European Journal of Cardiovascular Medicine

Heart failure (HF) is a complex syndrome arising when the heart is unable to maintain adequate circulation to meet metabolic demands or does so only at elevated filling pressures. Left ventricular ejection fraction (LVEF) has traditionally stratified HF into reduced LVEF (HFrEF, <40%) and preserved LVEF (HFpEF, ≥50%).¹ In 2016, an intermediate category of heart failure with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) was introduced to capture patients who did not fit neatly into the established dichotomy. Since then, HFmrEF has emerged as a distinct phenotype warranting targeted study, with early registry data suggesting it shares characteristics with both HFrEF and HFpEF.^2,3

Observational studies have reported HFmrEF prevalence between 10% and 25% of HF cohorts in Europe and North America, with ischemic heart disease predominating as the underlying etiology. In these populations, HFmrEF patients often present at intermediate ages, display a mixed comorbidity profile, and experience outcomes that lie between those of HFrEF and HFpEF.⁴ Yet most large registries have underrepresented low- and middle-income regions, leaving critical gaps regarding HFmrEF in South Asia, where patients tend to develop HF at younger ages and with higher burdens of hypertension, diabetes, and coronary artery disease.^5,6

In India, data on HFmrEF are scant. Single-center studies from tertiary hospitals suggest HFmrEF accounts for approximately 20–26% of HF admissions, but these studies lack longitudinal follow-up and detailed characterization of outcomes.⁷ Moreover, regional variations in healthcare access, diagnostic capabilities, and treatment availability may influence both prevalence and prognosis. Without robust local data, clinicians must extrapolate from Western guidelines when managing HFmrEF in Indian patients, potentially leading to suboptimal care.⁸

Understanding the natural history of HFmrEF requires both cross-sectional and prospective analyses. Cross-sectional studies delineate prevalence and baseline characteristics, but they cannot capture LVEF transitions over time a key question, since HFmrEF may represent a transitional phase, with some patients progressing to HFrEF, some reverting to HFpEF, and others remaining stable.^7,8 Western longitudinal cohorts report that up to 30–40% of HFmrEF patients experience LVEF deterioration over one year, while 15–25% improve to HFpEF. These transitions have prognostic significance: patients whose LVEF declines generally have worse outcomes, whereas those whose LVEF improves tend to have lower mortality and rehospitalization rates.⁹

Major adverse cardiovascular events (MACE), including ischemic events, stroke, and arrhythmias, contribute substantially to morbidity and healthcare utilization in HFmrEF. Yet data on MACE rates within this subgroup are limited, particularly in South Asia. Quantifying one-year MACE alongside mortality and rehospitalization rates can inform risk stratification and management strategies, such as the need for aggressive secondary prevention or arrhythmia monitoring.^8,10

Given these knowledge gaps, a comprehensive prospective study in an Indian tertiary care center is warranted. Accurate phenotyping by LVEF is essential to determine the true burden of HFmrEF among acute decompensated HF admissions. Rigorous baseline characterization can help reveal unique features of HFmrEF in this population. Identifying predictors of LVEF transition and adverse outcomes such as ischemic burden, arrhythmic events, renal function, or biomarkers can enable personalized management strategies. The present study was designed with a primary aim to evaluate one-year all-cause and cardiovascular mortality as well as rehospitalization rates in HFmrEF patients presenting with acute decompensated heart failure. Secondary aims included (1) assessing the trajectory of LVEF over one year, (2) analyzing rates of MACE—composite ischemic events, stroke, and ventricular arrhythmias, (3) examining the transitional nature of HFmrEF and its prognostic consequences, and (4) identifying clinical, echocardiographic, and laboratory predictors of LVEF transition and adverse outcomes.

This prospective cohort study was conducted at the Department of Cardiology, Medical College Hospital, from March 2021 through April 2022, with follow-up extending to April 2023. Patients admitted with acute decompensated heart failure (ADHF) underwent baseline transthoracic echocardiography. After obtaining institutional ethical clearance and written informed consent, consecutive patients aged over 18 years presenting with acute decompensated heart failure (ADHF) were enrolled. Heart failure was confirmed using the Framingham criteria, and patients with incomplete baseline data or who declined participation were excluded.

Participants: Those with a left ventricular ejection fraction (LVEF) of 41–49% which met criteria for heart failure with mildly reduced ejection fraction (HFmrEF) were eligible. Inclusion criteria comprised age ≥18 years, Framingham criteria confirmation of heart failure, baseline LVEF 41–49%, and written informed consent for longitudinal evaluation. Exclusion criteria included refusal of consent, anticipated noncompliance with follow-up, or loss to follow-up before study completion.

Sample size: Sample size calculation was based on a published HFmrEF prevalence of 17.8% in a similar registry, yielding a requirement of 230 patients to achieve 95% confidence with 5% precision. 

Procedure: At enrollment, demographic data, medical history, comorbidities, and heart failure etiology were recorded. Laboratory evaluations included serum creatinine, blood urea nitrogen, lipid profile, and liver function tests. Echocardiography was performed using a Philips EPIQ7C machine with an M4S transducer, and LVEF was calculated by Simpson’s biplane method according to American Society of Echocardiography guidelines. All participants received guideline-directed medical therapy for heart failure.

Participants were scheduled for follow-up visits at 3, 6, and 12 months. When in-person visits were not possible, structured telephone interviews were conducted. Data collected during follow-up included vital status, cause of death (ascertained from hospital records or death certificates), hospital readmissions (with reasons and durations), and occurrence of major adverse cardiovascular events (MACE)—defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. At 12 months, repeat echocardiography was performed to reassess LVEF and categorize patients as having progressed to HFrEF (LVEF < 40%), remained HFmrEF (LVEF 41–49%), or improved to HFpEF (LVEF ≥ 50%).The primary endpoints were one-year all-cause mortality, cardiovascular mortality, and heart failure rehospitalization. Secondary endpoints included incidence of MACE and LVEF transition categories.

Statistical Analysis: Statistical analysis was performed using appropriate software packages. Continuous variables were expressed as mean ± SD and compared using paired t-tests. Categorical variables were presented as counts and percentages and compared using chi-square tests. Kaplan–Meier survival curves were constructed for time-to-event outcomes, and Cox proportional hazards regression identified independent predictors of mortality and rehospitalization. Statistical analyses were performed using SPSS v25, and a two-sided p < 0.05 was considered significant. The Institutional Ethics Committee approved the protocol, and all subjects provided written informed consent.

Table 1: One-Year Mortality and Rehospitalization in HFmrEF

Table 1 describes one‐year all‐cause and cardiovascular mortality alongside rehospitalization rates in the HfmrEF cohort. Among 59 patients, 8 (13.6%) died from any cause over 12 months, of whom 6 (10.2%) succumbed to cardiovascular events and 2 (3.4%) died of noncardiac causes. Rehospitalizations occurred in over half the cohort (52.5%), with 18 patients (30.5%) readmitted specifically for heart failure. These findings underscore the substantial risk of both mortality and recurrent decompensation in HfmrEF, highlighting the need for vigilant follow-up and optimization of medical therapy to reduce hospital readmissions.

Table 2: Major Adverse Cardiovascular Events (MACE) at One Year

Table 2 details major adverse cardiovascular events (MACE) within one year. A composite MACE endpoint occurred in 31 patients (52.5%), driven by ischemic events in 7 (11.9%), stroke in 4 (6.8%), and ventricular tachycardia in 2 (3.4%). The high composite MACE rate reflects the multifaceted cardiovascular risk in HFmrEF, where ischemic and arrhythmic complications contribute significantly to morbidity. Targeted risk factor modification, antithrombotic strategies, and arrhythmia surveillance may therefore be critical components of comprehensive care in this group.

Table 3: Left Ventricular Ejection Fraction Trajectory at One Year

Table 3 presents the trajectory of left ventricular ejection fraction over one year. Of the 59 HFmrEF patients, 18 (30.5%) experienced a decline in LVEF into the HFrEF range (<40%), 27 (45.8%) remained stable within 41–49%, and 14 (23.7%) improved to the HFpEF range (≥50%). This distribution illustrates the transitional nature of HFmrEF, with substantial proportions deteriorating or improving, reinforcing the importance of serial imaging to guide therapy adjustments and prognostic counseling.

Table 4: Cardiac Mortality Causes in HFmrEF Group (n = 6)

Table 4 breaks down the specific causes of cardiac mortality among the 6 cardiovascular deaths. Half of these deaths (3/6) were due to ischemic events, while one each (16.7%) resulted from ventricular tachycardia, progressive heart failure, and stroke. These data highlight the diverse mechanisms leading to fatal outcomes in HFmrEF, emphasizing the imperative to address both ischemia and arrhythmia risks, optimize heart failure treatment, and implement secondary prevention strategies to reduce cardiac mortality in this intermediate‐EF population.

Figure 1: Kaplan–Meier Curve of One-Year Cardiac Survival in HFmrEF Patients

This survival curve illustrates cardiac-specific survival over 12 months among patients with heart failure with mildly reduced ejection fraction. The cumulative survival remains at 100% through four months, declines to 98% at month 4, 95% at month 6, and stabilizes at 90% from month 8 onward. These results indicate that most cardiac deaths occurred between four- and eight-months post-enrolment, resulting in a 90% cardiac survival rate at one year.

HFmrEF occupies a diagnostic and therapeutic gray zone between HFrEF and HFpEF. Emerging evidence suggests that HFmrEF patients share both ischemic etiologies and treatment responses characteristic of HFrEF, as well as demographic and comorbidity profiles akin to HFpEF. However, regional data from South Asia is scarce with our study being conducted to address this gap by delineating the clinical features and outcomes of HFmrEF in an Indian tertiary care setting, providing context for subsequent comparative analyses.

The one‐year outcomes for HFmrEF patients in our cohort reveal a notable burden of both mortality and rehospitalization. With 13.6% all‐cause mortality and 10.2% cardiovascular mortality, our results are consistent with Zhang et al., who reported 12% one‐year mortality in a Chinese HFmrEF cohort, and Li et al., who found 11% cardiovascular deaths in the China‐HF registry.^11,12 Noncardiac mortality (3.4%) underscores the importance of comorbidity management. The 52.5% rehospitalization rate, including 30.5% for recurrent heart failure, parallels the 50% readmission rate reported by Thomas et al. in the Trivandrum registry, highlighting that more than half of HFmrEF patients experience clinical deterioration within a year.¹³ These high event rates emphasize that HFmrEF is not a benign intermediary phenotype but one requiring intensive follow‐up, optimization of guideline‐directed therapies, and proactive strategies such as remote monitoring and early intervention to mitigate rehospitalizations and improve survival.¹⁴

The composite MACE rate of 52.5% at one year underscores the high burden of adverse cardiovascular events in HFmrEF patients, with ischemic events (11.9%), stroke (6.8%), and ventricular tachycardia (3.4%) contributing significantly to morbidity. These findings align with Feng et al.’s multicenter Asian study, which reported a 48% composite MACE rate in HFmrEF over one year, driven largely by recurrent ischemia and arrhythmias.¹⁵ Similarly, Zhang et al. observed 53% MACE in HFmrEF patients, with ischemic cardiovascular events accounting for 12% and cerebrovascular accidents for 5%.¹¹ The occurrence of ventricular tachycardia, though less frequent, emphasizes the arrhythmic risk inherent in this phenotype, as noted by Kozman et al. in the SwedeHF registry, where 4% of HFmrEF patients experienced serious ventricular arrhythmias requiring intervention.¹⁶ Collectively, these data highlight the need for comprehensive preventive strategies in HFmrEF, including aggressive management of atherosclerotic risk factors, tailored antithrombotic and anticoagulation regimens to mitigate stroke risk, and vigilant arrhythmia monitoring and therapy to reduce sudden cardiac events.

The LVEF trajectory data reveal the highly dynamic nature of HFmrEF, with 30.5% of patients deteriorating to HFrEF, 45.8% remaining stable within the mid-range category, and 23.7% improving to HFpEF over one year. These findings closely align with an observational study which reported that of HFmrEF patients who transitioned, 56.4% moved to the HFpEF category, while 43.6% declined to HFrEF.¹⁷ Similarly, Gu et al. reported that HFmrEF patients exhibited the greatest LVEF variability among all heart failure phenotypes, with substantial bidirectional transitions over follow-up.¹⁸ The relatively high rate of deterioration (30.5%) parallels findings from previously published evidence, which noted that 25-39% of HFmrEF patients experience LVEF decline, often associated with diabetes, ischemic heart disease, and higher symptom severity.¹⁹ Conversely, the 23.7% improvement rate is consistent with studies showing that younger patients, females, those with non-ischemic etiology, and those receiving optimal guideline-directed medical therapy are more likely to experience LVEF recovery.²⁰ These transition patterns underscore the critical importance of serial echocardiographic monitoring in HFmrEF patients, as LVEF trajectory carries significant prognostic implications with deterioration associated with increased mortality and hospitalization, while improvement confers better outcomes and may influence decisions regarding device therapy and intensity of medical management.

The distribution of cardiac mortality causes in our HFmrEF cohort underscores the heterogeneous pathways to fatal outcomes. Ischemic events accounted for 50% of cardiovascular deaths, mirroring findings in Zhang et al.’s Chinese cohort where myocardial infarction was the leading cause of death among HFmrEF patients.¹¹ The occurrence of ventricular tachycardia in 16.7% of cardiac deaths highlights the arrhythmic risk, consistent with Kozman et al.’s SwedeHF registry report of sudden cardiac death and malignant arrhythmias in 18% of HFmrEF fatalities.¹⁶ Progressive heart failure as a cause of death (16.7%) aligns with data from Savarese et al., who noted pump failure as a significant mortality driver in mid‐range EF patients, albeit to a lesser extent than in HFrEF.⁴ The stroke‐related death (16.7%) reflects the cerebrovascular risk in HFmrEF, similar to Li et al.’s finding of stroke contributing to 15% of cardiovascular mortality in the China‐HF registry.¹² These varied mechanisms underscore the necessity of comprehensive management encompassing revascularization, optimized heart failure therapies, vigilant arrhythmia monitoring, and stroke prevention strategies to reduce mortality in this intermediate EF population.

The Kaplan–Meier curve demonstrates that cardiac survival among HFmrEF patients remains at 100% for the first four months, declines modestly to 98% at month 4 and 95% at month 6, and then plateaus at 90% from month 8 through one year. This pattern highlights a concentrated period of cardiac mortality between four- and eight-months post‐enrolment, after which no additional cardiac deaths occurred.²¹ These findings underscore the critical window for intensified surveillance and intervention early in follow‐up to maximize one‐year cardiac survival in HFmrEF patients.

The study’s single‐center design at a tertiary care hospital may limit generalizability to community and primary‐care settings. The modest sample size of 59 HFmrEF patients constrains statistical power for subgroup analyses and multivariable modeling. Follow‐up was limited to one year, precluding long‐term outcome assessment and late LVEF transitions. Additionally, unmeasured confounders—such as socioeconomic status, adherence to therapy, and biomarker levels—could influence outcomes but were not systematically captured. Consecutive enrollment and standardized echocardiographic assessment ensured a representative HFmrEF cohort and reliable LVEF measurement. The prospective design with rigorous one‐year follow‐up allowed comprehensive capture of mortality, rehospitalization, MACE, and LVEF trajectory. Detailed characterization of ischemic burden, arrhythmic events, and valvular pathology provided nuanced insights into HFmrEF pathophysiology in a South Asian population, filling a critical gap in regional HF literature.

The high rates of mortality (13.6%), rehospitalization (52.5%), and MACE (52.5%) underscore that HFmrEF is a clinically serious phenotype requiring aggressive management. Predominant ischemic etiology, concentrated cardiac deaths between four and eight months, and substantial LVEF transitions highlight the need for early intensive surveillance, guideline‐directed medical therapy akin to HFrEF protocols, timely revascularization, arrhythmia monitoring, and serial imaging to guide therapeutic adjustments and secondary prevention strategies in HFmrEF patients.

Heart failure with mildly reduced ejection fraction represents one‐quarter of acute decompensated HF admissions in our South Indian cohort, carrying substantial morbidity and mortality. A 13.6% one‐year mortality and 52.5% rehospitalization rate, coupled with a 52.5% MACE rate and significant LVEF transitions, underscore HFmrEF’s clinical seriousness. Predominant ischemic etiology, arrhythmic risk, and early mortality between four and eight months highlight the necessity for aggressive, HFrEF‐aligned therapies, vigilant arrhythmia surveillance, timely revascularization, and serial imaging to optimize patient outcomes.

1. Istratoaie S, Frost CL, Donal E. Non-Invasive Hemodynamic Assessment of Heart Failure With Preserved Ejection Fraction. Korean Circ J. 2025;55(3):165-184.
2. Andronic AA, Mihaila S, Cinteza M. Heart Failure with Mid-Range Ejection Fraction - a New Category of Heart Failure or Still a Gray Zone. Maedica (Bucur). 2016;11(4):320-324.
3. Nair A, Tuan LQ, Jones-Lewis N, Raja DC, Shroff J, Pathak RK. Heart Failure with Mildly Reduced Ejection Fraction: A Phenotype Waiting to Be Explored. Journal of Cardiovascular Development and Disease. 2024;11(5):148.
4. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol. 2022;19(2):100-116.
5. Ang N, Chandramouli C, Yiu K, Lawson C, Tromp J. Heart Failure and Multimorbidity in Asia. Curr Heart Fail Rep. 2023;20(1):24-32.
6. Agbor VN, Ntusi NAB, Noubiap JJ. An overview of heart failure in low- and middle-income countries. Cardiovasc Diagn Ther. 2020;10(2):244-251.
7. Shukkoor AA, George NE, Radhakrishnan S, Velusamy S, Gopalan R, Kaliappan T, et al. Clinical characteristics and outcomes of patients admitted with acute heart failure: insights from a single-center heart failure registry in South India. Egypt Heart J. 2021;73(1):38.
8. Omer MH, Shchendrygina A, Ahmad O, Saldarriaga C, Goldfeder de Gracia S, Alhussain M, et al. Differences in the management of heart failure with preserved ejection fraction among physicians from Europe, the Middle East and North Africa: an international survey. Open Heart. 2025;12(2):e003548.
9. Stoicescu L, Crişan D, Morgovan C, Avram L, Ghibu S. Heart Failure with Preserved Ejection Fraction: The Pathophysiological Mechanisms behind the Clinical Phenotypes and the Therapeutic Approach. International Journal of Molecular Sciences. 2024;25(2):794.
10. Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(1):241.
11. Zhang Y, Gao C, Greene SJ, Greenberg BH, Butler J, Yu J, et al. Clinical performance and quality measures for heart failure management in China: the China‐Heart Failure registry study. Esc Heart Failure. 2022;10(1):342–52.
12. Feng J, Zhang Y, Zhang J. Epidemiology and Burden of Heart Failure in Asia. JACC Asia. 2024;4(4):249-264.
13. Shukkoor AA, George NE, Radhakrishnan S, Velusamy S, Gopalan R, Kaliappan T, et al. Clinical characteristics and outcomes of patients admitted with acute heart failure: insights from a single-center heart failure registry in South India. Egypt Heart J. 2021;73(1):38.
14. Bak M, Choi JO. Optimization of guideline-directed medical treatment for heart failure patients with reduced ejection fraction. Korean J Intern Med. 2023;38(5):595-606.
15. He F, Page JH, Tandi J, Ghosh A, Liman C, Sarkar J, et al. Major Adverse Cardiovascular Event Risk Prediction in Asian Patients After Myocardial Infarction: A Novel, Dynamic, Machine-learning Approach. J Asian Pac Soc Cardiol. 2023;2:e25.
16. Kozman K, Giulia Ferrannini, Benson L, Ulf Dahlström, Hage C, Savarese G, et al. Etiology of Heart Failure Across the Ejection Fraction Spectrum and Association With Prognosis. JACC Heart Failure. 2025;13(8):102491–1.
17. Webb J, Draper J, Fovargue L, Sieniewicz B, Gould J, Claridge S, et al. Is heart failure with mid range ejection fraction (HFmrEF) a distinct clinical entity or an overlap group? IJC Heart & Vasculature. 2018;21:1–6.
18. Gu J, Yin ZF, Zhang HL, Fan YQ, Zhang JF, Wang CQ. Characteristics and outcomes of transitions among heart failure categories: a prospective observational cohort study. ESC Heart Fail. 2020;7(2):616-625.
19. Liu Z, Zhu Y, Zhang L, Wu M, Huang H, Peng K, et al. Impact of signs and symptoms on the prognosis of patients with HFmrEF. BMC Cardiovascular Disorders. 2023;23(1):420.
20. Oommen SG, Man RK, Talluri K, Nizam M, Kohir T, Aviles MA, et al. Heart Failure With Improved Ejection Fraction: Prevalence, Predictors, and Guideline-Directed Medical Therapy. Cureus. 2024;16(6):e61790.
21. Wu Y, Cheng Y, Fu S, Yuan J, Shen J, Cai S. Risk analysis of cardiac disease mortality within 3 months in patients with lung cancer after surgery: A real-world cohort study. J Int Med Res. 2025;53(9):3000605251378947.