Lower Incidence Of Cardiovascular Disease Research Articles

Epigenetic mechanisms regulate sex differences in cardiac reparative functions of bone marrow progenitor cells

Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients. However, meta-analysis data from these trials suggest a better functional outcome in postmenopausal women as compared with aged-matched men. Mechanisms governing sex-specific cardiac reparative activity in BMSCs, with and without the influence of sex hormones, remain unexplored. To discover these mechanisms, Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. F-EPCs and OVX EPCs show a lower inflammatory profile and promote enhanced cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in M-EPCs compared with F-EPCs and OVX-EPCs. Our study unveiled that functional sex differences in EPCs are, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering the sex of donor cells for progenitor-based tissue repair.

Replacement of Saturated Fatty Acids from Meat by Dairy Sources in Relation to Incident Cardiovascular Disease: The European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study

BackgroundProspective observational data revealed lower cardiovascular disease (CVD) incidence with modeled replacement of saturated fatty acids (SFA) from total meat by total dairy, but it is unknown what the associations are of replacing SFA from types of meat by types of dairy with CVD incidence. ObjectivesThis study aimed to investigate the associations of replacing SFA from total, red, processed, and poultry meat by SFA from total dairy, milk, cheese, and yogurt with the incidence of CVD. MethodsWe analyzed longitudinal data from 21,841 participants of the European Prospective Investigation into Cancer and Nutrition-Norfolk study (56.4% female; age, 40–79 years). Dietary data were collected by food frequency questionnaires at baseline (1993–1997). Incident fatal or nonfatal CVD (n = 5902), coronary artery disease (CAD; n = 4215), stroke (total: n = 2544; ischemic: n = 1113; hemorrhagic: n = 449) were identified up to 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression for the risk associated with replacement of 2.5% of energy from SFA from meat by dairy, adjusted for sociodemographic, lifestyle, energy, dietary, and cardiometabolic factors. ResultsReplacing SFA from total meat by total dairy was associated with a lower CVD incidence (HR: 0.89; 95% CI: 0.82, 0.96) and CAD (HR: 0.88; 95% CI: 0.80, 0.96). Replacing SFA from processed meat by cheese was associated with lower CVD (HR: 0.77; 95% CI: 0.68, 0.88); CAD (HR: 0.77; 95% CI: 0.66, 0.90), and stroke (HR: 0.81; 95% CI: 0.67, 0.99). Similarly, replacing SFA from red meat by cheese was associated with lower CVD (HR: 0.86; 95% CI: 0.76, 0.97). Higher incidence of stroke was found with replacement of SFA from poultry by milk (HR: 2.06; 95% CI: 1.09, 3.89), yogurt (HR: 2.55; 95% CI: 1.27, 5.13), or cheese (HR: 1.96; 95% CI: 1.04, 3.70), but the CI were relatively large, owing to low, narrow range of poultry SFA intake. ConclusionsFindings indicate that different SFA-rich foods at baseline have differential associations with CVD risk. If confirmed by further studies, these findings could be used to inform specific food-based dietary guidance.

RED BLOOD CELL INDICES IN PATIENTS WITH CARDIOVASCULAR DISEASES AT A TERTIARY CARE HOSPITAL PESHAWAR

Cardiovascular diseases are a major cause of health loss worldwide, regardless of a country's income, social status, or demographics. Many studies have reported a link between haematological parameters and cardiovascular diseases in patients. This study aimed to determine the red blood cell indices in patients with cardiovascular diseases at a tertiary care hospital in Peshawar. The study was conducted for six months, from January 1, 2023, to June 30, 2023, at the Pathology Department of Afridi Medical Complex and Teaching Hospital. Blood samples were taken from patients in EDTA vacutainers, and their haematological parameters were determined in the laboratory. The patients' clinical examinations, history, name, gender, age, and previous laboratory investigations were recorded in a proforma designed for this research. The data were analyzed using IBM SPSS version 23. The study enrolled 80 patients with cardiovascular diseases, including 44 (55%) male and 36 (45%) female patients. The mean age of the study participants was 47 years, with a standard deviation of ±12.3. The mean (±SD) haemoglobin, red blood cell count, hematocrit, mean corpuscular haemoglobin, red cell distribution width-SD, and red cell distribution width-CV were 13.99 (±1.86) (g/dl), 4.49 (±0.55) (million/cm3), 40.72 (±5.81), 28.99 (±2.22), 62.06 (±6.99), and 16.87 (±3.39), respectively. The study concludes that red blood cell indices such as red cell distribution width, haemoglobin, and mean corpuscular volume play a significant role in the pathogenesis of cardiovascular diseases. Routine health examinations and proactive precautions may help lower cardiovascular disease incidence.

Ideal cardiovascular health and cardiovascular related events: a systematic review and meta-analysis.

The aim of this study was to systematically review and quantitatively summarise the evidence on the association between Life Simple's 7 (LS7) and multiple cardiovascular diseases (CVD) and cardiometabolic diseases (CMD). EMBASE and PubMed were searched from January 2010 to March 2022 for observational studies that investigated the association between ideal cardiovascular health (CVH) with CVD or CMD outcomes in an adult population. Two reviewers independently selected studies according to the eligibility criteria, extracted data, and evaluated risk of bias. Data were analysed with a random-effect meta-analysis. This meta-analysis included 59 studies (1,881,382 participants). Participants with ideal CVH had a considerably lower risk of a variety of CVDs and CMDs as compared to those with poor CVH, varying from 40% lower risk for atrial fibrillation (AF) (HR = 0.60 [95% CI 0.44-0.83]) to 82% lower risk for myocardial infarction (HR = 0.18 [95% CI 0.12-0.28]). Intermediate CVH was associated with 27%-57% lower risk in CVDs and CMDs compared to poor CVH, with the highest hazard for AF (HR = 0.73 [95% CI 0.59-0.91]), and the lowest hazard for peripheral arterial disease (HR = 0.43 [95% CI 0.30-0.60]). Ideal and moderate CVH were associated with a lower incidence of CVDs and CMDs than poor CVH. LS7 holds significant potential for promoting overall CVH and thereby contributing to the prevention of CVDs.

Association of remnant cholesterol with CVD incidence: a general population cohort study in Southwest China

BackgroundEmerging evidence has indicated that remnant cholesterol (RC) could predict cardiovascular disease (CVD) incidence. Nevertheless, the relationship between RC and CVD risk, especially within the general Chinese population, remains scarce.ObjectiveThe present research aimed to assess whether RC concentrations and CVD outcomes in general Chinese adults are related.MethodsThe Cox proportional hazard model was established to explore the relationship between RC and the outcomes of CVD and CVD subgroups. A restricted cubic spline (RCS) was utilized to investigate the dose–response connection between RC and the risk of CVD outcomes, and the ROC curve was used to calculate the corresponding cutoff values. Moreover, stratified analysis was conducted to investigate the potential effect modification in the association between RC and CVD outcomes.ResultsSignificant positive associations were found between elevated categorical RC and increased risk of CVD (HR Q4, 1.80; 95% CI 1.15–2.79; P-value = 0.008), atherosclerotic cardiovascular disease (HR Q4, 2.00; 95% CI 1.22–3.27; P-value = 0.007), stroke (HR Q4, 1.66; 95% CI 1.02–2.69; P-value = 0.040), and ischemic stroke (HR Q4, 1.87, 95% CI 1.08–3.25; P-value = 0.034), respectively. Our study suggested that the incidence of CVD outcomes increased when RC levels were above 0.75 mmol/L. Importantly, the CVD risks related to RC were more likely to be those found in subjects aged above 60 years, women, subjects with BMI <24 kg/m2, and subjects with hypertension and unhealthy diet patterns.ConclusionsAberrant high level of RC is associated with elevated CVD risk, independent of low-density lipoprotein cholesterol (LDL-C). Our data reveal urgent primary prevention for subjects with high RC levels to a low incidence of CVD, especially for the elderly, women, and those with hypertension and unhealthy diet patterns.

17β-Estradiol inhibits hydrogen peroxide-induced senescence and apoptosis in human umbilical vein endothelial cells by regulating the THBS1/TGF-β/Smad axis

Before menopause, females exhibit a lower incidence of cardiovascular disease than age-matched males, possibly owing to the protective effects of sex hormones. 17β-estradiol (17β-E2) protects against oxidative stress-induced injury by suppressing thrombospondin-1 (THBS1) expression in endothelial cells. Here, we examined the role of 17β-E2-mediated THBS1 suppression in preventing cell senescence and apoptosis. Human umbilical vein endothelial cells (HUVECs) were cultivated and treated with siRNA or overexpression plasmids to regulate THBS1. H2O2, estrogen-activity modulating drugs, and LY2109761 (a TGF-β kinase inhibitor) treatments were applied. THBS1 knockdown repressed, and its overexpression aggravated, H2O2-induced cell injury, affecting cell death, proliferation, senescence, and apoptosis. 17β-E2 inhibited THBS1 mRNA and protein expression time- and dose-dependently, by targeting ERβ. THBS1 overexpression blocked 17β-E2 from preventing H2O2-induced injury, significantly activating the TGF-β/Smad pathway. 17β-E2 inhibited H2O2-induced oxidative stress by downregulating THBS1 expression and TGF-β/Smad signaling in HUVECs. The THBS1/TGF-β/Smad axis could thus be a therapeutic target.

Association of seafood consumption with cardiovascular disease among adults in Qingdao, China

Background and aimsThe relationship between seafood consumption and cardiovascular disease (CVD) is controversial, and studies have not considered competing risk events. Our study examined the association between a full range of seafood consumption and CVD incidence and mortality based on the Qingdao Diabetes Prevention Program. Methods and resultsWe followed up 5285 participants without CVD at baseline until December 31, 2021. CVD cases and deaths were identified through record linkage with the Qingdao CVD Surveillance System and the Qingdao Death Surveillance System, respectively. Information on seafood consumption was obtained using a food frequency questionnaire. We used the Cox proportional hazard model and the competing risk model to evaluate the association between all types of seafood consumption and CVD incidence and mortality. During a median follow-up of 11.4 years, 122 CVD cases and 75 deaths occurred. After adjustment for potential confounders, compared with nonconsumers, seafood consumption of 300–500 and > 500 g/week was associated with a lower risk of CVD incidence [hazards ratio and 95 % confidence interval (CI): 0.54 (0.29–0.99) and 0.49 (0.26–0.91), respectively]. However, seafood consumption of >500 g/week had a significantly lower risk of CVD mortality [subdistribution hazard ratio and 95 % CI: 0.40 (0.17–0.95)], but it was insignificant in other groups. ConclusionSeafood consumption of 300–500 g/week and >500 g/week was associated with a lower CVD incidence and mortality. Our findings provide evidence of the recommendations of the 2022 Dietary Guidelines for Chinese residents and may guide the promotion of strategies for CVD prevention.

Impact of Mediterranean Diet on Lipid Composition in the Colaus-PsyColaus Study.

High adherence to the Mediterranean diet (MD) has been associated with lower incidence of cardiovascular disease, increased HDL-cholesterol levels, and decreased triglycerides (TG), and total and LDL cholesterol levels. We aimed to assess the association of MD adherence at baseline with the lipid profile both cross-sectionally and prospectively in a sample of apparently healthy community-dwelling subjects. We conducted three cross-sectional studies using data from follow-ups 1 (FU1, 2009-2012), 2 (FU2, 2014-2017), and 3 (FU3, 2018-2021) of CoLaus|PsyCoLaus, a population-based sample from Lausanne, Switzerland. Dietary intake was assessed with a food frequency questionnaire. Two MD scores (Trichopoulou and Vormund) were computed, ranging from 0 (low) to 9 (high). In total, LDL and HDL cholesterol and TG were assessed. Incident dyslipidemia was defined as hypolipidemic treatment at FU2 or FU3. Overall, 4249 participants from FU1 (53.7% women, 57.6 ± 10.5 years, Trichopoulou 4.0 ± 1.5, Vormund 4.7 ± 1.9) were included. Neither MD score correlated significantly with the lipid markers and similar results were obtained according to the hypolipidemic status. Among the 3092 untreated FU1 participants with FU2 and FU3 data, 349 (11.3%) developed dyslipidemia by FU2 or FU3. No difference in MD scores was found between participants who developed dyslipidemia and those who did not (4.1 ± 1.5 vs. 4.0 ± 1.5 and 4.8 ± 1.8 vs. 4.8 ± 1.9 for Trichopoulou and Vormund, respectively, p > 0.05). Finally, no associations were found between MD score and lipid changes at 5 or 10 years. Contrary to other studies, adherence to MD at baseline did not show any significant effects on lipid composition/incident dyslipidemia in Colaus|PsyCoLaus participants.

Preserved vegetable consumption and its association with mortality among 440,415 people in the China Kadoorie Biobank

BackgroundFresh vegetable consumption has been associated with lower incidence of cardiovascular disease (CVD). However, whether preserved vegetable consumption is linked with CVD and mortality remains unclear. This study aimed to assess the associations of preserved vegetable consumption with all-cause and cause-specific mortality.MethodsA total of 440,415 participants free of major chronic diseases, aged 30–79 years, were enrolled from 10 diverse regions in China between 2004 and 2008 and were followed up for an average of 10 years. Preserved vegetable consumption was assessed using a validated food frequency questionnaire. Cause-specific hazard models with the consideration of competing risk from various deaths were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality.ResultsDuring 4,415,784 person-years of follow-up, we documented 28,625 deaths. After adjustment for major risk factors, preserved vegetable consumption was marginally associated with higher CVD mortality (P = 0.041 for trend and P = 0.025 for non-linearity) but not associated with cancer mortality and total mortality. For specific causes of death, consuming preserved vegetables was associated with higher hemorrhagic stroke mortality. The multivariable-adjusted HRs (95% CIs) of hemorrhagic stroke mortality compared with non-consumers were 1.32 (1.17–1.50) for 1–3 days/week and 1.15 (1.00–1.31) for regular consumers (≥4 days/week) (P = 0.006 for trend and P < 0.001 for non-linearity). In addition, regular preserved vegetable consumption was associated with increased risk of digestive tract cancer mortality [HR (95% CI): 1.13 (1.00–1.28); P = 0.053 for trend] and esophageal cancer mortality [HR (95% CI): 1.45 (1.17–1.81); P = 0.002 for trend].ConclusionsFrequent consumption of preserved vegetables was associated with higher risk of mortality from hemorrhagic stroke and esophageal cancer in China. Our findings suggest limiting preserved vegetable consumption might be protective for premature death from hemorrhagic stroke and digestive tract cancer.

In this Issue.

HomeCirculation ResearchVol. 132, No. 7In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published30 Mar 2023https://doi.org/10.1161/RES.0000000000000608Circulation Research. 2023;132:791is related toDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeDestabilization of Atherosclerotic Plaque by Bilirubin DeficiencyIntegrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyDiscovery of Trans-Acting Long Non-Coding RNAs that Regulate Smooth Muscle Cell Phenotype (p 795)Download figureDownload PowerPointShi et al identify long non-coding RNAs that regulate a phenotype switch in smooth muscle cells.Vascular smooth muscle cells (VSMCs) are a major contributing cell type in the progression of coronary artery disease (CAD) and become pathological by transitioning into a highly proliferative and migratory state. In searching for factors that regulate this transition—which could thus reveal ways to stop it—Shi and colleagues focused on the potential role of long non-coding RNAs (lncRNAs), many of which are regulatory in nature. Human coronary artery SMCs (HCASMCs) were subjected to various CAD stimuli and the expression changes of lncRNAs were analyzed. From the many differentially expressed lncRNAs, the team focused on two—ZIPPOR and TNS1-AS2, which were down- and up-regulated respectively relative to unstimulated cells. Interestingly, functional analysis of these two revealed that, despite being differently affected by CAD stimuli, repression of either led to similar effects in HCASMCs—increased migration and proliferation and increased expression of ZEB2, a master regulator of SMC phenotype transition. Both ZIPPOR and TNS1-AS2 were also found to interact directly with the ZEB2 protein to suppress its expression.While it is not known if these lncRNAs influence CAD progression, their suppression of SMC transition suggests such investigations are warranted.Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency (p 812)Download figureDownload PowerPointLow bilirubin aggravates atherosclerosis in mice, report Chen et al.Bilirubin is a yellowish pigment formed during the breakdown of red blood cells and is ordinarily processed by the liver and excreted. Liver dysfunction can cause a severe build-up of bilirubin resulting in jaundice, but a more modest elevation is associated with lower levels of cardiovascular disease (CVD). Indeed, people with higher levels of the pigment have a lower incidence of CVD, while coronary artery disease patients with especially low levels of bilirubin have less stable plaques and worse outcomes. To investigate how bilirubin might protect against CVD, Chen and colleagues engineered atherosclerosis-prone mice to produce less of the pigment, and compared them with control mice whose bilirubin levels were normal. A lack of bilirubin worsened atherosclerosis in multiple ways. For example, the test animals had increased levels of blood lipids, increased systemic inflammation and oxidative stress, evidence of endothelial dysfunction, and increased plaque instability. While the latter appeared to result from infiltration of inflammatory cells and increased expression of the pro-inflammatory enzyme, MPO, the molecular details behind bilirubin’s other effects are yet to be determined. Nonetheless, the findings lead the way for further research into whether modifying levels of bilirubin might help lower CVD risk.Integrated Proteomics Unveils Regulation of Cardiac Myocyte Hypertrophic Growth by a Nuclear cAMP Nanodomain Under the Control of PDE3A2 (p 828)Download figureDownload PowerPointA PDE3A2-controlled cAMP nanodomain regulates cardiomyocyte hypertrophy, say Subramaniam et al.Within cardiomyocytes, cAMP conveys beta-adrenergic receptor (βAR) signals to boost the strength and frequency of the heart’s contractions. But cAMP has other jobs within cells and its interactions with specific factors at specific subcellular nanodomains are thought to regulate task execution. One such factor is the enzyme PDE, which degrades cAMP. There are many different isoforms of PDE and they are thought to occupy and specify different nanodomains. Subramaniam and colleagues investigated the proteins associating with individual PDE isoforms when cardiomyocytes were stimulated with isoproterenol—a βAR agonist—and in this way discovered that βAR-activated PDE3A2 nanodomains associate with the transcription regulators SMAD4 and HDAC1, are located in the nucleus, and normally repress the expression of genes involved in hypertrophy. Sure enough, inhibition of PDE3 enabled cAMP-induced activation of hypertrophy genes and resulted in cardiomyocyte growth. PDE3 inhibitors are inotropic drugs that provide short term benefits to heart failure patients, but can worsen the condition if used long term. The finding that PDE3 inhibition led to cAMP-induced hypertrophy may thus partly explain the detrimental effects of such drugs on the heart, say the authors. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesDiscovery of Transacting Long Noncoding RNAs That Regulate Smooth Muscle Cell PhenotypeHuitong Shi, et al. Circulation Research. 2023;132:795-811Destabilization of Atherosclerotic Plaque by Bilirubin DeficiencyWeiyu Chen, et al. Circulation Research. 2023;132:812-827Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte HypertrophyGunasekaran Subramaniam, et al. Circulation Research. 2023;132:828-848 March 31, 2023Vol 132, Issue 7 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000608PMID: 36996178 Originally publishedMarch 30, 2023 PDF download Advertisement

Primary prevention of cardiovascular disease in women with a Mediterranean diet: systematic review and meta-analysis

BackgroundDietary modification is a cornerstone of cardiovascular disease (CVD) prevention. A Mediterranean diet has been associated with a lower risk of CVD but no systematic reviews have evaluated this relationship...

Abstract P418: Dietary Glutamine and Glutamate in Relation to Cardiovascular Disease and Mortality in Adults With Type 2 Diabetes

Background: The potential health effects of dietary glutamine and glutamate have been studied in healthy populations, but evidence among individuals with type 2 diabetes (T2D) who have altered macronutrient metabolism and elevated cardiovascular disease (CVD) risk is limited. Objectives: We aimed to examine dietary glutamine and glutamate in relation to subsequent risk of CVD, including coronary heart disease and stroke, and all-cause and cause-specific mortality among individuals with T2D. Methods: We prospectively followed 15,040 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1980-2014, Health Professionals Follow-Up Study: 1986-2018). Diet was repeatedly assessed using validated food frequency questionnaires every 2-4 years since baseline. Associations of energy-adjusted glutamine and glutamate intake, as well as their ratio, with CVD risk and mortality were assessed using Cox proportional hazards models with adjustments for demographics, dietary and lifestyle factors, and medical history. Results: During 196,955 and 225,371person-years of follow-up in participants with T2D, there were 2,927 incident CVD cases and 4,898 deaths, respectively. Higher intake of glutamine was associated with lower risk of incident CVD, total mortality and CVD mortality: comparing extreme quintiles, the HRs (95%CIs) were 0.88 (0.77, 0.99), 0.85 (0.77, 0.94), and 0.82 (0.69, 0.98), respectively (all P trend &lt;0.05). In contrast, higher intake of glutamate was associated with higher risk of incident CVD, total mortality, and CVD mortality; the HRs were 1.30 (1.15, 1.46), 1.19 (1.08, 1.31), and 1.42 (1.21, 1.67), respectively (all P trend &lt;0.05). Furthermore, comparing extreme quintiles, higher dietary glutamine-to-glutamate ratio was associated with lower risk of CVD incidence (0.84 (0.75, 0.95)), total mortality (0.83 (0.76, 0.91)), and CVD mortality (0.69 (0.59, 0.80)). In addition, compared with participants without increment in glutamine-to-glutamate ratio from pre- to post-diabetes diagnosis, those who increased the ratio had a 15% (3%, 25%) lower CVD mortality. Conclusions: In patients with T2D, dietary glutamine and glutamate demonstrated divergent associations with CVD incidence and mortality, and higher dietary glutamine-to-glutamate ratio was significantly associated with lower CVD incidence and mortality. These data suggest a potential critical role of these two amino acids in the etiology of cardiometabolic diseases and early deaths also among adults with T2D.

Cardiovascular Disease and Sex

One of the primary causes of death worldwide is cardiovascular disease (CVD). Women typically have a lower incidence of CVD than men, however after acute cardiovascular events, women have a higher mortality and worse prognosis. Different CVDs, such as coronary heart disease, stroke, heart failure, and aortic diseases, exhibit these sex variances. These differences have raised serious concerns so sex consideration is significant for the prevention, diagnosis, treatment, and management of CVD. In order to highlight the need of taking sex differences into account when determining cardiovascular risk, this study seeks to offer an overview of sex-related differences in numerous common CVDs as well as an analysis of potential factors linked with the disparities. Future studies should focus on how to define and include sex-related indicators into the methods currently used for cardiovascular risk assessment and management.

Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels

ObjectiveThe liver-derived circulating PCSK9 enhances the degradation of the LDL receptor (LDLR) in endosomes/lysosomes. PCSK9 inhibition or silencing is presently used in clinics worldwide to reduce LDL-cholesterol, resulting in lower incidence of cardiovascular disease and possibly cancer/metastasis. The mechanism by which the PCSK9-LDLR complex is sorted to degradation compartments is not fully understood. We previously suggested that out of the three M1, M2 and M3 subdomains of the C-terminal Cys/His-rich-domain (CHRD) of PCSK9, only M2 is critical for the activity of extracellular of PCSK9 on cell surface LDLR. This likely implicates the binding of M2 to an unknown membrane-associated “protein X” that would escort the complex to endosomes/lysosomes for degradation. We reported that a nanobody P1.40 binds the M1 and M3 domains of the CHRD and inhibits the function of PCSK9. It was also reported that the cytosolic adenylyl cyclase-associated protein 1 (CAP1) could bind M1 and M3 subdomains and enhance the activity of PCSK9. In this study, we determined the 3-dimensional structure of the CHRD-P1.40 complex to understand the intricate interplay between P1.40, CAP1 and PCSK9 and how they regulate LDLR degradation. MethodsX-ray diffraction of the CHRD-P1.40 complex was analyzed with a 2.2 Å resolution. The affinity and interaction of PCSK9 or CHRD with P1.40 or CAP1 was analyzed by atomic modeling, site-directed mutagenesis, bio-layer interferometry, expression in hepatic cell lines and immunocytochemistry to monitor LDLR degradation. The CHRD-P1.40 interaction was further analyzed by deep mutational scanning and binding assays to validate the role of predicted critical residues. Conformational changes and atomic models were obtained by small angle X-ray scattering (SAXS). ResultsWe demonstrate that PCSK9 exists in a closed or open conformation and that P1.40 favors the latter by binding key residues in the M1 and M3 subdomains of the CHRD. Our data show that CAP1 is well secreted by hepatic cells and binds extracellular PCSK9 at distinct residues in the M1 and M3 modules and in the acidic prodomain. CAP1 stabilizes the closed conformation of PCSK9 and prevents P1.40 binding. However, CAP1 siRNA only partially inhibited PCSK9 activity on the LDLR. By modeling the previously reported interaction between M2 and an R-X-E motif in HLA-C, we identified Glu567 and Arg549 as critical M2 residues binding HLA-C. Amazingly, these two residues are also required for the PCSK9-induced LDLR degradation. ConclusionsThe present study reveals that CAP1 enhances the function of PCSK9, likely by twisting the protein into a closed configuration that exposes the M2 subdomain needed for targeting the PCSK9-LDLR complex to degradation compartments. We hypothesize that “protein X”, which is expected to guide the LDLR-PCSK9-CAP1 complex to these compartments after endocytosis into clathrin-coated vesicles, is HLA-C or a similar MHC-I family member. This conclusion is supported by the PCSK9 natural loss-of-function Q554E and gain-of-function H553R M2 variants, whose consequences are anticipated by our modeling.

High fiber diet attenuate the inflammation and adverse remodeling of myocardial infarction via modulation of gut microbiota and metabolites.

High intake of dietary fiber is associated with lower incidence of cardiovascular diseases. Dietary fiber, functions as a prebiotic, has a significant impact on intestinal bacteria composition and diversity. The intestinal flora and metabolites generated by fermentation of dietary fiber not only affect the health of intestine but also play a role in many extra-intestinal diseases, such as obesity, diabetes and atherosclerosis. However, the role and the mechanism by which a high fiber diet contributes to the development of myocardial infarction is still unclear. Here we used an in vivo mouse model to investigate whether dietary fiber intake could protect against myocardial infarction. Our study demonstrated high fiber diet significantly improved cardiac function, reduced infarct size and prevented adverse remodeling following myocardial infarction. The protective effects of high fiber diet had a strong relation with its attenuation of inflammation. Moreover, we observed that high fiber diet could modulate the composition of intestinal flora and differentially impacted metabolites production, including the biosynthesis of bile acids and linoleic acid metabolism. Overall, the findings of this study provided mechanistic insights into the curative effect of dietary fiber on myocardial infarction with a specific emphasis on the potential role of microbiota-metabolism-immunity interactions.

Egg Consumption, Cardiovascular Disease and Cardiometabolic Risk Factors: The Interaction with Saturated Fatty Acids. Results from the ATTICA Cohort Study (2002-2012).

Purpose: To examine the association of egg intake with 10-year risk of cardiovascular disease (CVD) and other cardiometabolic risk factors in a sample of individuals of Mediterranean origin. Methods: In 2001−2002, n = 1514 men and n = 1528 women (>18 years old) from the greater Athens area, Greece, were enrolled. Information on any egg intake, eaten as a whole, partly or in recipes was assessed via a validated semi-quantitative food frequency questionnaire. Follow-up for CVD evaluation (2011−2012) was achieved in n = 2020 participants (n = 317 CVD cases). Results: Ranking from lowest (<1 serving/week) to intermediate (1−4 servings/week) and high (4−7 servings/week) egg consumption tertiles, lower CVD incidence was observed (18%, 9% and 8%, respectively, p-for-trend = 0.004). Unadjusted analysis revealed that 1−3 eggs/week and 4−7 eggs/week were associated with a 60% and 75%, respectively, lower risk of developing CVD compared with the reference group (<1 egg/week). When adjusting for sociodemographic, lifestyle and clinical factors, significance was retained only for 1−3 eggs/week (hazard ratio (HR) = 0.53, 95% confidence interval (95% CI) = 0.28, 1.00). When total saturated fatty acid (SFA) intake was taken into account, this inverse association was non-significant. Multi-adjusted analysis revealed that in participants of low SFA intake, 1 serving/day increase in egg intake resulted in 45% lower risk of developing CVD. In the case of higher SFA consumption, only 1−3 eggs/week seemed to protect against CVD (HR = 0.25, 95% CI = 0.07, 0.86). In the case of intermediate cardiometabolic disorders, no significant trend was observed. Conclusions: Overall dietary habits principally in terms of SFA intake may be detrimental to define the role of eggs in cardiac health.

Long-Term Alcohol Consumption Caused a Significant Decrease in Serum High-Density Lipoprotein (HDL)-Cholesterol and Apolipoprotein A-I with the Atherogenic Changes of HDL in Middle-Aged Korean Women.

Light-to-moderate alcohol drinking is associated with a low incidence of cardiovascular disease (CVD) via an elevation of high-density lipoproteins-cholesterol (HDL-C), particularly with the short-term supplementation of alcohol. However, there is no information on the change in the HDL qualities and functionalities between non-drinkers and mild drinkers in the long-term consumption of alcohol. This study analyzed the lipid and lipoprotein profiles of middle-aged Korean female non-drinkers, mild-drinkers, and binge-drinkers, who consumed alcohol for at least 10 years. Unexpectedly, the serum levels of HDL-C and apolipoprotein A-I (apoA-I) were decreased significantly depending on the alcohol amount; the binge-drinker group showed 18% and 13% lower HDL-C (p = 0.011) and apoA-I levels (p = 0.024), respectively, than the non-drinker group. Triglyceride (TG) and oxidized species, malondialdehyde (MDA), and low-density lipoproteins (LDL) levels were significantly elevated in the drinker groups. Interestingly, the binge-drinker group showed 1.4-fold higher (p = 0.020) cholesterol contents in HDL2 and 1.7-fold higher (p < 0.001) TG contents in HDL3 than those of the non-drinker group. The mild-drinker group also showed higher TG contents in HDL3 (p = 0.032) than the non-drinker group, while cholesterol contents were similar in the HDL3 of all groups. Transmission electron microscopy (TEM) showed that the non-drinker group showed a more distinct and clear particle shape of the LDL and HDL image with a larger particle size than the drinker group. Electrophoresis of LDL showed that the drinker group had faster electromobility with a higher smear band intensity and aggregation in the loading position than the non-drinker group. The HDL level of binge drinkers showed the lowest paraoxonase activity, the highest glycated extent, and the most smear band intensity of HDL and apoA-I, indicating that HDL quality and functionality were impaired by alcohol consumption. In conclusion, long-term alcohol consumption in middle-aged women, even in small amounts, caused a significant decrease in the serum HDL-C and apoA-I with atherogenic changes in LDL and HDL, such as an increase in TG and MDA content with a loss of paraoxonase activity.

Cardiovascular complications of Cushings syndrome: Impact on morbidity and mortality.

Cardiovascular complications of Cushings syndrome: Impact on morbidity and mortality.

Obesity-Related Chronic Kidney Disease: Principal Mechanisms and New Approaches in Nutritional Management.

Obesity is the epidemic of our era and its incidence is supposed to increase by more than 30% by 2030. It is commonly defined as a chronic and metabolic disease with an excessive accumulation of body fat in relation to fat-free mass, both in terms of quantity and distribution at specific points on the body. The effects of obesity have an important impact on different clinical areas, particularly endocrinology, cardiology, and nephrology. Indeed, increased rates of obesity have been associated with increased risk of cardiovascular disease (CVD), cancer, type 2 diabetes (T2D), dyslipidemia, hypertension, renal diseases, and neurocognitive impairment. Obesity-related chronic kidney disease (CKD) has been ascribed to intrarenal fat accumulation along the proximal tubule, glomeruli, renal sinus, and around the kidney capsule, and to hemodynamic changes with hyperfiltration, albuminuria, and impaired glomerular filtration rate. In addition, hypertension, dyslipidemia, and diabetes, which arise as a consequence of overweight, contribute to amplifying renal dysfunction in both the native and transplanted kidney. Overall, several mechanisms are closely related to the onset and progression of CKD in the general population, including changes in renal hemodynamics, neurohumoral pathways, renal adiposity, local and systemic inflammation, dysbiosis of microbiota, insulin resistance, and fibrotic process. Unfortunately, there are no clinical practice guidelines for the management of patients with obesity-related CKD. Therefore, dietary management is based on the clinical practice guidelines for the nutritional care of adults with CKD, developed and published by the National Kidney Foundation, Kidney Disease Outcome Quality Initiative and common recommendations for the healthy population. Optimal nutritional management of these patients should follow the guidelines of the Mediterranean diet, which is known to be associated with a lower incidence of CVD and beneficial effects on chronic diseases such as diabetes, obesity, and cognitive health. Mediterranean-style diets are often unsuccessful in promoting efficient weight loss, especially in patients with altered glucose metabolism. For this purpose, this review also discusses the use of non-classical weight loss approaches in CKD, including intermittent fasting and ketogenic diet to contrast the onset and progression of obesity-related CKD.

Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults

Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date. To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD). At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed. Total fiber intake and sources of fiber (cereal, vegetable, and fruit). Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis. Of 4125 individuals, 0.1% (n = 3) were Asian or Pacific Islander, 4.4% (n = 183) were Black, 0.3% (n = 12) were Native American, 95.0% (n = 3918) were White, and 0.2% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4%]; and 3942 individuals of other races and ethnicitites [95.6%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5% for interleukin 18 to 14.2% for C-reactive protein, and 16.1% for their primary principal component. Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.