Using Rapamycin in cats with HCM – a cardiologists advice

Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial.

Kaplan J.L, Rivas V.N, Walker A.L, et al. J Am Vet Med Assoc. 2023;261(11):1628–1637.

Published 2023 Jul 26. doi:10.2460/javma.23.04.0187

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A controversial paper to kick things off – and understandably one of the most commonly asked-about studies at the moment, from vets and owners alike. With feline hypertrophic cardiomyopathy (HCM) affecting so many cats – often with devastating outcomes, the idea of a once-weekly drug that may reverse myocardial hypertrophy has generated huge excitement. Online forums and social media have already crowned rapamycin as a new “wonder drug” for feline HCM. But do we have the full picture? Is it truly as ‘risk free’ as some sources suggest? Let’s take a look.

What is rapamycin and how does it work?

Rapamycin (Sirolimus) is not new to medicine. It’s a macrolide inhibitor widely used in human renal transplant patients alongside other immunosuppressants, improving survival and reducing organ rejection rates. It binds to ‘targets of rapamycin’ (TOR), inhibiting DNA and protein synthesis, arresting the B-cell cycle, blocking cytokine-induced T-cell proliferation, and reducing immunoglobulin synthesis.

How does this relate to the heart?

Two multiprotein complexes – mTORC1 and mTORC2, regulate normal cardiovascular health. Chronic haemodynamic stress can activate mTORC1, driving pathological cardiac muscle hypertrophy. This is the key rationale for rapamycin use in HCM.

• mTORC1 is highly sensitive to rapamycin.
• mTORC2 and plays key roles in glucose/lipid metabolism and cardiomyocyte survival. It requires prolonged exposure to rapamycin to be interrupted. Chronic inhibition can lead to unwanted insulin resistance and reduced glucose sensitivity.

Intermittent dosing therefore aims to maximise mTORC1 inhibition while limiting unwanted mTORC2 effects. Previous mouse and human studies have shown that mTORC1 inhibition can reverse pathological left ventricular (LV) hypertrophy, and canine models of ageing hearts demonstrated improved systolic/diastolic indices with treatment.

Who was included in the RAPACAT cohort?

This was a randomised, double-blinded, placebo-controlled trial across two tertiary centres, enrolling cats with non-obstructive, preclinical HCM.

Inclusion criteria: Cats had to meet all of the following:

• Asymptomatic, with no evidence of congestive heart failure (CHF) on echocardiography or thoracic radiographs
• No evidence of severe LV outflow tract obstruction (LVOTO), past/current aortic thromboembolism (ATE), or haemodynamically significant arrhythmias
• No other acquired or congenital cardiac disease
• No concurrent non-cardiac disease (hypertension, hyperthyroidism, diabetes, renal dysfunction, or moderate–severe anaemia)
• Not be receiving long-term corticosteroids or other medications besides NSAIDs, antibiotics, clopidogrel, or ACE inhibitors
• No significant diet change during the study period

43 cats were enrolled; 36 completed the 180-day follow-up.

What was the study objective?

To assess the effects of once-weekly delayed-release rapamycin on:

• Echocardiographic parameters
• Biomarkers: NT-proBNP (B-type natriuretic protein) and cTnI (cardiac troponin)
• Routine biochemistry

Study groups:

• Placebo
• Low-dose rapamycin: 0.3 mg/kg
• High-dose rapamycin: 0.6 mg/kg

What were the outcomes?

Echocardiography

• Low-dose rapamycin had a significant effect on LV hypertrophy compared to the high-dose group, thought to reflect maximising mTORC1 inhibition while minimising mTORC2-related adverse effects.

Biomarkers

• NT-proBNP moderately correlated with changes in myocardial wall thickness.
• cTnI correlation could not be assessed.

Pros and cons of the study

Pros:

• Cats in the study tolerated rapamycin administration (useful considering medication compliance with cats can be tricky)
• Rapamycin may prevent or delay progression of LV hypertrophy (this could be really beneficial for our patients)
• More significant effect in the low-dose group, suggesting 0.3 mg/kg weekly may be optimal (more cost effective and lower drug burden)

Cons:

• Short study duration (6 months) – no long-term data reflecting the effects of rapamycin on:
  • Myocardial changes
  • Lifespan or disease progression
  • CHF, ATE, arrhythmias, sudden death
  • Quality of life
• Cats with significant LVOT obstruction were excluded – effects in this group are unknown, despite hypothesis that would not be an issue
• Cats with CHF were excluded – we do not know if or how rapamycin could be safely used once CHF develops
• Small sample size – and wide variation in genotype/phenotype in feline HCM is likely influences response
• Notable adverse events potentially linked to rapamycin:
  • 2 cats developed CHF
  • 1 cat died suddenly
  • 1 cat developed diabetes and ketoacidosis (likely due to mTORC2 inhibition, with predisposing factors: obesity and early blood and urine parameters overlooked at day 120)
• Other possible rapamycin-associated effects included progression of cardiac disease, GI signs, urinary/renal issues, and systemic abnormalities.
  • 2 events were judged “probably related”, 14 “possibly related”, and others inconclusive.
• High-dose group too small to reliably compare dosing strategies
• Missed doses were allowed (<25% total), and the study did not report how many cats this affected – potentially significant given the long dosing interval.

Our thoughts (for now)

It has been a long time since a new therapeutic direction has emerged for feline HCM, and this study is an important step in exploring potential future interventions with rapamycin. While the results seem promising, we must avoid giving false hope to owners. Rapamycin is not without risk – it may not be justifiable when applying it to our patients with no clinical signs of HCM and a normal quality of life. The inclusion criteria for cats were highly specific, which means there will be large numbers of our patients that we cannot predict outcomes for. We have no data beyond six months, and no information on how to proceed if one of these asymptomatic cats develops CHF or other complications while receiving the drug.

The study has certainly sparked owner interest – a positive trend in many ways – but the online narrative often oversimplifies the findings. This places the responsibility on vets to remain informed and to guide owners through the nuances of the limited research that we have at present. In suitable individual cases, if an owner is made aware of all of the risks in order to make an informed decision, trialling response to treatment with close monitoring may be worthwhile. But for now, rapamycin is promising, but in our opinion far from ready for widespread clinical use.

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