Earlier onset of diabesity‐Induced adverse cardiac remodeling in female compared to male mice

Bowden, Marissa A; Tesch, Gregory H; Julius, Tracey L; Rosli, Sarah; Love, Jane E; Ritchie, Rebecca H

doi:10.1002/oby.21072

Cited by 21 publications

(23 citation statements)

References 41 publications

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“…In exploratory analyses, we found complex sex- and race-based heterogeneity in cardiac structural associations with pericardial fat, including greater hypertrophy and concentric LV remodeling in females, and a non-linear relationship between pericardial fat and LV function in African Americans. While these observations arise from secondary analyses and require confirmation in larger, emerging multi-ethnic cohorts worldwide, they are concordant with prior laboratory and clinical research: in animal models of obesity and diabetes, cardiac remodeling is observed early in the pathogenesis of obesity/diabetes 41 , and HF with preserved LV ejection fraction risk is higher specifically in older, obese women 42 . Furthermore, African-Americans harbor a disproportionate risk of subclinical LV dysfunction 43 and higher CVD-related mortality 44 .…”

Section: Discussionsupporting

confidence: 71%

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure

Shah

Anderson

Ding

et al. 2017

JACC: Cardiovascular Imaging

129

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Objectives To determine the associations between local (pericardial) fat and incident CV disease (CVD) events and cardiac remodeling independent of markers of overall adiposity. Background The impact of pericardial fat—a local fat depot encasing the heart—on myocardial function and long-term cardiovascular (CV) prognosis independent of systemic consequences of adiposity or hepatic fat is an area of active debate. Methods We studied 4,234 participants enrolled in the Multi-Ethnic Study of Atherosclerosis with concomitant cardiac magnetic resonance (CMR) imaging and computed tomographic (CT) measurements for pericardial fat volume and hepatic attenuation (a measure of liver fat). Poisson and Cox regression were used to estimate the annualized risk of incident hard atherosclerotic CVD (ASCVD), all-cause death, heart failure, all-cause CVD, hard CHD and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between CMR indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates. Results MESA participants with higher pericardial and hepatic fat were more likely to be older, more frequently male, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipdemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (IQR 11.6–12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio [SHR] 1.22, 95% confidence interval [CI] 1.10–1.35, P=0.0001; hepatic fat by CT was not significantly associated with hard ASCVD (SHR 0.96, 95% CI 0.86–1.08, P=0.52). Higher pericardial fat was associated with greater indexed LV mass (37.8 vs. 33.9 g/m2.7, highest vs. lowest quartile, P<0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest vs. lowest quartile, P<0.01). In adjusted models, a higher pericardial fat volume was associated with greater LV mass (P<0.0001) and concentricity (P<0.0001). Conclusion Pericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation and CT measures of hepatic fat.

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Section: Discussionsupporting

confidence: 71%

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure

Shah

Anderson

Ding

et al. 2017

JACC: Cardiovascular Imaging

129

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“…However, diabetes induced cardiac remodeling in mice was increased in females at an earlier stage than in males. This was measured by prohypertrophic and prooxidant gene expression as well as cardiomyocyte size ( 287 ).…”

Section: Cardiovascular Complicationsmentioning

confidence: 99%

Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus

2016

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The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

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“…Db/db mouse is a model of T2DM with leptin receptor insensitivity characterized by significant obesity, fasting hyperglycemia, hyperinsulinemia, and insulin resistance. It also develops changes in cardiac structure and function similar to those in T2DM patients . Recent studies have confirmed that functional and morphological alterations in db/db hearts are consistent with DCM …”

Section: Introductionmentioning

confidence: 74%

“…It also develops changes in cardiac structure and function similar to those in T2DM patients. 16 Recent studies have confirmed that functional and morphological alterations in db/db hearts are consistent with DCM. 17,18 In this study, we aimed to investigate the association of GRK2 with early DCM by estimating the expression of GRKs both in the myocardium of diabetic mice and in the PBMCs of patients with early DCM.…”

Section: Introductionmentioning

confidence: 91%

G protein‐coupled receptor kinase‐2: A potential biomarker for early diabetic cardiomyopathy

Lai

Yang

et al. 2019

Journal of Diabetes

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Background G protein‐coupled receptor kinase‐2 (GRK2) has been shown as a key regulator of cardiac function, and the myocardial GRK2 levels are mirrored by the levels in peripheral blood mononuclear cells (PBMCs). In this study, we evaluated the myocardial and PBMCs GRK2 levels in early diabetic cardiomyopathy (DCM). Methods C57BL/KS‐db/db male diabetic mice at 12 weeks of age, as the type 2 diabetes (T2DM) animal model of early DCM were evaluated. Forty‐four T2DM patients with left ventricular diastolic dysfunction (LVDD), without evidence of hypertension, coronary artery diseases, congestive heart failure, and diabetic complications and without evidence of ischemia in a maximal treadmill exercise test, were recruited as the DM + LVDD group; 30 age‐matched T2DM patients without LVDD were recruited as the DM control group. Left ventricular diastolic function was evaluated by cardiac tissue Doppler. The pseudonormal pattern of ventricular filling and E′/A′ < 1 were regarded as LVDD. Results Compared to 8‐week‐old diabetic mice and 12‐week‐old control mice, GRK2‐mRNA level and expression in myocardial tissues of 12‐week‐old diabetic mice were significantly increased, as well as the left ventricular wall thickness and systolic function. And the collagen volume fraction (CVF), collagen‐3 expression, P53 expression, and cell apoptotic rate in the myocardium of 12‐week‐old diabetic mice elevated as well. The GRK2‐mRNA level in PBMCs of DM with LVDD was significantly higher than in DM control without LVDD. Conclusions GRK2 expression increased in the myocardial tissue and the PBMCs at the early stage of DCM. These data support further research on the role of GRK2 as the clinical biomarker for early DCM.

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Earlier onset of diabesity‐Induced adverse cardiac remodeling in female compared to male mice

Cited by 21 publications

References 41 publications

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure

Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus

G protein‐coupled receptor kinase‐2: A potential biomarker for early diabetic cardiomyopathy

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