European Journal of Cardiovascular Medicine

Heart failure (HF) represents a major and growing public health challenge worldwide, exerting profound clinical, economic, and societal burdens. Characterized by the heart’s inability to pump sufficient blood to meet metabolic demands, HF manifests along a continuum of left ventricular (LV) ejection fraction (EF).^1,2 Historically, HF was dichotomized into reduced EF (HFrEF, EF < 40%) and preserved EF (HFpEF, EF ≥ 50%). However, the 2016 European Society of Cardiology guidelines and subsequent international consensus introduced a mid‐range category such as heart failure with mildly reduced ejection fraction (HFmrEF), defined by an EF of 41–49% to acknowledge the unique clinical characteristics and therapeutic uncertainties of this intermediate group.³

The recognition of HFmrEF has stimulated considerable debate regarding its pathophysiology, prognosis, and optimal management. Early observational studies suggested that HFmrEF shares features with both HFrEF and HFpEF, leading some investigators to view it as a transitional phase rather than a distinct phenotype.⁴ Patients with HFmrEF often exhibit ischemic heart disease, intermediate levels of neurohormonal activation, and variable responses to guideline‐directed medical therapies. In clinical trials, outcomes for HFmrEF have frequently fallen between those of HFrEF and HFpEF, but data are limited by underrepresentation and heterogeneous definitions across studies. This uncertainty underscores the need to characterize the epidemiology and natural history of HFmrEF, particularly in under‐studied populations.⁵

In India, the burden of HF is compounded by a rapidly aging population, rising prevalence of risk factors such as hypertension, diabetes, and coronary artery disease, and constrained healthcare resources. Epidemiological data on HF phenotypes in South Asia remain sparse, with few large‐scale studies delineating the distribution of HFrEF, HFmrEF, and HFpEF in real‐world settings. Published registries from Europe and North America have estimated HFmrEF prevalence at 10–25%, but whether similar proportions exist in Indian cohorts—where patients tend to present at younger ages and with more advanced comorbidities—is unclear. Furthermore, regional variations in HF etiology, notably a higher prevalence of ischemic heart disease and rheumatic heart disease in South Asia, may influence the relative frequencies and clinical profiles of EF subtypes.^3,6

Accurate phenotyping of HF is critical for guiding management strategies. Established therapies for HFrEF, including angiotensin‐converting enzyme inhibitors, beta‐blockers, and mineralocorticoid receptor antagonists, have demonstrated survival benefits, yet their efficacy in HFmrEF remains inadequately tested. Conversely, therapeutic approaches for HFpEF have largely focused on symptomatic relief, with limited evidence of mortality reduction. For HFmrEF patients, who often fall outside major randomized trials treatment decisions are frequently extrapolated from HFrEF or HFpEF paradigms, potentially leading to suboptimal care. Therefore, understanding the prevalence and clinical characteristics of HFmrEF in diverse settings is a prerequisite for designing targeted interventional studies and developing evidence‐based guidelines.^7,8

Beyond therapeutic implications, insight into the demographic and phenotypic profile of HFmrEF patients informs prognosis and health‐system planning. Age, sex, comorbidity burden, and etiology influence hospitalization rates, resource utilization, and long‐term outcomes. In many Indian tertiary care centers, acute decompensated HF patients are disproportionately younger and exhibit high rates of ischemic heart disease, hypertension, and diabetes. These factors not only shape the initial presentation but also affect readmission and mortality risks, highlighting the need for region‐specific data to tailor preventive and management strategies.^9,10

Despite the clinical importance of HFmrEF, few studies have comprehensively described its prevalence and characteristics in India. Existing literature often aggregates HF subtypes or focuses solely on HFrEF, leaving a knowledge gap regarding the mid‐range group. Moreover, most prior research originates from single-center experiences with small sample sizes, limiting generalizability. A systematic, well‐powered cross‐sectional analysis of consecutive acute decompensated HF admissions would address this gap by providing robust prevalence estimates, delineating demographic and etiological patterns, and comparing HFmrEF with HFrEF and HFpEF cohorts within the same healthcare environment. This study was therefore undertaken at a tertiary care cardiology center in Southern India to define the proportion of HFmrEF among patients presenting with acute decompensated HF.

A hospital-based cross-sectional observational study was conducted in the Department of Cardiology at the Medical College Hospital between March 2021 and April 2022 to estimate the prevalence and characterize the clinical profile of HFmrEF. After obtaining institutional ethical clearance and written informed consent, 230 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: Patients aged over 18 years presenting with acute decompensated heart failure (ADHF) and meeting the Framingham criteria for heart failure were eligible for inclusion. All participants provided written informed consent and underwent baseline evaluation, including echocardiographic measurement of left ventricular ejection fraction. Patients were excluded if they declined consent, had incomplete baseline clinical or imaging data, or were otherwise unable to complete the initial assessment.

Sample Size: Sample size is calculated based on CSI-Kerala Acute Heart Failure Registry (CSIKAHFR) data by Stigi et al, which was presented in, scientific sessions, AHA 2019, which showed heart failure with mid-range ejection fraction (HFmrEF) prevalence of 17.8%.¹¹ The calculation yielding a requirement of 230 patients to achieve 95% confidence with 5% precision.

Interventions: Each participant underwent a detailed baseline assessment that included demographic data, medical history, comorbidities, clinical presentation, and laboratory tests which included renal function, lipid profile, and liver enzymes recorded on a structured proforma. Transthoracic echocardiography was performed using a Philips EPIQ7C machine with an M4S transducer, and left ventricular ejection fraction (LVEF) was measured by Simpson’s biplane method. Patients were stratified into HFrEF (LVEF < 40%), HFmrEF (LVEF 41–49%), and HFpEF (LVEF ≥ 50%) groups.

Statistical Analysis: Statistical analyses were carried out using SPSS software: continuous variables were expressed as mean ± SD and compared using one-way ANOVA, while categorical variables were reported as proportions and analyzed using the chi-square test. A p value < 0.05 was considered statistically significant

Figure 1: Distribution of Heart Failure Phenotypes (n = 230)

HFrEF: Heart Failure with Reduced Ejection Fraction; HFmrEF: Heart Failure with Mildly Reduced Ejection Fraction; HFpEF: Heart Failure with Preserved Ejection Fraction

Figure 1 shows that in a cohort of 230 patients with acute decompensated heart failure, heart failure with reduced ejection fraction (HFrEF) was the most common phenotype, seen in 107 patients (46.5%). Heart failure with mildly reduced ejection fraction (HFmrEF) was diagnosed in 59 patients (25.7%), while heart failure with preserved ejection fraction (HFpEF) was observed in 64 patients (27.8%).

Table 1: Demographic and Clinical Characteristics of HFmrEF Patients (n = 59)

NYHA: New York Heart Association (Functional Class); BMI: Body Mass Index; eGFR: Estimated Glomerular Filtration Rate.

Among patients with HFmrEF (n=59), the mean age was 59 years with a standard deviation of 14 years, and males accounted for 76.3% (45/59). Dyspnea was the predominant symptom, present in 93.2% of these patients. The majority of patients were classified as New York Heart Association (NYHA) functional class II (78.0%). Peripheral edema was observed in 30.5% of HFmrEF patients. The mean body mass index (BMI) was 25.3 ± 3.8 kg/m², and mean estimated glomerular filtration rate (eGFR) was 76.4 ± 25.8 mL/min/1.73m². (Table 1)

Table 2: Etiology and Risk Factors in HFmrEF Patients (n = 59)

AWMI: Anterior Wall Myocardial Infarction; IWMI: Inferior Wall Myocardial Infarction; NSTEMI: Non-ST Elevation Myocardial Infarction

The etiology and risk factors in the HFmrEF group showed a high prevalence of ischemic heart disease (74.6%). Among ischemic events, anterior wall myocardial infarction (AWMI) was the most common (39.0%), followed by non-ST elevation myocardial infarction (NSTEMI) (16.9%), inferior wall myocardial infarction (IWMI) (10.2%), and unstable angina (8.5%). Hypertension and diabetes mellitus were prevalent in 62.7% and 45.8% of patients respectively, whereas dyslipidemia and smoking history were noted in 20.3% each. (Table 2)

Table 3: Comparison of Ischemic Heart Disease Prevalence Across HF Phenotypes

HFrEF: Heart Failure with Reduced Ejection Fraction; HFmrEF: Heart Failure with Mildly Reduced Ejection Fraction; HFpEF: Heart Failure with Preserved Ejection Fraction

Comparing ischemic heart disease (IHD) prevalence across heart failure phenotypes revealed that IHD was significantly more common in HFmrEF (74.6%) than in HFpEF (42.2%) (p = 0.01). The prevalence in HFrEF was 66.4%. (Table 3)

Table 4: Electrocardiographic and Echocardiographic Findings in HFmrEF (n = 59)

LVH: Left Ventricular Hypertrophy; ECG: Electrocardiogram

Within HFmrEF patients, electrocardiographic left ventricular hypertrophy (LVH) was seen in 18.7% (11/59), which was significantly different compared to other HF groups (p = 0.033). Regional wall motion abnormalities in the left anterior descending (LAD) artery territory were present in 37.8% of patients (p < 0.001). Valvular heart disease was identified in 12.5% of HFmrEF patients, with statistical significance compared to other groups (p = 0.006). (Table 4).

HFmrEF, defined as left ventricular ejection fraction of 41–49%, was introduced in the 2016 European Society of Cardiology guidelines to acknowledge an intermediate phenotype between reduced and preserved EF. Global registries report HFmrEF prevalence of 10–25% among heart failure cohorts, with ischemic heart disease predominating, but data from South Asia remain scarce.¹² Patients in India often present at younger ages with high rates of hypertension, diabetes, and coronary artery disease, potentially altering phenotype distributions.⁵ Accurate characterization of HFmrEF is critical, as emerging evidence suggests these patients may derive benefit from therapies established for reduced EF and exhibit outcomes distinct from both reduced and preserved EF groups. Understanding the prevalence, demographic profile, and clinical characteristics of HFmrEF within Indian populations is therefore essential to guide tailored management strategies, inform guideline development, and optimize resource allocation in regions facing a growing cardiovascular disease burden.

The phenotype distribution in our cohort was 46.5% (HFrEF), 25.7% (HFmrEF), and 27.8% (HFpEF) which aligns closely with large international registries. In the ESC‐HF‐LT registry, Savarese G et al reported 60% HFrEF, 24% HFmrEF, and 16% HFpEF among 12,440 patients, highlighting a somewhat higher HFrEF burden but comparable mid‐range prevalence.¹³ Similarly, Stolfo D et al.’s analysis of 47 072 Swedish HF patients found 53% HFrEF, 23% HFmrEF, and 24% HFpEF, underlining stable phenotype proportions in Western populations.¹⁴ The Trivandrum Heart Failure Registry led by Shukkoor AA et al. observed 65.9% HFrEF, 20.0% HFmrEF, and 14.0% HFpEF in an Indian cohort, suggesting regional variation with lower HFmrEF and HFpEF rates yet a persistently dominant HFrEF phenotype.¹⁵ Zhang et al. described 56% HFrEF, 22% HFmrEF, and 22% HFpEF in a Chinese multicenter study, while Li et al. reported 49% HFrEF, 22% HFmrEF, and 29% HFpEF in the China‐HF registry, both echoing our balanced phenotype distribution.^16,17

The demographic and clinical characteristics of our HFmrEF cohort closely align with established patterns reported in international literature. Our finding of a mean age of 59 ± 14 years and 76.3% male predominance is consistent with Özlek et al., who noted that HFmrEF patients tend to be younger and more predominantly male compared to HFpEF patients.¹⁸ Similar age demographics were reported by Zhang et al. in a Chinese cohort (mean age 61 ± 13 years, 72% male) and by Matsumoto et al. in the PARADIGM-HF analysis, where younger age was characteristic of heart failure patients across ejection fraction categories.^16,19 The male predominance in HFmrEF aligns with findings from the Swedish Heart Failure Registry, where 60.8% of 9,019 HFmrEF patients were male, and the APOLLON study, which reported 57.7% male predominance in their HFmrEF group.^13,18

The near-universal presence of dyspnea in our cohort (93.2%) mirrors the typical symptomatic presentation described across heart failure phenotypes, with dyspnea being the cardinal symptom regardless of ejection fraction category. Our observation that 78.0% of patients were NYHA class II reflects the intermediate severity profile characteristic of HFmrEF, where patients demonstrate functional limitations that are typically less severe than those seen in advanced HFrEF but more pronounced than stable HFpEF presentations. The prevalence of peripheral edema (30.5%) in our study falls within the expected range for heart failure patients, as noted in various registries where edema presentations vary based on volume status and therapeutic interventions at time of assessment.^20,21

The mean BMI of 25.3 ± 3.8 kg/m² in our HFmrEF patients is comparable to findings reported in other contemporary studies. Özlek et al. found similar BMI values in their HFmrEF cohort, and Matsumoto et al. noted that BMI patterns in heart failure patients often reflect regional dietary and lifestyle factors.^18,19 Our preserved kidney function with mean eGFR of 76.4 ± 25.8 mL/min/1.73m² is particularly noteworthy, as chronic kidney disease is frequently associated with heart failure across all ejection fraction categories. Previously published evidence demonstrated that eGFR below normal values is strongly associated with mortality in heart failure patients, making our relatively preserved renal function a potentially favorable prognostic indicator. The maintenance of adequate kidney function in our HFmrEF cohort may reflect earlier disease recognition or more effective management of comorbidities that typically contribute to cardiorenal syndrome progression.²²

The high prevalence of ischemic heart disease (74.6%) in our HFmrEF cohort strongly aligns with international registries and reinforces the established pattern that HFmrEF shares more etiological similarities with HFrEF than HFpEF. This finding is remarkably consistent with Savarese et al.'s comprehensive review, which demonstrated ischemic heart disease as the predominant etiology in HFmrEF patients across multiple studies, and the ESC-HF-LT Registry's finding of 41.8% ischemic prevalence in HFmrEF compared to only 23.7% in HFpEF.¹³ The predominance of anterior wall myocardial infarction (39.0%) in our study reflects the substantial myocardial injury typically associated with left anterior descending artery occlusion and aligns with Tromp J et al.'s observation that HFmrEF patients frequently have previous myocardial infarction and are more likely to be hospitalized for acute coronary syndrome.²³ Our comorbidity prevalence—hypertension (62.7%) and diabetes mellitus (45.8%)—closely mirrors international patterns, with Sinan et al. reporting 78% hypertension in Turkish HFmrEF patients and Pop-Busui et al. demonstrating 40-47% diabetes prevalence across heart failure phenotypes, particularly in Asian populations reaching 44.2%.^24,25 The relatively lower prevalence of dyslipidemia and smoking (20.3% each) compared to some Western registries may reflect regional differences, but these findings collectively support the conceptual framework of HFmrEF as an intermediate, predominantly ischemic phenotype that bridges HFrEF and HFpEF, as demonstrated by Kozman et al.'s recent SwedeHF registry analysis showing ischemic etiology dominance in both HFrEF and HFmrEF.²⁶

Our finding that ischemic heart disease was significantly more prevalent in HFmrEF (74.6%) compared to HFpEF (42.2%; p=0.01) while showing similar rates to HFrEF (66.4%) strongly reinforces the established pattern that HFmrEF shares more etiological similarities with HFrEF than HFpEF, as extensively documented in the literature. Savarese et al.'s comprehensive review emphasized that HFmrEF demonstrates "high prevalence of ischemic heart disease" and is "more similar to HFrEF in others, in particular with regard to the high prevalence of ischaemic heart disease in these patients", while Li et al. demonstrated that HFmrEF patients had significantly higher rates of coronary artery disease compared to HFpEF patients in their comparative analysis.^13,17 This ischemic predominance supports Tromp et al.'s global registry findings showing that ischemic etiology dominates in HFmrEF across diverse populations.²³ The presence of electrocardiographic left ventricular hypertrophy in 18.7% of our HFmrEF patients, significantly different from other phenotypes (p=0.033), aligns with established patterns of structural remodeling in ischemic heart disease. Bristow et al. demonstrated that eccentric pathologic hypertrophy is the most common ventricular myocardial disease process causing heart failure in patients under 75 years, characterized by increased LV volumes and progressive contractile dysfunction, which is consistent with the LVH patterns observed in our ischemic-predominant HFmrEF cohort.²⁷ The high prevalence of regional wall motion abnormalities in the LAD territory (37.8%; p<0.001) provides crucial pathophysiological insights, as Espersen et al. demonstrated that wall motion abnormalities in any regional LV wall are independently associated with incident heart failure development.²⁷ The predominance of LAD territory involvement mirrors our finding of anterior wall myocardial infarction being the most common ischemic event (39.0%), as anterior wall infarctions typically result from LAD occlusion and are associated with larger areas of myocardial damage and higher likelihood of subsequent ventricular dysfunction. Finally, the identification of valvular heart disease in 12.5% of HFmrEF patients with statistical significance (p=0.006) reflects the etiological heterogeneity characteristic of this intermediate phenotype, as valvular disease can contribute to the development of mildly reduced ejection fraction through chronic volume or pressure overload mechanisms, distinguishing HFmrEF from the predominantly ischemic HFrEF and hypertensive/diastolic HFpEF phenotypes.²³

The study's primary limitation is its single-center design from a tertiary care facility, which may limit generalizability to broader populations and primary care settings. The cross-sectional nature precludes assessment of temporal changes in ejection fraction or long-term outcomes, while the sample size of 59 HFmrEF patients, though adequate for prevalence estimation, may be insufficient for robust subgroup analyses. However, the study provides significant advantages through its consecutive patient enrollment, standardized echocardiographic assessments using established guidelines, and comprehensive clinical characterization of an understudied population in South Asia. The clinical implications are substantial: the 25.7% HFmrEF prevalence establishes regional epidemiological data crucial for healthcare planning, while the high ischemic burden (74.6%) supports treating HFmrEF patients with guideline-directed medical therapies established for HFrEF rather than approaches used for HFpEF. The predominance of anterior wall myocardial infarction and LAD territory wall motion abnormalities provides pathophysiological insights that may guide revascularization strategies. Most importantly, the demonstrated similarities between HFmrEF and HFrEF regarding ischemic etiology, demographic profile, and structural abnormalities support the emerging consensus that HFmrEF represents an intermediate phenotype requiring targeted therapeutic approaches rather than being classified as a transitional state between distinct entities.

HFmrEF affects one-quarter of acute heart failure patients in our South Indian cohort, predominantly affecting middle-aged males with high ischemic burden. The similarities between HFmrEF and HFrEF regarding demographics, etiology, and structural abnormalities support targeted therapeutic approaches. This phenotype's distinct characteristics from HFpEF underscore the importance of ejection fraction-based classification for optimal management strategies and clinical decision-making.

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