Hibernating Squirrels May Hold Clues To Treating Heart Failure
By Ashley Zehnder, CEO and cofounder, Fauna Bio
Heart failure with preserved ejection fraction (HFpEF) has emerged as one of the most prevalent and challenging forms of heart failure in modern clinical practice — primarily affecting women. This is a type of heart failure where the heart becomes stiffer due to inflammation and resulting fibrosis (scarring), which increases with age and metabolic disease/obesity. There are very few drugs approved to treat this type of heart failure, and the currently approved drugs do little to alter the clinical course of the disease. It is unclear exactly why HFpEF is more prevalent in women, but may be due to a higher risk of inflammation and microvascular dysfunction. Additionally, traditional risk factors, such as obesity, diabetes, hypertension, and coronary artery disease (CAD), may preferentially contribute to development of HFpEF in women. Emerging data suggest that sex-specific risk factors, like early menopause, adverse pregnancy outcomes, and other reproductive factors, are also important risk factors for HFpEF in women.
Historically, less funding has gone to studying heart failure in women, and women have been underrepresented in preclinical heart failure research as well as clinical trials. Only ~4% of funding for cardiovascular research goes to women, contributing to our lack of knowledge about how to treat heart failure in women, including HFpEF. An estimated 3 million patients in the United States, and more than 20 million worldwide, live with the disease — a number that continues to rise as populations age. Yet despite its growing clinical and societal burden, HFpEF remains an area where therapeutic progress has been frustratingly limited.
One reason is that HFpEF does not fit neatly into the paradigms that guided earlier heart failure drug development. Unlike heart failure with reduced ejection fraction, HFpEF is not defined by a single mechanical failure of the heart. Instead, it reflects a convergence of systemic dysfunction, including impaired mitochondrial energetics, chronic inflammation, autonomic nervous system imbalance, and vascular and microvascular abnormalities. This biological complexity has made HFpEF difficult to model, stratify, and treat using traditional approaches.
A Need For New Therapies
As a result, much of today’s HFpEF treatment landscape relies on repurposed therapies. Drugs originally developed for diabetes, obesity, hypertrophic cardiomyopathy, or other forms of heart failure have been adapted for HFpEF after demonstrating modest benefit. While some of these agents reduce hospitalizations or improve selected endpoints, they were not designed with HFpEF biology as their starting point. Overall outcomes remain sobering: only about one-third of patients diagnosed with HFpEF are alive five years later, underscoring the limits of incremental progress.
The unmet need is even more pronounced in patients with HFpEF complicated by pulmonary hypertension, commonly referred to as group 2 pulmonary hypertension. This population represents a more advanced and severe disease phenotype, characterized by worse exercise tolerance, higher morbidity, and increased mortality. Current treatment strategies largely focus on downstream hemodynamic effects rather than the upstream biological drivers of disease progression, and there are no approved therapies specifically designed to modify the underlying pathophysiology of HFpEF with pulmonary hypertension.
Increasingly, research points to two interconnected processes as central to HFpEF progression: mitochondrial dysfunction within cardiomyocytes and maladaptive activation of the sympathetic nervous system. Impaired mitochondrial energy production reduces myocardial efficiency and resilience, while chronic sympathetic overactivity exacerbates diastolic dysfunction, promotes adverse remodeling, and worsens clinical outcomes. Despite their importance, these mechanisms have historically been difficult to target directly with pharmacologic therapies.
Hibernating Mammals
To identify new ways forward, Fauna Bio has turned to an unconventional but instructive source: hibernating mammals. Species such as the 13-lined ground squirrels undergo repeated cycles of profound metabolic suppression and reactivation during hibernation. Over a single hibernation season, these animals can experience dozens of episodes of ischemic stress, yet they recover cardiac function without developing chronic heart failure. Remarkably, they do so using the same core genes found in humans but with regulatory programs that promote resilience, repair, and energy efficiency rather than progressive dysfunction.
Studying these animals has provided insight into biological pathways that tightly couple autonomic regulation with mitochondrial function in heart cells. Human genomic analyses have reinforced the relevance of these pathways by demonstrating associations with HFpEF, cardiopulmonary performance, and circulating biomarkers linked to disease severity. Together, these findings suggest that HFpEF may be driven not only by structural abnormalities but also by dysregulation of conserved stress-response systems that evolved to protect the heart.
Paving A Path Forward
Fauna’s drug was discovered through examining natural mechanisms of cardiac repair in hibernating squirrels, which experience ischemic damage to their hearts as much as 25 times over a six-month period. It functions by improving mitochondrial function in heart cells (providing the heart with more energy) as well as regulating the sympathetic nervous system, which can be overactive in heart failure and result in worse outcomes for patients. It represents what can result from taking a step back and considering what we can learn from animals that are using the same genes we have as humans, but in ways that allow them to reverse disease.
Preclinical data emerging from this line of inquiry indicates that modulating such pathways can attenuate dysfunctional sympathetic signaling and improve mitochondrial performance in cardiomyocytes. In animal models, interventions targeting these mechanisms have demonstrated efficacy in both HFpEF and HFpEF with pulmonary hypertension, supporting the concept that addressing upstream biology may yield broader and more durable benefits than therapies focused solely on vascular tone or metabolic comorbidities.
For drug development leaders, the implications are clear. HFpEF is unlikely to be meaningfully addressed through repurposing alone. Progress will require therapies intentionally designed around disease-relevant biology, informed by human genetics, systems biology, and translational models that more accurately reflect the complexity of the condition. Learning from natural models of cardiac resilience, such as hibernating squirrels, offers a compelling example of how stepping outside conventional frameworks can reveal new therapeutic possibilities.
Ultimately, success in HFpEF should be measured not only by statistical significance in clinical trials but by whether new approaches can meaningfully change the trajectory of a disease that has long resisted standard treatment strategies. For a patient population that is older, predominantly female, and historically underserved by cardiovascular innovation, the need to rethink how we approach HFpEF has never been more urgent.
About The Author
Ashley Zehnder is cofounder and chief executive officer of Fauna Bio. She has been recognized for her work by the San Francisco Business Times’ Women Who Lead in Life Sciences. She was listed as an Emerging Woman Founder in Bio by the Wave Summit, and she represented Fauna Bio for Fortune’s AI Minute. She has spoken at numerous events promoting the use of AI and novel genomics in drug discovery. She mentors early-stage founders through her work with On Deck Longevity Biotech and Nucleate Bio. She is a boarded avian veterinarian and her prior research focused on translational science, earning a Ph.D. in cancer biology from Stanford University.