# The fat‐heart entanglement and the role of ‘osteopontin mechanics’ in cardiometabolic senescence

## TL;DR

Osteopontin (OPN) connects fat and heart health, contributing to heart disease risk in obesity and showing potential as a biomarker and treatment target.

## Contribution

This paper highlights OPN's role in linking fat dysfunction to heart disease through aging-related pathways.

## Key findings

- OPN levels rise in obesity, driving inflammation and insulin resistance.
- OPN is linked to vascular inflammation and heart failure with preserved ejection fraction.
- Reducing OPN improves heart function in experimental models.

## Abstract

Residual cardiovascular (CV) risk persists despite therapeutic advances. Obesity is heterogeneous, and visceral adipose tissue (VAT) dysfunction (‘adiposopathy’) complicates risk stratification. Osteopontin (OPN) is a pleiotropic mediator implicated in VAT inflammation, senescence‐associated pathways, atherosclerosis and myocardial remodelling.

We performed a narrative synthesis of preclinical and clinical evidence on OPN across three domains: (i) VAT biology and senescence‐associated secretory phenotype (SASP); (ii) atherosclerosis and plaque vulnerability; and (iii) myocardial fibrosis/remodelling and cardiometabolic heart failure. We also summarize biomarker and therapeutic implications.

OPN is increased in obesity, particularly within VAT, where it contributes to SASP‐related signalling, macrophage dysfunction, low‐grade systemic inflammation, insulin resistance and cardiometabolic risk. Clinical and translational studies link circulating and tissue OPN levels to vascular inflammation, plaque vulnerability and adverse CV events. In the myocardium, OPN appears to act as a remodelling‐specific mediator connecting extracardiac adiposity‐related signals to interstitial fibrosis, with the strongest evidence in heart failure with preserved ejection fraction and diabetic cardiomyopathy. Across settings, OPN shows promise as an early biomarker for detection and risk stratification. Experimental modulation of OPN attenuates fibrosis and improves cardiac function in multiple models, supporting its candidacy as a mechanistic therapeutic target.

OPN likely bridges the fat–heart axis through senescence‐related pathways and may help explain residual CV risk in obesity‐related cardiometabolic disease. Standardized assays, prospective validation and interventional studies are required to establish clinical utility for OPN as a biomarker and therapeutic target.