Review Proposes Senescence-Associated Secretory Phenotype Drives Cardiac Lymphatic Dysfunction in HFpEF

A narrative review proposes that cellular senescence and its paracrine secretory phenotype damage cardiac lymphatic vessels, establishing a novel senescence-lymphatic axis that could be targeted with senolytic therapies to treat heart failure with preserved ejection fraction.

A narrative review published in Cardiology in Review has advanced a novel mechanistic framework proposing that cellular senescence and its paracrine effector, the senescence-associated secretory phenotype (SASP), orchestrate a progressive impairment of cardiac lymphatic function.

The author, Ahmed Wael Moftah, synthesizes molecular geroscience, lymphatic biology, and cardiac physiology to argue that this SASP-mediated lymphatic endothelial dysfunction amplifies myocardial interstitial edema, chronic inflammation, and fibrotic remodeling.

The review highlights the therapeutic potential of senolytic and senomorphic interventions to preserve lymphatic integrity, while also noting challenges in cardiac lymphatic imaging, targeted drug delivery, and the clinical development of anti-aging therapies in elderly, multimorbid patient populations.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and therapeutically challenging cardiovascular condition with an incomplete pathophysiological understanding.

By framing HFpEF as a disease downstream of cellular senescence and lymphatic failure, the review provides a distinct biological rationale for deploying senotherapies within the cardiovascular field, transitioning the disease from an intractable clinical syndrome to a targetable geroscience pathway.

The integration of cellular senescence into HFpEF pathobiology could expand the potential clinical indications for companies developing senolytics and senomorphics, which have historically focused on localized indications like osteoarthritis, ophthalmology, or pulmonary fibrosis.

If the senescence-lymphatic axis is validated in preclinical and clinical models, it would open a high-prevalence cardiovascular market for geroscience platforms, though clinical trials will face safety and delivery hurdles unique to fragile elderly patient cohorts.

Preclinical studies evaluating whether existing senolytic or senomorphic candidates can prevent or reverse cardiac lymphatic vessel degradation and resolve interstitial edema in animal models of HFpEF.