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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.

SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.

Objective The Asian American population in the U.S. comprises various, ethnically diverse subgroups. Traditionally, this population has been studied as a single, aggregated group, potentially masking differences in risk among subgroups. Analyses using disaggregated data can help better characterize the health needs of different Asian subpopulations and inform targeted, effective public health interventions. We assessed the prevalence of cardiovascular disease (CVD) risk factors and atherosclerotic CVD (ASCVD) and their associations with socioeconomic factors among Chinese, Asian Indian, Filipino and Other Asian subjects, compared with non-Hispanic White (NHW) subjects in the U.S. Methods : Cross-sectional study using data from 298,286 adults from the National Health Interview Survey (NHIS) from 2007 to 2018. We utilized chi-squared tests to compare characteristics across subgroups. Weighted proportions and unadjusted and adjusted logistic regression models were utilized to examine the associations between Asian subgroups, self-reported CVD risk factors and self-reported ASCVD, as well as between socioeconomic factors within each Asian subgroup. Results : Asian Indian subjects had the highest prevalence of diabetes (12.5%), while Filipino subjects had the highest prevalence of hyperlipidemia (27.7%), hypertension (29.8%) and obesity (19.8%). Despite this, the prevalence of self-reported ASCVD was lower in all Asian groups compared with NHWs. Chinese subjects had the lowest odds of having each of the CVD risk factors assessed. Conclusion : We found considerable heterogeneity in the distribution of risk factors as well as ASCVD among Asian subgroups in the US. Compared with health system or community-based reports, the prevalence of risk factors and ASCVD may be underestimated in some Asian NHIS subgroups. There is an urgent need for efforts to improve recruitment of Asian participants of heterogeneous socioeconomic backgrounds in national surveys, as well as to perform a thorough assessment of risk factors and disease in this population, not relying solely on self-report., Graphical abstract Image, graphical abstract

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.

Objectives To develop a fully automatic multiview shape constraint framework for comprehensive coronary artery calcium scores (CACS) quantification via deep learning on nonenhanced cardiac CT images. Methods In this retrospective single-centre study, a multi-task deep learning framework was proposed to detect and quantify coronary artery calcification from CT images collected between October 2018 and March 2019. A total of 232 non-contrast cardiac-gated CT scans were retrieved and studied (80 % for model training and 20 % for testing). CACS results of testing datasets (n = 46), including Agatston score, calcium volume score, calcium mass score, were calculated fully automatically and manually at total and vessel-specific levels, respectively. Results No significant differences were found in CACS quantification obtained using automatic or manual methods at total and vessel-specific levels (Agatston score: automatic 535.3 vs. manual 542.0, P = 0.993; calcium volume score: automatic 454.2 vs. manual 460.6, P = 0.990; calcium mass score: automatic 128.9 vs. manual 129.5, P = 0.992). Compared to the ground truth, the number of calcified vessels can be accurate recognized automatically (total: automatic 107 vs. manual 102, P = 0.125; left main artery: automatic 15 vs. manual 14, P = 1.000 ; left ascending artery: automatic 37 vs. manual 37, P = 1.000; left circumflex artery: automatic 22 vs. manual 20, P = 0.625; right coronary artery: automatic 33 vs. manual 31, P = 0.500). At the patient’s level, there was no statistic difference existed in the classification of Agatston scoring (P = 0.317) and the number of calcified vessels (P = 0.102) between the automatic and manual results. Conclusions The proposed framework can achieve reliable and comprehensive quantification for the CACS, including the calcified extent and distribution indicators at both total and vessel-specific levels.

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.

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

Aims: Taller stature has been associated with increased risk of atrial fibrillation (AF). AF and heart failure (HF) often co-occur but the association between height and risk of HF in older adults has not been well studied. We have examined the association between height and incident AF and incident HF in older adults. Methods: Prospective study of 3346 men aged 60-79 years with no diagnosed HF, myocardial infarction or stroke at baseline (1998-2000) followed up for a mean period of 16 years, in whom there were 294 incident HF cases and 456 incident AF. Men were divided into 5 height groups: 183.0 cms based on the 25th, 50th, 75th and 95th centiles distribution of height. Results: CVD risk factors tended to decrease with increasing height but a positive association was seen between height and electrocardiographic QRS duration and incident AF. Both short stature (183.0 cm) was associated with significantly increased risk of HF in age-adjusted analysis compared to those in the second height quartile [HR (95 %CI) = 1.62 (1.15, 2.26) and 2.04 (1.23, 3.39) respectively]. In short men the increased risk remained after adjustment for adverse CVD risk factors; in tall men the association was largely associated with AF and QRS duration. Conclusion: Tall stature is associated with significantly increased risk of AF leading to increased risk of HF. Short stature was associated with increased HF risk which was not explained by known adverse CVD risk factors.

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.

Background & Aims Sarcopenia and frailty are recognised as important factors in later stages of liver disease. However, their role in non-alcoholic fatty liver disease (NAFLD) is not yet fully understood. In this study we investigate the associations of MRI-measured adverse muscle composition (AMC: low muscle volume and high muscle fat) with poor function, sarcopenia, and metabolic comorbidity within NAFLD in the large UK Biobank imaging study. Methods A total of 9,545 participants were included. Liver fat, fat-tissue free muscle volume, and muscle fat infiltration were quantified using a rapid MRI protocol and automated image analysis (AMRA® Researcher). For each participant, a personalised muscle volume z-score (sex- and body size-specific) was calculated and combined with muscle fat infiltration for AMC detection. The following outcomes were investigated: functional performance (hand grip strength, walking pace, stair climbing, falls) and metabolic comorbidities (coronary heart disease, type 2 diabetes). Sarcopenia was detected by combining MRI thresholds for low muscle quantity and low hand grip strength according to the European working group definition. Results The prevalence of sarcopenia in NAFLD (1.6%) was significantly lower (p, Graphical abstract, Highlights • The role of sarcopenia and frailty in NAFLD is not yet fully understood. • Magnetic resonance imaging enables quantification of muscle composition. • Myosteatosis in combination with low muscle volume characterises an adverse muscle composition. • Adverse muscle composition is a novel NAFLD phenotype associated with poor function and metabolic comorbidity. • Sarcopenia guidelines can be strengthened by including cut-offs for muscle fat.

In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the Low Density Lipoprotein Receptor (LDLR) gene as the first gene where mutations cause the Familial Hypercholesterolaemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE), and that the plasma LDL-C concentration and risk of premature Coronary Heart Disease (CHD) differs according to the specific locus and associated molecular cause. It is now possible to use Next Generation Sequencing (NGS) to sequence all exons of all four genes, processing 96 patient samples in one sequencing run, increasing the speed of test results and reducing costs. This has resulted in the identification of many novel FH-causing variants, but also some "Variants of Unknown Significance (VUSs)" which require further evidence to classify as pathogenic or benign. The identification of the FH-causing variant in an index case can be used as an unambiguous and rapid test for other family members. An FH-causing variant can be found in 20%-40% of patients with the FH phenotype, and we now appreciate that in the majority of patients without a monogenic cause, a polygenic aetiology for their phenotype is highly likely. Compared to those with a monogenic cause, these patients have significantly lower risk of future CHD. The use of these molecular genetic diagnostic methods in the characterization of FH is a prime example of the utility of precision or personalised medicine.

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

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.

Introduction Erectile dysfunction (ED) is a common risk factor in men and its incidence increases with age. Ageing and older men frequently have comorbidities such as cardiovascular diseases (CVD), diabetes mellitus (DM), hypertension, chronic obstructive pulmonary disease and dyslipidaemia; likewise, they concurrently refer to a clinician for impairments in sexual function, mostly for ED. The association of ED and other organic, multi-organic or even systemic diseases is widely described, with a specific emphasis on the fact that they often share common pathophysiological factors and mechanisms. Thus we reviewed previous reports assessing the role of ED as a sentinel marker of overall men’s health. Discussion ED is considered an important sentinel marker for CVD. Numerous studies have highlighted the predictive role of ED for subsequent CV events in patients with a silent history of coronary artery disease. Indeed, ED might be considered as a clinical manifestation of a generalised vascular disease, and it should provoke clinicians to check for CVDs in those patients complaining of impaired erectile function. This concept appears to be even more important for men with DM, where ED has already been shown to have a significant predictive ability for major vascular complications. Moreover, data from large population-based studies showed that ED is a significant predictor of all-cause mortality, in addition to CV outcomes. The severity of erectile function is assessed with the International Index of Erectile Function-Erectile Function domain score, and this has emerged as a proxy for men’s general health status, as assessed with the Charlson Comorbidity Index score. Conclusions Patients complaining of ED should be evaluated with a comprehensive medical and sexual history, and a thorough physical examination, regardless of their age, considering ED as an opportunity to screen for the presence of health-threatening concomitant comorbidities.

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.

In this review we identify whether problems encountered in urology, such as erectile dysfunction, have a bearing on general health, in particular cardiovascular health. Testosterone, traditionally regarded as the hormone subserving male reproductive and sexual functioning, appears to have a much wider role. Recent findings show that testosterone is involved in the metabolic control of glucose and lipids, of strength of bone and muscle, and psychological aspects such as mood and energy. Serum testosterone levels decline with ageing, free testosterone levels more so than total testosterone. At least 10 publications have shown that low testosterone levels are associated with an increased risk of death. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and cardiovascular morbidity and mortality. There is a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin levels predict a higher incidence of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses part of the unfavourable risk profile for the development of diabetes and atherosclerosis, thus also improving risk factors for erectile dysfunction. We conclude that urologists diagnosing and treating erectile problems are in a unique position to include general aspects of men’s health in their work, and thus contribute to general health and to cardiovascular health in particular.

Background Tumour necrosis factor alpha (TNFα) is a pro-inflammatory cytokine implicated in atherosclerotic plaque formation. We investigated whether circulating TNFα is prospectively associated with myocardial infarction (MI) or stroke in the older general population, independently of established cardiovascular risk factors and other inflammatory markers related to CHD risk. Methods We measured baseline TNFα concentrations in stored serum samples of 362 incident MI and 299 incident stroke cases and controls (2 per case, frequency matched by age, gender and town) who were ‘nested’ in parallel prospective studies of 4252 men and 4286 women aged 60–79 years assessed in general practices in 24 British towns in 1998–2000 and followed up for an average 7 years for fatal and non-fatal MI and stroke. Results TNFα levels were 11.4% (95% CI 9.5, 13.3%) higher among MI cases than controls; geometric mean 1.84 pg/mL compared to 1.63 pg/mL, p (difference)

Objectives The endopeptidase matrix metalloproteinase-9 (MMP-9) is implicated in atherosclerotic plaque rupture. We investigate prospective associations between MMP-9 and MI or stroke in an older general population cohort, accounting for established and novel cardiovascular risk factors. Methods Baseline serum MMP-9 was measured in incident MI (n = 368) and stroke (n = 299) cases and two controls per case, ‘nested’ in prospective studies of 4252 men and 4286 women aged 60–79 years, sampled from General Practices in Britain in 1998–2000, with 7-year follow-up for fatal and non-fatal MI and stroke. Results Geometric mean MMP-9 was 528 ng/mL (IQR 397, 743) in MI cases compared to 501 ng/mL (IQR 370, 743) in controls, p = 0.10. Participants in the top compared to bottom third of MMP-9 levels had an age-adjusted odds ratio for MI of 1.53 (95% CI 1.09, 2.13), which attenuated to 1.18 (95% CI 0.81, 1.70) after adjustment for established and novel cardiovascular risk factors. There was weak evidence that OR differed according to pre-existing CVD; the OR for MI in 187 participants with pre-existing CVD was 2.20 (1.04, 4.64) and 1.24 (0.84, 1.82) in 715 participants without (LR test for interaction p = 0.06). Geometric mean MMP-9 levels were higher in stroke cases than controls; 522 ng/mL (IQR 363, 673) vs 487 (IQR 393, 704), p = 0.045; however adjustments similarly attenuated the associations. Conclusions While serum MMP-9 is univariately associated with risk of MI and stroke, it is not a strong independent risk marker for either.