Introduction
Hypertrophic cardiomyopathy (HCM) has emerged as one of the most prevalent yet elusive heart conditions in cats. Unlike humans, where HCM is comparatively rare, this silent disease affects up to 1 in 6 cats, with certain breeds like Maine Coons and Ragdolls facing an even higher risk due to genetic predispositions. The challenge? HCM often progresses undetected for years, thickening the heart's left ventricle walls and slowly diminishing its ability to pump blood efficiently. Traditional treatments aim to alleviate symptoms but rarely address the core of the disease itself—the gradual and abnormal thickening of the heart muscle. As research on advanced therapies intensifies, rapamycin has emerged as a particularly promising agent with the potential to target the underlying pathophysiology of HCM.
Rapamycin’s potential lies in its ability to regulate the mammalian target of rapamycin (mTOR), a cellular “master regulator” that governs both growth signals and the pace of essential repair processes. By inhibiting overactive mTOR, rapamycin not only decreases unhealthy cellular proliferation but also reactivates a critical cleanup pathway known as autophagy. This dual action helps heart cells clear away damaged components and maintain more efficient function. Unlike traditional treatments, which center on symptom management, rapamycin operates at the molecular level to slow or even halt the progression of HCM by reducing pathological growth signals in cardiac tissue.
In this review, we will examine these underlying mechanisms in greater depth and explore the latest research on rapamycin’s effects against HCM—offering insights that may shape future strategies for managing this silent but significant feline heart disease.
Hypertrophic Cardiomyopathy (HCM): A Silent Heart Disease in Cats
The heart's muscles play a vital role in maintaining circulation. They continuously contract to pump blood throughout the body and ensure that organs receive the oxygen and nutrients they need. The heart's thickest muscle, the left ventricle, is especially important because it generates the force needed to push blood into the aorta and out to the body. This powerful pumping action is essential for sustaining life, as it keeps blood moving effectively from the heart to the lungs and back again in a carefully balanced cycle.
However, like any muscle, the heart can change over time. Aging, genetic factors, or underlying conditions can cause the heart muscles to thicken or stiffen, impacting their ability to contract and relax smoothly. When the heart's muscle walls become too thick or rigid, it can make it harder for the heart to fill with and pump out blood effectively. These changes can lead to various health issues, as the heart's ability to supply the body with oxygenated blood becomes compromised.
These changes are especially pronounced in hypertrophic cardiomyopathy (HCM), a condition in which the muscle walls of the left ventricle become abnormally thickened. This thickening limits the heart's ability to relax between beats, restricting blood flow and forcing the heart to work harder to pump blood effectively. Over time, this added strain can lead to more severe heart problems, such as difficulty breathing, fatigue, and even heart failure if left unmanaged.
Although HCM is considered relatively rare in humans, it’s surprisingly common in the feline world, affecting an estimated 1 in 6 cats, with certain breeds—particularly Maine Coons and Ragdolls—displaying a clear genetic predisposition [2]. Many of these cats may appear perfectly healthy for years; they might show no visible symptoms while their heart walls quietly thicken and their pumping efficiency gradually declines. In fact, veterinarians often first suspect HCM upon detecting a cardiac murmur or gallop rhythm during routine check-ups—or if screening with biomarkers like NT-proBNP (N-terminal pro–B-type natriuretic peptide) suggests growing cardiac stress.
One of HCM’s key dangers is its stealthy progression. While humans with HCM commonly experience symptoms such as chest pain or fainting, cats are far less likely to cough or display overt signs until the disease has advanced. In severe cases, HCM can lead to congestive heart failure, accompanied by fluid accumulation in or around the lungs, or even to arterial thromboembolism (blood clots), which can result in painful limb paralysis. This silent nature underscores the importance of regular cardiovascular evaluations, especially for high-risk breeds or cats with a family history of cardiac disease.
However, current treatments for HCM focus only on symptom relief rather than addressing the root cause of the disease. This highlights the need for advanced therapies that could halt or even reverse heart muscle thickening, improving heart health and extending the lifespan of cats.
Current Conventional Treatments for Feline HCM
When treating hypertrophic cardiomyopathy (HCM) in cats, veterinarians often rely on medications to manage symptoms and ease the strain on the heart. The most commonly prescribed drugs include:
- Beta-blockers: These medications slow the heart rate and lower blood pressure, helping the heart muscle relax and function more efficiently. By reducing the heart's workload, beta-blockers can alleviate some HCM symptoms, like difficulty breathing and fatigue.
- Calcium channel blockers: These drugs aid in relaxing the heart muscle by blocking calcium from entering the cells of the heart and blood vessels. Calcium is necessary for muscle contractions, so limiting its entry into the heart's cells reduces the stiffness of the left ventricle. This allows the heart to fill and pump blood more effectively, supporting overall circulation.
- Diuretics: A primary challenge for cats with HCM is fluid buildup in the lungs, making breathing difficult. This occurs when the heart's reduced efficiency causes fluid to leak into the lungs. Diuretics, or "water pills," help reduce this fluid buildup by encouraging the kidneys to remove excess fluid through urine. This decreases pressure on the heart and eases breathing.
- ACE inhibitors: These drugs lower blood pressure and ease the heart's workload by blocking the formation of the angiotensin-converting enzyme (ACE), which constricts blood vessels. ACE inhibitors help the heart pump blood more efficiently by relaxing the blood vessels.
Despite offering a spectrum of options for symptom relief, these medications do not combat the core pathophysiology of HCM—the progressive and often insidious thickening of the left ventricle. In other words, while they reduce the functional burden on a diseased heart, the disease process itself can continue unabated. Over time, cats may still experience shortened lifespans and diminished quality of life, underscoring the need for new interventions that target the biological drivers of HCM rather than just its side effects.
Because most current HCM therapies merely alleviate symptoms—slowing the heart rate, easing fluid buildup, or reducing blood pressure—veterinarians and researchers continue to search for treatments that target the underlying causes of the disease. After all, even with improved comfort and reduced respiratory distress, the heart muscle continues to thicken in many cats. This gap between symptom management and disease modification has led to a wave of investigations centered on novel strategies that affect molecular drivers of HCM.
Rapamycin as a Novel Approach for Feline HCM
For years, veterinarians and researchers alike have struggled to manage HCM in cats, often resorting to strategies that primarily alleviate symptoms—such as beta-blockers or diuretics—rather than halting the disease’s underlying progression. Today, however, a new frontier in treatment has emerged: rapamycin, a compound that promises to do more than merely mask clinical signs. By specifically targeting the intricate biological processes that lead to HCM, rapamycin opens up the possibility of both treating and preventing the disease in one fell swoop.
Originally discovered in soil samples from Easter Island (Rapa Nui), rapamycin initially gained attention in human medicine for its immunosuppressive properties and its ability to inhibit tumor growth. In the context of feline HCM, though, its most compelling feature lies in how it interacts with the heart’s abnormal growth patterns at the molecular level. Ongoing research suggests that rapamycin’s capacity to modulate cellular growth pathways might help counteract the thickening of the heart muscle, offering a more direct therapeutic approach than conventional treatments that simply manage fluid buildup or control heart rate.
The mTOR Pathway: Master Switch of Cellular Growth and Recycling
Rapamycin exerts its effects by inhibiting the mTOR pathway. Think of mTOR as the cell’s master regulator—a molecular switchboard that integrates environmental signals, particularly the availability of nutrients and growth factors. When resources are plentiful and growth signals abound, mTOR activates a cascade of biochemical events that encourage cells to multiply and synthesize proteins. Imagine providing a cat unlimited access to food—the nutrients from that food will stimulate mTOR to grow the cell—this has a lot of implications that we will review throughout his article on aging.
However, the picture changes markedly when nutrients become scarce—or when rapamycin steps in to block mTOR activity. In these low-resource circumstances, mTOR reduces its pro-growth directives and switches the cell into a resource-conserving mode. Central to this mode is the activation of autophagy, the cell’s built-in recycling mechanism. During autophagy, the cell disassembles and salvages old, misfolded proteins and damaged organelles, recovering valuable building blocks such as amino acids and fatty acids. Beyond energy conservation, this cleanup process helps maintain proteostasis—the balance of properly folded and functional proteins—reducing the potential for inflammation or cellular damage.
This is going to be important when we talk about how rapamycin targets HCM pathogenesis. By inhibiting mTOR, rapamycin effectively encourages cells to spend more time in this self-renewing, maintenance mode—a process that could be especially valuable for heart cells burdened by excessive growth stimuli in HCM.
The Problem: Chronic Overactivation of mTOR
Imagine a car with its accelerator pedal stuck to the floor: the engine races unchecked, fuel consumption skyrockets and vital components risk overheating. On a cellular level, something similar happens when mTOR remains in perpetual “growth” mode. Rather than toggling between periods of robust growth and debris clearance, cells keep enlarging and proliferating, much like a car that never slows down for inspection or repairs.
As cats (and humans) age, mTOR activity often becomes excessively active, shifting from balanced cellular regulation to a kind of overdrive. In youth, mTOR provides just the right level of support for cell growth during development, but this “hyperactive” state in older individuals can fuel a variety of health issues. One especially notable effect is the thickening of the heart muscle in cardiac hypertrophy—which compromises the heart’s pumping ability and can lead to heart failure.
Indeed, animal studies have consistently linked excessive mTOR activity to the development of HCM, cementing it as a critical factor in disease progression [5, 6].
Ordinarily, cells require downtime to self-repair and clear waste through autophagy, the built-in recycling mechanism that reclaims damaged proteins and worn-out components. But if mTOR remains “stuck on,” the cell’s housekeeping is postponed indefinitely, and toxic debris accumulates. Over time, this relentless stress on the system contributes not just to HCM, but also to a range of age-associated conditions—cancers, neurodegenerative diseases, and more.
Rapamycin as a Molecular “Brake” on mTOR
Because of its ability to recalibrate mTOR’s balance, rapamycin has emerged as one of the most promising tools to address the chronic overactivation of mTOR in aging cells. Rapamycin acts like a brake on this runaway engine. By selectively inhibiting the overactivity of mTOR, rapamycin restores equilibrium between growth and maintenance, slowing down the harmful processes that drive HCM.
Studies suggest that lowering mTOR activity can not only slow disease progression but may also extend healthspan by forestalling the cascade of dysfunction linked to chronic overactivation.
In cats suffering from HCM, recent research and clinical trials indicate that by strategically applying this “brake,” rapamycin could preserve heart function in ways that exceed conventional treatments. This positions rapamycin at the forefront of a new wave of interventions designed to tackle cardiac disease at its molecular origins, rather than merely mitigating its outward manifestations [5, 6].
Given rapamycin’s unique ability to rein in overactive mTOR and restore the balance between cellular growth and repair, it’s hardly surprising that researchers have begun exploring its potential in feline HCM. By shifting the focus from symptom control to cellular-level intervention, these studies highlight a fresh perspective on how we might manage—and possibly alter—the course of this difficult condition. In the sections that follow, we analyze the pioneering research shaping our understanding of rapamycin’s role in feline HCM.
Rapamycin for Feline HCM: Findings from a Pioneering Pilot Study
In a groundbreaking pilot study titled Multi-Omic, Histopathologic, and Clinicopathologic Effects of Once-Weekly Oral Rapamycin in a Naturally Occurring Feline Model of Hypertrophic Cardiomyopathy: A Pilot Study, Rivas et al. (2023) investigated how delayed-release (DR) rapamycin affects cats with a naturally occurring, genetic form of hypertrophic cardiomyopathy (HCM) [7]. The research team treated nine cats over the course of eight weeks with weekly doses of DR rapamycin, testing both low (0.15 mg/kg) and high (0.30 mg/kg) dosages to evaluate safety and effectiveness.
Unlike immediate-release formulations, delayed-release rapamycin is engineered to release the drug more gradually, allowing for sustained therapeutic levels while reducing the likelihood of side effects. This carefully managed release profile proved promising: neither dose group experienced significant adverse reactions, suggesting that DR rapamycin is generally well tolerated by feline patients.
Dose-Dependent Reduction in Heart Muscle Thickening
One of the study’s most noteworthy discoveries was that rapamycin reduced myocardial hypertrophy (thickening of heart muscle) in a dose-dependent manner—the higher 0.30 mg/kg dose demonstrated a more pronounced effect. This finding is critical for cats with HCM, as the thickening of heart muscle often undermines cardiac efficiency and can lead to heart failure. By attenuating hypertrophy, rapamycin seemed to preserve or even enhance heart function over time.
Increases in Cellular Autophagy—Revving Up the Cell’s “Cleanup Crew”
One of the study’s most noteworthy discoveries was that rapamycin stimulated autophagy, the cell’s built-in recycling system that dismantles and removes damaged proteins and organelles. This effect was observed through elevated markers associated with autophagic flux—an indication that the heart cells were shifting into a more protective, maintenance-focused state. In the context of cardiac health, heightened autophagy is especially relevant; left unchecked, cellular debris and misfolded proteins can accumulate in the heart, compounding stress on already overworked heart muscle cells.
The authors proposed that by enhancing autophagic turnover, rapamycin alleviates intracellular congestion and helps maintain a healthier cellular environment. This cleanup mechanism could be key to slowing disease progression, given that HCM often involves ongoing structural remodeling in heart tissue. In practical terms, heart cells burdened by excessive thickening may benefit from a process that clears dysfunctional components and recycles nutrients—much like regularly cleaning a busy workshop to keep machines running smoothly.
The findings also hint at broader benefits beyond immediate symptom relief. By reducing the toxic buildup of cellular waste, autophagy may help temper inflammatory cascades that otherwise intensify cardiac damage. The study’s authors point out that enhanced autophagic flux could potentially improve the overall resilience of heart muscle cells, giving them a better chance to cope with metabolic or oxidative stress—both common threads in cardiac hypertrophy and heart failure. In essence, rapamycin’s capacity to jump-start this cellular “cleanup crew” may be as crucial to its therapeutic potential as its direct influence on cardiac growth signals.
Multi-Omic Insights: Transcriptomics and Proteomics
In a forward-thinking move, the research team employed both transcriptomic and proteomic analyses to gain a comprehensive view of how rapamycin might alter heart tissue at a molecular level. By examining gene expression (via transcriptomics) and protein abundance (via proteomics), they captured a more nuanced picture of the cellular shifts that could underlie rapamycin’s therapeutic benefits.
Transcriptomic Findings
Transcriptomic analysis—often performed through techniques like RNA sequencing (RNA-seq)—revealed an increased activity of genes tied to extracellular matrix (ECM) regulation and ribosomal proteins. ECM components play a critical role in structural support and signal transduction within cardiac tissue, so changes in ECM-related gene expression could reflect an adaptive remodeling that aids the heart in responding more flexibly to stress. Meanwhile, the rise in ribosomal proteins suggests that heart cells under rapamycin’s influence may be upregulating or optimizing their capacity for protein synthesis, potentially repairing or replacing structural components more effectively.
Proteomic Findings
On the protein side, proteomics (commonly leveraging mass spectrometry) pointed to notable shifts that support rapamycin’s multifaceted impact on the heart. For instance, anti-clotting potentials emerged as key highlights, with reduced abundance of proteins linked to thrombus formation. This finding raises the intriguing possibility that rapamycin might help lower the risk of thromboembolism, a significant concern in advanced HCM cases. The study further identified a reduction in several inflammatory proteins, hinting at an anti-inflammatory effect that could limit the damage associated with chronic inflammation in the heart. Since inflammation is often a perpetuating factor in cardiac hypertrophy, mitigating it could slow the overall progression of HCM.
Taken as a whole, these multi-omic outcomes underscore the idea that rapamycin’s benefits extend well beyond simply dampening mTOR. By shifting gene expression, fine-tuning protein abundance, and modulating pathways tied to clotting and inflammation, rapamycin appears to recalibrate the heart’s molecular landscape. Although the authors caution that larger-scale studies are required—especially to gauge long-term safety and durability of these effects—this pilot investigation strongly implies that targeting multiple biological pathways could yield a more thorough approach to HCM management.
Crucially, this study marks the first time that multi-omic data have been gathered from cats with subclinical HCM, shedding light on rapamycin’s potential impact before overt clinical signs manifest. The dose-dependent decline in heart muscle thickness, combined with the uptick in autophagy, points to rapamycin as a potential preventive or disease-modifying therapy rather than a mere symptomatic treatment. By intervening at the cellular and molecular levels that drive hypertrophy, rapamycin could supplement—or possibly even surpass— traditional symptom-oriented treatments. The authors contend that, with further validation, rapamycin might one day help veterinarians address both the structural underpinnings and the long-term outcomes of feline HCM, emphasizing early intervention and a shift away from reactive medicine.
Building on the pilot findings from Rivas et al. (2023)—which highlighted rapamycin’s ability to reduce myocardial hypertrophy and boost autophagy without substantial side effects—another significant milestone was reported in 2023. Known as the RAPACAT Trial, this study further explored rapamycin’s potential in feline hypertrophic cardiomyopathy (HCM) by broadening the scope to include more subjects and higher dosing regimens.
The RAPACAT Trial: Expanding the Evidence for Rapamycin in Feline HCM
In this pivotal study, Kaplan and colleagues set out to determine whether delayed-release (DR) rapamycin could mitigate ventricular hypertrophy in 43 client-owned cats with subclinical HCM [8]. The cats were randomly divided into three groups—placebo, low-dose DR rapamycin (0.3 mg/kg), or high-dose DR rapamycin (0.6 mg/kg)—each administered orally once a week. To ensure scientific rigor, the research team meticulously controlled the randomization process so that no major differences in age, weight, or clinical status existed among the groups at the start.
Measuring the Heart’s Response
The study’s primary endpoint was the maximum thickness of the left ventricular (LV) wall, a standard marker used to gauge the severity of hypertrophy. After 180 days, cats in the low-dose rapamycin group displayed a significantly lower LV wall thickness compared to those receiving placebo—evidence that rapamycin may help prevent or at least delay further thickening of the heart muscle in cats with subclinical HCM. This finding underscores rapamycin’s potential role not just in managing symptoms, but in modifying the disease’s progression at a fundamental level.
Safety and Tolerability
Every 60 days, cats underwent echocardiograms, blood pressure measurements, routine blood work, and urine analysis to track any emerging side effects. Owners also maintained diaries documenting unusual behaviors and completed a cardiac health questionnaire at each visit. Encouragingly, no major differences in adverse events emerged among the three groups, suggesting that DR rapamycin was generally well tolerated. However, one cat in the rapamycin group developed diabetic ketoacidosis (DKA)—an outcome highlighting the need for careful monitoring, especially in cats prone to or at risk for diabetes mellitus (DM).
Implications and Future Directions
When taken together with the results from the RAPACAT Trial offers compelling evidence that rapamycin can reduce pathological hypertrophy and increase autophagy in feline HCM, without incurring widespread adverse effects. The study’s randomized design and longer follow-up period add credence to the idea that rapamycin could play a preventative or disease-modifying role, potentially slowing the march of HCM in cats before clinical signs become severe.
While further research is certainly warranted—particularly regarding optimal dosing strategies, long-term safety, and metabolic considerations—these data suggest that rapamycin-based therapies have a place in treating feline HCM. By addressing the underlying cellular misregulation that propels HCM rather than merely easing its symptoms, rapamycin holds the promise of fundamentally altering the trajectory of this common cardiac disease.
With the RAPACAT Trial reinforcing earlier pilot findings that rapamycin can curb HCM in cats, an essential question remains: How does rapamycin actually safeguard the feline heart? In what follows, we delve into the underlying biological mechanisms—specifically its influence on mTOR signaling and cellular cleanup—that appear to make rapamycin a formidable ally against HCM.
How Rapamycin Benefits Cardiovascular Health in Cats?
Rapamycin offers several mechanisms to support cardiovascular health, particularly in cats with HCM. The key to its effects lies in its action on mTOR, a complex often described as the cell's "master controller," directing when cells should grow, divide, and build new structures. While mTOR's signals are essential for normal processes like muscle growth and healing, issues arise when it becomes overactive—especially in heart cells.
In HCM, this excessive activity promotes maladaptive cardiac hypertrophy or unhealthy heart muscle thickening, which can compromise the heart's ability to pump blood effectively. Rapamycin acts as a "brake" on mTOR's overactivity, reducing its signaling to prevent the problematic growth that makes it difficult for the heart to function properly [12, 13].
Rapamycin helps reduce this excessive thickening by inhibiting mTOR, allowing the heart muscle to remain more flexible and functional. This is crucial for maintaining effective blood circulation through pulmonary and systemic circulation. In pulmonary circulation, blood is sent to the lungs, where it collects oxygen, while in systemic circulation, oxygen-rich blood is delivered throughout the body. Blood carries oxygen and nutrients like fuel powering a machine, which tissues and organs use to produce the energy essential for survival. Once depleted of oxygen, blood returns to the heart and is pumped through the pulmonary circulation to the lungs to replenish its oxygen levels. Rapamycin's regulation of mTOR helps prevent the thickening that can interfere with this vital cycle, reducing strain on the heart and improving blood flow.
In cats with HCM, the overgrowth of heart muscle compromises blood flow to the lungs and the body. As circulation diminishes, less blood reaches the lungs, limiting oxygen uptake, and less blood reaches critical organs, which may receive insufficient oxygen to produce the energy they need. This restricted blood flow can lead to ischemia, where organs do not get enough oxygen. Rapamycin reduces the risk of ischemia by preventing cardiac muscle thickening, ensuring consistent oxygen and nutrient delivery to tissues, and enhancing the cat's overall health and vitality.
Ischemia can also affect the heart itself. Like other organs, the heart relies on its blood vessels, called coronary vessels, to receive oxygen and nutrients for energy production. With HCM, blood flow to the heart can become restricted, leading to weakness and potential death of heart muscle cells. Rapamycin helps protect the feline heart from ischemic injury by reducing energy demands, allowing it to function efficiently even with reduced oxygen supply. It's like running a machine on a low-power setting to prevent overheating or burnout. Rapamycin supports the heart's resilience under stress, helping to extend pets' overall cardiovascular health.
Another important benefit of rapamycin in pets is its ability to reactivate autophagy. As described earlier, autophagy is a cellular cleanup process that removes old, damaged, or unnecessary parts of cells. This is especially crucial for the heart, a constantly working organ that needs to stay in optimal condition. In HCM, autophagy can become disrupted, accumulating damaged cell components that hinder the heart's efficiency. Rapamycin "reboots" autophagy, enabling cells to remove damaged parts, keeping the heart healthier and more resilient over time. Think of it as a factory restarting its cleaning crew to prevent machinery from clogging—rapamycin's effect on autophagy ensures that heart cells in cats stay in top shape, essential for their ongoing health and quality of life.
Rapamycin helps maintain cardiovascular health in cats and slows the progression of heart disease by preventing maladaptive hypertrophy and promoting autophagy. This dual effect not only enhances the heart's short-term function but may also extend the lifespan of cats with HCM, acting as a protective measure to support the heart's long-term health—similar to routine maintenance that keeps a car running smoothly for longer.
Rapamycin’s Wider Promise: Extending Healthy Lifespan
Intriguingly, rapamycin’s benefits might extend beyond cardiac health alone. One 2016 study investigating short-term rapamycin administration in middle-aged mice [9] revealed up to a 60% increase in lifespan, accompanied by beneficial shifts in gut microbiota—specifically, a rise in segmented filamentous bacteria within the small intestine, a change associated with positive aging outcomes. Taken together, these findings suggest that rapamycin may not only slow the progression of feline HCM but also offer broader longevity benefits for our pets, pointing to a future where cats enjoy healthier, more vibrant lives.
By bridging short-term heart protection with potential long-term health gains, rapamycin stands out as a compelling candidate in the veterinary toolbox. Its multi-faceted impact on cellular growth and maintenance may well reshape how we approach the care of cats with HCM—and, by extension, many other age-related conditions.
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