Unraveling Heart Failure Phenotypes: A Systematic Review and Meta-Analysis of Peak Oxygen Uptake and its Determinants

Understanding the impact of heart failure (HF) phenotype on peak oxygen uptake (peak V˙ O2) is essential for advancing personalized treatment strategies and enhancing patient outcomes. Therefore, we conducted a systematic review and meta-analysis of the evidence examining differences in peak V˙ O2 (primary objective) and its determinants (secondary objectives) between patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF). Studies comparing peak V˙ O2 in HFrEF vs HFpEF were found through PubMed (1967-2024), Scopus (1981-2024), and Web of Science (1985-2024). Data extraction and methodologic quality assessment were completed by 2 independent coders. Differences between HFrEF and HFpEF were compared using weighted mean difference (WMD) and 95% confidence intervals (95% CIs) derived from random effects meta-analysis. After screening 3107 articles, 25 unique studies were included in the analysis for the primary outcome (HFrEF n = 3783; HFpEF n = 3279). Peak V˙ O2 (WMD: -1.6 mL/kg/min, 95% CI: -2.3 to -0.8 mL/kg/min), and peak exercise measures of cardiac output (WMD: -1.1 L/min, 95% CI: -2.1 to -0.2 L/min), stroke volume (WMD: -10.1 mL, 95% CI: -16.6 to -3.7 mL), heart rate (WMD: -4 bpm, 95% CI: -6 to -2 bpm), and left ventricular ejection fraction (WMD: -28.2%, 95% CI: -32.6% to -23.8%) were significantly lower while peak exercise arterial-venous oxygen difference was significantly higher in HFrEF compared with HFpEF (2.3 mL/dL, 95% CI: 1.6-2.9 mL/dL). Our findings highlight distinct physiological impairments along the oxygen cascade in HFrEF compared with HFpEF, with direct implications for the management and treatment strategies of these HF subtypes.