Treating enlarged hearts in cats with rapamycin

Researchers publishing in Journal of the American Veterinary Medical Association conducted a feline clinical study and found that rapamycin is effective against enlarged hearts in cats.

A well-known drug for a well-known problem

Rapamycin, also known as sirolimus, is one of the best known and most commonly taken compounds for longevity. The key metabolic inhibiting factor, the mechanistic target of rapamycin (mTOR), has two protein complexes, mTORC1 and mTORC2, both of which have substantial downstream effects, including on the cardiovascular system [1]. In this and other organs, mTORC1 inhibition has positive effects, while mTORC2 inhibition has negative effects. However, rapamycin affects mTORC1 much more acutely and mTORC2 only long-term, meaning that intermittent dosing can be an effective strategy [2].

Hypertrophic cardiomyopathy (HCM), the unhealthy enlargement of the walls of the heart, affects about 15% of domestic cats and is often found to have no clear cause [3]. This disease is largely incurable with downstream therapies and, just like in humans, often leads to heart failure and death. As rapamycin has been shown to be effective in a mouse model of cardiac hypertrophy [4] and another study found that it improves the hearts of dogs [5]these researchers decided to see if it was also effective in cats.

Conducted as a human clinical trial

Because this study was conducted on companion animals recruited from the general population, it was conducted much like a human trial. This study was completely blinded and the owners signed informed consent forms. One-third of enrolled cats received placebo, one-third received low-dose delayed-release rapamycin (0.3 mg/kg), and the final third received high-dose delayed-release rapamycin (0.6 mg/kg). .

Attempting to treat HCM before it becomes a problem, this study focused on subclinical HCM with no other diagnoses; Cats with serious health problems were excluded from the study, as were cats over the age of 12 (in human years, the approximate retirement age). These cats were 6 years old, with a wide variety of ages. Fifty-three cats were screened and 36 of them completed this 180-day study.

Although a substantial number of adverse events occurred in this study, they applied mostly equally to all three groups. Although one cat in the high-dose group died of diabetic ketoacidosis, rapamycin was not found to be a statistically significant cause of any adverse events. Rapamycin has also not been found to cause changes in body weight, heart rate, systolic blood pressure, quality of life, or biochemical measurements.

Not all of these groups started with the same maximum wall thickness (MWT). The placebo group, on average, had thicker walls than the treatment groups. After 60 days, these groups didn’t change much, with the low-dose group having the walls thinned slightly. However, after 180 days, the walls of the placebo group thickened substantially, which did not occur in any of the rapamycin-treated groups.

Researchers have also found a biomarker for the development of feline HCM. Cats with more N-terminal pro-B-type natriuretic peptide (NTproBNP) at baseline were substantially more likely to develop thicker walls. Rapamycin appeared to attenuate this correlation and reduce NTproBNP, although these differences did not reach the level of statistical significance.

Finding the right dose

With the effects of mTORC1 and mTORC2 in mind, these researchers believe that low-dose delayed-release rapamycin appears to be more effective and potentially safer than its high-dose counterpart, at least in cats with HCM.

This study had some limitations, including the relatively small study groups and the lack of direct measurements of mTORC1 and mTORC2. This study also focused on rapamycin itself rather than rapalogs which only affect mTORC1. The researchers stress that more studies would be needed to determine whether their approach has an appreciable effect on lifespan and long-term HCM.

Literature

[1] Sciarretta, S., Forte, M., Frati, G., & Sadoshima, J. (2018). New insights into the role of mTOR signaling in the cardiovascular system. Traffic research, 122(3), 489-505.

[2] Arriola Apelo, SI, Neuman, JC, Baar, EL, Syed, FA, Cummings, NE, Brar, HK, … & Lamming, DW (2016). Alternative therapeutic regimens with rapamycin mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging cell, 15(1), 28-38.

[3] Kittleson, MD and Ct, E. (2021). Feline cardiomyopathies: 2. Hypertrophic cardiomyopathy. Journal of feline medicine and surgery, 23(11), 1028-1051.

[4] Shioi, T., McMullen, JR, Tarnavski, O., Converso, K., Sherwood, MC, Manning, WJ, & Izumo, S. (2003). Rapamycin attenuates load-induced cardiac hypertrophy in mice. Circulation, 107(12), 1664-1670.

[5] Urfer, SR, Kaeberlein, TL, Mailheau, S., Bergman, PJ, Creevy, KE, Promislow, DE, & Kaeberlein, M. (2017). A randomized controlled trial to establish the effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience, 39117-127.