Cardiac reverse remodeling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.

Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for patients with HFpEF. Using a two-hit HfpEF murine model, we studied cardiac reverse remodeling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-mo-old male and female C57Bl6/J mice the heart's response to angiotensin II (ANG II; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, ANG II and/or the HFD were stopped, and VE was started for an additional 4 wk. ANG II and ANG II + HFD (metabolic-hypertensive stress, MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodeling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodeling in female mice only. CH and LV concentric remodeling were reversed 4 wk after stopping ANG II, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared with controls. In the RR group, compared with MHS animals, 60% of the DEGs were downregulated. In an HfpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodeling.NEW & NOTEWORTHY Using a two-hit murine model of heart failure with preserved ejection fraction (HfpEF), combining elevated blood pressure, obesity, and exercise intolerance in male and female animals, we showed that correction of hypertension, normalization of the diet, and introduction of voluntary exercise could help reverse the remodeling of the left ventricle and double exercise capacity. We also identify genes that escape normalization after myocardial recovery and differences between males' and females' responses to stress and recovery.

Age and sex hormones modulate left ventricle regional response to angiotensin II in male and female mice.

Age, hypertension, and the female sex are among the risk factors in the development of heart failure with preserved ejection fraction. We studied by standard and speckle-tracking echocardiography (STE), the response of the left ventricle (LV) to aging and angiotensin II continuous infusion (ANG II; 1.5 mg/kg/day for 28 days) in 2- and 12-mo-old male and female C57Bl6/J mice. We also investigated the effects of the loss of sex steroids by gonadectomy (GDX). To do so, we used STE data from 48 points or regions of interest (ROIs) around the LV endocardium from B-mode images and generated profiles of maximal strain, strain rate (SR), and reverse SR for each experimental group of mice. In young mice, LV strain, strain rate (SR), and reverse SR profile levels were higher in females than in males. Aging was characterized by concentric LV remodeling and a decrease of strain, SR, and reverse SR. GDX at 6 wk of age slowed normal cardiac growth in male mice. In females, GDX reduced LV strain, SR, and reverse SR but did not influence cardiac growth. ANG II caused similar levels of hypertrophy in young and older mice. In young mice, ANG II had little effect on STE parameters, whereas in older animals, strain, SR, and reverse SR were reduced, mainly for the LV posterior wall. In older GDX mice, hypertrophic response to ANG II was decreased compared with intact animals. Generating detailed STE profile for the LV wall can help detect differences linked to sex, age, or a stressor better than global strain measurements.NEW & NOTEWORTHY We propose a new method for the study of regional strain data by analyzing individually the software-generated 48 regions of interest (ROI) from an LV wall tracing in B-mode. This helps obtain a more comprehensive profile of strain data. Using these new tools, we studied in mice how sex, sex hormones, age, or a pathological stress influenced strain parameters. We show that for similar cardiac hypertrophy, regional strain shows important differences related to sex, sex hormones, and age.