Understanding the pathophysiological mechanisms underlying heart failure with preserved ejection fraction (HFpEF) and developing effective treatments remains a major challenge in the cardiology (1). Despite recent advances, the upstream drivers of chronic inflammation and cardiac dysfunction have largely escaped therapeutic targeting. Aging is strongly associated with HFpEF, and cellular senescence has been proposed to play a role in this process (2). In this context, the study by D. Silva et al. investigates the role of cellular senescence in the development and progression of HFpEF and explores its association with inflammation, cardiac fibrosis, and dysfunction (3).
Using the ZSF-1 obese rat HFpEF model, which recapitulates key features of the human HFpEF phenotype (4), the authors demonstrate that immune dysregulation and the accumulation of senescent cells precede the onset of cardiac dysfunction. Young ZSF-1 obese rats exhibited immune alterations typically associated with aging, including an increase in circulating myeloid cells and activated natural killer cells. In parallel, the proportion of bone marrow hematopoietic progenitor cells was reduced. Senescent peripheral blood mononuclear cells were consistently more abundant in young ZSF-1 obese rats, even before cardiac dysfunction was fully established, and displayed a pro-inflammatory secretory phenotype. This systemic inflammation also contributed to endothelial injury and senescence. Furthermore, increased immune cell infiltration was detected in the hearts of ZSF-1 obese rats, accompanied by enhanced endothelial activation and a reduction in endothelial cell numbers. In contrast, fibroblast abundance and expression of profibrotic genes were increased. Notably the presence of senescent cells was also detected in another animal model of HFpEF, relying also on hypertension and metabolic alterations, the L-NAME plus high fat diet model. Overall, these results indicate that premature senescence of immune cells precedes the accumulation of senescent cells in the myocardium and triggers a systemic pro-inflammatory environment leading to endothelial damage, immune cell infiltration, and ultimately, cardiac fibrosis. Indeed, the findings support the involvement of inflammageing in HFpEF development and progression (5). Notably, some of these changes were also identified in patient samples, where increased circulating senescent leukocytes correlated with disease severity and relevant biomarkers such as B-type natriuretic peptide (BNP).
Importantly, pharmacological clearance of senescent cells with the senolytic agent Navitoclax reduced inflammation, attenuated cardiac fibrosis, and improved vascular function in this experimental model of HFpEF. Early treatment with Navitoclax also decreased systemic inflammation and BNP levels, enhanced renal function, and alleviated pulmonary edema. These findings suggest that senotherapeutics may represent a novel strategy for the management of HFpEF by targeting the underlying disease-driving mechanisms. Within this conceptual framework, it is also tempting to speculate that other interventions known to modulate biological aging, such as caloric restriction, metformin, or rapalogs (6), might likewise slow the development and progression of HFpEF.
In conclusion, this study provides proof-of-principle that systemic clearance of senescent cells can ameliorate HFpEF, largely by attenuating the extra-cardiac contributors to the syndrome. From a translational perspective, the timing of intervention appears to be critical, with early administration of senolytics conferring the greatest benefit. This underscores the need for future studies to define optimal treatment windows. At the same time, the long-term safety and selectivity of senotherapeutic strategies require careful evaluation, as systemic elimination of senescent cells may carry unintended consequences.
