Characterization of a mouse model of obesity-related fibrotic cardiomyopathy that recapitulates features of human heart failure with preserved ejection fraction

Abstract

<p class="first" id="d851310e152">Heart failure with preserved ejection fraction (HFpEF) is caused, or exacerbated by, a wide range of extracardiac conditions. Diabetes, obesity, and metabolic dysfunction are associated with a unique HFpEF phenotype, characterized by inflammation, cardiac fibrosis, and microvascular dysfunction. Development of new therapies for HFpEF is hampered by the absence of reliable animal models. The leptin-resistant <i>db</i>/ <i>db</i> mouse has been extensively studied as a model of diabetes-associated cardiomyopathy; however, data on the functional and morphological alterations in <i>db</i>/ <i>db</i> hearts are conflicting. In the present study, we report a systematic characterization of the cardiac phenotype in <i>db</i>/ <i>db</i> mice, focusing on the time course of functional and histopathological alterations and on the identification of sex-specific cellular events. Although both male and female <i>db</i>/ <i>db</i> mice developed severe obesity, increased adiposity, and hyperglycemia, female mice had more impressive weight gain and exhibited a modest but significant increase in blood pressure. <i>db</i>/ <i>db</i> mice had hypertrophic ventricular remodeling and diastolic dysfunction with preserved ejection fraction; the increase in left ventricular mass was accentuated in female mice. Histological analysis showed that both male and female <i>db</i>/ <i>db</i> mice had cardiomyocyte hypertrophy and interstitial fibrosis, associated with marked thickening of the perimysial collagen, and expansion of the periarteriolar collagen network, in the absence of replacement fibrosis. In vivo and in vitro experiments showed that fibrotic changes in <i>db</i>/ <i>db</i> hearts were associated with increased collagen synthesis by cardiac fibroblasts, in the absence of periostin, α-smooth muscle actin, or fibroblast activation protein overexpression. Male <i>db</i>/ <i>db</i> mice exhibited microvascular rarefaction. In conclusion, the <i>db</i>/ <i>db</i> mouse model recapitulates functional and histological features of human HFpEF associated with metabolic dysfunction. Development of fibrosis in <i>db</i>/ <i>db</i> hearts, in the absence of myofibroblast conversion, suggests that metabolic dysfunction may activate an alternative profibrotic pathway associated with accentuated extracellular matrix protein synthesis. </p><p id="d851310e217"> <b>NEW &amp; NOTEWORTHY</b> We provide a systematic analysis of the sex-specific functional and structural myocardial alterations in <i>db</i>/ <i>db</i> mice. Obese diabetic C57BL6J <i>db</i>/ <i>db</i> mice exhibit diastolic dysfunction with preserved ejection fraction, associated with cardiomyocyte hypertrophy, interstitial/perivascular fibrosis, and microvascular rarefaction, thus recapitulating aspects of human obesity-related heart failure with preserved ejection fraction. Myocardial fibrosis in <i>db</i>/ <i>db</i> mice is associated with a matrix-producing fibroblast phenotype, in the absence of myofibroblast conversion, suggesting an alternative mechanism of activation. </p>