One Syndrome, Many Faces: A Unified Perspective on Heart Failure Phenotypes

Area of Science:

• Cardiology
• Pathophysiology
• Translational Medicine

Background:

• Heart failure (HF) is traditionally classified into reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) phenotypes based on left ventricular ejection fraction (EF).
• EF-based classification, while practical, faces challenges due to inconsistent definitions and blurring of categories in clinical trials.
• This ambiguity hinders precise diagnosis and targeted treatment strategies for heart failure.

Purpose of the Study:

• To challenge the traditional EF-based phenotyping of heart failure.
• To propose a unified, mechanistically driven model of heart failure as a single entity with variable manifestations.
• To explore common pathophysiological mechanisms across all HF phenotypes.

Main Methods:

• Comprehensive review of existing literature on heart failure pathophysiology and clinical classifications.
• Analysis of molecular, cellular, and systemic mechanisms implicated in different HF phenotypes.
• Synthesis of evidence supporting a spectrum-based model of heart failure.

Main Results:

• Emerging data indicate shared underlying mechanisms across all HF phenotypes, irrespective of EF.
• Common pathways include neurohormonal activation, inflammation, mitochondrial dysfunction, fibrosis, and apoptosis.
• The traditional EF categories may not accurately reflect distinct pathophysiological entities.

Conclusions:

• Heart failure should be viewed as a single clinical syndrome with manifestations varying along a spectrum.
• A unified, mechanistically driven model can improve diagnostic precision and therapeutic targeting in HF.
• Reframing HF research based on shared mechanisms, rather than EF stratification, is crucial for advancing treatment.