Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study

SIMPLE SUMMARY: Hypertrophic cardiomyopathy (HCM) is the single most common cardiomyopathy in cats with no available therapeutic options in the asymptomatic period of the disease. The mechanisms by which rapamycin may exert effects at the level of the heart muscle remains elusive. This pilot study investigates the effects of oral intermittent low-dose rapamycin in HCM-affected cats at the level of the heart muscle, plasma, and urine. Treatment with rapamycin remains well tolerated in HCM-affected cats with no adverse events. Anti-inflammatory effects of rapamycin treatment in cardiac tissues were observed. Dose-responsive effects of rapamycin on autophagy were identified. Changes in the abundance of metabolic protein in tissue and plasma were observed. Rapamycin leads to an underabundance of complement and coagulation cascade proteins. Minimal effects on fat and cholesterol metabolism, lipid, neuron projection, and blood microparticle proteins were observed in the plasma and urine samples of cats pre- and post-treatment with rapamycin. Taken altogether, rapamycin treatment continues to show great mechanistic promise in addressing the pathophysiologic features of HCM as well as the possible disease sequalae of thromboembolism. ABSTRACT: Hypertrophic cardiomyopathy (HCM) remains the single most common cardiomyopathy in cats, with a staggering prevalence as high as 15%. To date, little to no direct therapeutical intervention for HCM exists for veterinary patients. A previous study aimed to evaluate the effects of delayed-release (DR) rapamycin dosing in a client-owned population of subclinical, non-obstructive, HCM-affected cats and reported that the drug was well tolerated and resulted in beneficial LV remodeling. However, the precise effects of rapamycin in the hypertrophied myocardium remain unknown. Using a feline research colony with naturally occurring hereditary HCM (n = 9), we embarked on the first-ever pilot study to examine the tissue-, urine-, and plasma-level proteomic and tissue-level transcriptomic effects of an intermittent low dose (0.15 mg/kg) and high dose (0.30 mg/kg) of DR oral rapamycin once weekly. Rapamycin remained safe and well tolerated in cats receiving both doses for eight weeks. Following repeated weekly dosing, transcriptomic differences between the low- and high-dose groups support dose-responsive suppressive effects on myocardial hypertrophy and stimulatory effects on autophagy. Differences in the myocardial proteome between treated and control cats suggest potential anti-coagulant/-thrombotic, cellular remodeling, and metabolic effects of the drug. The results of this study closely recapitulate what is observed in the human literature, and the use of rapamycin in the clinical setting as the first therapeutic agent with disease-modifying effects on HCM remains promising. The results of this study establish the need for future validation efforts that investigate the fine-scale relationship between rapamycin treatment and the most compelling gene expression and protein abundance differences reported here.