Study Background and Disease Burden
Heart failure with preserved ejection fraction (HFpEF) constitutes nearly half of heart failure (HF) cases globally and primarily affects elderly populations. Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF is characterized by a baseline left ventricular ejection fraction (LVEF) equal to or greater than 50%. Despite normal or near-normal systolic function, patients with HFpEF suffer from significant morbidity and mortality due to a complex pathophysiology involving diastolic dysfunction, myocardial stiffness, systemic inflammation, and comorbidities.
Sudden cardiac death (SCD) and ventricular tachyarrhythmias are recognized fatal complications traditionally linked to HFrEF. However, in HFpEF, the role of LVEF changes over time as a predictor of lethal arrhythmias and mortality has been insufficiently studied. While baseline LVEF is a known marker for risk stratification in HF, the prognostic significance of a longitudinal decline in LVEF among HFpEF patients remains unclear. Understanding this relationship is critical, given that LVEF decline may indicate disease progression toward a more adverse phenotype, necessitating altered management strategies.
Study Design
This investigation utilized retrospective data from the CHART-2 (Chronic Heart Failure Analysis and Registry in the Tohoku District-2) Study, a large-scale observational registry encompassing patients with heart failure in Japan. A cohort of 1,453 patients initially diagnosed with HFpEF (defined as LVEF ≥50%) at registration was included. The mean age was 73 years, with women representing 39% of participants.
Patients were categorized based on their LVEF measured at a prespecified 1-year follow-up visit into three groups: those maintaining an LVEF ≥50% (n=1,316), those with a mild decline to LVEF 36–50% (n=120), and those with a severe decline to LVEF ≤35% (n=17).
The primary composite endpoint encompassed incident ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death (SCD). Assessment of all-cause mortality supplemented the endpoint analysis. Median duration of follow-up was 7.9 years, permitting evaluation of long-term outcomes.
Key Findings
During follow-up, 79 patients (5.4%) experienced the composite event of VT, VF, or SCD. Incidence was significantly higher among those whose LVEF declined below 50% at 1 year compared to those who preserved LVEF ≥50% (11.7% versus 4.8%, P < 0.001). All-cause mortality was also elevated in the LVEF decline group (62.8% vs. 51.8%, P = 0.006).
Crucially, after adjustment for confounding variables, a decline in LVEF to below 50% was independently associated with nearly double the risk of the composite endpoint (adjusted hazard ratio 1.99, 95% confidence interval 1.04–3.79, P = 0.04). This association highlights that even a mild reduction in LVEF in HFpEF patients portends increased vulnerability to fatal ventricular arrhythmias and sudden death.
Though the subgroup with LVEF ≤35% was small (n=17), this cohort similarly exhibited a heightened event rate, supporting a dose-response relationship between the degree of LVEF decline and adverse outcomes.
Expert Commentary
The CHART-2 study addresses a critical knowledge gap regarding longitudinal changes in cardiac function among patients traditionally classified as having preserved EF heart failure. The findings emphasize that HFpEF is a dynamic syndrome in which systolic function may deteriorate over time, conferring additional risk beyond initial diagnostic categorization.
Experts note practical implications: routine serial echocardiographic monitoring of LVEF is essential for risk stratification in HFpEF. Declines in LVEF should prompt reassessment of therapeutic strategy, including consideration for intensified medical therapy and possibly device therapy in select patients at risk of ventricular tachyarrhythmias.
Mechanistically, LVEF decline may reflect myocardial remodeling, fibrosis, or ischemic injury—factors known to predispose to arrhythmogenesis. These data also call into question the strict dichotomy between HFpEF and HFrEF, suggesting a continuum of systolic impairment contributing to mortality risk.
Limitations include retrospective design and potential residual confounding, as well as the relatively small number of patients with severe LVEF decline, which may limit generalizability. Nevertheless, the long median follow-up and adjustment for multiple covariates strengthen the validity of the conclusions.
Conclusion
This analysis from the CHART-2 Study demonstrates that in patients with HFpEF, even a mild decline in left ventricular ejection fraction to below 50% is independently associated with elevated risks of ventricular tachyarrhythmias, sudden cardiac death, and all-cause mortality. Clinical management of HFpEF should incorporate not only baseline LVEF assessment but also routine monitoring to detect and address declines in systolic function.
Future prospective studies are warranted to establish whether therapeutic interventions guided by serial LVEF measurement can improve arrhythmic outcomes and survival in this population. Clinicians should remain vigilant to LVEF changes during follow-up to optimize care for HFpEF patients.
References
1. Ito T, Noda T, Nochioka K, et al. Association of a mild or an important decline in left ventricular ejection fraction with ventricular tachyarrhythmias, sudden cardiac death and all-cause death in heart failure with preserved ejection fraction: A report from the CHART-2 Study. Europace. 2025 Aug 29:euaf184. doi: 10.1093/europace/euaf184. Epub ahead of print. PMID: 40879292.
2. Packer M. Utility and Limitations of Left Ventricular Ejection Fraction in Heart Failure Patients. J Am Coll Cardiol. 2020;75(20):2656-2661.
3. Shah SJ, Borlaug BA, Kitzman DW, et al. Research Priorities for Heart Failure with Preserved Ejection Fraction: National Heart, Lung, and Blood Institute Working Group Summary. Circulation. 2020;141(9):e615-e623.
