Excess Risk Of Cardiovascular Disease Research Articles

Abstract MP60: Prediabetes and Undiagnosed Diabetes Predisposing Women to Excess Risk of Cardiovascular Disease

Objective: Women with type 2 diabetes (T2DM) have a 25-50% higher risk of cardiovascular disease (CVD) than their men counterparts. The reasons for this sex disparity are incompletely understood. We sought to examine if pre-diabetes (preDM) and undiagnosed T2DM are associated with a greater magnitude of CVD risk in women than in men. Methods: We pooled CVD-free individuals (N=18,745) from the Atherosclerosis Risk in Communities, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. CVD outcomes included incident coronary heart disease (CHD) (myocardial infarction, CHD death, or cardiac procedures including percutaneous coronary interventions, bypass surgery, or coronary revascularization), stroke (ischemic or hemorrhagic stroke), and a composite atherosclerotic CVD (ASCVD) (any CHD condition or stroke). Multivariable Cox models examined the outcomes associated with preDM (fasting glucose [FG] 100-125 mg/dL or HbA1c 5.7-6.4%) or undiagnosed T2DM (FG ≥126 mg/dL or HbA1c ≥6.5% and without a DM diagnosis or anti-diabetes medication use) adjusted for age, race/ethnicity, education, BMI, blood pressure, total cholesterols, smoking, anti-hypertensive and lipid-lowering medications, and cohort indicator. An interaction term sex x preDM or undiagnosed DM was added to models to test the sex modifying effect. We consider p-interaction<0.2 as significant. Results: During a median follow-up of 17 years, the adjusted model showed that preDM was significantly associated with a higher risk of CHD (Hazard ratio 1.09, 95%CI 1.04-1.14), stroke (1.08, 1.04-1.13), and ASCVD (1.09, 1.04-1.14) in women, but not in men (1.04, 0.99-1.1 for CHD, 1.03, 0.98-1.08 for stroke, and 1.03, 0.98-1.09 for ASCVD, respectively). Undiagnosed T2DM was significantly associated with the risk of CHD (1.27, 1.16-1.4 in women and 1.17, 1.05-1.3 in men), stroke (1.32, 1.21-1.45 in women and 1.2, 1.09-1.32 in men), and ASCVD (1.27, 1.16-1.4 in women and 1.15, 1.03-1.29 in men) in both sexes but with more pronounced effect in women (P-interactions ≤0.11). In racial-stratified analysis, a higher magnitude of CVD risk associated with preDM or undiagnosed DM was also found in non-Hispanic (NH) white women and NH-black women than in their men counterparts. Conclusions: PreDM and undiagnosed DM predispose women to excess CVD risk, possibly due to women’s higher susceptibility to metabolic dysfunction at a lower glucose level and the prolonged unmanaged time for risk factors relative to men. T2DM screening and risk factor control should be enhanced in both sexes to reduce future CVD risk, particularly in women.

Abstract P162: Sex Differences in Cardiometabolic Biomarkers During Pre-Diabetes

Background: Diabetes (DM) diminishes female protection against cardiovascular disease (CVD). Women with DM face excess CVD risk than men partly due to women’s greater deterioration in risk factors before DM. In this study, we compared sex differences in biomarkers that reflect distinct pathophysiological pathways during the pre-diabetes (pre-DM) stage. Method: A cross-sectional analysis was performed based on pooled data from Atherosclerosis Risk in Communities Study and the Jackson Heart Study. We used multivariable linear regressions to examine the associations between sex and biomarkers (log-transformed) representative of inflammation, lipoprotein, adipokine, kidney function, cardiac injury/stress, and thrombosis, adjusted for age, race, and BMI, among CVD-free individuals with pre-DM. We validated the results in a sensitivity analysis, including those that eventually progressed into DM during the follow-up. We used the false discovery rate method to adjust multiple comparisons. Results: Among 5975 individuals with pre-DM, the mean age was 54.2 years, 2853 (48%) were women, and 2022 (34%) were non-Hispanic blacks. In the adjusted models, inflammatory biomarkers, including high-sensitivity c-reactive proteins (β coefficient 0.2, P=2.9 x 10 -9 ), fibrinogen (β 0.19, P=2.8E-12), and absolute lymphocyte (β 0.25, P=2.54 x 10 -7 ), and cardiac injury/stress biomarker, NT-proBNT (β 0.14, P=0.0002) were higher in women than men with pre-DM. Additionally, lipoprotein(a) (β 0.19, P=4.96 x 10 -13 ) and apolipoproteins A1 (β 0.61, P=2.81x 10 -120 ), and adipokines including leptin (β 1.1, P=2.62 x 10 -123 ) and adiponectin (β 0.56, P=1.94 x 10 -12 ) were all higher in women with pre-DM. In contrast, kidney function markers, albumin (β -0.24, P=2.79 x 10 -9 ) and creatinine (β -1.1, P=1x 10 -100 ), and thrombosis biomarker, homocysteine (β -0.5, P=9.09 x 10 -19 ) were higher in men with pre-DM than in their women counterparts. These sex differences remained generally unchanged among 2320 individuals that progressed into DM. Conclusion: Biomarkers differ significantly between sexes during the pre-DM state. The inflammatory, lipoprotein, adipokine, and cardiac stress biomarkers were higher in women with pre-DM, while kidney function and thrombosis biomarkers were higher in men with pre-DM. Future mechanistic studies are warranted to delineate pathophysiological pathways characterized by these biomarkers contributing to sex disparities of CVD risk in DM.

Abstract P523: Joint Improvement Scale of Loneliness and Traditional Risk Factor Control, and Incident Cardiovascular Disease in Diabetes Patients

Background: Emerging evidence has shown a higher rate of loneliness and social isolation among patients with diabetes, and loneliness and isolation has been associated with high risk of cardiovascular disease (CVD). Hypothesis: We investigated the extent to which the risks of CVDs could be lowered by improvement of loneliness and social isolation, individually or in conjunction with controlling traditional risk factors in diabetic patients. Methods: A total of 18,783 participants diagnosed with diabetes from the UK Biobank were included. A two-item scale and a three-item scale were used to assess the improvement of loneliness and isolation status, respectively. The degree of traditional risk-factor control was defined as the number of glycated hemoglobin (HbA1c), blood pressure (BP), low-density-lipoprotein cholesterol (LDL-C), smoking and microalbumin reaching the target range. Results: During a mean follow-up of 10.7 years, 3,129 incident total CVD events were documented, including 2,627 coronary heart disease (CHD) and 721 stroke. We found that each point increase in loneliness improvement scale was significantly associated with an 11% lower risk of CVD (HR, 95%CI, 0.89, 0.84-0.93) and a 12% lower risk of CHD (HR, 95%CI, 0.88, 0.83-0.93), but not with stroke. The improvement scale of social isolation was not associated with CVDs. Loneliness showed greater relative importance than lifestyle risk factors in preventing CVD among diabetic patients. We found a significant additive interaction between loneliness and the degree of traditional risk-factor control on the risk of CVDs ( P for additive interaction=0.002). Moreover, compared with non-diabetes controls, the diabetes-related excess CVD risk might be eliminated when three or more risk factors were controlled in non-lonely patients, but more than four are required in lonely patients. Conclusion: Among diabetes patients, improvement of loneliness is associated with a lower risk of CVD and shows an additive interaction with traditional risk factor control.

Association between coeliac disease and cardiovascular disease: prospective analysis of UK Biobank data

ObjectivesTo investigate whether people with coeliac disease are at increased risk of cardiovascular disease, including ischaemic heart disease, myocardial infarction, and stroke.DesignProspective analysis of a large cohort study.SettingUK Biobank database.Participants469...

OR02-5 Coronary Microvascular Dysfunction is Present Among Well-Treated Asymptomatic Persons with HIV, Similar to Those with Diabetes

Abstract Persons with HIV (PWH) who are well-treated on antiretroviral therapies (ART) have a 1.5-2.0 fold increased risk of cardiovascular disease (CVD) compared to persons without HIV (PWOH). A unique cardiovascular phenotype is seen in HIV such that traditional cardiovascular risk factors alone to do not account for this excess CVD risk. Coronary microvascular dysfunction may promote subendocardial ischemia and cardiomyocyte injury and provide a potential underlying mechanism for the atherosclerotic and myocardial disease prevalent in HIV. We assessed coronary microvascular function among those with HIV, comparing to those without HIV and with diabetes (DM). 39 PWH with no known history of CVD or DM, required to be on stable ART and virologically controlled (HIV viral load <200 copies/mL), underwent coronary 13N-ammonia PET/CT to evaluate coronary flow reserve (CFR)—a measure of microvascular dysfunction calculated by the ratio of peak coronary flow during regadenoson stress to rest. CFR was corrected using the rate pressure product, which integrates resting blood pressure and heart rate. A 0.1 unit reduction in CFR is associated with a 8% increase in hazard of CV events. Comparisons of CFR were made to PWOH from a database of higher risk clinical referrals who were matched approximately 2: 1 based on demographics and traditional risk factors and to those with diabetes and no known history of CVD recruited as part of a prior study evaluating CFR. Overall group comparisons for CFR were analyzed with the Wilcoxon/Kruskal-Wallis test, and if significant, the Mann-Whitney U test was employed for two-group comparisons. PWH(74% male, age 55±7years, BMI 32±6kg/m2, duration HIV 20±8years, duration ART 16±7years, CD4+ count 801±333cells/ul) were similar to PWOH(n=69, 74% male, age 55±8years, BMI 32±6kg/m2) and persons with DM(n=63, 63% male, age 55±8years, BMI 32±5kg/m2). CFR was significantly different among groups: PWOH 2.76(2.37,3.36), PWH 2.47(1.92,2.93), DM 2.31(1.98,2.84), overall P=.003. CFR was significantly reduced when comparing to PWH to PWOH(P=.02) as was DM to PWOH(P=.001) and did not differ when comparing PWH to DM(P=.68). Total cholesterol 182(168,205)mg/dL, LDL 108(77,127)mg/dL, triglycerides 159(88,219)mg/dL, and current tobacco use 23% were overall significantly higher among PWH (overall P<.03 for each comparison). Controlling for group status (PWH vs. PWOH) and either total cholesterol or current tobacco use, only group status remained significantly and independently related to CFR (group status P=.02 and .01, respectively). Subclinical coronary microvascular dysfunction is present among asymptomatic, chronically infected PWH on ART who demonstrate good immunological control. This study demonstrates for the first time CFR is reduced compared to higher risk PWOH and comparable to those with DM, regardless of traditional CVD risk factors, and further highlights well-treated HIV as a CVD-risk enhancing factor similar to diabetes. The implications of reduced CFR in HIV warrants further investigation. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Erectile dysfunction, phosphodiesterase-5 inhibitor use and risk of cardiovascular disease and mortality in people with diabetes: A systematic review and meta-analysis

BackgroundPhosphodiesterase-5 inhibitors (PDE5-Is), used in the management of erectile dysfunction (ED), have potential cardioprotective benefits. The impact of PDE5-Is on reducing adverse cardiovascular outcomes in patients with diabetes mellitus (DM) and ED is uncertain. Using a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs), we evaluated if (i) the association of PDE5-Is in people with ED and DM and their risk of cardiovascular disease (CVD) and mortality and (ii) ED confers an excess risk of CVD and mortality in patients with DM compared with no DM. MethodsStudies were identified from MEDLINE, Embase, the Cochrane Library, Web of Science citation search and search of bibliographies to April 2022. Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. ResultsEighteen unique studies reported on the cardiovascular impact of ED in patients with and without DM. In the general population, the RRs (95% CIs) of ED for composite CVD/MACE, all-cause mortality, CHD and stroke were 1.43 (1.31–1.55), 1.47 (1.31–1.65), 1.59 (1.39–1.82), and 1.34 (1.15–1.56), respectively. The respective estimates were 1.68 (1.15–2.45), 1.40 (0.90–2.18), 1.41 (1.24–1.61) and 1.32 (1.09–1.60) in the diabetes population. Interaction analyses suggested similar risk in both populations. Six studies reported the cardiovascular effects of PDE5-Is in people with ED and DM. Limited RCT data showed no significant differences in the risk of major adverse cardiac event (MACE), coronary heart disease (CHD) and all-cause mortality comparing PDE5-I use with non-use: RRs (95% CIs) of 3.47 (0.17–69.19), 1.31 (0.10–16.54) and 0.35 (0.12–1.05), respectively. ConclusionsED confers no excess risk of CVD and mortality in patients with DM compared with no DM. Limited and inadequately powered data shows no significant differences in the risk of adverse cardiovascular outcomes comparing use of PDE5-Is with non-use in patients with ED and DM.PROSPERO Registration: CRD42022324537

Abstract P021: Degree Of Risk Factor Control And Incident Cardiovascular Diseases In Patients With Hypertension

Introduction: Hypertensive patients have a higher risk of cardiovascular complications than non-hypertensive individuals. Hypothesis: We assessed the hypothesis that the joint risk factor control could attenuate hypertension-related excess risk of cardiovascular diseases (CVD) in hypertensive patients. Methods: We included 100368 participants with diagnosed hypertension from the UK Biobank, and matched them with 256875 controls, from 2006 to 2021. Hypertensive patients were categorized by the number of risk factors that met the recommended guideline: smoking, blood pressure, albuminuria, and low-density lipoprotein cholesterol. The Cox proportional hazards models were used to estimate associations between the degree of risk factor control and the risk of CVD. Results: Among hypertensive patients, each additional risk factor control was related to 14 to 21% lower risks of CVD events; and the group with optimal risk factor control was associated with the lowest risk (HR [95%CI], 0.59 [0.55-0.63] for CVD, 0.63 [0.58-0.69] for coronary heart disease, 0.43 [0.36-0.50] for stroke, and 0.53 [0.46-0.60] for heart failure). The hypertension-related excess risks of stroke and heart failure in those with optimal risk factor control were diminished to be not different from non-hypertensive controls. The protective associations of joint risk factor control and risks of CVD events were stronger among men than women (p for interaction < 0.001). Conclusions: Among hypertensive patients, the degree of risk factor control is inversely associated with risks of CVD events and optimal risk factor control may considerably attenuate or eliminate the hypertension-related excess risk.

Cardiovascular Disease in Adults with Type 1 Diabetes: Looking Beyond Glycemic Control.

Despite improvements in treatment, people with type 1 diabetes continue to have increased cardiovascular disease (CVD) risk. Glycemic control does not fully explain this excess CVD risk, so a greater understanding of other risk factors is needed. The authors review the relationship between glycemia and CVD risk in adults with type 1 diabetes and summarize evidence regarding other factors that may explain risk beyond glycemia. Insulin resistance, weight gain, sex differences, genetics, inflammation, emerging markers of risk, including lipid subclasses and epigenetic modifications, and future directions are discussed. As glycemic control improves, an increased focus on other CVD risk factors is warranted in type 1 diabetes. Novel markers and precision medicine approaches may improve CVD prediction, but a lack of type 1 diabetes-specific guidelines for lipids, blood pressure, and physical activity are likely impediments to optimal CVD prevention in this high-risk population.

Long-term risk of cardiovascular disease mortality among classic Hodgkin lymphoma survivors.

The temporal trend of cardiovascular disease (CVD) mortality in patients with classic Hodgkin lymphoma (cHL) throughout follow-up remains unclear. This study aimed to assess this temporal trend in patients with cHL. This multicenter cohort included 15,889 patients with cHL diagnosed between 1983 and 2015, covering all ages. The proportional mortality ratio, cumulative incidence of cause-specific mortality accounting for competing risk, standard mortality ratio, and absolute excess risk were analyzed. Among patients in stage I and stage II cHL, the proportional mortality ratio for CVD exceeded that for cHL, after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In recent decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even remained unchanged among some populations. Patients with stage I or stage II disease experienced a higher risk of CVD mortality than the general population in almost all follow-up intervals. The absolute excess CVD risk among patients in stage I reached 48.5. The risk of CVD mortality exceeded that of cHL and other neoplasms and became the leading cause of death over time, among patients with stage I or stage II disease. More effective measures should be taken to reduce the risk of CVD mortality. Among patients with stage I and stage II classic Hodgkin lymphoma (cHL), the proportional mortality ratio of cardiovascular disease (CVD) exceeded that of cHL after approximately 60 or 120 months of follow-up, respectively. For almost all the patients with stage I or stage II disease, the cumulative incidence of CVD mortality exceeded that of cHL and other neoplasms over time. In the past several decades, the risk of cHL mortality declined sharply, but the risk of CVD mortality among patients with cHL declined quite slowly or even unchanged among some populations. CVD exceeded cHL and has become the leading cause of death over time.

Diabesity phenotype and the risks of cardiovascular disease and subclinical atherosclerosis: A prospective cohort study.

The aim of this study was to investigate the associations of diabesity with incident cardiovascular disease (CVD) and subclinical atherosclerosis. The prospective cohort study included 8,006 participants without baseline CVD. Diabesity was categorized as (i) normal glucose tolerance (NGT) with nonobesity; (ii) NGT with obesity; (iii) prediabetes with nonobesity; (iv) prediabetes with obesity; (v) diabetes with nonobesity; and (vi) diabetes with obesity. The hazard ratios (HRs) for incident CVD and odds ratios (ORs) for subclinical atherosclerosis associated with diabesity categories were examined. Compared with the category of NGT with nonobesity, the categories of NGT with obesity (HR 1.68; 95% CI: 1.10-2.57), diabetes with nonobesity (HR 1.42; 95% CI: 1.08-1.88), and diabetes with obesity (HR 1.78; 95% CI: 1.24-2.55) were associated with higher risks of CVD. Prediabetes with or without obesity conferred no excess risk for CVD but higher risks for subclinical atherosclerosis. The diabetes with obesity category was associated with the highest risk for elevated pulse pressure (OR 3.07; 95% CI: 2.06-4.58) and albuminuria (OR 3.39; 95% CI: 2.31-4.99), and diabetes with or without obesity showed comparable ORs for elevated brachial-ankle pulse wave velocity. The association patterns between diabesity and CVD risks support the value of diabesity as a prevention target for CVD.

Specialist and Patient Perspectives on Strategies to Improve Cardiovascular Disease Prevention Among Persons Living with Psoriatic Disease.

Psoriasis is an immune-mediated disease associated with excess risk for cardiovascular disease (CVD). Guidelines recognize psoriasis as a CVD risk enhancer; however, psoriasis patients often do not have CVD risk factors identified nor managed. This study examines strategies to improve CVD prevention care from the perspective of dermatologists and patients with psoriasis. Qualitative interviews were conducted using the Consolidated Framework for Implementation Research to examine the perspectives of physicians (N = 16) and patients with psoriatic disease (N = 16) on barriers/facilitators to CVD prevention. Interviews were transcribed and coded using an integrated approach designed to enhance reliability and validity using NVivo software. We found three major themes suggesting areas to target for the future: (1) Appropriateness: perceptions of whether CVD care should be deployed in this setting by both clinicians and patients, (2) Feasibility: whether CVD prevention care could be integrated into the current structure of specialist practice, and (3) Care Coordination: an interest by all parties to better integrate a team approach in CVD preventative care to reduce duplicative efforts, work practically in an already existing system rather than reinventing the wheel, and progress with the patients' best interests in mind. These findings will inform the design of a clinical trial comparing the effectiveness of specialist clinician implementation of CVD guideline-based prevention care in patients with psoriasis. Ultimately, this study aims to increase the lifespan and health of patients living with psoriatic disease by decreasing barriers to their receiving appropriate CVD prevention care.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and Cardiovascular Risk in Patients With Rheumatoid Arthritis: A Cross-Sectional Study of Chinese Cohort.

BackgroundThe nomenclature from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) is considered to identify more cardiovascular disease (CVD) risks in the general population. Patients with rheumatoid arthritis (RA) carry an excess risk for CVD. However, the prevalence of MAFLD and its relationship with CVD risks in RA have not been reported.MethodsThis cross-sectional study retrospectively analyzed clinical data from a Chinese RA cohort. MAFLD was diagnosed according to the criteria proposed by an international expert panel from 22 countries in 2020. CVD risk in patients with RA was estimated by the Prediction for Atherosclerotic Cardiovascular Disease Risk in China with a 1.5 multiplication factor.ResultsAmong 513 included patients with RA, 78.4% were women and the mean ± SD age was 51.8 ± 12.6 years. The prevalence of MAFLD was 21.4%. There were 10.9% patients with RA concomitated with CVD events and 32.4% with a high-estimated 10-year CVD risk. Besides a higher liver fibrosis score and a higher ratio of advanced fibrosis, RA patients with MAFLD had a higher rate of CVD events (17.3 vs. 9.2%) and a higher proportion of high estimated 10-year CVD risk (55.5 vs. 26.1%) than those without. Multivariate logistic regression analysis showed that MAFLD was associated with an increase in CVD events [adjusted odds ratio (AOR) = 2.190, 95% CI 1.135–4.227] and high estimated 10-year CVD risk (AOR = 2.483, 95% CI 1.412–4.365, all p < 0.05).ConclusionMetabolic dysfunction-associated fatty liver disease was associated with increased CVD risk in patients with RA, which implies the importance of early detection and management of MAFLD in patients with RA.

Duration of diabetes and the risk of major cardiovascular events in women and men: A prospective cohort study of UK Biobank participants

AimsDiabetes has been associated with a greater excess risk of cardiovascular disease (CVD) in women than men. We investigated whether there are also sex differences in the association of diabetes duration and the risk of CVD. MethodsData were used from 18,961 (40% women) individuals with type 2 diabetes, without a history of CVD, in the UK Biobank. Sex-specific incidence rates were calculated by diabetes duration. Cox proportional hazards analyses estimated multiple-adjusted sex-specific hazard ratios (HR) and women-to-men ratio of HRs (RHR). ResultsOver a median follow-up of 11 years, 1,506 (29% women) CVD events were documented. Compared with men, women had lower multiple-adjusted incidence rates of CVD per 10,000 person-years for all categories of diabetes duration. Duration of diabetes was associated with an increased risk of CVD in both sexes. A 5-year increase in diabetes duration was associated with an approximately similar excess risk of about 20% for each of the three endpoints, in both sexes. Conclusions/InterpretationThe increased risk of CVD associated with longer duration of diabetes is similar in women and men, and thus cannot explain the higher excess risk from diabetes in women in this study population.

Sex Differences in Cardiovascular Prevention in Type 2: Diabetes in a Real-World Practice Database.

Women with type 2 diabetes mellitus (T2DM) have a 40% excess risk of cardiovascular diseases (CVD) compared to men due to the interaction between sex and gender factors in the development, risk, and outcomes of the disease. Our aim was to assess differences between women and men with T2DM in the management and degree of control of cardiovascular risk factors (CVRF). This was a matched cross-sectional study including 140,906 T2DM subjects without previous CVD and 39,186 T2DM subjects with prior CVD obtained from the System for the Development of Research in Primary Care (SIDIAP) database. The absolute and relative differences between means or proportions were calculated to assess sex differences. T2DM women without previous CVD showed higher levels of total cholesterol (12.13 mg/dL (0.31 mmol/L); 95% CI = 11.9–12.4) and low-density lipoprotein cholesterol (LDL-c; 5.50 mg/dL (0.14 mmol/L); 95% CI = 5.3–5.7) than men. The recommended LDL-c target was less frequently achieved by women as it was the simultaneous control of different CVRF. In secondary prevention, women showed higher levels of total cholesterol (16.89 mg/dL (0.44 mmol/L); 95% CI = 16.5–17.3), higher levels of LDL-c (8.42 mg/dL (0.22 mmol/L); 95% CI = 8.1–8.8), and higher levels of triglycerides (11.34 mg/dL (0.13 mmol/L); 95% CI = 10.3–12.4) despite similar rates of statin prescription. Recommended targets were less often achieved by women, especially LDL-c < 100 mg/dL (2.59 mmol/L). The composite control was 22% less frequent in women than men. In conclusion, there were substantial sex differences in CVRF management of people with diabetes, with women less likely than men to be on LDL-c target, mainly those in secondary prevention. This could be related to the treatment gap between genders.

Roles of Cardiometabolic Factors in Mediating the Causal Effect of Type 2 Diabetes on Cardiovascular Diseases: A Two-Step, Two-Sample Multivariable Mendelian Randomization Study.

ObjectiveThe objective of this study is to investigate the roles of cardiometabolic factors (including blood pressure, blood lipids, thyroid function, body mass, and insulin sensitivity) in mediating the causal effect of type 2 diabetes (T2DM) on cardiovascular disease (CVD) outcomes.DesignTwo-step, two-sample multivariable Mendelian randomization (MVMR) study.SettingInternational genome-wide association study (GWAS) consortia data.ExposureType 2 diabetes, blood pressure: systolic blood pressure (SBP), diastolic blood pressure (DBP); blood lipids: low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG); thyroid function: hyperthyroidism, hypothyroidism; body mass index (BMI), waist-hip-ratio (WHR), and insulin sensitivity.Main OutcomesCardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke.MethodsSummary-level data for exposures and main outcomes were extracted from GWAS consortia. We used two-sample MR to illustrate the causal effect of T2DM on CVD subtypes and regression-based MVMR to quantify the possible mediation effects of cardiometabolic factors on CVD.ResultsEach additional unit of log odds of T2DM increased 16% risk of CHD [odds ratio (OR): 1.16, 95% CI: 1.12–1.21], 15% risk of myocardial infarction (MI) (OR: 1.15, 95% CI: 1.10–1.20), and 10% risk of stroke (OR: 1.10, 95% CI: 1.06–1.13). In mediation analysis, SBP, DBP, and TG were found as main mediators, while the mediation effects of other cardiometabolic factors were not significant. The proportion of total effect of T2DM on CHD mediated by SBP, DBP, and TG was 16% (95% CI: 8–24%), 7% (95% CI: 1–13%) and 10% (95% CI: 2–18%), respectively. Mediation effect of SBP and DBP on MI and stroke, TG on MI was also prominent, while mediation effect of TG on stroke was not significant. The combined mediation effect of all the three mediators accounted for 29%, 26%, and 13% of the total effect of T2DM on CHD, MI, and stroke, respectively.ConclusionSystolic blood pressure, DBP, and TG mediate a substantial proportion of the causal effect of T2DM on CVD and thus interventions on these factors might reduce the considerable excess risk of CVD among patients with T2DM.

Interaction between smoking and diabetes in relation to subsequent risk of cardiovascular events

BackgroundWhether smoking modifies the associations of diabetes and risk factor management with subsequent risk of cardiovascular disease (CVD), and whether the smoking related CVD risk differs among people with and without diabetes are unclear. This study aimed to examine the associations and interactions of smoking, diabetes, and risk factor management in relation to incident CVD.MethodsThis nationwide, population-based, prospective cohort study of 20 communities from various geographic regions recruited adults aged 40 years or older during 2011–2012. The follow-up survey was conducted between 2014 and 2016. This study included 126,181 participants who were free from CVD at baseline.ResultsStudy participants included 19,397 current smokers (15.4%), 6,049 former smokers (4.8%), and 100,735 never smokers (79.8%). Mean (SD) age ranged from 55.8 (8.6) years to 60.7 (9.1) years. Compared with never smokers, heavy smokers exhibited a greater risk of CVD events among participants with diabetes (multivariable-adjusted hazard ratio [HR], 1.45; 95% CI, 1.17–1.78) than among participants without diabetes (HR, 1.20; 95% CI, 1.01–1.42; P for interaction = 0.006). Compared with participants without diabetes, participants with diabetes who were never smokers and had 5 or more controlled risk factors showed no significantly excess CVD risk (HR, 0.93; 95% CI, 0.71–1.22), but the cardiovascular benefits from risk factor management were counteracted among participants with diabetes who were current smokers (HR, 1.28; 95% CI, 0.77–2.14) or former smokers (HR, 1.22; 95% CI, 0.66–2.28).ConclusionsSmoking and diabetes interacted with each other in relation to increased risk of CVD events, and the beneficial effect of risk factor management on CVD risk among participants with diabetes was attenuated by current or former smoking.

The Association Between Multiparity and Adipokine Levels: The Multi-Ethnic Study of Atherosclerosis.

Background: Multiparity is a risk factor for cardiovascular disease (CVD). However, the mechanisms of this relationship are unknown. Adipokines may predispose multiparous women to certain cardiometabolic complications that can increase their risk of future CVD. Materials and Methods: We studied 973 female participants of the Multi-Ethnic Study of Atherosclerosis free of CVD, who had complete data on parity and adipokines measured at Examination 2 or 3 (randomly assigned). Parity was categorized as nulliparity, 1-2, 3-4, and ≥5 live births. Multivariable linear regression was used to evaluate the association of parity with leptin, resistin, and adiponectin levels. Results: The women had mean age of 65 ± 9 years. After adjustment for age, race/ethnicity, study site, education, menopause status, smoking, physical activity, use of hormone therapy, and waist circumference, a history of grand multiparity (≥5 live births) was associated with 11% higher resistin levels (95% confidence interval [CI] 0-23) and 3-4 live births was associated with 23% higher leptin levels (95% CI 7-42), compared with nulliparity. After adjustment for computed tomography-measured visceral fat, the association of 3-4 live births with leptin remained significant. There were no significant associations of parity with adipokines after further adjustment for additional CVD risk factors. Multigravidity (but not parity) was inversely associated with adiponectin levels. Conclusions: In a multiethnic cohort of women, greater parity was associated with resistin and leptin; however, this association was attenuated after accounting for CVD risk factors. Dysregulation of adipokines could contribute to the excess CVD risk associated with multiparity. Further studies are needed to determine whether adipokines independently mediate the relationship between multiparity and CVD. Clinical trials registration: The MESA cohort is registered at NCT00005487.

Sex-Related Differences in Cardiovascular Disease Risk Profile in Children and Adolescents with Type 1 Diabetes.

Cardiovascular disease (CVD) is the primary cause of higher and earlier morbidity and mortality in people with type 1 diabetes (T1D) compared to people without diabetes. In addition, women with T1D are at an even higher relative risk for CVD than men. However, the underlying pathophysiology is not well understood. Atherosclerotic changes are known to progress early in life among people with T1D, yet it is less clear when excess CVD risk begins in females with T1D. This review explores the prevalence of classical CVD risk factors (such as glycemic control, hypertension, dyslipidemia, obesity, albuminuria, smoking, diet, physical inactivity), as well as of novel biomarkers (such as chronic inflammation), in children and adolescents with T1D with particular regard to sex-related differences in risk profile. We also summarize gaps where further research and clearer clinical guidance are needed to better address this issue. Considering that girls with T1D might have a more adverse CVD risk profile than boys, the early identification of and sex-specific intervention in T1D would have the potential to reduce later CVD morbidity and excess mortality in females with T1D. To conclude, based on an extensive review of the existing literature, we found a clear difference between boys and girls with T1D in the presence of individual CVD risk factors as well as in overall CVD risk profiles; the girls were on the whole more impacted.

English

BACKGROUND Diabetes mellitus (DM) single-handedly accounts for 75 – 90 % of excess coronary artery disease (CAD) risk seen in persons suffering from it and it also enhances and amplifies the effects of other traditional cardiovascular risk factors. After adjusting for concomitant risk factors such as hypertension and hyperlipidemia, there still remains an excess risk for cardiovascular disease (CVD) in people with diabetics. In this study, we wanted to evaluate left ventricular (LV) systolic and diastolic dysfunction in normotensive diabetic patients. METHODS A cross sectional comparative study was performed from January 2016 to September 2017 on 50 diabetics and 50 age and sex matched healthy controls. Adult patients of both sexes with diabetes mellitus who are normotensive were included as cases. Patients with known heart disease, chronic kidney disease, thyroid disorders were excluded from the study. 2D transthoracic echocardiogram (ECHO) with M mode was used for assessing systolic and diastolic function. RESULTS Mean ejection fraction was lower in patients group (59.76) as compared to control group (64.74) with 8 % of cases with a value of&lt; 50 %. Fractional shortening was also lower in patients (29.14) compared to controls (34.86) with 12 % patients having a value of &lt; 25 %. E/A ratio was 1.12 in patients when compared to 1.36 in controls with 32 % of patients having value &lt; 1. Mean isovolumic relaxation time was 96.52 in patients when compared to 87.42 in controls with 24 % patients having value &gt; 100 msec. CONCLUSIONS Normotensive diabetics are prone to left ventricular dysfunction. Diastolic dysfunction is more common than systolic dysfunction. KEYWORDS Diabetes Mellitus, Systolic Dysfunction, Diastolic Dysfunction, Cardiovascular Disease

Associations of Hepatosteatosis With Cardiovascular Disease in HIV-Positive and HIV-Negative Patients: The Liverpool HIV-Heart Project.

Hepatosteatosis (HS) has been associated with cardiovascular disorders in the general population. We sought to investigate whether HS is a marker of cardiovascular disease (CVD) risk in HIV-positive individuals, given that metabolic syndrome is implicated in the increasing CVD burden in this population. To investigate the association of HS with CVD in HIV-positive and HIV-negative individuals. We analyzed computed tomography (CT) images of 1306 subjects of whom 209 (16%) were HIV-positive and 1097 (84%) HIV-negative. CVD was quantified by the presence of coronary calcification from both dedicated cardiac CT and nondedicated thorax CT. HS was diagnosed from CT data sets in those with noncontrast dedicated cardiac CT and those with venous phase liver CT using previously validated techniques. Previous liver ultrasound was also assessed for the presence of HS. The HIV-positive group had lower mean age (P < 0.005), higher proportions of male sex (P < 0.005), and more current smokers (P < 0.005). The HIV-negative group had higher proportions of hypertension (P < 0.005), type II diabetes (P = 0.032), dyslipidemia (P < 0.005), statin use (P = 0.008), and HS (P = 0.018). The prevalence of coronary calcification was not significantly different between the groups. Logistic regression (LR) demonstrated that in the HIV-positive group, increasing age [odds ratio (OR): 1.15, P < 0.005], male sex (OR 3.37, P = 0.022), and HS (OR 3.13, P = 0.005) were independently associated with CVD. In the HIV-negative group, increasing age (OR: 1.11, P < 0.005), male sex (OR 2.97, P < 0.005), current smoking (OR 1.96, P < 0.005), and dyslipidemia (OR 1.66, P = 0.03) were independently associated with CVD. Using a machine learning random forest algorithm to assess the variables of importance, the top 3 variables of importance in the HIV-positive group were age, HS, and male sex. In the HIV-negative group, the top 3 variables were age, hypertension and male sex. The LR models predicted CVD well, with the mean area under the receiver operator curve (AUC) for the HIV-positive and HIV-negative cohorts being 0.831 [95% confidence interval (CI): 0.713 to 0.928] and 0.786 (95% CI: 0.735 to 0.836), respectively. The random forest models outperformed LR models, with a mean AUC in HIV-positive and HIV-negative populations of 0.877 (95% CI: 0.775 to 0.959) and 0.828 (95% CI: 0.780 to 0.873) respectively, with differences between both methods being statistically significant. In contrast to the general population, HS is a strong and independent predictor of CVD in HIV-positive individuals. This suggests that metabolic dysfunction may be attributable to the excess CVD risk seen with these patient groups. Assessment of HS may help accurate quantification of CVD risk in HIV-positive patients.