Cellular Senescence and SASP Drive HFpEF Pathology, Offering Therapeutic Targets

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of all heart failure cases, with its prevalence sharply increasing with age. Unlike HFrEF (reduced ejection fraction) which often stems from acute cardiomyocyte loss, HFpEF is characterized by a complex, aging-associated pathology involving systemic inflammation and multi-organ dysfunction. A critical link between aging and HFpEF pathology is the accumulation of senescent cells and their secretion of the Senescence-Associated Secretory Phenotype (SASP) within the cardiovascular system. SASP promotes a dysfunctional microenvironment and myocardial fibrosis through pro-inflammatory factors, chemokines, and extracellular matrix-remodeling proteins, driving myocardial stiffness.

This review systematically analyzed and synthesized existing literature on the role of cellular senescence and the Senescence-Associated Secretory Phenotype (SASP) in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Researchers explored how senescent cell accumulation and SASP contribute to the dysfunctional microenvironment and myocardial fibrosis characteristic of HFpEF. The study aimed to elucidate the underlying pathogenic mechanisms and identify promising therapeutic strategies targeting senescence and SASP to mitigate HFpEF progression. No specific experimental models, doses, or endpoints were generated by this review itself, as it consolidates prior research.

The review highlights that cellular senescence, a state of permanent cell cycle arrest in response to damage, accumulates in aging tissues and is a central amplifier of myocardial stiffness in HFpEF. Senescent cells secrete the Senescence-Associated Secretory Phenotype (SASP), a complex mixture of pro-inflammatory factors, chemokines, and extracellular matrix-remodeling proteins. This SASP creates a dysfunctional microenvironment that actively promotes myocardial fibrosis, a hallmark of HFpEF pathology. > The accumulation of senescent cells and their SASP within the cardiovascular system forms a critical link between aging and HFpEF pathology, driving systemic inflammation and multi-organ dysfunction. This mechanism contrasts sharply with HFrEF, where acute cardiomyocyte loss and ischemic injury are typically the primary drivers. The review posits that targeting cellular senescence and the SASP represents a promising avenue for novel therapeutic interventions in HFpEF, moving beyond current standard-of-care limitations.