Prevalence and prognosis of aortic valve diseases in patients hospitalized with heart failure with mildly reduced ejection fraction.

AIMS: Data regarding the characterization and outcomes of patients with heart failure (HF) with mildly reduced ejection fraction (HFmrEF) is scarce. This study investigates the characteristics and prognostic impact of native aortic valve diseases (AVD) in patients with HFmrEF. METHODS AND RESULTS: Consecutive patients hospitalized with HFmrEF (i.e. left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. The prognostic impact of native aortic valve stenosis (AS), aortic valve regurgitation (AR) and mixed AVD (MAVD) was investigated for the primary endpoint of long-term all-cause mortality during a median follow-up of 30 months. Kaplan-Meier, univariable and multivariable Cox proportional analyses were applied. From a total of 2106 patients hospitalized with HFmrEF, the prevalence of AS and AR was 16.5% and 31.2%, respectively (MAVD 7.8%). The presence of moderate/severe AS was associated with a higher risk of long-term all-cause mortality (44.8% vs. 28.7%; p = 0.001) and HF-related rehospitalization (18.6% vs. 12.0%; p = 0.001), even after multivariable adjustment (mortality: hazard ratio [HR] 1.320; 95% confidence interval [CI] 1.035-1.684; p = 0.025; HF-related rehospitalization: HR 1.570; 95% CI 1.101-2.241; p = 0.013). Interestingly, even mild AS was associated with increased risk of long-term all-cause mortality compared to patients without AS (HR 1.477; 95% CI 1.101-1.982; p = 0.009). In contrast, the presence of AR was not associated with long-term outcomes after multivariable adjustment. CONCLUSIONS: The presence of AS, but not AR, was independently associated with increased risk of all-cause mortality and HF-related rehospitalization in patients with HFmrEF. Even milder stages of AS were associated with impaired prognosis.

Prognosis and Treatment Strategies for Atrial Fibrillation in Heart Failure with Mildly Reduced Ejection Fraction.

OBJECTIVE: The study investigates the prognosis of atrial fibrillation (AF) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). BACKGROUND: Data concerning the prognostic impact of AF in patients with HFmrEF is scarce. METHODS: Consecutive patients with HFmrEF (i.e., left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. Patients with AF were compared to patients without with regard to the primary composite endpoint of all-cause mortality and HF-related rehospitalization at 30 months (median follow-up). Statistical analyses included Kaplan-Meier analyses, multivariable Cox proportional regression analyses and propensity score matching. RESULTS: 2,148 patients with HFmrEF were included with an overall prevalence of AF of 43%. The presence of AF was associated with higher risk of the primary composite endpoint all-cause mortality and HF-related rehospitalization at 30 months (HR = 2.068; 95% CI 1.802-2.375; p = 0.01), which was confirmed after propensity-score matching (HR = 1.494; 95% CI 1.216-1.835; p = 0.01). AF was an independent predictor of both all-cause mortality (HR = 1.340; 95% CI 1.066-1.685; p = 0.01) and HF-related rehospitalization (HR = 2.061; 95% CI 1.538-2.696; p = 0.01). Finally, rhythm control may be associated with lower risk of all-cause mortality compared to rate control for AF (HR = 0.342; 95% CI 0.199-0.587; p = 0.01). CONCLUSION: AF affects 43% of patients with HFmrEF and represents an independent predictor of adverse long-term prognosis.

By now, limited data regarding the prognostic impact of comorbidities in heart failure with mildly reduced ejection fraction (HFmrEF) is available, contributing to the overall limited evidence regarding the treatment of patients with HFmrEF. The present study investigates the prognostic impact of the presence of atrial fibrillation (AF) on the long-term prognosis of patients with HFmrEF using a large retrospective study of 2,148 patients hospitalized with HFmrEF from 2016 to 2022. AF was prevalent in 43% of patients with HFmrEF and independently associated with an increased risk of the composite of long-term all-cause mortality and HF-related rehospitalization. Adverse prognosis in patients with concomitant AF was confirmed using multivariable Cox regression analyses and propensity score matching. Finally, the achievement of rhythm control may be associated with a lower risk of long-term all-cause mortality. Further studies are needed to demonstrated the effect of rhythm control and catheter ablation for AF in patients with HFmrEF.

Effect of severity and etiology of chronic kidney disease in patients with heart failure with mildly reduced ejection fraction.

OBJECTIVE: The study investigates the prognostic impact of the severity and etiology of chronic kidney disease (CKD) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). BACKGROUND: Data regarding the outcomes in patients with CKD in HFmrEF is scarce. METHODS: Consecutive patients with HFmrEF were retrospectively included at one institution from 2016 to 2022. Prognosis of patients with different stages and etiologies of CKD was investigated with regard to the primary endpoint of all-cause mortality at 30 months. RESULTS: A total of 2155 consecutive patients with HFmrEF were included with an overall prevalence of CKD of 31%. Even milder stages of CKD (i.e., KDIGO stage 3a) were associated with an increased risk of 30-months all-cause mortality (HR = 1.242; 95% CI 1.147-1.346; p = 0.001). However, long-term prognosis did not differ in patients with KDIGO stage 5 compared to patients with stage 4 (HR = 0.886; 95% CI 0.616-1.275; p = 0.515). Furthermore, the highest risk of HF-related rehospitalization was observed in patients with KDIGO stages 3b and 4 (log rank p ≤ 0.015), whereas patients with KDIGO stage 5 had a lower risk of HF-related rehospitalization compared to patients with KDIGO stage 4 (HR = 0.440; 95% CI 0.228-0.849; p = 0.014). In contrast, the etiology of CKD was not associated with the risk of 30-month all-cause mortality (log rank p ≥ 0.347) and HF-related rehospitalization (log rank p ≥ 0.149). CONCLUSION: In patients with HFmrEF, even milder stages of CKD were independently associated with increased risk of 30-months all-cause mortality.

Characteristics Associated with Ventricular Tachyarrhythmias and Their Prognostic Impact in Heart Failure with Mildly Reduced Ejection Fraction.

Background: The occurrence of ventricular tachyarrhythmias represents an established risk factor of mortality in heart failure (HF). However, data concerning their prognostic impact in heart failure with mildly reduced ejection fraction (HFmrEF) is limited. Therefore, the present study aims to investigate patient characteristics associated with ventricular tachyarrhythmias and their prognostic impact in patients with HFmrEF. Methods: Consecutive patients hospitalized with HFmrEF (i.e., left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. The prognosis of patients with HFmrEF and different types of ventricular tachyarrhythmias (i.e., non-sustained ventricular tachycardia (nsVT), sustained VT (sVT), and ventricular fibrillation (VF) was investigated for the primary endpoint of long-term all-cause mortality at 30 months. Secondary endpoints included in-hospital all-cause mortality and long-term HF-related rehospitalization at 30 months. Results: From a total of 2184 patients with HFmrEF, 4.4% experienced ventricular tachyarrhythmias (i.e., 2.0% nsVT, 0.7% sVT, and 1.6% VF). The occurrence of nsVT was associated with higher New York Heart Association (NYHA) functional class, whereas the incidence of sVT/VF was associated with acute myocardial infarction and ischemic heart disease. However, nsVT (25.0%; HR = 0.760; 95% CI 0.419-1.380; p = 0.367) and sVT/VF (28.8%; HR = 0.928; 95% CI 0.556-1.549; p = 0.776) were not associated with a higher risk of long-term all-cause mortality compared to patients with HFmrEF without ventricular tachyarrhythmias (31.5%). In-hospital cardiovascular mortality was more frequently observed in patients with HFmrEF and sVT/VF compared to those with HFmrEF but without sustained ventricular tachyarrhythmias (7.7% vs. 1.5%; p = 0.004). Finally, the risk of rehospitalization for worsening HF was not affected by the presence of ventricular tachyarrhythmias. Conclusions: The occurrence of ventricular tachyarrhythmias in patients hospitalized with HFmrEF was low and not associated with long-term prognosis.

Prognostic impact of prior LVEF in patients with heart failure with mildly reduced ejection fraction.

AIMS: As there is limited evidence regarding the prognostic impact of prior left ventricular ejection fraction (LVEF) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), this study investigates the prognostic impact of longitudinal changes in LVEF in patients with HFmrEF. METHODS: Consecutive patients with HFmrEF (i.e. LVEF 41-49% with signs and/or symptoms of HF) were included retrospectively in a monocentric registry from 2016 to 2022. Based on prior LVEF, patients were categorized into three groups: stable LVEF, improved LVEF, and deteriorated LVEF. The primary endpoint was 30-months all-cause mortality (median follow-up). Secondary endpoints included in-hospital and 12-months all-cause mortality, as well as HF-related rehospitalization at 12 and 30 months. Kaplan-Meier and multivariable Cox proportional regression analyses were applied for statistics. RESULTS: Six hundred eighty-nine patients with HFmrEF were included. Compared to their prior LVEF, 24%, 12%, and 64% had stable, improved, and deteriorated LVEF, respectively. None of the three LVEF groups was associated with all-cause mortality at 12 (p ≥ 0.583) and 30 months (31% vs. 37% vs. 34%; log rank p ≥ 0.376). In addition, similar rates of 12- (p ≥ 0.533) and 30-months HF-related rehospitalization (21% vs. 23% vs. 21%; log rank p ≥ 0.749) were observed. These findings were confirmed in multivariable regression analyses in the entire study cohort. CONCLUSION: The transition from HFrEF and HFpEF towards HFmrEF is very common. However, prior LVEF was not associated with prognosis, likely due to the persistently high dynamic nature of LVEF in the follow-up period.

Effect of anaemia and iron deficiency in heart failure with mildly reduced ejection fraction.

OBJECTIVE: The present study aims to clarify the prevalence and prognostic impact of anaemia and iron deficiency in patients with heart failure with mildly reduced ejection fraction (HFmrEF). BACKGROUND: The prognostic impact of anaemia and iron deficiency in HFmrEF has not yet been clarified. METHODS: Consecutive patients with HFmrEF were retrospectively included at one institution from 2016 to 2022. Patients with anaemia (i.e. haemoglobin <13 g/dL in males and < 12 g/dL in females) were compared to patients without, respectively patients with or without iron deficiency. The primary endpoint was all-cause mortality at 30 months (median follow-up), secondary endpoints comprised HF-related rehospitalisation. RESULTS: Two thousand one hundred and fifty four patients with HFmrEF with a median haemoglobin level of 12.2 g/dL were included. Anaemia was present in 52% of patients with HFmrEF and associated with a higher risk of all-cause mortality (44% vs. 18%; HR = 3.021; 95% CI 2.552-3.576; p =.001) and HF-related rehospitalisation (18% vs. 8%; HR = 2.351; 95% CI 1.819-3.040; p =.001) at 30 months, which was confirmed after multivariable adjustment. Although iron status was infrequently assessed in anaemics with HFmrEF (27%), the presence of iron deficiency was associated with higher risk of rehospitalisation for worsening HF (25% vs. 15%; HR = 1.746; 95% CI 1.024-2.976; p =.038), but not all-cause mortality (p =.279) at 30 months. CONCLUSION: Anaemia and iron deficiency are very common in atleast half of patients with HFmrEF and independently associated with adverse long-term prognosis.

Effect of Heart Failure Pharmacotherapies in Patients with Heart Failure with Mildly Reduced Ejection Fraction.

OBJECTIVE: The study sought to comprehensively investigate the effect of heart failure (HF) pharmacotherapies in patients with heart failure with mildly reduced ejection fraction (HFmrEF). BACKGROUND: In the absence of randomized controlled trials, guideline recommendations concerning HF-related therapies in patients with HFmrEF are limited. METHODS: Consecutive patients hospitalized with HFmrEF were retrospectively included at one institution from 2016 to 2022. The prognostic value of treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, receptor blockers or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) was investigated for all-cause mortality at 30 months (median follow-up) and HF-related rehospitalization. RESULTS: 2,109 patients with HFmrEF were included. Treatment with BB (27.0% vs. 35%; HR = 0.737; 95% CI 0.617-0.881; p = 0.001), ACEi/ARB/ARNI (25.9% vs. 37.6%; HR = 0.612; 95% CI 0.517-0.725; p = 0.001) and SGLT2i (11.9% vs. 29.5%; HR = 0.441; 95% CI 0.236-0.824; p = 0.010) was associated with lower risk of 30-months all-cause mortality, which was still demonstrated after multivariable adjustment and propensity score matching. In contrast, MRA treatment was not associated with long-term prognosis. The risk of HF-related rehospitalization was not affected by HF pharmacotherapies. Finally, the lowest risk of long-term all-cause mortality was observed in patients with combined use of BB, ACEi/ARB/ARNI and SGLT2i (HR = 0.456; 95% CI 0.227-0.916; p = 0.027). CONCLUSION: BB, ACEi/ARB/ARNI and SGLT2i were independently associated with lower risk of all-cause mortality in patients with HFmrEF, specifically when applied as combined "HF triple therapy". Randomized studies are needed to investigate the effect of HF-related pharmacotherapies in patients with HFmrEF.

Although heart failure with mildly reduced ejection fraction (HFmrEF) affects one out of four patients with heart failure (HF), limited evidence regarding HF pharmacotherapies for the treatment of patients with HFmrEF is available. The present study investigates the treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, receptor blockers or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on long-term outcomes using a large registry-based dataset of 2,109 patients hospitalized with HFmrEF. Treatment with BB, ACEi/ARB/ARNI and SGLT2i was independently associated with a lower risk of long-term all-cause mortality, even after multivariable adjustment and propensity score matching, specifically when applied in combination. In contrast, MRA treatment was not associated with outcomes in the present study. The present study supports the evidence that patients with HFmrEF may benefit from HF pharmacotherapies similar than patients with HF with reduced ejection fraction (HFrEF).

Obesity Paradox in Heart Failure with Mildly Reduced Ejection Fraction.

Objective: The study investigates the prognostic impact of body mass index (BMI) in patients hospitalized with heart failure with mildly reduced ejection fraction (HFmrEF). Background: Limited data regarding the prognostic impact of BMI in patients with HFmrEF is available. Methods: Consecutive patients with HFmrEF (ie, left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. Risk stratification was performed according to WHO-defined BMI groups. The primary endpoint was all-cause mortality at 30 months (median follow-up). Kaplan-Meier, uni- and multivariable Cox proportional regression analyses were applied for statistics. Results: 1832 consecutive patients with HFmrEF were included with a median BMI of 26.7 kg/m2 (IQR 24.0-30.8 kg/m2). Patients with lowest BMI (ie, 18.5-24.9 kg/m2) were associated with highest risk of all-cause mortality at 30 months compared to patients with higher BMI values (40.0% vs 29.0% vs 21.4% vs 20.9%; log rank p = 0.001; HR = 0.721; 95% CI 0.656-0.793; p = 0.001). Even after multivariable adjustment, higher BMI values were associated with improved survival at 30 months (HR = 0.963; 95% CI 0.943-0.985; p = 0.001). In contrast, the risk of HF- related rehospitalization at 30 months was not affected by BMI (log rank p = 0.064). Conclusion: In patients hospitalized with HFmrEF, lower BMI was associated with increased risk of all-cause mortality at 30 months, suggesting an obesity paradox in HFmrEF.

Prognostic value of mitral valve regurgitation in patients with heart failure with mildly reduced ejection fraction.

BACKGROUND: Although mitral valve regurgitation (MR) is a common valvular heart disease in patients with heart failure (HF), there is a paucity of data on the characterization and outcomes of patients with HF with mildly reduced ejection fraction (HFmrEF) and concomitant MR. METHODS: From 2016 to 2022, consecutive patients hospitalized with HFmrEF (i.e., left ventricular ejection fraction from 41% to 49% and signs and/or symptoms of HF) were retrospectively included at one institution. Patients with MR were compared with patients without MR. Further risk stratification was performed according to MR severity and etiology (i.e., primary vs. secondary MR). The primary end point was all-cause mortality at 30 months (median follow-up), and the key secondary end point was hospitalization for worsening HF. RESULTS: Of 2181 patients hospitalized with HFmrEF, 59% presented with mild, 10% with moderate, and 2% with severe MR. MR was associated with increased all-cause mortality at 30 months (HR = 1.756; 95% CI 1.458-2.114; p = 0.001), with higher risk in more advanced stages. Furthermore, MR patients had higher risk of HF-related re-hospitalization at 30 months (HR = 1.560; 95% CI 1.172-2.076; p = 0.002). Even after multivariable adjustment, mild, moderate, and severe MR were still associated with all-cause mortality. Finally, the risk of all-cause mortality was lower in patients with secondary MR compared with patients with primary MR (HR = 0.592; 95% CI 0.366-0.956; p = 0.032). CONCLUSION: MR is common in HFmrEF and independently associated with higher risk of all-cause mortality and HF hospitalization.

Prognostic Implications of Type 2 Diabetes Mellitus in Heart Failure with Mildly Reduced Ejection Fraction.

BACKGROUND: Data regarding the characterization and outcomes of diabetics with heart failure with a mildly reduced ejection fraction (HFmrEF) is scarce. This study investigates the prevalence and prognostic impact of type 2 diabetes in patients with HFmrEF. METHODS: Consecutive patients with HFmrEF (i.e., left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. Patients with type 2 diabetes (dia-betics) were compared to patients without (i.e., non-diabetics). The primary endpoint was all-cause mortality at 30 months. Statistical analyses included Kaplan-Meier, multivariable Cox regression analyses and propensity score matching. RESULTS: A total of 2169 patients with HFmrEF were included. The overall prevalence of type 2 diabetes was 36%. Diabetics had an increased risk of 30-months all-cause mortality (35.8% vs. 28.6%; HR = 1.273; 95% CI 1.092-1.483; p = 0.002), which was confirmed after multivariable adjustment (HR = 1.234; 95% CI 1.030-1.479; p = 0.022) and propensity score matching (HR = 1.265; 95% CI 1.018-1.572; p = 0.034). Diabetics had a higher risk of HF-related rehospitalization (17.8% vs. 10.7%; HR = 1.714; 95% CI 1.355-2.169; p = 0.001). Finally, the risk of all-cause mortality was increased in diabetics treated with insulin (40.7% vs. 33.1%; log-rank p = 0.029), whereas other anti-diabetic pharmacotherapies had no prognostic impact in HFmrEF. CONCLUSIONS: Type 2 diabetes is common and independently associated with adverse long-term prognosis in patients with HFmrEF.

Prognostic impact of chronic obstructive pulmonary disease in patients with heart failure with mildly reduced ejection fraction.

BACKGROUND: The aging population has led to a significant increase in heart failure (HF) patients. Related to demographic changes, the burden with comorbidities was shown to increase in patients with HF. Whereas chronic obstructive pulmonary disease (COPD) was yet demonstrated to be associated with adverse outcomes in patients with HF, the prognostic impact of COPD in HF with mildly reduced ejection fraction (HFmrEF) has not yet been clarified. OBJECTIVE: The study investigates the prognostic impact of COPD in patients hospitalized with HFmrEF. METHODS: Consecutive patients with HFmrEF were retrospectively included at one institution from 2016 to 2022. Patients with COPD were compared to patients without with regard to the primary endpoint all-cause mortality at 30 months (median follow-up). Secondary endpoints comprised in-hospital mortality, HF-related re-hospitalization, cardiac re-hospitalization and major adverse cardiac and cerebrovascular events (MACCE) at 30 months. RESULTS: A total of 2184 patients with HFmrEF were included with a prevalence of COPD of 12.0 %. Patients with COPD were older (median 77 vs. 75 years; p = 0.025), had increased burden of cardiovascular comorbidities and more advanced HF symptoms. At 30 months, patients with COPD had an increased risk of all-cause mortality compared to patients without (45 % vs. 30 %; HR = 1.667; 95 % CI 1.366-2.034; p = 0.001), alongside with a higher risk of re-hospitalization for worsening HF (20 % vs. 12 %; HR = 1.658; 95 % CI 1.218-2.257; p = 0.001). CONCLUSION: COPD is independently associated with adverse outcomes in patients hospitalized with HFmrEF.

Diagnostic and Prognostic Value of Aminoterminal Prohormone of Brain Natriuretic Peptide in Heart Failure with Mildly Reduced Ejection Fraction Stratified by the Degree of Renal Dysfunction.

Limited data concerning the diagnostic and prognostic value of blood-derived biomarkers in heart failure with mildly reduced ejection fraction (HFmrEF) is available. This study investigates the diagnostic and prognostic value of aminoterminal prohormone of brain natriuretic peptide (NT-proBNP) in patients with HFmrEF, stratified by the estimated glomerular filtration rate (eGFR). Consecutive patients with HFmrEF were retrospectively included at one institution from 2016 to 2022. First, the diagnostic value of NT-proBNP for acute decompensated heart failure (ADHF) was tested. Thereafter, the prognostic value of NT-proBNP levels was tested for 30-months all-cause mortality in patients with ADHF. From a total of 755 patients hospitalized with HFmrEF, the rate of ADHF was 42%. Patients with ADHF revealed higher NT-proBNP levels compared to patients without (median 5394 pg/mL vs. 1655 pg/mL; p = 0.001). NT-proBNP was able to discriminate ADHF with an area under the curve (AUC) of 0.777 (p = 0.001), with the highest AUC in patients with eGFR ≥ 60 mL/min (AUC = 0.800; p = 0.001), and no diagnostic value was seen in eGFR < 30 mL/min (AUC = 0.576; p = 0.210). Patients with NT-proBNP levels > 3946 pg/mL were associated with higher rates of all-cause mortality at 30 months (57.7% vs. 34.4%; HR = 2.036; 95% CI 1.423-2.912; p = 0.001), even after multivariable adjustment (HR = 1.712; 95% CI 1.166-2.512; p = 0.006). In conclusion, increasing NT-proBNP levels predicted the risk of ADHF and all-cause mortality in patients with HFmrEF and preserved renal function; however, NT-proBNP levels were not predictive in patients with HFmrEF and eGFR < 30 mL/min.

Prognostic Implications of Septal Hypertrophy in Patients with Heart Failure with Mildly Reduced Ejection Fraction.

Cardiac remodeling is frequently observed in patients with heart failure (HF) and serves as an indicator of disease progression and severity. Septal hypertrophy represents an aspect of remodeling that can be easily assessed via an echocardiographic measurement of the interventricular septal end diastole (IVSd), but it has not been evaluated for its prognostic value, particularly in patients with heart failure with mildly reduced ejection fraction (HFmrEF). We retrospectively included 1881 consecutive patients hospitalized with HFmrEF (i.e., a left ventricular ejection fraction of 41-49% and signs and/or symptoms of HF) at one institution during a study period from 2016 to 2022. Septal hypertrophy, defined as an IVSd > 12 mm, was prevalent in 34% of the HFmrEF patients. Although septal hypertrophy was not associated with all-cause mortality at 30 months (median follow-up) (HR = 1.067; 95% CI: 0.898-1.267; p = 0.460), it was associated with an increased risk of hospitalization due to worsening HF at 30 months (HR = 1.303; 95% CI: 1.008-1.685; p = 0.044), which was confirmed even after multivariable adjustment (HR = 1.340; 95% CI: 1.002-1.792; p = 0.049) and propensity score matching (HR = 1.399; 95% CI: 1.002-1.951; p = 0.048). Although septal hypertrophy was not associated with the risk of all-cause mortality in patients with HFmrEF, it was identified as an independent predictor of long-term HF-related rehospitalization.

Prognostic impact of acute decompensated heart failure in patients with heart failure with mildly reduced ejection fraction.

AIMS: This study sought to determine the prognostic impact of acute decompensated heart failure (ADHF) in patients with heart failure with mildly reduced ejection fraction (HFmrEF). ADHF is a major complication in patients with heart failure (HF). However, the prognostic impact of ADHF in patients with HFmrEF has not yet been clarified. METHODS AND RESULTS: Consecutive patients hospitalized with HFmrEF (i.e. left ventricular ejection fraction 41-49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. The prognosis of patients with ADHF was compared with those without (i.e. non-ADHF). The primary endpoint was long-term all-cause mortality. Secondary endpoints included in-hospital all-cause mortality and long-term HF-related re-hospitalization. Kaplan-Meier, multivariable Cox proportional regression, and propensity score matched analyses were performed for statistics. Long-term follow-up was set at 30 months. A total of 2184 patients with HFmrEF were included, ADHF was present in 22%. The primary endpoint was higher in ADHF compared to non-ADHF patients with HFmrEF [50% vs. 26%; hazard ratio (HR) = 2.269; 95% confidence interval (CI) 1.939-2.656; P = 0.001]. Accordingly, the secondary endpoint of long-term HF-related re-hospitalization was significantly higher (27% vs. 10%; HR = 3.250; 95% CI 2.565-4.118; P = 0.001). A history of previous ADHF before the index hospitalization was associated with higher rates of long-term HF-related re-hospitalization (42% vs. 23%; HR = 2.073; 95% CI 1.420-3.027; P = 0.001), but not with long-term all-cause mortality (P = 0.264). CONCLUSION: ADHF is a common finding in patients with HFmrEF associated with an adverse impact on long-term prognosis.