Graduate Student University of California Davis School of Veterinary Medicine Davis, California, United States
Abstract: Background - Therapies to treat and prevent feline hypertrophic cardiomyopathy (HCM) are lacking. The mammalian target of rapamycin (mTOR) is a master regulator of cell growth, metabolism, and protein synthesis, and represents a therapeutic target for HCM. A recent clinical trial demonstrated that mTOR inhibition via chronic delayed-release (DR) rapamycin administration halts progression of left ventricular wall thickness with no adverse events or clinical pathology derangements, however, molecular effects of rapamycin in cats with HCM remain unknown.
Hypothesis/Objectives - This study aimed to characterize the multiomic effects of weekly low- and high-dose, oral, DR rapamycin in HCM-affected colony cats via RNA-sequencing and proteomic profiling. We further aimed to assess clinicopathologic, cardiac biomarker, and histopathologic responses to therapy.
Animals - Twelve purpose-bred cats were studied (3 low-dose HCM+, 3 high-dose HCM+, 3 untreated HCM+, and 3 untreated control).
Methods - Plasma and urine samples were obtained at day 0 and 56 of DR rapamycin dosing. Tissue samples (left ventricular posterior wall and interventricular septum) were obtained at necropsy on day 60. RNA-sequencing was performed on all tissues and LC-MS profiling was performed on day 0 and 56 plasma and urine and day 60 tissues.
Results - Differential transcript and relative protein expression analyses revealed intrinsic molecular effects between and within treatment groups with no safety or tolerability concerns identified via clinical pathology.
Conclusions and clinical importance - Results highlight pathways impacted in HCM-affected cats receiving oral DR rapamycin and provide key insights into multiomic differences observed in disease.
