Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with...

Area of Science:

• Cardiology
• Metabolomics
• Genomics

Background:

• Heart failure with preserved ejection fraction (HFpEF) is characterized by exercise intolerance due to multi-organ system limitations.
• The metabolic and genetic basis of these exercise deficits and their impact on HFpEF severity and prognosis are not fully understood.

Purpose of the Study:

• To comprehensively characterize exercise physiologic deficits in HFpEF patients using invasive cardiopulmonary exercise testing (iCPET).
• To identify metabolite signatures associated with these deficits and their prognostic significance.
• To explore shared metabolic mechanisms between HFpEF and its comorbidities through genetic analysis.

Main Methods:

• Utilized iCPET, metabolite profiling, and genomics to assess seven exercise deficits in HFpEF patients.
• Applied LASSO regression to identify metabolite signatures of exercise deficits.
• Analyzed associations with clinical data, cardiac MRI, and incident heart failure (HF) in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n=6345).
• Mapped deficit-implicated metabolites to genetic variations in large HF (n≈2M) and comorbidity GWAS datasets.

Main Results:

• HFpEF patients exhibited a wide spectrum of cardiac and extra-cardiac exercise deficits.
• Having ≥5 exercise deficits significantly increased the hazard of cardiovascular events or mortality (HR 3.90).
• Metabolite signatures of exercise deficits, particularly the PCWP/CO slope, predicted incident HF (HR 1.43 per SD).
• Metabolic signatures improved HFpEF risk prediction by ≈20% when added to traditional factors.
• Genes linked to exercise deficits were enriched in HF GWAS and shared with HFpEF comorbidities like obesity, renal disease, and diabetes.

Conclusions:

• Exercise responses and circulating metabolite signatures are critical in HFpEF development and prognosis.
• These findings provide a framework for stratifying HFpEF subphenotypes.
• Highlights the importance of targeting shared metabolic pathways in HFpEF and its comorbidities.