Exercise as a Cornerstone Therapy for Cardiovascular-Kidney-Metabolic Syndrome: A Stage-Informed, Mechanistic, and Integrative Framework.

OBJECTIVE

Cardiovascular-kidney-metabolic (CKM) syndrome reflects convergent vascular, renal, hepatic, and skeletal muscle pathways that are modifiable with exercise. Clinical application remains fragmented without a stage-informed framework.

METHODS

This review provides a stage-informed, mechanistic, and pragmatic framework for CKM exercise prescription. Metabolic dysfunction-associated steatotic liver disease is positioned as a central driver, integrating exercise with contemporary pharmacotherapy and equitable real-world delivery.

RESULTS

Synthesizing evidence from 2022 onward, we standardize organ-system specific outcomes and safety targets for endothelial function, autonomic balance, skeletal muscle oxidative capacity, systemic inflammation, hepatic steatosis, and cardiorenal function. Frequency-intensity-time-type-based prescriptions are detailed for CKM stages 0-4. Modalities are compared by physiologic targets and pragmatic attributes. Implementation strategies pair structured training with sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and nutritional support for metabolic dysfunction-associated steatotic liver disease. We outline practical monitoring pathways, translating heart-rate reserve or oxygen-uptake reserve to perceived exertion, when formal testing is unavailable.

CONCLUSION

Across CKM stages, multimodal exercise that combines moderate-intensity continuous training, high-intensity interval training, and resistance training produces reproducible improvements in VO2 peak, endothelial function, hepatic steatosis, blood pressure, and functional status when dosed to minimal effective thresholds and tracked with harmonized outcomes. Embedding exercise within guideline-directed therapy, nutritional support, equity-aware delivery, and scalable monitoring is recommended for maximal clinical impact. Future trials should prioritize phenotype-guided dosing and unified endpoint sets.