overall population and the subpopulation. Lp(a) HORIZON will determine the effect of pelacarsen on cardiovascular morbidity and mortality in patients with elevated Lp(a) and established CVD. NCT 04023552.

In a randomized trial involving patients with high-risk vascular disease, the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers but was not associated with a lower rate of cardiovascular events than placebo. Pharmacologic reduction of the low-density lipoprotein (LDL) cholesterol level with statins substantially decreases the risks of death and complications from cardiovascular causes. 1 , 2 Considerable interest has focused on the identification of approaches that might further reduce cardiovascular-event rates among high-risk patients. 3 Epidemiologic studies have shown inverse associations between high-density lipoprotein (HDL) cholesterol levels and cardiovascular outcomes, 4 – 6 a correlation that persists despite treatment with statins. 7 Nevertheless, therapeutic interventions that raise the HDL cholesterol level have not been shown to reduce cardiovascular risk. Cholesteryl ester transfer protein (CETP) modulates the transfer of esterified cholesterol from HDL to apolipoprotein B–containing lipoproteins. 8 Two . . .

Elevated levels of lipoprotein(a) in the plasma are a risk factor for cardiovascular disease, and lowering levels can be achieved with antisense oligonucleotide targeting LPA messenger RNA, which encodes lipoprotein(a). This trial tested whether the same effect can be achieved in persons with established cardiovascular disease.

AbstractObjectiveTo determine the association between levels of low density lipoprotein cholesterol (LDL-C) and all cause mortality, and the concentration of LDL-C associated with the lowest risk of all cause mortality in the general population.DesignProspective cohort study.SettingDenmark; the Copenhagen General Population Study recruited in 2003-15 with a median follow-up of 9.4 years.ParticipantsIndividuals randomly selected from the national Danish Civil Registration System.Main outcome measuresBaseline levels of LDL-C associated with risk of mortality were evaluated on a continuous scale (restricted cubic splines) and by a priori defined centile categories with Cox proportional hazards regression models. Main outcome was all cause mortality. Secondary outcomes were cause specific mortality (cardiovascular, cancer, and other mortality).ResultsAmong 108 243 individuals aged 20-100, 11 376 (10.5%) died during the study, at a median age of 81. The association between levels of LDL-C and the risk of all cause mortality was U shaped, with low and high levels associated with an increased risk of all cause mortality. Compared with individuals with concentrations of LDL-C of 3.4-3.9 mmol/L (132-154 mg/dL; 61st-80th centiles), the multivariable adjusted hazard ratio for all cause mortality was 1.25 (95% confidence interval 1.15 to 1.36) for individuals with LDL-C concentrations of less than 1.8 mmol/L (<70 mg/dL; 1st-5th centiles) and 1.15 (1.05 to 1.27) for LDL-C concentrations of more than 4.8 mmol/L (>189 mg/dL; 96th-100th centiles). The concentration of LDL-C associated with the lowest risk of all cause mortality was 3.6 mmol/L (140 mg/dL) in the overall population and in individuals not receiving lipid lowering treatment, compared with 2.3 mmol/L (89 mg/dL) in individuals receiving lipid lowering treatment. Similar results were seen in men and women, across age groups, and for cancer and other mortality, but not for cardiovascular mortality. Any increase in LDL-C levels was associated with an increased risk of myocardial infarction.ConclusionsIn the general population, low and high levels of LDL-C were associated with an increased risk of all cause mortality, and the lowest risk of all cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL).

In a randomized trial involving patients at high cardiovascular risk, the cholesteryl ester transfer protein inhibitor obicetrapib reduced low-density lipoprotein cholesterol levels by 29.9% at 84 days.

The impact of serum uric acid on cardiovascular outcomes in the LIFE study. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study demonstrated the superiority of a losartan-based regimen over atenolol-based regimen for reduction of cardiovascular (CV) morbidity and mortality. It has been suggested that the LIFE study results may be related to the effects of losartan on serum uric acid (SUA). SUA has been proposed as an independent risk factor for CV morbidity and death. Cox regression analysis was used to assess relationship of SUA and treatment regimens with the LIFE primary composite outcome (CV death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke). Baseline SUA was significantly associated with increased CV events [hazard ratio (HR) 1.024 (95% CI 1.017–1.032) per 10 μmol/L, P < 0.0001] in the entire study population. The association was significant in women [HR = 1.025 (1.013–1.037), P < 0.0001], but not in men [HR = 1.009 (0.998–1.019), P = 0.108]. After adjustment for Framingham risk score (FRS), SUA was no longer significant in the entire study population [HR = 1.006 (0.998–1.014), P = 0.122] or in men [HR = 1.006 (0.995–1.017), P = 0.291], but was significant in women [HR = 1.013 (1–1.025), P = 0.0457]. The baseline-to-end-of-study increase in SUA (standard deviation, SD) was greater (P < 0.0001) in atenolol-treated subjects (44.4 ± 72.5 μmol/L) than in losartan-treated subjects (17.0 ± 69.8 μmol/L). SUA as a time-varying covariate was strongly associated with events (P < 0.0001) in the entire population. The contribution of SUA to the treatment effect of losartan on the primary composite end point was 29% (14%-107%), P = 0.004. The association between time-varying SUA and increased CV risk tended to be stronger in women (P < 0.0001) than in men (P = 0.0658), although the gender-outcome interaction was not significant (P = 0.079). The increase in SUA over 4.8years in the LIFE study was attenuated by losartan compared with atenolol treatment, appearing to explain 29% of the treatment effect on the primary composite end point. The association between SUA and events was stronger in women than in men with or without adjustment of FRS.

The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies. EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show—by using two 8-d laboratory protocols—that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8–15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3–29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.