Investigating the Effects of High Intensity Exercise in a Preclinical Mouse Model of Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart condition. Features of adverse cardiac remodeling in HCM include reduced left ventricular (LV) size, enlarged left atria (LA) interstitial cardiac fibrosis, and impaired cardiac metabolism. Concomitant with the deleterious remodeling is reduced cardiorespiratory capacity (i.e., pVO2), an important prognostic factor associated with increased risk of heart failure (HF) and mortality in patients with HCM. Given the prevalence and health vulnerabilities for HCM patients, new approaches are needed to address disease progression.

The effects of exercise and alteration of metabolism in HCM remain unclear. Concerns about the impact of high intensity exercise (HIE) on the disease progression remain despite evidence to the contrary. Clinical studies involving HIE in HF and cardiovascular disease patients have demonstrated superior improvements in pVO2, positive cardiac remodeling, and reduced mortality. Evidence also implicates dysregulation of substrate utilization in the pathology of HCM hearts including fatty acid metabolism seen in other disease states including cardiac aging. Together, this raises questions whether HIE or altering metabolism in HCM can modify disease progression.

Our primary objective was to determine the effects of HIE on HCM. Using a transgenic cardiac troponin (cTnT-delta160E or TG) mouse model, we initially detected a phenotype that recapitulates HCM features in patients. TG mice demonstrated reduced pVO2, and other decrements in functional capacity. Through echocardiography, mice demonstrated left ventricular (LV) hypertrophy, reduced left ventricular end diastolic (LVED) volumes, hypercontractility, enlarged left atria (LA), and diastolic dysfunction. Our hypothesis was that HIE would improve pVO2 and attenuate and/or reverse adverse cardiac remodeling in TG mice.

We tested whether a translationally designed 6-week High Intensity Interval Training (HIIT) treadmill protocol would improve pVO2. Trained female TG and wildtype (nTG), as well as nTG male mice improved pVO2 following the intervention period. HIIT also led to improvements in rotarod acceleration and endurance capacity, highlighting the generalizability to different modalities that measure functional capacity. In parallel, we also designed a Rotarod HIIT (RotaHIIT) protocol as an alternative exercise training model that improves pVO2, and will be broadly applicable for a range of research investigations. Echocardiography did not reveal any exercise-provoked physiologic changes including LV hypertrophy or increased LVED. HIIT did not exacerbate any existing morphologic or functional abnormalities present in TG mice, nor did it worsen interstitial cardiac fibrosis. HIIT did increase percent lean mass in a subset of trained mice, which could be a contributing factor to improved pVO2. Together, our data demonstrate that HIIT improves pVO2 in a mouse model of HCM, without adverse events or worsening of disease pathology

In two separate studies, we evaluated the effects of two well established anti-aging pharmacologic treatments, Acarbose (ACA) and Rapamycin (RAP), on cardiac aging in a UM-HET3 mouse model. Cardiac aging shares pathologic features of HCM, including LV hypertrophy and impaired fatty acid metabolism. ACA treatment resulted in improved rotarod functional capacity, reduced cardiac hypertrophy, enrichment of peroxisomal proteins and reversed age-related cardiac lipid species (e.g., lysophosphtidylcholines and triaclyglycerides). RAP treatment also improved functional capacity and reduced cardiac hypertrophy but had lesser effects on lipid species. ACA or RAP treatment effects were largely consistent whether drug treatments were started in early or late in life, however, sex differences were observed in certain outcomes. These data support the significance of systemic manipulation of the metabolic milieu in cardiac disease conditions.