Supra-normal and mildly reduced ejection fraction in women -An overlooked vulnerable subpopulation in heart failure.

BACKGROUND: Recently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. METHODS: The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. RESULTS: In HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and ß-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). CONCLUSIONS: In women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

Renin-angiotensin system inhibitors for patients with mild or moderate chronic kidney disease and heart failure with mildly reduced or preserved ejection fraction.

BACKGROUND: Renin-angiotensin system inhibitors (RASI) reduce adverse cardiovascular events in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤40% and mild or moderate chronic kidney disease (CKD). However, RASI administration rate and its association with long-term outcomes in patients with CKD complicated by HF with LVEF >40% remain unclear. METHODS: We analyzed 1923 consecutive patients with LVEF >40% registered within the multicenter database for hospitalized HF. We assessed RASI administration rate and its association with all-cause mortality among patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR]: 30-60 mL/min/1.73 m2). Exploratory subgroups included patients grouped by age (<80, ≥80 years), sex, previous HF hospitalization, B-type natriuretic peptide (higher, lower than median), eGFR (30-44, 45-59 mL/min/1.73 m2), systolic blood pressure (<120, ≥120 mmHg), LVEF (41-49, ≥50%), and mineralocorticoid receptor antagonists (MRA) use. RESULTS: Among patients with LVEF >40%, 980 (51.0%) had mild or moderate CKD (age: 81 [74-86] years; male, 52.6%; hypertension, 69.7%; diabetes, 25.9%), and 370 (37.8%) did not receive RASI. RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use. After multivariable adjustments, RASI use was independently associated with lower all-cause mortality over a 2-year median follow-up (hazard ratio: 0.58, 95% confidence interval: 0.43-0.79, P = 0.001), and the mortality rate difference was predominantly due to cardiac death, consistent in all subgroups. CONCLUSIONS: Approximately one-third of HF patients with mild or moderate CKD and LVEF >40% were discharged without RASI administration and demonstrated relatively guarded outcomes.

Rationale and protocol of the LAQUA-HF trial: a factorial randomised controlled trial evaluating the effects of neurohormonal and diuretic agents on health-status reported outcomes in heart failure patients.

INTRODUCTION: The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects. METHODS AND ANALYSIS: In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint. ETHICS AND DISSEMINATION: The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. TRIAL REGISTRATION NUMBER: UMIN000045229.

Prevalence and clinical characteristics of diabetic cardiomyopathy in patients with acute heart failure.

BACKGROUND AND AIMS: Diabetic cardiomyopathy refers to cases of diabetes mellitus (DM) complicated by cardiac dysfunction in the absence of cardiovascular disease and hypertension. Its epidemiology remains unclear due to the high rate of coexistence between DM and hypertension. Therefore, this study aimed to examine the prevalence and clinical characteristics of diabetic cardiomyopathy among patients with acute heart failure (HF). METHODS AND RESULTS: This multicenter, retrospective study included 17,614 consecutive patients with acute HF. DM-related HF was defined as HF complicating DM without known manifestations of coronary artery disease, significant valvular heart disease, or congenital heart disease, while diabetic cardiomyopathy was defined as DM-related HF without hypertension. Univariable and multivariable logistic regression analyses were performed to identify factors associated with in-hospital mortality. Diabetic cardiomyopathy prevalence was 1.6 % in the entire cohort, 5.2 % in patients with acute HF complicating DM, and 10 % in patients with DM-related HF. Clinical characteristics, including the presence of comorbidities, laboratory data on admission, and factors associated with in-hospital mortality, significantly differed between the diabetic cardiomyopathy group and the DM-related HF with hypertension group. The in-hospital mortality rate was significantly higher in patients with diabetic cardiomyopathy than in patients with DM-related HF with hypertension (7.7 % vs. 2.8 %, respectively; P < 0.001). CONCLUSION: The prevalence of diabetic cardiomyopathy was 1.6 % in patients with acute HF, and patients with diabetic cardiomyopathy were at high risk for in-hospital mortality. The clinical characteristics of patients with diabetic cardiomyopathy were significantly different than those of patients with DM-related HF with hypertension.

Forecasting the Acute Heart Failure Admissions: Development of Deep Learning Prediction Model Incorporating the Climate Information.

BACKGROUND: Climate is known to influence the incidence of cardiovascular events. However, their prediction with traditional statistical models remains imprecise. METHODS AND RESULTS: We analyzed 27,799 acute heart failure (AHF) admissions within the Tokyo CCU Network Database from January 2014 to December 2019. High-risk AHF (HR-AHF) day was defined as a day with the upper 10th percentile of AHF admission volume. Deep neural network (DNN) and traditional regression models were developed using the admissions in 2014-2018 and tested in 2019. Explanatory variables included 17 meteorological parameters. Shapley additive explanations were used to evaluate their importance. The median number of incidences of AHF was 12 (9-16) per day in 2014-2018 and 11 (9-15) per day in 2019. The predicted AHF admissions correlated well with the observed numbers (DNN: R2 = 0.413, linear regression: R2 = 0.387). The DNN model was superior in predicting HR-AHF days compared with the logistic regression model [c-statistics: 0.888 (95% CI: 0.818-0.958) vs 0.827 (95% CI: 0.745-0.910): P = .0013]. Notably, the strongest predictive variable was the 7-day moving average of the lowest ambient temperatures. CONCLUSIONS: The DNN model had good prediction ability for incident AHF using climate information. Forecasting AHF admissions could be useful for the effective management of AHF.

Association between Non-Lipid Residual Risk Factors and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Pitavastatin: An Observation from the REAL-CAD Study.

AIMS: We aimed to investigate the association between non-lipid residual risk factors and cardiovascular events in patients with stable coronary artery disease (CAD) who achieved low-density lipoprotein cholesterol (LDL-C) ＜100 mg/dL from the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. METHODS: The REAL-CAD study was a prospective, multicenter, open-label trial. As a sub-study, we examined the prognostic impact of non-lipid residual risk factors, including blood pressure, glucose level, and renal function, in patients who achieved LDL-C ＜100 mg/dL at 6 months after pitavastatin therapy. Each risk factor was classified according to severity. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina requiring emergency hospitalization. RESULTS: Among 8,743 patients, the mean age was 68±8.2 years, and the mean LDL-C level was 84.4±18 mg/dL. After adjusting for the effects of confounders, an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 showed the highest risk of the primary outcome (hazard ratio [HR] 1.92; 95% confidence interval [CI] 1.45-2.53). The combination of eGFR ≤ 60 and hemoglobin A1c (HbA1c) ≥ 6.0% also showed the highest risk of all-cause death (HR, 2.42; 95% CI, 1.72-3.41). CONCLUSIONS: In patients with stable CAD treated with pitavastatin and who achieved guidelines-directed levels of LDL-C, eGFR and HbA1c were independently associated with adverse events, suggesting that renal function and glycemic control could be residual non-lipid therapeutic targets after statin therapy.

Adult-onset idiopathic peripheral pulmonary artery stenosis.

BACKGROUND: Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. METHODS: We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. RESULTS: 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. CONCLUSIONS: In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.

Initiation and Up-Titration of Guideline-Based Medications in Hospitalized Acute Heart Failure Patients　- A Report From the West Tokyo Heart Failure Registry.

BACKGROUND: Despite recommendations from clinical practice guidelines to initiate and titrate guideline-directed medical therapy (GDMT) during their hospitalization, patients with acute heart failure (AHF) are frequently undertreated. In this study we aimed to clarify GDMT implementation and titration rates, as well as the long-term outcomes, in hospitalized AHF patients.Methods and Results: Among 3,164 consecutive hospitalized AHF patients included in a Japanese multicenter registry, 1,400 (44.2%) with ejection fraction ≤40% were analyzed. We assessed GDMT dosage (ß-blockers, renin-angiotensin inhibitors, and mineralocorticoid-receptor antagonists) at admission and discharge, examined the contributing factors for up-titration, and evaluated associations between drug initiation/up-titration and 1-year post-discharge all-cause death and rehospitalization for HF via propensity score matching. The mean age of the patients was 71.5 years and 30.7% were female. Overall, 1,051 patients (75.0%) were deemed eligible for GDMT, based on their baseline vital signs, renal function, and electrolyte values. At discharge, only 180 patients (17.1%) received GDMT agents up-titrated to >50% of the maximum titrated dose. Up-titration was associated with a lower risk of 1-year clinical outcomes (adjusted hazard ratio: 0.58, 95% confidence interval: 0.35-0.96). Younger age and higher body mass index were significant predictors of drug up-titration. CONCLUSIONS: Significant evidence-practice gaps in the use and dose of GDMT remain. Considering the associated favorable outcomes, further efforts to improve its implementation seem crucial.

End-of-Life Discussions and Their Timing for Patients With Cardiovascular Diseases　- From the Perspective of Bereaved Family Members.

BACKGROUND: Enhanced discussions regarding end-of-life (EOL) are crucial to provide appropriate care for seriously ill patients. However, the current status of EOL discussions, especially their timing and influencing factors, among patients with cardiovascular diseases (CVD) remains unknown.Methods and Results: We conducted a cross-sectional questionnaire survey of bereaved family members of CVD patients who died at 10 tertiary care institutes in Japan. In all, 286 bereaved family members (38.2% male; median age 66.0 [interquartile range 58.0-73.0] years) of CVD patients were enrolled; of these, 200 (69.9%) reported that their families had had EOL discussions with physicians. The major topic discussed was resuscitation (79.0%), and 21.5% discussed the place of EOL care. Most discussions were held during hospitalization of the patient (88.2%). More than half (57.1%) the discussions were initiated less than 1 month before the patient died, and 22.6% of family members felt that this timing of EOL discussions was late. Bereaved family members' perception of late EOL discussions was associated with the family members aggressive attitude towards life-prolonging treatment, less preparedness for bereavement, and less satisfaction with EOL care. CONCLUSIONS: Approximately 70% of bereaved family members of CVD patients had EOL discussions, which were often held shortly before the patient died. Further research is required to establish an ideal approach to EOL discussions at an appropriate time, which may improve the quality of EOL care.

Temporal Trends in Heart Failure Management and Outcomes: Insights From a Japanese Multicenter Registry of Tertiary Care Centers.

Background The management of heart failure (HF) has markedly changed, due to changes in demographics and the emergence of novel pharmacotherapies. However, detailed analyses on the temporal trends in characteristics and outcomes among patients with HF are scarcely available. This study aimed to assess the temporal trends over 11 years in clinical management and outcomes in patients with HF. Methods and Results We analyzed data from a multicenter registry of hospitalized patients with acute HF, including 6877 patients registered from 2011 to 2021. Age-adjusted mortality was calculated using standardized mortality ratios. During the study period, mean age increased from 75.2 years in 2011 to 2012 to 76.4 years in 2020 to 2021 (P for trend <0.001). The proportion of HF with reduced ejection fraction (HFrEF, left ventricular ejection fraction <40%) remained constant (from 43.4% to 42.7%, P for trend=0.38). The median duration of hospital stays (from 15 to 17 days, P for trend<0.001) had increased. As for the implementation of guideline-directed medical therapy, the use of mineralocorticoid receptor antagonist at discharge increased in patients with HFrEF (from 44.3% to 60.2%, P for trend<0.001). There was also an increase in the use of sodium-glucose cotransporter-2 inhibitors following their approval for use. The age-adjusted 1-year mortality decreased in patients with HFrEF (from 18.0% to 9.3%, P for trend<0.001) but not in patients with non-HFrEF (left ventricular ejection fraction ≥40%; from 9.2% to 9.5%, P for trend=0.79). Conclusions Hospitalized patients with HF have been aging over the past decade. Their long-term outcomes after discharge have improved predominantly because of decreased mortality in patients with HFrEF.

Association of pre-hospital precipitating factors with short- and long-term outcomes of acute heart failure patients: A report from the WET-HF2 registry.

BACKGROUND: Interest in clinical course preceding heart failure (HF) exacerbation has grown, with a greater emphasis placed on patients' clinical factors including precipitant factor (PF). Large-scale studies with precise PF documentation and temporal-outcome variation remain limited. METHODS: We reviewed prospectively collected 2412 consecutive patient-level records from a multicenter Japanese registry of hospitalized patients with HF (West Tokyo Heart Failure2 Registry: 2018-2020). Patients were categorized based on PFs: behavioral (i.e., poor adherence to physical activity, medicine, or diet regimen), treatment-required (i.e., anemia, arrhythmia, ischemia, infection, thyroid dysfunction or other conditions as suggested exacerbating factors), and no-PF. The composite outcomes of HF rehospitalization and death within 1 year after discharge and HF rehospitalization were individually assessed. RESULTS: Median patient age was 78 years (interquartile range: 68-85 years), and 1468 (61%) patients had documented PFs, of which 356 (15%) were considered behavioral. The behavioral PF group were younger, more male and had past HF hospitalization history compared to those in the other groups (all p < 0.05). Although risk of in-hospital death was lower in the behavioral PF group, their risk of composite outcome was not significantly different from the treatment-required group (hazard ratio [HR] 1.19 [95% confidence interval {CI} 0.93-1.51]) and the no-PF group (HR 1.28 [95%CI 1.00-1.64]). Furthermore, the risk of HF rehospitalization was higher in the behavioral PF group than in the other two groups (HR 1.40 [95%CI 1.07-1.83] and HR 1.39 [95%CI 1.06-1.83], respectively). CONCLUSION: Despite a better in-hospital prognosis, patients with behavioral PFs were at significantly higher risk of HF rehospitalization.

Which congestion presentation pattern on the physical findings is associated with future adverse events? A cluster analysis in the multicenter acute heart failure registry.

BACKGROUND: Clinical congestion is the most frequent reason for hospital admission in patients with acute heart failure (AHF). However, few studies have investigated the patterns and prognostic implication of the physical congestion using unbiased and robust statistical methods. METHODS: A hierarchical agglomerative clustering analysis was performed in the multicenter Japanese AHF registry (N = 3151) with the distance calculated by Jaccard's distance for jugular vein distention (JVD), leg edema, S3, crackles, and orthopnea. The primary outcome was a composite of cardiac death and heart failure readmission within 1-year. RESULTS: At the time of admission, the median number of prevalent congestive signs was 2. We identified three phenogroups: 'no physical congestions' (N = 251); 'congestion without JVD' (N = 1415); and 'congestion with JVD' (N = 1495). Patients in 'no physical congestion' were the youngest (median 75 [62, 83] years) with the lowest systolic blood pressure (122 [106, 142] mmHg). Patients in 'congestion without JVD', and 'congestion with JVD' were similar in terms of age (77 [67, 84] vs. 78 [69, 84] years) and systolic blood pressure (138 [118, 160] vs. 137 [118, 158] mmHg). While 30-day mortality was similar (4.0%, 3.7%, and 4.3% in 'no physical congestion,' 'congestion without JVD,' and 'congestion with JVD', respectively), the patients in 'congestion with JVD' were at the highest risk for the primary outcome (adjusted hazard ratio 1.79, 95% CI 1.26-2.55 when 'no physical congestion' was a reference). CONCLUSIONS: Our clustering analysis demonstrated that congestion signs, particularly JVD, allowed identification of AHF phenogroups with distinct clinical characteristics and long-term outcomes.

Improved prediction of sudden cardiac death in patients with heart failure through digital processing of electrocardiography.

AIMS: Available predictive models for sudden cardiac death (SCD) in heart failure (HF) patients remain suboptimal. We assessed whether the electrocardiography (ECG)-based artificial intelligence (AI) could better predict SCD, and also whether the combination of the ECG-AI index and conventional predictors of SCD would improve the SCD stratification among HF patients. METHODS AND RESULTS: In a prospective observational study, 4 tertiary care hospitals in Tokyo enrolled 2559 patients hospitalized for HF who were successfully discharged after acute decompensation. The ECG data during the index hospitalization were extracted from the hospitals' electronic medical record systems. The association of the ECG-AI index and SCD was evaluated with adjustment for left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) class, and competing risk of non-SCD. The ECG-AI index plus classical predictive guidelines (i.e. LVEF ≤35%, NYHA Class II and III) significantly improved the discriminative value of SCD [receiver operating characteristic area under the curve (ROC-AUC), 0.66 vs. 0.59; P = 0.017; Delong's test] with good calibration (P = 0.11; Hosmer-Lemeshow test) and improved net reclassification [36%; 95% confidence interval (CI), 9-64%; P = 0.009]. The Fine-Gray model considering the competing risk of non-SCD demonstrated that the ECG-AI index was independently associated with SCD (adjusted sub-distributional hazard ratio, 1.25; 95% CI, 1.04-1.49; P = 0.015). An increased proportional risk of SCD vs. non-SCD with an increasing ECG-AI index was also observed (low, 16.7%; intermediate, 18.5%; high, 28.7%; P for trend = 0.023). Similar findings were observed in patients aged ≤75 years with a non-ischaemic aetiology and an LVEF of >35%. CONCLUSION: To improve risk stratification of SCD, ECG-based AI may provide additional values in the management of patients with HF.

Phenotyping of Elderly Patients With Heart Failure Focused on Noncardiac Conditions: A Latent Class Analysis From a Multicenter Registry of Patients Hospitalized With Heart Failure.

Background The burden of noncardiovascular conditions is becoming increasingly prevalent in patients with heart failure (HF). We aimed to identify novel phenogroups incorporating noncardiovascular conditions to facilitate understanding and risk stratification in elderly patients with HF. Methods and Results Data from a total of 1881 (61.2%) patients aged ≥65 years were extracted from a prospective multicenter registry of patients hospitalized for acute HF (N=3072). We constructed subgroups of patients with HF with preserved ejection fraction (HFpEF; N=826, 43.9%) and those with non-HFpEF (N=1055, 56.1%). Latent class analysis was performed in each subgroup using 17 variables focused on noncardiovascular conditions (including comorbidities, Clinical Frailty Scale, and Geriatric Nutritional Risk Index). The latent class analysis revealed 3 distinct clinical phenogroups in both HFpEF and non-HFpEF subgroups: (1) robust physical and nutritional status (Group 1: HFpEF, 41.2%; non-HFpEF, 46.0%); (2) multimorbid patients with renal impairment (Group 2: HFpEF, 40.8%; non-HFpEF, 41.9%); and (3) malnourished patients (Group 3: HFpEF, 18.0%; non-HFpEF, 12.1%). After multivariable adjustment, compared with Group 1, patients in Groups 2 and 3 had a higher risk for all-cause death over the 1-year postdischarge period (hazard ratio [HR], 2.79 [95% CI, 1.64-4.81] and HR, 2.73 [95% CI, 1.39-5.35] in HFpEF; HR, 1.96 [95% CI, 1.22-3.14] and HR, 2.97 [95% CI, 1.64-5.38] in non-HFpEF; respectively). Conclusions In elderly patients with HF, the phenomapping focused on incorporating noncardiovascular conditions identified 3 phenogroups, each representing distinct clinical outcomes, and the discrimination pattern was similar for both patients with HFpEF and non-HFpEF. This classification provides novel risk stratification and may aid in clinical decision making.

Cardiovascular vs. non-cardiovascular deaths after heart failure hospitalization in young, older, and very old patients.

AIMS: The long-term outcome in patients with heart failure (HF) after hospitalization may vary substantially depending on their age and left ventricular ejection fraction (LVEF). We aimed to assess the relative rates of cardiovascular death (CVD) and non-CVD based on the age and how the rates differ under the updated LVEF classification system. METHODS AND RESULTS: Consecutively registered hospitalized patients with HF (N = 3558; 39.7% women with a mean age of 73.9 ± 13.3 years) were followed for a median of 2 (interquartile range, 0.8-3.1) years. The CVDs and non-CVDs were evaluated based on age [young (<65 years), older (65-84 years), and very old (≥85 years)] and LVEF classification [HF with preserved EF (HFpEF; LVEF ≥50%) and non-HFpEF (LVEF <50%)]. The adverse clinical events were adjudicated independently by a central committee. Overall, 1505 (42.3%) had HFpEF [young: n = 182 (12.1%), older: n = 894 (59.4%), very old: n = 429 (28.5%)], and 2053 (57.7%) had non-HFpEF [young: n = 575 (28.0%), older: n = 1159 (56.5%), very old: n = 319 (15.5%)]. During the follow-up, the crude incidence of all-cause death was higher in non-HFpEF than in HFpEF across all age groups (non-HFpEF vs. HFpEF, young: 10.4% vs. 5.5%, log-rank P = 0.10; older: 26.6% vs. 20.9%, log-rank P = 0.002; very old: 36.7% vs. 31.7%, log-rank P = 0.043). CVDs accounted for more than half of all deaths in non-HFpEF (young 65.0%, older 64.2%, and very old 55.6%), whereas the proportion of CVDs remained less than half in HFpEF (young 50.0%, older 41.2%, very old 38.2%). HF readmission was associated with subsequent all-cause death in non-HFpEF [hazard ratio (HR): 1.72, 95% confidence interval (CI): 1.41-2.09, P < 0.001], but not in HFpEF (HR: 1.12, 95% CI: 0.87-1.43, P = 0.39). CONCLUSIONS: The probability of a non-CVD increases in both LVEF categories with advancing age, but that it is greater in the HFpEF category. The findings indicate that mitigating CV-related outcomes alone may be insufficient for treating HF in older population, particularly in the HFpEF category.

Low blood pressure and guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

BACKGROUND: Patients with heart failure (HF) presenting with low blood pressure (BP) have been underrepresented in large-scale clinical trials. We investigated the characteristics and implementation of conventional guideline-directed medical therapy (GDMT; renin-angiotensin system inhibitors and ß-blockers) in patients with low BP hospitalized for HF with systolic dysfunction. METHODS: Conventional GDMT was evaluated by discharge BP among 2043 consecutive patients with HF and left ventricular ejection fraction (LVEF) < 50% in the WET-HF registry. Among the 708 (34.7%) patients with lower discharge BP (≤ 100 mmHg; the lower tertiles), exploratory subgroups included patients with previous HF hospitalization, inotrope use, New York Heart Association (NYHA) III-IV class, and lower estimated glomerular filtration rate (eGFR) and LVEF (lower than median value). We evaluated the risk-adjusted association between GDMT implementation and 2-year adverse events (all-cause mortality or HF rehospitalization). RESULTS: Among the 2043 patients (age 74 [63-82] years), the median systolic BP was 108 (98-120) mmHg. Among patients with lower BP, GDMT prescription rate was 62.7%, and GDMT use was associated with decreased adverse events (HR:0.74, 95%CI:0.58-0.94). GDMT prescription rates were lower among higher-NYHA class and lower-eGFR subgroups compared with their reference subgroups, and directionally similar outcomes were noted in all subgroups (favoring GDMT use); however, this association was somewhat attenuated in the lower-eGFR group (HR:0.87, 95%CI:0.64-1.17). CONCLUSIONS: Conventional GDMT use was associated with decreased adverse outcomes in most patients with HF compounded by systolic dysfunction and low BP, albeit caution is warranted in patients with renal dysfunction.

Malnutrition in real-world patients hospitalized for heart failure with preserved ejection fraction and its potential impact on generalizability of EMPEROR-Preserved trial.

BACKGROUND: Despite the benefits of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin, its suitability for patients with heart failure (HF) in the real-world setting remains unclear. Considering the unique pharmacological profile of SGLT2i (e.g., glucose excretion leading to calorie loss) and increasingly aging patients with HF, applicability of trials' finding in patients with malnutrition is important. METHODS: We examined 1633 consecutive patients with a preserved left ventricular ejection fraction (LVEF; >40%) enrolled in a multicenter-based acute HF registry. After applying the EMPEROR-Preserved eligibility criteria, we compared the baseline characteristics of trial-eligible and actual trial participants, and patients with and without malnutrition among the trial-eligible group. Malnutrition was assessed by the geriatric nutritional risk index (GNRI). The trial-eligible patients were divided into high (GNRI≥92) and low (GNRI<92) nutritional groups, and a composite endpoint comprising all-cause death and HF rehospitalization was evaluated. RESULTS: Majority (70.2%) of the analyzed patients were eligible for the EMPEROR-Preserved trial (age: 77 ± 12 years and body mass index [BMI]: 22.0 ± 4.1 kg/m2), but were older and had lower BMIs than the actual trial participants. Notably, 51.9% of the eligible patients were at high risk for malnutrition and had a higher rate of the composite endpoint than non-malnourished counterparts (HR 1.27, 95%CI 1.04-1.56, P = 0.020). The difference in outcomes was predominantly due to mortality from non-cardiac causes. CONCLUSIONS: Mostly patients with HF in a real-world setting met the EMPEROR-Preserved criteria; however, approximately half were at high risk for malnutrition with poorer outcomes owing to non-cardiac-related causes.

Association of Potassium Level at Discharge with Long-Term Mortality in Hospitalized Patients with Heart Failure.

Dyskalemia (hypokalemia and hyperkalemia) is a common comorbidity of heart failure (HF). Although dyskalemia is associated with poor prognosis, different prognostic impacts of hypo- and hyperkalemia remain vastly unclear. This study investigated the association of dyskalemia with prognosis in HF patients, especially the mode of death and left ventricular ejection fraction (LVEF). The multicenter study included 3398 patients hospitalized for HF. Patients were divided into three groups based on serum potassium levels at discharge: hypokalemia (<3.5 mEq/L; n = 115 (3.4%)), normokalemia (3.5−5.0 mEq/L; n = 2960 (87.1%)), and hyperkalemia (≥5.0 mEq/L; n = 323 (9.5%)). Two-year all-cause, cardiac, and non-cardiac mortality was evaluated. Association of serum potassium with two-year mortality demonstrated a U-shaped curve, with a worse prognosis for patients with hypokalemia. All-cause mortality at two-years did not differ among the three groups. Hypokalemia was associated with 2-year cardiac death (adjusted hazard ratio (HR), 2.60; 95% confidence interval (CI), 1.20−5.64) in HF with reduced ejection fraction (HFrEF; LVEF < 40%), but not in non-HFrEF. Regardless of LVEF, hyperkalemia was not independently associated with any mortality. Hypokalemia was independently associated with cardiac death, particularly in HFrEF patients. Such an association was not observed in hyperkalemia regardless of LVEF.

Association between class of foundational medication for heart failure and prognosis in heart failure with reduced/mildly reduced ejection fraction.

We clarified the association between changes in the number of foundational medications for heart failure (FMHF) during hospitalization for worsening heart failure (HF) and post-discharge prognosis. We retrospectively analyzed a combined dataset from three large-scale registries of hospitalized patients with HF in Japan (NARA-HF, WET-HF, and REALITY-AHF) and patients diagnosed with HF with reduced or mildly reduced left ventricular ejection fraction (HFr/mrEF) before admission. Patients were stratified by changes in the number of prescribed FMHF classes from admission to discharge: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor blockers. Primary endpoint was the combined endpoint of HF rehospitalization and all-cause death within 1 year of discharge. The cohort comprised 1113 patients, and 482 combined endpoints were observed. Overall, FMHF prescriptions increased in 413 (37.1%) patients (increased group), remained unchanged in 607 (54.5%) (unchanged group), and decreased in 93 (8.4%) (decreased group) at discharge compared with that during admission. In the multivariable analysis, the increased group had a significantly lower incidence of the primary endpoint than the unchanged group (hazard ratio 0.56, 95% confidence interval 0.45-0.60; P < 0.001). In conclusion, increase in FMHF classes during HF hospitalization is associated with a better prognosis in patients with HFr/mrEF.