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Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators may attenuate PCSK9-induced low-density lipoprotein receptor (LDLR) degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol (LDL-C). A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In addition, five compounds 15, 18, 22, (R)-22, and (S)-22 showed better performance in the low-density lipoprotein, labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound 22, selected for in vivo evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human ether-à-go-go related gene (hERG) inhibition assay indicated the potential druggability for compound 22, which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia., Graphical abstract A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Compound 22 demonstrated significant reductions of TC and LDL-C in hyperlipidemic hamsters, which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.Image 1

Highlights • Individuals with ANGPTL3 loss-of-function mutations have reduced cholesterol levels, triglyceride levels, and risk of coronary heart disease, making ANGPTL3 a potential therapeutic target. • An antisense oligonucleotide inhibitor of ANGPTL3 and a monoclonal antibody against ANGPTL3 have been advanced into clinical trials, with encouraging results to date. • A distinct approach to targeting ANGPTL3 would be therapeutic gene editing in patients to induce permanent loss of function mutations mimicking those in individuals with naturally occurring cardioprotective mutations., Summary Hyperlipidemia is a major causal risk factor for atherosclerosis and coronary heart disease (CHD). Angiopoietin-like 3 (ANGPTL3) has emerged as a promising molecular target to reduce CHD risk due to its regulation of all 3 major lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Here, the authors review the discovery of ANGPTL3, the role of ANGPTL3 in lipoprotein metabolism, and the genetic association between naturally occurring ANGPTL3 loss-of-function mutations and CHD. In light of the favorable consequences of ANGPTL3 deficiency, various therapeutic strategies to target ANGPTL3 are currently in development, including a monoclonal antibody, an antisense oligonucleotide, and gene editing., Central Illustration

Objective: To assess oral antihyperglycemic agents (OAHA) and/or statin treatment initiation in patients with type 2 diabetes (T2D) and time from diagnosis to both types of treatment initiation and intensification. Research design and methods: We reviewed 662 retrospective medical records of patients with T2D diagnosed by 31 general practitioner or specialist sites across Mexico, Argentina, and Brazil. Demographic and clinical information was abstracted from patients’ medical records and summarized using descriptive statistics. Between-group differences were assessed with Student’s t-test for continuous variables and Fisher’s exact test for categorical variables. The starting time of each therapy (OAHA and statins, separately) was assessed using Kaplan-Meier estimates. Results: At diagnosis, patients’ mean age was 53 years; 44% had hypertension, 42% were obese, and 23% had dyslipidemia. During the 2-year follow-up, 95% of patients received OAHAs but only 29% of those eligible for statins received this prescription. Mean ± SD and median (Q1, Q3) time to first OAHA was 59 ± 141 days and 1 (1, 31) day, respectively, and 230 ± 232 days and 132 (30, 406) days, respectively, for a statin. During follow-up, 51–53% of patients with HbA1c/FPG values above target did not intensify hyperglycemia treatment. Conclusion: Dyslipidemia treatment in patients with T2D was delayed despite its known deleterious effect on atherosclerosis development and β-cell mass/function. Anti-hyperglycemic treatment was not intensified when targets were not attained. This prescriptive inertia needs to be corrected because attainment of HbA1c treatment goals becomes more difficult, favoring the development of diabetes complications. Keywords: Type 2 diabetes, Dyslipidemia, Treatment initiation, Clinical inertia, Antihyperglycemic agent, Statin

Objective To clarify the role of dietary carbohydrate, glycemic index (GI), and glycemic load (GL) in progression from health to coronary heart disease (CHD) by determining disease-nutrient risk relation (RR) values needed for intake ranges within jurisdictions and across the globe. Methods We performed a literature search of MEDLINE and EMBASE for prospective cohort studies that used truly valid dietary instruments in heathy adults published from January 1, 2000, to June 5, 2018. Relevant observations were extracted by 2 reviewers independently. We used dose-response meta-analysis accounting for nonindependence of results within studies. Bradford-Hill criteria were used to assess causality. Results Eligible studies had a mean follow-up of 11 years (range, 5-19 years), were conducted in North America, Europe, and East Asia, and yielded combined RRs of 1.44 (95% CI, 1.25-1.65) per 65 g/d GL (11 studies) and 1.24 (95% CI, 1.12-1.38) per 10 U GI (10 studies) (glucose scale). The CHD-carbohydrate RR on GI was 1.66 (95% CI, 1.23-2.25) per 98 g/d of carbohydrates per 10 units GI. The 65 g/d GL, 10 U GI, and 98 g/d carbohydrate values corresponded to oral intakes from the 10th to the 90th percentiles within sampled populations. Inconsistencies were minor (I2≤20%), as were small-study effects (P=.61 for GL and P=.26 for GI). Funnel plots were symmetric. Cubic spline dose-response meta-analysis yielded RRs as follows: across the global range for GL (55-290 g/d), 5.5 (95% CI, 3.1-9.8) (I2=0); for GI (47-82 U), 2.71 (95% CI, 1.47-4.40) (I2=0); and for the CHD-carbohydrate dependence on GI (50-80 U), 4.57 (95% CI, 1.86-11.4) (I2=16%). Bradford-Hill criteria indicated that these relations were probably causal. Conclusion Strong and probably causal CHD-GL and GI RRs exist within populations. The RRs were remarkably higher across global exposures. The results support the consideration of these markers of carbohydrate food quality in dietary guidelines for general populations. Trial Registration PROSPERO Identifier: CRD42013004504

Purpose To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. Design Retinal imaging examination as part of the European Prospective Investigation into Cancer—Norfolk Eye Study. Participants Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. Methods Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. Main Outcomes Measures Retinal arteriolar and venular tortuosity and width. Results In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%–3.3% per 5 kg/m 2 ), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%–3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%–10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2–2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3–0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4–1.0 per 5 kg/m 2 ), HbA1c level (0.4 μm; 95% CI, –0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7–4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3–2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7–2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%–7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%–1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%–6.4%), and in those with prevalent stroke (8.3%; 95% CI, –0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6–1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4–0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0–0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7–1.6 μm per 1 mmol/l). Conclusions Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

After training as a gastroenterologist in the UK, the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant, he introduced the use of plasma exchange to treat familial hypercholesterolemia (FH) homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH. Further investigation of metabolic defects in FH revealed that a significant proportion of LDL in homozygotes and heterozygotes was produced directly via a VLDL-independent pathway. Management of heterozygous FH has been greatly facilitated by statins and proprotein convertase subtilisin/kexin type 9 inhibitors but remains dependent upon lipoprotein apheresis in homozygotes. In a recent analysis of a large cohort treated with a combination of lipid-lowering measures, survival was markedly enhanced in homozygotes in the lowest quartile of on-treatment serum cholesterol. Emerging therapies could further improve the prognosis of homozygous FH; whereas in heterozygotes, the current need is better detection.

Obesity has reached epidemic proportions in the United States and in much of the westernized world, contributing to considerable morbidity. Several of these obesity-related morbidities are associated with greater risk for death with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 penetrates human cells through direct binding with angiotensin-converting enzyme 2 receptors on the cell surface. Angiotensin-converting enzyme 2 expression in adipose tissue is higher than that in lung tissue, which means that adipose tissue may be vulnerable to COVID-19 infection. Obese patients also have worse outcomes with COVID-19 infection, including respiratory failure, need for mechanical ventilation, and higher mortality. Clinicians need to be more aggressive when treating obese, especially severely obese, patients with COVID-19 infection.

Background Anthocyanins, one of the major plant bioactive substances, possess anti-oxidative and anti-inflammatory capacity. However, their dose–response relationship has remained unclear. The present study investigated the dose–response relationship of anthocyanins with oxidative stress and inflammation in subjects with dyslipidemia. Design and Participants: A total of 169 participants with dyslipidemia were randomly assigned to placebo (n = 43), anthocyanins 40 mg/day (n = 44), 80 mg/day (n = 40), or 320 mg/day (n = 42) groups. Urine 8-iso-prostaglandin F2α (8-iso-PGF2α), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and serum malonaldehyde (MDA), total superoxide dismutase (T-SOD), UA (uric acid), interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured at baseline, at 6 weeks, and at 12 weeks. Results Anthocyanin supplementation (320 mg/day) for 6 weeks significantly improved T-SOD versus baseline (P, Graphical abstract Image 1, Highlights • Anthocyanins improve oxidative stress in a dose-response manner. • Anthocyanins improve anti-inflammatory capacity in a dose-response manner. • 80 mg/day anthocyanin could reach the threshold level for producing beneficial functions after 12-week intervention. • Anthocyanins prevent the progression of metabolic diseases in subjects with dyslipidemia.

To assess the efficacy and short-term outcomes of adherence to statin therapy among coronary heart disease (CHD) patients following their hospital discharge, we enrolled 615 CHD patients who were prescribed statins from The First Affiliated Hospital of Chongqing Medical University in China between February 1st and October 31st of 2013. Statin adherence was evaluated by identifying the proportion of patients who remained adherent or became non-adherent to statin therapy over 4–8 months post-discharge from the hospital. The composite outcomes included all-cause mortality and re-hospitalization with cardiovascular disease. We found that 15.9% patients were non-adherent to their statin therapies and that coronary artery stenosis

Data presented in this article are supplementary data to our primary article ‘Association of Alcohol Consumption and Aortic Calcification in Healthy Men Aged 40–49 Years for the ERA JUMP Study’ [1]. In this article, we have presented supplementary tables showing the independent association of alcohol consumption with coronary artery calcification using Tobit conditional regression and ordinal logistic regression. Keywords: Alcohol, Coronary, Atherosclerosis, Calcification, Men

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects., Central Illustration

Background Chronic Hepatitis C virus (HCV) infection and liver cirrhosis may be associated with atherosclerosis and coronary artery disease (CAD). There are two phases to atherosclerosis, Subclinical and Clinical. Assessment of atherosclerosis may be started at its Subclinical phase by the evaluation of Epicardial Fat Thickness (EpFT) and Carotid Intima Thickness (CIMT). Aim of the study The aim of the study was to evaluate Clinical and Subclinical atherosclerosis in chronic HCV patients with and without liver cirrhosis by evaluating CIMT and EpFT and correlating the results with Child-Pugh functional scoring of cirrhosis as well as with ultrasound and laboratory parameters that define the severity of liver disease. Patients and methods This study involved 64 chronic HCV patients that were divided into two groups: 24 patients without liver cirrhosis and 40 patients with liver cirrhosis in addition to 20 apparently healthy volunteers serving as control. All of the 84 subjects were subjected to the following: Clinical evaluation; Routine Laboratory Evaluation (CBC, Liver Function Tests, Renal Function Tests, Serum electrolytes, Cholesterol, Triglycerides, HBs antigen and HCV antibody); ECG; Abdominal ultrasound; Echocardiographic evaluation of segmental wall motion abnormalities and EpFT and B-Mode Carotid ultrasonography for evaluation of CIMT. Results In the cirrhotic HCV group, the CIMT and EpFT were both significantly increased [Compared to control group (p = 0.000), compared to the non-cirrhotic HCV group (p = 0.000)]. In the non-cirrhotic HCV group, the CIMT and EpFT were both significantly increased compared to the control group with a p-value of 0.003 for CIMT and 0.048 for EpFT. The CIMT and EpFT were also positively correlated with each other (r = 0.456, p = 0.001). There was a statistically significant increase in the EpFT and CIMT in Child class B patients compared to Child class A (p = 0.007 for CIMT and p = 0.028 for EpFT) and in Child class C patients compared to Child class B patients (p = 0.001 for CIMT and 0.005 for EpFT). CIMT and EpFT were correlated positively with AST (r = 0.385, p = 0.002 for CIMT, and r = 0.379, p = 0.003 for EpFT), Total Bilirubin (r = 0.378, p = 0.003 for CIMT, and r = 0.384, p = 0.002 for EpFT), INR% (r = 0.456, p = 0.001 for CIMT, and r = 0.384, p = 0.001 for EpFT), CRP (r = 0.378, p = 0.003 for CIMT, and r = 0.386, p = 0.002 for EpFT), spleen span (r = 0.417, p = 0.001 for CIMT, and r = 0.437, p = 0.001 for EpFT) and portal Vein Diameter (r = 0.372, p = 0.003 for CIMT, and r = 0.379, p = 0.003 for EpFT). CIMT and EpFT were correlated negatively with Albumin (r = −0.379, p = 0.003 for CIMT, and r = −0.370, p = 0.003 for EpFT), platelets count (r = −0.382, p = 0.002 for CIMT, and r = −0.378, p = 0.003 for EpFT) and Liver Span (r = −0.433, p = 0.001 for CIMT, and r = −0.424, p = 0.001 for EpFT). Conclusion EpFT and CIMT significantly increased in chronic hepatitis C virus patients especially in those with cirrhosis and closely correlated with each other. Their thickness also correlated with the Child-Pugh functional scoring of cirrhosis as well as with ultrasound and laboratory parameters that define the severity of liver disease. The echocardiographic assessment of EpFT and the carotid Doppler assessment of CIMT may provide appropriate and simple screening markers for subclinical atherosclerosis and cardiovascular risk in chronic HCV patients with and without cirrhosis.

The Framingham Risk Score (FRS) was developed to quantify a patient's coronary heart disease (CHD) risk. Non-exercise estimated CRF (e-CRF) may provide a clinically practical method for describing cardiorespiratory fitness. We computed e-CRF and tested its association with the FRS and CHD. Male participants (n = 29,854) in the Aerobics Center Longitudinal Study (ACLS) who completed a baseline examination between 1979–2002 were followed for 12 years to determine incident CHD defined by self-report of myocardial infarction, revascularization, or CHD mortality. e-CRF was defined from a 7-item scale and categorized using age-specific tertiles. Multivariable survival analysis determined associations between FRS, e-CRF, and CHD. Interaction between e-CRF and FRS was tested by stratified analysis by ‘low’ and ‘moderate or high’ 10-year CHD risk. Men with high e-CRF were significantly (p-value, Highlights • Men with low e-CRF had a higher proportion of CHD events compared to high-fit men. • E-CRF was a protective factor of CHD in crude and adjusted analysis. • E-CRF could be used to capture patient CRF during clinic visits.

Despite continued advances in health care, the cardiovascular disease (CVD) mortality rate has plateaued in recent years and appears to be trending upward. Poor diet is a leading cause of obesity and type 2 diabetes mellitus, which are leading contributors to CVD morbidity and mortality. Although dietary modification is a cornerstone of CVD prevention, implementation in clinical practice is limited by inadequate formal training in nutrition science. In this report, we review the individual components of a heart-healthy diet, evidence-based dietary recommendations, and the impact of diet on CVD risk factor prevention and management. Furthermore, we examine the unique difficulties of dietary counseling in low-socioeconomic-status environments and provide an evidence-based approach to better serve these populations. We utilized PubMed searches in adults with no date restriction with the following search terms: “carbohydrate,” “fat,” protein,” “DASH,” “Mediterranean,” “plant-based,” “vegetarian,” “cardiovascular disease,” “obesity,” “weight loss,” “diabetes,” “socioeconomic status,” and “race.” In this review, we demonstrate that patients should focus on implementing a general diet plan that is high in fruits, whole grains, legumes, and nonstarchy vegetables while low in trans-fats, saturated fats, sodium, red meat, refined carbohydrates, and sugar-sweetened beverages. The Dietary Approaches to Stop Hypertension, Mediterranean, and vegetarian diets have the most evidence for CVD prevention. Clinicians should understand the barriers that patients may face in terms of access to healthy dietary choices. Further research is needed to determine the dietary changes that are most economically, socioculturally, and logistically feasible to reduce these barriers. Improvement in diet is a public health priority that can lead to a significant population-level reduction in CVD morbidity and mortality. It is imperative that clinicians understand current dietary practice guidelines and implement evidence-based dietary counseling in those at high risk for CVD.

Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD. Keywords: Cholesterol/metabolism, LDL oxidation, Lipidomics, CVD, Cholesterol ester hydroperoxides, Cholesterol uptake, Lipid peroxidation, LXR, LDLR

On January 2020, WHO confirmed the epidemic outbreak of SARS-CoV-2 as a Health Emergency of International Concern. The aim of this meta-meta-analysis is quantifying meta-analytic findings on the association of cardiovascular disease (CVD) comorbidities and COVID-19 severity. Findings suggest that chances of getting severe COVID-19 disease in patients with CVD is greater than those without CVD. Also, prevalence of CVD in patents with COVID-19 is 0.08 (95% CI = 0.07–0.08). The OR as 3.44 indicates that the odds of getting severe COVID-19 is more than 3 times higher in those with CVD. Also, prevalence of hypertension in patient with COVID-19 is 0.27 (95%CI = 0.27–0.28) and the OR as 2.68 indicates that the odds of getting severe COVID-19 in cases with high blood pressure is more than 2.5 times higher than those without hypertension. It is rational to suppose that persons with coronary artery disease are prone to severe viral infection thereby, guideline-directed diagnosis and medical therapy is vital in CVD patients., Graphical abstract Image 1, Highlights • Studies demonstrates thatthe association of CVD comorbidities and COVID-19 severity. • Persons with coronary artery disease are prone to severe viral infection such as COVID-19. • Underlying basic diseases such as hypertension and CVD are risk factors for disease progression and development.

Inherited arrhythmias, such as cardiomyopathies and cardiac ion channelopathies, along with coronary heart disease (CHD) are three most common disorders that predispose adults to sudden cardiac death. In the last three decades, causal genes in inherited arrhythmias have been successfully identified. At the same time, it has become evident that the genetic architectures are more complex than previously known. Recent advancements in DNA sequencing technology (next generation sequencing) have enabled us to study such complex genetic traits. This article discusses indications for genetic testing of patients with inherited arrhythmias. Further, it describes the benefits and challenges that we face in the era of next generation sequencing. Finally, it briefly discusses genetic counseling, in which a multidisciplinary approach is required due to the increased complexity of the genetic information related to inherited arrhythmias. (C) 2016 Japanese Heart Rhythm Society. Published by Elsevier B.V

Highlights • Data on percutaneous coronary intervention (PCI) in Vietnam is scarce. • This study reported patient characteristics and in-hospital outcomes following PCI. • These novel results contribute to benchmarking PCI practices in Vietnam., Background Little is known about percutaneous coronary intervention (PCI) practices and outcomes in low-and middle-income nations, despite its rapid uptake across Asia. For the first time, we report on clinical characteristics and in-hospital outcomes for patients undergoing PCI at a leading cardiac centre in Vietnam. Methods Information on characteristics, treatments, and outcomes of patients undergoing PCI was collected into the first PCI registry through direct interviews using a standardised form, medical record abstraction, and reading PCI imaging data on secured disks. Subgroup analysis was also conducted to explore gender differences. Results Between September 2017 and May 2018, 1022 patients undergoing PCI were recruited from a total of 1041 procedures. The mean age was 68.3 years and two thirds were male. While 54.4% of patients presented with acute coronary syndromes, the rate of ST-elevation myocardial infarction was 14.5%. The majority of lesions were classified as type B2 and C and the radial artery was the most common access location for PCI (79.2%). The use of drug-eluting stents was universal and the angiographic success rate was 99.4%. Cardiac complications following PCI were rare with the exception of major bleeding (2.0%). Female patients were older with relatively more comorbidities and a higher incidence of major bleeding than males (p

While a mean age at menopause of 51 years has been reported in the United States (U.S.), some U.S. women experience menopause before age 45, possibly increasing risk of cardiovascular mortality; however, the role in all-cause and cerebrovascular-related mortality is unclear. The purpose of this study was to investigate the association between age at menopause and all-cause and cause-specific mortality by race, hormone replacement therapy (HRT) use, and smoking status. REasons for Geographic and Racial Differences in Stroke (REGARDS) is a population-based study of 30,239 participants aged ≥45 years enrolled between 2003 and 2007 of whom 14,361 were postmenopausal women. Age at menopause was defined as, Highlights • Increased all-cause mortality risk in ever-HRT users with menopause before age 45 • HRT use modified the association of menopause before age 45 and CHD mortality. • There were no differences in associations examined by race or smoking status.

Background: Lifestyle modification (LSM) such as prudent diet, physical activity, avoidance of smoking, and maintaining a healthy weight may considerably decrease the risk for coronary artery disease. Objective: The primary objective of this study was to develop a new LSM scoring system and investigate the correlation between adherence to LSM and incidence of major adverse cardiac events (MACEs) at 12-month follow-up. Method: A total of 1000 consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) were included in this prospective single-center study. Manipal lifestyle modification score (MLSMS) was developed by using five lifestyle-related factors. Adherence to LSM at the baseline and subsequent follow-ups was determined by using MLSMS. The MACE at 1-, 6-, and 12-month follow-up were analyzed. Results: There was a significant reduction in overall adherence to LSM (p

Modern medicine is overwhelmed by a plethora of both established risk factors and novel biomarkers for diseases. The majority of this information is expressed by probabilistic measures of association such as the odds ratio (OR) obtained by calculating differences in average “risk” between exposed and unexposed groups. However, recent research demonstrates that even ORs of considerable magnitude are insufficient for assessing the ability of risk factors or biomarkers to distinguish the individuals who will develop the disease from those who will not. In regards to coronary heart disease (CHD), we already know that novel biomarkers add very little to the discriminatory accuracy (DA) of traditional risk factors. However, the value added by traditional risk factors alongside simple demographic variables such as age and sex has been the subject of less discussion. Moreover, in public health, we use the OR to calculate the population attributable fraction (PAF), although this measure fails to consider the DA of the risk factor it represents. Therefore, focusing on CHD and applying measures of DA, we re-examine the role of individual demographic characteristics, risk factors, novel biomarkers and PAFs in public health and epidemiology. In so doing, we also raise a more general criticism of the traditional risk factors’ epidemiology. We investigated a cohort of 6103 men and women who participated in the baseline (1991–1996) of the Malmö Diet and Cancer study and were followed for 18 years. We found that neither traditional risk factors nor biomarkers substantially improved the DA obtained by models considering only age and sex. We concluded that the PAF measure provided insufficient information for the planning of preventive strategies in the population. We need a better understanding of the individual heterogeneity around the averages and, thereby, a fundamental change in the way we interpret risk factors in public health and epidemiology., Highlights • There is a plethora of differences in “average” risk between exposed and unexposed groups of individuals. • Individual heterogeneity around average values is seldom considered in Public Health. • Measures of discriminatory accuracy (DA) informs on the underlying individual heterogeneity. • Most know risk factors and other categorizations associated with diseases have low DA. • We need a fundamental change in the way we investigate risk factors and other categorizations in Public Health.

Summary Precision medicine strives to delineate disease using multiple data sources—from genomics to digital health metrics—in order to be more precise and accurate in our diagnoses, definitions, and treatments of disease subtypes. By defining disease at a deeper level, we can treat patients based on an understanding of the molecular underpinnings of their presentations, rather than grouping patients into broad categories with one-size-fits-all treatments. In this review, the authors examine how precision medicine, specifically that surrounding genetic testing and genetic therapeutics, has begun to make strides in both common and rare cardiovascular diseases in the clinic and the laboratory, and how these advances are beginning to enable us to more effectively define risk, diagnose disease, and deliver therapeutics for each individual patient., Central Illustration

Objective Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported. Methods and results Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of 3H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls. Conclusions Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet., Highlights • Hepatocyte ERα contributes to reverse cholesterol transport and protects against atherosclerosis development. • Hepatocyte ERα promotes HDL function as well as liver cholesterol uptake and whole-body cholesterol removal. • Hepatocyte ERα may be a control point in atherosclerosis for females.

Ischaemic diseases remain a major cause of morbidity and mortality despite continuous advancements in medical and interventional treatments. Moreover, available drugs reduce symptoms associated with tissue ischaemia, without providing a definitive repair. Cardiovascular regenerative medicine is an expanding field of research that aims to improve the treatment of ischaemic disorders through restorative methods, such as gene therapy, stem cell therapy, and tissue engineering. Stem cell transplantation has salutary effects through direct and indirect actions, the latter being attributable to growth factors and cytokines released by stem cells and influencing the endogenous mechanisms of repair. Autologous stem cell therapies offer less scope for intellectual property coverage and have limited scalability. On the other hand, off-the-shelf cell products and derivatives from the stem cell secretome have a greater potential for large-scale distribution, thus enticing commercial investors and reciprocally producing more significant medical and social benefits. This review focuses on the paracrine properties of cardiac stem cells and pericytes, two stem cell populations that are increasingly attracting the attention of regenerative medicine operators. It is likely that new cardiovascular drugs are introduced in the next future by applying different approaches based on the refinement of the stem cell secretome.

OBJECTIVES: The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis. BACKGROUND: Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear. METHODS: We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events. RESULTS: We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 × 10(-11)). We found no evidence for biases to account for these findings. CONCLUSIONS: Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD.

HP and HPR are related and contiguous genes in strong linkage disequilibrium (LD), encoding haptoglobin and haptoglobin-related protein. These bind and chaperone free Hb for recycling, protecting against oxidation. A copy number variation (CNV) within HP (Hp1/Hp2) results in different possible haptoglobin complexes which have differing properties. HPR rs2000999 (G/A), identified in meta-GWAS, influences total cholesterol (TC) and LDL-cholesterol (LDL-C). We examined the relationship between HP CNV, HPR rs2000999, Hb, red cell count (RCC), LDL-C and TC in the British Women's Heart and Health Study (n = 2779 for samples having CNV, rs2000999, and phenotypes). Analysing single markers by linear regression, rs2000999 was associated with LDL-C (β = 0.040 mmol/L, p = 0.023), TC (β = − 0.040 mmol/L, p = 0.019), Hb (β = − 0.044 g/dL, p = 0.028) and borderline with RCC (β = − 0.032 × 1012/L, p = 0.066). Analysis of CNV by linear regression revealed an association with Hb (Hp1 vs Hp2, β = 0.057 g/dL, p = 0.004), RCC (β = 0.045 × 1012/L, p = 0.014), and showed a trend with LDL-C and TC. There were 3 principal haplotypes (Hp1-G 36%; Hp2-G 45%; Hp2-A 18%). Haplotype comparisons showed that LDL-C and TC associations were from rs2000999; Hb and RCC associations derived largely from the CNV. Distinct genotype–phenotype effects are evident at the genetic epidemiological level once LD has been analysed, perhaps reflecting HP–HPR functional biology and evolutionary history. The derived Hp2 allele of the HP gene has apparently been subject to malaria-driven positive selection. Haptoglobin-related protein binds Hb and apolipoprotein-L, i.e. linking HPR to the cholesterol system; and the HPR/apo-L complex is specifically trypanolytic. Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents., Highlights ► HP CNV/HPR SNP haplotype analysis shows association of HP CNV with Hb levels/RCC. ► HP CNV/HPR SNP haplotype analysis shows association of HPR SNP with LDL-C/TC. ► The HP CNV/Hb-related association may be via Hp2 allele advantage in malaria zones. ► The HPR SNP/cholesterol association is likely via apolipoproteins in TLF-1 and -2. ► We infer that HP CNV duplication preceded HPR SNP mutation.

BACKGROUND AND AIMS: IL-18 expression is up-regulated in atherosclerotic plaques, and higher levels are seen in obese and Type 2 Diabetic individuals. More recently, a possible role for IL-18 in glucose and energy homeostasis has been suggested.METHODS AND RESULTS: We investigated variation within the IL18 gene and its association with measures of obesity and the metabolic syndrome. Five IL18 tagging single nucleotide polymorphisms (rs1946519, rs2043055, rs549908, rs360729, rs3882891) were selected and genotyped in the Gene-Diet Attica Investigation on childhood obesity (GENDAI) (age range 10-14 yrs); in young European men in the second European Atherosclerosis Research offspring Study (EARSII), an offspring study (age range 18-28 yrs) and in a group of healthy women from the Greek Obese Women study (GrOW) (age range 18-74 yrs). Six common haplotypes were observed. In GrOW, Hap6 (Frequency-2.6%) was associated with higher insulin levels (pCONCLUSION: Association of IL18 variation with insulin levels and estimates of insulin resistance were only observed in our adult study, suggesting that the effects of IL-18 are only associated with increasing age. Taken together with the association of IL18 variants with post-prandial measures, this provides support for IL-18 as a metabolic factor.

Highlights ► Associations of exposures with mortality may be confounded by existing ill health. ► We used a son's height as an instrument for parents’ height to avoid confounding. ► Parents of taller sons had lower cardiovascular and respiratory disease mortality. ► Parents of taller sons had higher mortality from cancer. ► Previous studies of height are not substantially confounded by existing ill health., Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,1 or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents’ height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49 cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health.