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The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values. 950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1–100, or >100). We calculated 5-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata. Median follow-up was 5·8 years (IQR 5·7–5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1–100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99–9·25) for coronary heart disease, and of 2·57 (1·48–4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment. CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources. National Institutes of Health–National Heart, Lung, and Blood Institute.

Coronary artery disease (CAD) is a complex, multifactorial disease caused, in particular, by inflammation and cholesterol metabolism. At the molecular level, the role of tissue-specific signaling pathways leading to CAD is still largely unexplored. This study relied on two main resources: (1) genes with impact on atherosclerosis/CAD, and (2) liver-specific transcriptome analyses from human and mouse studies. The transcription factor activating transcription factor 3 (ATF3) was identified as a key regulator of a liver network relevant to atherosclerosis and linked to inflammation and cholesterol metabolism. ATF3 was predicted to be a direct and indirect (via MAF BZIP Transcription Factor F (MAFF)) regulator of low-density lipoprotein receptor (LDLR). Chromatin immunoprecipitation DNA sequencing (ChIP-seq) data from human liver cells revealed an ATF3 binding motif in the promoter regions of MAFF and LDLR. siRNA knockdown of ATF3 in human Hep3B liver cells significantly upregulated LDLR expression (p < 0.01). Inflammation induced by lipopolysaccharide (LPS) stimulation resulted in significant upregulation of ATF3 (p < 0.01) and subsequent downregulation of LDLR (p < 0.001). Liver-specific expression data from human CAD patients undergoing coronary artery bypass grafting (CABG) surgery (STARNET) and mouse models (HMDP) confirmed the regulatory role of ATF3 in the homeostasis of cholesterol metabolism. This study suggests that ATF3 might be a promising treatment candidate for lowering LDL cholesterol and reducing cardiovascular risk.

Endothelial progenitor cells (EPCs) are implicated in protection against vascular disease. However, studies using angiography alone have reported conflicting results when relating EPCs to epicardial coronary artery disease (CAD) severity. Moreover, the relationship between different EPC types and the coronary microcirculation is unknown. We therefore investigated the relationship between EPC populations and coronary epicardial and microvascular disease. Thirty-three patients with a spectrum of isolated left anterior descending artery disease were studied. The coronary epicardial and microcirculation were physiologically interrogated by measurement of fractional flow reserve (FFR), index of microvascular resistance (IMR) and coronary flow reserve (CFR). Two distinct EPC populations (early EPC and late outgrowth endothelial cells [OECs]) were isolated from these patients and studied ex vivo. There was a significant inverse relationship between circulating OEC levels and epicardial CAD severity, as assessed by FFR and angiography (r=0.371, p=0.04; r=-0.358, p=0.04; respectively). More severe epicardial CAD was associated with impaired OEC migration and tubulogenesis (r=0.59, p=0.005; r=0.589, p=0.004; respectively). Patients with significant epicardial CAD (FFR<0.75) had lower OEC levels and function compared to those without hemodynamically significant stenoses (p<0.05). In contrast, no such relationship was seen for early EPC number and function, nor was there a relationship between IMR and EPCs. There was a significant relationship between CFR and OEC function. EPC populations differ in regards to their associations with CAD severity. The number and function of OECs, but not early EPCs, correlated significantly with epicardial CAD severity. There was no relationship between EPCs and severity of coronary microvascular disease.

Objective To conduct a systematic review of the literature and meta-analyses to fill the gaps in knowledge on potassium intake and health.Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, Latin American and Caribbean Health Science Literature Database, and the reference lists of previous reviews.Study selection Randomised controlled trials and cohort studies reporting the effects of potassium intake on blood pressure, renal function, blood lipids, catecholamine concentrations, all cause mortality, cardiovascular disease, stroke, and coronary heart disease were included.Data extraction and synthesis Potential studies were independently screened in duplicate, and their characteristics and outcomes were extracted. When possible, meta-analysis was done to estimate the effects (mean difference or risk ratio with 95% confidence interval) of higher potassium intake by using the inverse variance method and a random effect model.Results 22 randomised controlled trials (including 1606 participants) reporting blood pressure, blood lipids, catecholamine concentrations, and renal function and 11 cohort studies (127 038 participants) reporting all cause mortality, cardiovascular disease, stroke, or coronary heart disease in adults were included in the meta-analyses. Increased potassium intake reduced systolic blood pressure by 3.49 (95% confidence interval 1.82 to 5.15) mm Hg and diastolic blood pressure by 1.96 (0.86 to 3.06) mm Hg in adults, an effect seen in people with hypertension but not in those without hypertension. Systolic blood pressure was reduced by 7.16 (1.91 to 12.41) mm Hg when the higher potassium intake was 90-120 mmol/day, without any dose response. Increased potassium intake had no significant adverse effect on renal function, blood lipids, or catecholamine concentrations in adults. An inverse statistically significant association was seen between potassium intake and risk of incident stroke (risk ratio 0.76, 0.66 to 0.89). Associations between potassium intake and incident cardiovascular disease (risk ratio 0.88, 0.70 to 1.11) or coronary heart disease (0.96, 0.78 to 1.19) were not statistically significant. In children, three controlled trials and one cohort study suggested that increased potassium intake reduced systolic blood pressure by a non-significant 0.28 (−0.49 to 1.05) mm Hg.Conclusions High quality evidence shows that increased potassium intake reduces blood pressure in people with hypertension and has no adverse effect on blood lipid concentrations, catecholamine concentrations, or renal function in adults. Higher potassium intake was associated with a 24% lower risk of stroke (moderate quality evidence). These results suggest that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the prevention and control of elevated blood pressure and stroke.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases responsible for tissue remodeling and degradation of extracellular matrix (ECM) proteins. MMPs may modulate various cellular and signaling pathways in atherosclerosis responsible for progression and rupture of atherosclerotic plaques. The effect of MMPs polymorphisms and the expression of MMPs in both the atherosclerotic plaque and plasma was shown. They are independent predictors of atherosclerotic plaque instability in stable coronary heart disease (CHD) patients. Increased levels of MMPs in patients with advanced cardiovascular disease (CAD) and acute coronary syndrome (ACS) was associated with future risk of cardiovascular events. These data confirm that MMPs may be biomarkers in plaque instability as they target in potential drug therapies for atherosclerosis. They provide important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification.

Epidemiological and clinical studies have over the years established that dyslipidemia constitutes the main risk factor for atherosclerosis. The inverse correlation between HDL cholesterol (HDL-C) levels and coronary heart disease morbidity and mortality identified HDL-C as an alternative pharmacological target to LDL-C and a potential anti-atherosclerosis marker. However, more recent data reinforced the principle of 'HDL quality' in atherosclerosis that refers to the functionality of HDL particle, as defined by its protein and lipid content, rather than HDL-C levels in plasma. Since HDL functionality depends on the genes and proteins of the HDL metabolic pathway, its apoprotein composition may serve as a surrogate marker of atheroprotection. In this manuscript we review the atheroprotective properties of HDL in relation to the proteins of HDL metabolic pathway and discuss what HDL-associated genes and proteins may reveal about HDL functionality in the assessment of coronary risk.

AbstractObjectivesTo investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and cardiometabolic health is causal.DesignTwo sample, bidirectional mendelian randomisation study.SettingGenetic data taken from various cohorts comprised of the general population (mostly individuals of European ancestry, plus a small proportion of other ancestries); follow-up analysis included individuals from the United Kingdom.ParticipantsSummary data were used from previous genome wide association studies (number of participants ranging from 83 198 to 339 224), which investigated traits related to cardiovascular or metabolic health, had the largest sample sizes, and consisted of the most similar populations while minimising sample overlap. A follow-up analysis included 337 112 individuals from the UK Biobank (54% female (n=181 363), mean age 56.87 years (standard deviation 8.00) at recruitment).Main outcome measuresSubjective wellbeing and 11 measures of cardiometabolic health (coronary artery disease; myocardial infarction; total, high density lipoprotein, and low density lipoprotein cholesterol; diastolic and systolic blood pressure; body fat; waist to hip ratio; waist circumference; and body mass index).ResultsEvidence of a causal effect of body mass index on subjective wellbeing was seen; each 1 kg/m2 increase in body mass index caused a −0.045 (95% confidence interval −0.084 to −0.006, P=0.02) standard deviation reduction in subjective wellbeing. Follow-up analysis of this association in an independent sample from the UK Biobank provided strong evidence of an effect of body mass index on satisfaction with health (β=−0.035 unit decrease in health satisfaction (95% confidence interval −0.043 to −0.027) per standard deviation increase in body mass index, P<0.001). No clear evidence of a causal effect was seen between subjective wellbeing and the other cardiometabolic health measures, in either direction.ConclusionsThese results suggest that a higher body mass index is associated with a lower subjective wellbeing. A follow-up analysis confirmed this finding, suggesting that the effect in middle aged people could be driven by satisfaction with health. Body mass index is a modifiable determinant, and therefore, this study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher body mass index on subjective wellbeing.

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration. Despite being studied in clinical trials, CETP inhibitors are not yet an approved treatment for coronary heart disease. Here, by analyzing results from clinical trials and drug target mendelian randomization studies, the authors demonstrate that previous failure of CETP inhibitors are likely compound and not drug target-related.

Endothelin 1 (ET-1) has been shown to have a key role in homeostasis and function of endothelium and maybe fundamental in the relationship between coronary heart disease (CHD) and periodontitis. In this trial, we assessed the influence on serum and salivary ET-1 levels of gingival health, CHD, periodontitis, or a combination of periodontitis-CHD. Clinical and periodontal parameters, were collected from periodontitis patients (n = 34), CHD patients (n = 34), periodontitis + CHD patients (n = 34), and from healthy patients (n = 34) together with saliva and serum samples. The median concentrations of salivary and serum ET-1 were significantly higher in the CHD patients [serum: 1.4(1.1–1.6) pg/ml; saliva 1.2 (0.9–1.6) µmol/g, p < 0.01] and in the periodontitis + CHD patients [serum: 1.7 (1.2–21.8) pg/ml; salivary 1.4(1–1.6) µmol/g, p < 0.001] respect to periodontitis and control patients. Through a univariate regression analysis, c-reactive protein (CRP) and CHD (both p < 0.001) and periodontitis (p = 0.029) were statistically correlated with ET-1 in serum. The multivariate regression analysis demonstrated that only CRP was the statistically predictor of ET-1 in serum(p < 0.001). The multivariate regression analysis in saliva demonstrated that, regarding ET-1 levels the only predictor were CRP (p < 0.001) and total cholesterol (p = 0.042). The present study evidenced that subjects with CHD and periodontitis plus CHD had higher serum and salivary levels of ET-1 compared to subjects with periodontitis and healthy controls. Moreover, only CRP remained a major predictor of increased ET-1 concentrations in both serum and saliva.