Rapamycin Use in Feline Hypertrophic Cardiomyopathy
Sponsored by PRN® Pharmacal
In the Literature
Kaplan JL, Rivas VN, Walker AL, et al. Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial. J Am Vet Med Assoc. 2023;261(11):1628-1637. doi:10.2460/javma.23.04.0187
The Research …
Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats, with an estimated prevalence of ≈15%.1 This condition causes progressive and irreversible thickening of the left ventricle in the absence of other heart disease or hormonal stimuli (eg, hyperthyroidism). Although some cats with HCM will remain subclinical, others will experience severe outcomes. These outcomes, which include left-sided congestive heart failure (CHF), arterial thromboembolism (ATE), and sudden death,2 make HCM a significant health threat in affected cats.
Rapamycin, also known as sirolimus, is being explored as a therapeutic strategy for targeting cardiac hypertrophy due to its ability to modulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In rodent models of heart disease, rapamycin has been shown to prevent and reverse cardiac hypertrophy. In addition, its use in human renal allograft patients is associated with reduced cardiac wall thickness.
This study assessed the effect of rapamycin on feline HCM. Forty-three client-owned cats were enrolled in a randomized, double-blinded, placebo-controlled clinical trial, with 36 cats completing all follow-up visits. All study participants had echocardiographic evidence of subclinical HCM in the absence of severe left ventricular (LV) outflow tract obstruction, systemic hypertension, endocrine disease, renal dysfunction, anemia, CHF, ATE, arrhythmias and other congenital/acquired cardiac diseases. Study participants were assigned to receive placebo; low-dose (0.3 mg/kg), delayed-release (DR) rapamycin; or high-dose (0.6 mg/kg) DR rapamycin by mouth once weekly. Cats were evaluated at 60, 120, and 180 days of treatment, with echocardiography performed at days 60 and 180.
In this study, once-weekly, low-dose (0.3 mg/kg) DR rapamycin altered the progression of maximum LV wall thickness over the 6-month treatment period. In the placebo group, maximum LV wall thickness increased from 7.99 mm to 8.77 mm. In cats receiving DR rapamycin, however, maximum LV wall thickness remained relatively constant or even decreased. Cats receiving low-dose rapamycin experienced a decrease in maximum LV wall thickness from 7.44 mm to 7.32 mm, and cats receiving high-dose rapamycin experienced a small increase from 7.5 mm to 7.66 mm. These results suggest that a low-dose DR formulation of rapamycin may effectively prevent or delay progression of hypertrophy in cats with subclinical HCM. The study authors postulate that intermittent, low-dose rapamycin regimens can optimize LV remodeling benefits and limit side effects linked to mTORC2 inhibition seen with higher-dose protocols.
Adverse events occurred in both the rapamycin treatment groups and the placebo group. Although overall adverse event rates did not differ significantly between groups, numerically, more serious adverse events occurred in the high-dose rapamycin group than in the other 2 groups. A single obese cat in this study developed diabetes mellitus during treatment, which progressed to diabetic ketoacidosis, suggesting that caution is warranted when treating cats with risk factors for diabetes mellitus. All other severe adverse events were associated with progression of the cat’s HCM and not associated with treatment.
… The Takeaways
Key pearls to put into practice:
According to the results of this study, DR rapamycin (ie, sirolimus) at a dose of 0.3 mg/kg once weekly may prevent or delay the progression of left ventricular hypertrophy in cats with subclinical HCM.
Administration of weekly DR rapamycin was well-tolerated in most cats at both doses used in this study.
Rapamycin should be used with caution in cats with risk factors for diabetes mellitus.
Future studies are warranted to determine if benefits of rapamycin can increase lifespan, reduce complications of HCM, and increase quality of life as well as to evaluate the effects of rapamycin on cats with left ventricular outflow tract obstruction.
Felycin®-CA1 (sirolimus delayed-release tablets) has been conditionally approved by the FDA for the management of ventricular hypertrophy in cats with HCM. Conditional approval indicates that the drug has a proven record of safety and “reasonable expectation of effectiveness” while additional efficacy data is still being collected.3
