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Sex differences in heart mitochondria regulate diastolic dysfunction.

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

SUBMITTER: Cao Y

PROVIDER: S-EPMC9253085 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Sex differences in heart mitochondria regulate diastolic dysfunction.

Cao Yang Y Vergnes Laurent L Wang Yu-Chen YC Pan Calvin C Chella Krishnan Karthickeyan K Moore Timothy M TM Rosa-Garrido Manuel M Kimball Todd H TH Zhou Zhiqiang Z Charugundla Sarada S Rau Christoph D CD Seldin Marcus M MM Wang Jessica J Wang Yibin Y Vondriska Thomas M TM Reue Karen K Lusis Aldons J AJ

Nature communications 20220704 1

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypoth ...[more]

PMID: 35787630

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Project description:BackgroundAlthough sex differences in cardiovascular diseases are recognised, including differences in incidence, clinical presentation, response to treatments, and outcomes, most of the practice guidelines are not sex-specific. Heart failure (HF) is a major public health challenge, with high health care expenditures, high prevalence, and poor clinical outcomes. The objective was to analyse the sex-specific association of socio-demographics, life-style factors and health characteristics with the prevalence of HF and diastolic left ventricular dysfunction (DLVD) in a cross-sectional population-based study.MethodsA random sample of 2001 65-84 year-olds underwent physical examination, laboratory measurements, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiography, and echocardiography. We selected the subjects with no missing values in covariates and echocardiographic parameters and performed a complete case analysis. Sex-specific multivariable logistic regression models were used to identify the factors associated with the prevalence of the diseases, multinomial logistic regression was used to investigate the factors associated to asymptomatic and symptomatic LVD, and spline curves to display the relationship between the conditions and both age and NT-proBNP.ResultsIn 857 men included, there were 66 cases of HF and 408 cases of DLVD (77% not reporting symptoms). In 819 women, there were 51 cases of HF and 382 of DLVD (79% not reporting symptoms). In men, the factors associated with prevalence of HF were age, ischemic heart disease (IHD), and suffering from three or more comorbid conditions. In women, the factors associated with HF were age, lifestyles (smoking and alcohol), BMI, hypertension, and atrial fibrillation. Age and diabetes were associated to asymptomatic DLVD in both genders. NT-proBNP levels were more strongly associated with HF in men than in women.ConclusionsThere were sex differences in the factors associated with HF. The results suggest that prevention policies should consider the sex-specific impact on cardiac function of modifiable cardiovascular risk factors.

Project description:Aldosterone infusion results in left ventricular hypertrophy (LVH) and hypertension and may involve profibrotic and proinflammatory mechanisms. In turn, hypertension is the major cause of diastolic heart failure (HF). Adiponectin, an adipose-derived plasma protein, exerts antiinflammatory and anti-hypertrophic effects and is implicated in the development of hypertension and systolic HF. We thus tested the hypothesis that hypoadiponectinemia in aldosterone-induced hypertension exacerbated cardiac remodeling and diastolic HF. Wild-type (WT) or adiponectin-deficient (APNKO) mice underwent saline or aldosterone infusion and uninephrectomy and were fed 1% salt water for 4 wk. Blood pressure was increased in aldosterone-infused WT (132 +/- 2 vs. 109 +/- 3 mm Hg; P < 0.01) and further augmented in APNKO mice (140 +/- 3 mm Hg; P < 0.05 vs. aldosterone-infused WT). LVH was increased in aldosterone-infused WT vs. WT mice (LV/body weight ratio, 4.8 +/- 0.2 vs. 4.1 +/- 0.2 mg/g) and further increased in aldosterone-infused APNKO mice (LV/body weight ratio, 6.0 +/- 0.4 mg/g). Left ventricular ejection fraction was not decreased in either aldosterone-infused WT or APNKO hearts. Pulmonary congestion however was worse in APNKO mice (P < 0.01). The ratio of early ventricular filling over late ventricular filling (E/A) and the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e'), measures of diastolic function, were increased in aldosterone-infused WT hearts and further increased in APNKO hearts (P < 0.05 for both). Renal function and cardiac fibrosis were no different between both aldosterone-infused groups. Aldosterone increased matrix metalloproteinase-2 expression in WT hearts (P < 0.05 vs. WT and P < 0.01 vs. APNKO). Myocardial atrial natriuretic peptide, interferon-gamma, and TNF-alpha expression were increased in aldosterone-infused WT hearts. Expression of these proteins was further increased in aldosterone-infused APNKO hearts. Therefore, hypoadiponectinemia in hypertension-induced diastolic HF exacerbates LVH, diastolic dysfunction, and diastolic HF. Whether or not adiponectin replacement prevents the progression to diastolic HF will warrant further study.

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Sex differences in heart mitochondria regulate diastolic dysfunction.

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Sex differences in heart mitochondria regulate diastolic dysfunction.

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