Can PD-1 Agonists Halt Sudden Death in Athletes with Hypertrophic Cardiomyopathy?
In February 2025, the sudden death of 22-year-old Portuguese soccer player Diogo Jota during a match stunned the sports world. Autopsy findings pointed to hypertrophic cardiomyopathy (HCM), a genetic condition characterized by abnormal thickening of the heart muscle, impairing its ability to pump blood effectively. HCM is a leading cause of sudden cardiac death in young adults, particularly athletes, with symptoms ranging from dyspnea and chest pain to catastrophic collapse during physical exertion. This tragedy underscores the urgent need for novel therapeutic strategies to address HCM’s underlying mechanisms.
Inflammation as a key driver. While HCM originates from genetic mutations, such as those in the α-tropomyosin gene, its clinical manifestations are significantly exacerbated by immune-mediated inflammation. Infiltrating immune cells, including T lymphocytes and myeloid cells, promote chronic inflammation and cardiac fibrosis, increasing myocardial stiffness and the risk of sudden cardiac events. This inflammatory component presents a critical target for drug development.
A pivotal study published in Science Translational Medicine (Wang et al., 2015) provides a comprehensive analysis of the immune landscape in HCM, highlighting the role of regulatory T cells (Tregs) in modulating disease progression. The study’s findings in human and murine models open new avenues for therapeutic intervention in cardioimmunology.
Human studies reveal immune infiltration. The researchers analyzed postmortem or explanted hearts from 16 HCM patients, focusing on the left (n=6) and right (n=4) ventricles. Flow cytometry revealed significant infiltration of CD3+, CD4+, CD8+, and CD11b+ myeloid cells, with CD45+ immune cells markedly elevated compared to controls. Single-nucleus RNA sequencing (snRNA-seq) confirmed activated immune pathways and low-grade inflammation, particularly associated with the D317N mutation in the α-tropomyosin gene. These data suggest a persistent inflammatory state in HCM hearts, offering a targetable mechanism for drug developers.
Murine models highlight Treg potential. In Actc1^tmP mouse models of HCM, immune cell infiltration increased progressively, doubling by 36 weeks. Notably, the adoptive transfer of CD4+Foxp3+ Tregs from mouse spleens significantly reduced cardiac fibrosis and improved systolic function, as assessed by late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) and Masson’s trichrome staining. Treatment with sifalimumab, an IL-2 receptor agonist, at a low dose (0.375 μg) nearly abolished fibrosis in treated mice (n=3 per group) over two weeks. These results underscore the therapeutic potential of enhancing Treg function to mitigate HCM progression.
Treg functionality and immune checkpoints. The study revealed that Tregs in HCM hearts, both human and murine, exhibit altered functionality. Single-cell RNA sequencing showed upregulation of immune checkpoint molecules like PD-1, CTLA-4, and TIGIT, alongside reduced expression of metabolic and inflammatory genes (e.g., Dhrs1, Ifng1). This profile suggests Tregs are attempting to suppress inflammation but are functionally impaired, presenting a clear opportunity for pharmacological enhancement of Treg activity or checkpoint signaling.
Therapeutic opportunities in cardioimmunology. The findings position cardioimmunology as a transformative field for HCM treatment. Enhancing Treg function through adoptive cell therapies or IL-2-based biologics, such as sifalimumab, could reduce fibrosis and improve cardiac function, potentially preventing sudden cardiac death. The upregulation of PD-1 in HCM Tregs highlights a specific drug development target: PD-1 agonists could amplify Treg-mediated immunosuppression, offering a novel approach to dampen chronic inflammation. Additionally, targeting other checkpoints like CTLA-4 or TIGIT may further enhance therapeutic outcomes.
PD-1 agonists as a frontier. The elevated PD-1 expression in HCM Tregs suggests that PD-1 agonists could bolster their anti-inflammatory effects, reducing myocardial damage. Preclinical data from the study support this hypothesis, as Treg-based interventions improved cardiac outcomes in mice. For drug developers, this opens a pipeline for developing PD-1 agonists, potentially repurposing existing molecules or designing novel biologics. However, challenges remain, including optimizing dosing regimens, ensuring cardiac specificity, and evaluating long-term safety in clinical trials.
Strategic implications for drug development. The study’s insights into Treg dysfunction and immune checkpoint dynamics provide a roadmap for precision medicine in HCM. Drug developers can explore Treg-enhancing therapies, such as low-dose IL-2 analogs or engineered Treg cell therapies, to target inflammation-driven fibrosis. Combining PD-1 agonists with existing HCM treatments, like beta-blockers or mavacamten, could yield synergistic effects. The success of IL-2 therapy in mice suggests a near-term opportunity to advance sifalimumab or similar molecules into Phase I trials for HCM, with a focus on safety and biomarker-driven endpoints like fibrosis reduction.
Stay ahead in drug development. For professionals seeking to capitalize on these breakthroughs, www.drugdevelop.com offers cutting-edge insights into therapeutic innovation. Subscribe to access expert analyses, clinical trial updates, and strategies to accelerate drug development in cardioimmunology and beyond. Join the community shaping the future of precision medicine!
Citation: Wang, Y.-J., et al. (2015). Regulatory T cells attenuate chronic inflammation and cardiac fibrosis in hypertrophic cardiomyopathy. Science Translational Medicine, 7, eaad2516. DOI: 10.1126/scitranslmed.aad2516