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AIMS: Low-density lipoprotein cholesterol (LDL-C), anaemia and low platelets have been associated with worse clinical outcomes in heart failure patients. We investigated the relationship between the combination of these three components and clinical outcome in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We examined the data of 1021 patients with HFpEF hospitalized with acute decompensated heart failure (HF) from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. The enrolled patients were classified into four groups by an LEP (LDL-C, Erythrocyte, and Platelet) score of 0 to 3 points, with 1 point each for LDL-C, erythrocyte and platelet values less than the cut-off values as calculated by receiver operating characteristic curve analysis. The endpoint, a composite of all-cause death and HF readmission, was evaluated among the four groups. Median follow-up duration was 579 [300, 978] days. Risk of the composite endpoint significantly differed among the four groups (P < 0.001). Kaplan-Meier analysis showed that the groups with an LEP score of 2 had higher risk of the composite endpoint than those with an LEP score of 0 or 1 (P < 0.001, and P = 0.013, respectively), while those with an LEP score of 3 had higher risk than those with an LEP score of 0, 1 or 2 (P < 0.001, P < 0.001 and P = 0.020, respectively). Cox proportional hazards analysis showed that an LEP score of 3 was significantly associated with the composite endpoint (P = 0.030). Kaplan-Meier analysis showed that risk of the composite of all-cause death and HF readmission was significantly higher in low LDL values (less than the cut-off values as calculated by receiver operating characteristic curve analysis) patients with statin use than in those without statin use (log rank P = 0.002). CONCLUSIONS: LEP score, which comprehensively reflects extra-cardiac co-morbidities, is significantly associated with clinical outcomes in HFpEF patients.

DOI： 10.1002/ehf2.14734

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The coexistence of heart failure is frequent and associated with higher mortality in patients with type 2 diabetes (T2DM), and its management is a critical issue. The WATCH-DM risk score is a tool to predict heart failure in patients with type 2 diabetes mellitus (T2DM). We investigated whether it could estimate outcomes in T2DM patients with heart failure with preserved ejection fraction (HFpEF). The WATCH-DM risk score was calculated in 418 patients with T2DM hospitalized for HFpEF (male 49.5%, age 80 ± 9 years, HbA1c 6.8 ± 1.0%), and they were divided into the "average or lower" (≤ 10 points), "high" (11-13 points) and "very high" (≥ 14 points) risk groups. We followed patients to observe all-cause death for 386 days (median). We compared the area under the curve (AUC) of the WATCH-DM score for predicting 1-year mortality with that of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score and of the Barcelona Bio-Heart Failure Risk (BCN Bio-HF). Among the study patients, 108 patients (25.8%) had average or lower risk scores, 147 patients (35.2%) had high risk scores, and 163 patients (39.0%) had very high risk scores. The Cox proportional hazard model selected the WATCH-DM score as an independent predictor of all-cause death (HR per unit 1.10, 95% CI 1.03 to 1.19), and the "average or lower" risk group had lower mortality than the other groups (p = 0.047 by log-rank test). The AUC of the WATCH-DM for 1-year mortality was 0.64 (95% CI 0.45 to 0.74), which was not different from that of the MAGGIC score (0.72, 95% CI 0.63 to 0.80, p = 0.08) or that of BCN Bio-HF (0.70, 0.61 to 0.80, p = 0.25). The WATCH-DM risk score can estimate prognosis in T2DM patients with HFpEF and can identify patients at higher risk of mortality.

DOI： 10.1038/s41598-024-52101-8

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BACKGROUND: The effectiveness of β-blocker in patients with heart failure with preserved ejection fraction (HFpEF) remains to be determined. We aimed to clarify the association between the use of β-blocker and prognosis according to the status of frailty. METHODS: We compared prognosis between HFpEF patients with and without β-blockers stratified with the Clinical Frailty Scale (CFS), using data from the PURSUIT-HFpEF registry (UMIN000021831). RESULTS: Among 1159 patients enrolled in the analysis (median age, 81.4 years; male, 44.7%), 580 patients were CFS ≤ 3, while 579 were CFS ≥ 4. Use of β-blockers was associated with a worse composite endpoint of all-cause death and heart failure readmission in patients with CFS ≥ 4 (adjusted hazard ratio (HR) 1.43, 95% CI 1.10-1.85, p = 0.007), but was not significantly associated with this endpoint in those with CFS ≤ 3 (adjusted HR 0.95, 95% CI 0.71-1.26, p = 0.719) in multivariable Cox proportional hazard models. These results were confirmed in a propensity-matched analysis (HR in those with CFS ≥ 4: 1.42, 95% CI 1.05-1.90, p = 0.020; that in those with CFS ≤ 3: 0.83, 95% CI 0.60-1.14, p = 0.249), and in an analysis in which patients were divided into CFS ≤ 4 and CFS ≥ 5. CONCLUSIONS: Use of β-blockers was significantly associated with worse prognosis specifically in patients with HFpEF and high CFS, but not in those with low CFS. Use of β-blockers in HFpEF patients with frailty may need careful attention.

DOI： 10.1007/s00392-023-02301-5

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OBJECTIVE: The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology. METHODS: This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated. RESULTS: Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15. CONCLUSIONS: Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

DOI： 10.1136/heartjnl-2023-323059

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BACKGROUNDS: Drug treatments of heart failure with preserved ejection fraction (HFpEF) have a little clinical benefit, but cardiovascular polypharmacy (CP) trend is observed in elderly HFpEF. We investigated the impact of CP on octogenarian with HFpEF. METHODS: We examined 783 consecutive octogenarians (≥80 years) enrolled in the PURSUIT-HFpEF registry. We defined medications for hypertension, dyslipidemia, heart failure (HF), coronary artery disease, stroke, peripheral artery disease, and atrial fibrillation as cardiovascular medications (CM). In this study, we defined CP as ≥5 CM. We investigated whether CP was correlated with the composite end point (CE) of all-cause mortality and HF rehospitalization. RESULTS: The proportion with CP was 51.9% (n = 406). Background characteristics correlated with CP were frailty, history of coronary artery disease, atrial fibrillation and left atrial dimension. Multivariable Cox proportional hazards analysis showed CP was significantly and independently correlated with CE (hazard ratio (HR): 1.31; 95% confidence Interval (CI): 1.01-1.70) in addition to age, clinical frailty scale, history of HF admission and N-terminal pro brain natriuretic peptide. Kaplan-Meier curve analysis showed that, compared with the non-CP group, the CP group had significantly higher risk of CE and HF (HR: 1.27; 95%CI: 1.04-1.56; P = 0.02 and HR: 1.46; 95%CI: 1.13-1.88; P < 0.01, respectively), but not any-cause death. In addition, diuretics were correlated with CE (HR: 1.61; 95%CI: 1.17-2.22; P < 0.01), but antithrombotic drugs and HFpEF medications were not. CONCLUSIONS: CP at discharge is a prognostic factor driven by HF rehospitalization in octogenarians with HFpEF. In these patients, diuretics may be correlated with the prognosis.

DOI： 10.1016/j.ijcard.2023.02.021

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AIMS: Patient reported outcomes (PROs) are gradually being incorporated into daily practice to assess individual health-related quality of life (QOL). However, despite accumulating evidence of the prognostic utility of heart failure (HF)-specific QOL indices, evidence on the generic QOL score is scarce, especially in patients with HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Patient data were extracted from the Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study. EuroQol 5 dimensions 5-level (EQ-5D-5L) data were obtained at discharge to evaluate patients' health-related QOL. The study population (n = 864) was divided into tertiles based on their EQ-5D-5L index as follows: low EQ-5D-5L 0.038-0.664 (n = 287), middle EQ-5D-5L 0.665-0.867 (n = 293), and high EQ-5D-5L 0.871-1.000 (n = 284). A total of 206 patients died over a mean follow-up period of 2.0 ± 1.2 years. Kaplan-Meier analysis revealed that the risk of mortality increased with the tertile of the EQ-5D-5L index (34% vs. 23% vs. 14%, P < 0.001). Cox multivariable analysis revealed that patients with EQ-5D-5L index in the low and middle tertiles had a significantly greater risk of mortality than those with EQ-5D-5L index in the high tertile [low EQ-5D-5L: adjusted hazard ratio (HR): 1.81 (1.12-2.92), P = 0.002, middle EQ-5D-5L: adjusted HR 1.91 (1.21-3.03), P = 0.006]. Among the dimensions of EQ-5D-5L, mobility (P = 0.014), self-care (P = 0.023) and usual activities (P = 0.008) were significant factors associated with all-cause mortality after multivariable adjustment. CONCLUSIONS: EQ-5D-5L is useful tool for risk stratification in patients with HFpEF.

DOI： 10.1002/ehf2.14270

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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OBJECTIVE: Our previously established machine learning-based clustering model classified heart failure with preserved ejection fraction (HFpEF) into four distinct phenotypes. Given the heterogeneous pathophysiology of HFpEF, specific medications may have favourable effects in specific phenotypes of HFpEF. We aimed to assess effectiveness of medications on clinical outcomes of the four phenotypes using a real-world HFpEF registry dataset. METHODS: This study is a posthoc analysis of the PURSUIT-HFpEF registry, a prospective, multicentre, observational study. We evaluated the clinical effectiveness of the following four types of postdischarge medication in the four different phenotypes: angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB), beta blockers, mineralocorticoid-receptor antagonists (MRA) and statins. The primary endpoint of this study was a composite of all-cause death and heart failure hospitalisation. RESULTS: Of 1231 patients, 1100 (83 (IQR 77, 87) years, 604 females) were eligible for analysis. Median follow-up duration was 734 (398, 1108) days. The primary endpoint occurred in 528 patients (48.0%). Cox proportional hazard models with inverse-probability-of-treatment weighting showed the following significant effectiveness of medication on the primary endpoint: MRA for phenotype 2 (weighted HR (wHR) 0.40, 95% CI 0.21 to 0.75, p=0.005); ACEi or ARB for phenotype 3 (wHR 0.66 0.48 to 0.92, p=0.014) and statin therapy for phenotype 3 (wHR 0.43 (0.21 to 0.88), p=0.020). No other medications had significant treatment effects in the four phenotypes. CONCLUSIONS: Machine learning-based clustering may have the potential to identify populations in which specific medications may be effective. This study suggests the effectiveness of MRA, ACEi or ARB and statin for specific phenotypes of HFpEF. TRIAL REGISTRATION NUMBER: UMIN000021831.

DOI： 10.1136/heartjnl-2022-322181

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Background Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammation markers. Their combined usefulness for estimating the prognosis of patients with heart failure with preserved ejection fraction (HFpEF) admitted for acute decompensated heart failure remains elusive. Methods and Results We investigated 1026 patients registered in the Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction. Both NLR and PLR values were measured at the time of admission. Comorbidity burden was defined as the number of occurrences of 8 common comorbidities of HFpEF. The primary end point was cardiac death. The patients were stratified into 3 groups based on the optimal cut-off values of NLR and PLR on the receiver operating characteristic curve analysis for predicting cardiac death (low NLR and PLR, either high NLR or PLR, and both high NLR and PLR). After a median follow-up of 429 days, 195 patients died, with 85 of these deaths attributed to cardiac causes. An increased comorbidity burden was significantly associated with a higher proportion of patients with high NLR (>4.5) or PLR (>193), or both. High NLR and PLR values were independently associated with cardiac death, and a combination of both values was the strongest predictor (hazard ratio, 2.66 [95% CI, 1.51%-4.70%], P=0.0008). A significant difference was found in the rate of cardiac death among the 3 groups stratified by NLR and PLR values. Conclusions The combination of NLR and PLR is useful for the prediction of postdischarge cardiac death in patients with acute HFpEF. Registration URL: ClinicalTrials.gov; Unique identifier: UMIN000021831.

DOI： 10.1161/JAHA.122.026326

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BACKGROUND: We recently reported that nearly half of patients with heart failure with preserved ejection fraction (HFpEF) did not show echocardiographic diastolic dysfunction (DD), but had normal diastolic function (ND) or indeterminate diastolic function (ID). However, the clinical course and outcomes of patients with HFpEF with ND or ID (ND/ID) remain unknown. METHODS: From the PURSUIT-HFpEF registry, we extracted 289 patients with HFpEF with ND/ID at discharge who had echocardiographic data at 1-year follow-up. Patients were classified according to the status of progression from ND/ID to DD at 1 year. Primary endpoint was a composite of all-cause death or HF rehospitalization. RESULTS: Median age was 81 years, and 138 (47.8%) patients were female. At 1 year, 107 (37%) patients had progressed to DD. The composite endpoint occurred in 90 (31.1%) patients. Compared to patients without progression to DD, those with progression had a significantly higher cumulative rate of the composite endpoint (P < 0.001) and HF rehospitalization (P < 0.001) after discharge and at the 1-year landmark (P = 0.030 and P = 0.001, respectively). Progression to DD was independently associated with the composite endpoint (hazard ratio (HR): 2.014, 95%CI 1.239-3.273, P = 0.005) and HF rehospitalization (HR: 2.362, 95%CI 1.402-3.978) after discharge. Age (odds ratio (OR): 1.043, 95%CI 1.004-1.083, P = 0.031), body mass index (BMI) (OR: 1.110, 95%CI 1.031-1.195, P = 0.006), and albumin (OR: 0.452, 95%CI 0.211-0.969, P = 0.041) were independently associated with progression from ND/ID to DD. CONCLUSIONS: More than one-third of HFpEF patients with ND/ID progressed to DD at 1 year and had poor outcomes. Age, BMI and albumin were independently associated with this progression. UMIN-CTR ID: UMIN000021831.

DOI： 10.1007/s00392-022-02121-z

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Two key echocardiographic parameters, left ventricular mass index (LVMI) and left atrial volume index (LAVI), are important in assessing structural myocardial changes in heart failure (HF) with preserved ejection fraction (HFpEF). However, the differences in clinical characteristics and outcomes among groups classified by LVMI and LAVI values are unclear.We examined the data of 960 patients with HFpEF hospitalized due to acute decompensated HF from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. Four groups were classified according to the cut-off values of LVMI and LAVI [LVMI = 95 g/m2 (female), 115 g/m2 (male) and LAVI = 34 mL/m2]. Clinical endpoints were the composite of HF readmission and all-cause death. Study endpoints among the 4 groups were evaluated. The composite endpoint occurred in 364 patients (37.9%). Median follow-up duration was 445 days. Kaplan-Meier analysis revealed significant differences in the composite endpoint among the 4 groups (P < 0.001). Cox proportional hazards analysis demonstrated that patients with increased LAVI alone were at significantly higher risk of HF readmission and the composite endpoints than those with increased LVMI alone (P = 0.030 and P = 0.024, respectively). Age, male gender, systolic blood pressure at discharge, atrial fibrillation (AF) hemoglobin, renal function, and LAVI were significant determinants of LVMI and female gender, AF, hemoglobin, and LVMI were significant determinants of LAVI.In HFpEF patients, increased LAVI alone was more strongly associated with HF readmission and the composite of HF readmission and all-cause death than those with increased LVMI alone.

DOI： 10.1536/ihj.23-277

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OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH. Haemodynamic changes in worsening heart failure (HF) can modify the characteristics of PH. However, the clinical features of PH after HF treatment in HFpEF remain unclear. We investigated the prevalence and clinical significance of the precapillary component of PH after HF treatment in HFpEF, using data from the Prospective Multicentre Observational Study of Patients with HFpEF (PURSUIT-HFpEF). METHODS: From the PURSUIT-HFpEF registry, 219 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into four groups according to the 2015 and 2018 PH definitions: non-PH, isolated postcapillary pulmonary hypertension (Ipc-PH), precapillary PH and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). The latter two were combined as PH with the precapillary component. RESULTS: Using the 2015 definition, we found that the prevalence of PH after HF treatment was 27% (Ipc-PH: 20%, precapillary PH: 3%, Cpc-PH: 4%). Applying the 2018 definition resulted in a doubled frequency of precapillary PH (6%). PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes and characterised by small left ventricular dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity. CONCLUSION: After initial HF treatment, 7% of hospitalised patients with HFpEF had precapillary component of PH according to the 2015 definition. Echocardiographic parameters of the left ventricle can contribute to the risk stratification of patients with HFpEF with a precapillary component of PH.

DOI： 10.1136/heartjnl-2022-321565

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BACKGROUND: Right ventricular (RV) to pulmonary artery (PA) uncoupling is known to be important for the prognosis of not only heart failure (HF) with reduced ejection fraction but also HF with preserved ejection fraction (HFpEF). We further investigated key factors in the poor prognosis for HFpEF patients with RV-PA uncoupling. METHODS: We studied 817 patients with HFpEF who were discharged alive in a multicentred cohort using post hoc analyses, with a primary endpoint of cardiac mortality or HF readmission. A total of 288 RV-PA uncoupled patients were observed, namely those with a tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure (PASP) ratio < 0.46 mm/mm Hg. RESULTS: Among the RV-PA uncoupled patients, 101 adverse outcomes occurred over a median of 340 days. Echocardiographic RV dimension (RVD) was significantly important for prognosis in both univariable and multivariable Cox regression testing (hazard ratio 1.044, 95% confidence interval 1.014-1.074, P = 0.0042, and hazard ratio 1.036, 95% confidence interval 1.001-1.072, P = 0.0438, respectively) considered with the covariates of age, atrial fibrillation, renal function, N-terminal pro-brain natriuretic peptide, and other echocardiographic parameters. We further divided the patients into 4 groups, first into 2 groups with a TAPSE/PASP either ≥ or < 0.46 mm/mm Hg, and then into 4 groups by RVD medians of 31.9 mm and 33.3 mm, respectively. Kaplan-Meier curve analysis showed that outcomes were worst in patients with a low TAPSE/PASP ratio and larger RVD (log-rank P < 0.0001). CONCLUSIONS: This multicentre observational study highlighted the further prognostic importance of larger RVD among HFpEF patients with RV-PA uncoupling.

DOI： 10.1016/j.cjco.2022.07.014

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The impact of changes in nutritional status during hospitalization on prognosis in patients with heart failure with preserved ejection fraction (HFpEF) remains unknown. We examined the association between changes in the Geriatric Nutritional Risk Index (GNRI) and prognosis during hospitalization in patients with HFpEF stratified by nutritional status on admission. Nutritional status did and did not worsen in 348 and 349 of 697 patients with high GNRI on admission, and in 142 and 143 of 285 patients with low GNRI on admission, respectively. Kaplan-Meier analysis revealed no difference in risk of the composite endpoint, all-cause death, or heart failure admission between patients with high GNRI on admission whose nutritional status did and did not worsen. In contrast, patients with low GNRI on admission whose nutritional status did not worsen had a significantly lower risk of the composite endpoint and all-cause death than those who did. Multivariable analysis revealed that worsening nutritional status was independently associated with a higher risk of the composite endpoint and all-cause mortality in patients with low GNRI on admission. Changes in nutritional status during hospitalization were thus associated with prognosis in patients with malnutrition on admission, but not in patients without malnutrition among those with HFpEF.

DOI： 10.3390/nu14204345

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OBJECTIVE: We aim to clarify the differences in the association between re-admission for heart failure (HF) and left atrial (LA) overload indices by sex in heart failure and a preserved ejection fraction (HFpEF). METHODS: We analyzed 898 HFpEF patients hospitalized for acute decompensated HF. Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for HF during the first year. RESULTS: The ratio of diastolic elastance to arterial elastance (p = 0.014), a relative index of LA pressure overload, in men and LA volume index (LAVI, p = 0.020) in women were significant for re-admission for HF during the first year in the multivariable Fine-Gray analysis. Stroke volume (SV)/LA volume (LAV), another index for LAV overload, was not a significant prognostic factor of re-admission for HF during this time. CONCLUSION: LA overload was an important prognostic factor for HF re-readmission during the first year after enrolment in patients with HFpEF, but the indices relating to LA overload differed by sex.

DOI： 10.3390/jcm11195910

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Background An association between uric acid (UA) and cardiovascular diseases, including heart failure (HF), has been reported. However, whether UA is a causal risk factor for HF is controversial. In particular, the prognostic value of lowering UA in patients with HF with preserved ejection fraction (HFpEF) is unclear. Methods and Results We enrolled patients with HFpEF from the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction) registry. We investigated whether UA was correlated with the composite events, including all-cause mortality and HF rehospitalization, in patients with hyperuricemia and HFpEF (UA >7.0 mg/dL). Additionally, we evaluated whether lowering UA for 1 year (≥1.0 mg/dL) in them reduced mortality or HF rehospitalization. We finally analyzed 464 patients with hyperuricemia. In multivariable Cox regression analysis, UA was an independent determinant of composite death and rehospitalization (hazard ratio [HR], 1.15 [95% CI, 1.03-1.27], P=0.015). We divided them into groups with severe and mild hyperuricemia according to median estimated value of serum UA (8.3 mg/dL). Cox proportional hazards models revealed the incidence of all-cause mortality was significantly higher in the group with severe hyperuricemia than in the group with mild hyperuricemia (HR, 1.73 [95% CI, 1.19-2.25], P=0.004). The incidence of all-cause mortality was significantly decreased in the group with lowering UA compared with the group with nonlowering UA (HR, 1.71 [95% CI, 1.02-2.86], P=0.041). The incidence of urate-lowering therapy tended to be higher in the group with lowering UA than in the group with nonlowering UA (34.9% versus 24.6%, P=0.06). Conclusions UA is a predictor for the composite of all-cause death and HF rehospitalization in patients with hyperuricemia and HFpEF. In these patients, lowering UA, including the use of urate-lowering therapy, may improve prognosis.

DOI： 10.1161/JAHA.122.026301

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DOI： 10.1161/CIRCHEARTFAILURE.122.009789

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BACKGROUND: Blood urea nitrogen (BUN) reflects decreased glomerular filtration rate (GFR). The effect of BUN on clinical outcomes, excluding the impact of GFR, in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. METHODS: We enrolled HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure (HF) from PURSUIT-HFpEF registry which was prospective, multicenter and observational study. For excluding the effect of renal function on BUN value, propensity score-matching was performed using the variables which were associated with GFR. The incidence of composite of all-cause death and HF readmission among the patients stratified by BUN and the association between BUN and echocardiographic parameters in HFpEF patients were evaluated. RESULTS: We finally analyzed 1029 patients. In the present study, BUN cut-off value was defined as 24.4 mg/dL, which was the median value in overall population. The high and low BUN groups consisted of 193 patients after 1:1 propensity score-matching, respectively. The median follow-up duration was 401 days and the composite endpoint occurred in 129 patients (33.4%). Kaplan-Meier analysis showed the high BUN group had a significantly greater risk of the composite endpoint than the low group in the propensity score-matched pairs (p = 0.032). BUN value significantly correlated with left atrial volume index by multiple regression analysis using echocardiographic parameters (standardized beta-coefficient = 0.139, p = 0.043). CONCLUSION: BUN was a useful marker for the composite of all-cause death and HF readmission, regardless of the baseline renal function and correlated with left atrial function in HFpEF patients. CLINICAL TRIAL REGISTRATION: UMIN000021831 <https://uplaod.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414>; PURSUIT-HFpEF.

DOI： 10.1016/j.ijcard.2022.06.061

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OBJECTIVE: The pathophysiological heterogeneity of heart failure with preserved ejection fraction (HFpEF) makes the conventional 'one-size-fits-all' treatment approach difficult. We aimed to develop a stratification methodology to identify distinct subphenotypes of acute HFpEF using the latent class analysis. METHODS: We established a prospective, multicentre registry of acute decompensated HFpEF. Primary candidates for latent class analysis were patient data on hospital admission (160 features). The patient subset was categorised based on enrolment period into a derivation cohort (2016-2018; n=623) and a validation cohort (2019-2020; n=472). After excluding features with significant missingness and high degree of correlation, 83 features were finally included in the analysis. RESULTS: The analysis subclassified patients (derivation cohort) into 4 groups: group 1 (n=215, 34.5%), characterised by arrythmia triggering (especially atrial fibrillation) and a lower comorbidity burden; group 2 (n=77, 12.4%), with substantially elevated blood pressure and worse classical HFpEF echocardiographic features; group 3 (n=149, 23.9%), with the highest level of GGT and total bilirubin and frequent previous hospitalisation for HF and group 4 (n=182, 29.2%), with infection-triggered HF hospitalisation, high C reactive protein and worse nutritional status. The primary end point-a composite of all-cause death and HF readmission-significantly differed between the groups (log-rank p<0.001). These findings were consistent in the validation cohort. CONCLUSIONS: This study indicated the feasibility of clinical application of the latent class analysis in a highly heterogeneous cohort of patients with acute HFpEF. Patients can be divided into 4 phenotypes with distinct patient characteristics and clinical outcomes. TRIAL REGISTRATION NUMBER: UMIN000021831.

DOI： 10.1136/heartjnl-2021-320270

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OBJECTIVES: The prognostic significance of an afterload-integrated diastolic index, the ratio of diastolic elastance (Ed) to arterial elastance (Ea) (Ed/Ea=[E/e']/[0.9×systolic blood pressure]), is valid for 1 year after discharge in older patients with heart failure with preserved ejection fraction (HFpEF). We aimed to clarify the association with changes in Ed/Ea from enrolment to 1 year and prognosis thereafter in patients with HFpEF. SETTING: A prospective, multicentre observational registry of collaborating hospitals in Osaka, Japan. PARTICIPANTS: We enrolled 659 patients with HFpEF hospitalised for acute decompensated heart failure (men/women: 296/363). Blood tests and transthoracic echocardiography were performed before discharge and at 1 year after. PRIMARY OUTCOME MEASURES: All-cause mortality and/or re-admission for heart failure were evaluated after discharge. RESULTS: High Ed/Ea assessed before discharge was a significant prognostic factor during the first, but not the second, year after discharge in all-cause mortality or all-cause mortality and/or re-admission for heart failure. When re-analysis was performed using the value of Ed/Ea at 1 year after discharge, high Ed/Ea was significant for the prognosis during the second year for both end points (p=0.012 and p=0.033, respectively). The poorest mortality during 1‒2 years after enrolment was observed in those who showed a worsening Ed/Ea during the first year associated with larger left ventricular mass index and reduced left ventricular ejection fraction. In all-cause mortality and/or re-admission for heart failure, the event rate during 1‒2 years was highest in those with persistently high Ed/Ea even after 1 year. CONCLUSIONS: Time-sensitive prognostic performance of Ed/Ea, an afterload-integrated diastolic index, was observed in older patients with HFpEF. TRIAL REGISTRATION NUMBER: UMIN000021831.

DOI： 10.1136/bmjopen-2021-059614

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Background Although potential therapeutic candidates for heart failure with preserved ejection fraction (HFpEF) are emerging, it is still unclear whether they will be effective in patients with left ventricular ejection fraction (LVEF) of 60% or higher. Our aim was to identify the clinical characteristics of these patients with HFpEF by comparing them to patients with LVEF below 60%. Methods and Results From a multicenter, prospective, observational cohort (PURSUIT-HFpEF [Prospective Multicenter Obsevational Study of Patients with Heart Failure with Preserved Ejection Fraction]), we investigated 812 consecutive patients (median age, 83 years; 57% women), including 316 with 50% ≤ LVEF <60% and 496 with 60% ≤ LVEF, and compared the clinical backgrounds of the 2 groups and their prognoses for cardiac mortality or HF readmission. Two hundred four adverse outcomes occurred at a median of 366 days. Multivariable Cox regression tests adjusted for age, sex, heart rate, atrial fibrillation, estimated glomerular filtration rate, N-terminal pro-B-type natriuretic peptide, and prior heart failure hospitalization revealed that systolic blood pressure (hazard ratio [HR], 0.925 [95% CI, 0.862-0.992]; P=0.028), high-density lipoprotein to C-reactive protein ratio (HR, 0.975 [95% CI, 0.944-0.995]; P=0.007), and left ventricular end-diastolic volume index (HR, 0.870 [95% CI, 0.759-0.997]; P=0.037) were uniquely associated with outcomes among patients with 50% ≤ LVEF <60%, whereas only the ratio of peak early mitral inflow velocity to velocity of mitral annulus early diastolic motion e'(HR, 1.034 [95% CI, 1.003-1.062]; P=0.034) was associated with outcomes among patients with 60% ≤ LVEF. Conclusions Prognostic factors show distinct differences between patients with HFpEF with 50% ≤ LVEF <60% and with 60% ≤ LVEF. These findings suggest that the 2 groups have different inherent pathophysiology. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414; Unique identifier: UMIN000021831 PURSUIT-HFpEF.

DOI： 10.1161/JAHA.122.025300

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AIMS: Application of the latent class analysis to acute heart failure with preserved ejection fraction (HFpEF) showed that the heterogeneous acute HFpEF patients can be classified into four distinct phenotypes with different clinical outcomes. This model-based clustering required a total of 32 variables to be included. However, this large number of variables will impair the clinical application of this classification algorithm. This study aimed to identify the minimal number of variables for the development of optimal subphenotyping model. METHODS AND RESULTS: This study is a post hoc analysis of the PURSUIT-HFpEF study (N = 1095), a prospective, multi-referral centre, observational study of acute HFpEF [UMIN000021831]. We previously applied the latent class analysis to the PURSUIT-HFpEF dataset and established the full 32-variable model for subphenotyping. In this study, we used the Cohen's kappa statistic to investigate the minimal number of discriminatory variables needed to accurately classify the phenogroups in comparison with the full 32-variable model. Cohen's kappa statistic of the top-X number of discriminatory variables compared with the full 32-variable derivation model showed that the models with ≥16 discriminatory variables showed kappa value of >0.8, suggesting that the minimal number of discriminatory variables for the optimal phenotyping model was 16. The 16-variable model consists of C-reactive protein, creatinine, gamma-glutamyl transferase, brain natriuretic peptide, white blood cells, systolic blood pressure, fasting blood sugar, triglyceride, clinical scenario classification, infection-triggered acute decompensated HF, estimated glomerular filtration rate, platelets, neutrophils, GWTG-HF (Get With The Guidelines-Heart Failure) risk score, chronic kidney disease, and CONUT (Controlling Nutritional Status) score. Characteristics and clinical outcomes of the four phenotypes subclassified by the minimal 16-variable model were consistent with those by the full 32-variable model. The four phenotypes were labelled based on their characteristics as 'rhythm trouble', 'ventricular-arterial uncoupling', 'low output and systemic congestion', and 'systemic failure', respectively. CONCLUSIONS: The phenotyping model with top 16 variables showed almost perfect agreement with the full 32-variable model. The minimal model may enhance the future clinical application of this clustering algorithm.

DOI： 10.1002/ehf2.13928

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BACKGROUND: Although recent studies have reported that drug-coated balloons (DCB) are non-inferior to drug-eluting stents (DES) for the treatment of native coronary arteries in a specific population, there is no available information concerning vasomotion after treatment with DCB. AIMS: The aim of this study was to prospectively compare coronary vasomotion in patients with small coronary artery disease treated with DCB versus DES. METHODS: Forty-two native lesions (2.0-3.0 mm) treated in our institution were randomly assigned to the DCB arm (n=19) or the bioabsorbable polymer everolimus-eluting stents arm (n=23) after successful predilation. At eight months after treatment, endothelium-dependent and -independent vasomotion was evaluated with intracoronary infusions in incremental doses of acetylcholine (right coronary artery: low dose 5 μg, high dose 50 μg; left coronary artery: low dose 10 μg, high dose 100 μg) and nitroglycerine (200 μg). The mean lumen diameter of the distal segment, beginning 5 mm and ending 15 mm distal to the edge of the treated segment, was quantitatively measured by angiography. RESULTS: The luminal dimension in the treated segment did not differ between groups at the follow-up angiography. The vasoconstriction after acetylcholine infusion was less pronounced in the DCB arm than in the DES arm (low-dose: 6±13% vs -3±18%, p=0.060; high-dose: -4±17% vs -21±29%, p=0.035). The response to nitroglycerine did not differ between groups (17±13% vs 17±22%, p=0.929). CONCLUSIONS: Vasoconstriction after acetylcholine infusion in the peri-treated region was less pronounced in the DCB arm than in the DES arm, suggesting that endothelial function in treated coronary vessels could be better preserved by DCB than by new-generation DES.

DOI： 10.4244/EIJ-D-21-00636

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY PERIODICALS, INC  

Aims Considerable variation in the relationships between the indices of left atrial (LA) volume and pressure could possibly affect the selection of medications or efforts to improve the prognoses of patients with heart failure and preserved ejection fraction (HFpEF). We aimed to clarify the association between the prognostic endpoint and LA overload indices in elderly patients with HFpEF.Methods and results We analysed 898 patients with HFpEF hospitalized for acute decompensated heart failure (men/ women: 406/492). Blood tests and transthoracic echocardiography were performed before discharge. The primary endpoint was re-admission for heart failure or all-cause mortality. Stroke volume (SV)/left atrial volume (LAV), an index for LA volume overload, was a significant prognostic factor of re-admission for heart failure in the multivariable Cox hazard analysis adjusted for comorbidities (hazard ratio (HR) 0.616, 95% confidence interval (CI) 0.430-0.882, P = 0.0081. Additionally, the ratio of diastolic elastance (Ed) to arterial elastance (Ea), an index for LA pressure overload, was also significant (HR 1.444, 95% CI 1.014-2.058, P = 0.041). Furthermore, Ed/Ea, but not SV/LAV, was a significant prognostic factor of all-cause mortality (HR 1.594, 95% CI 1.102-2.306, P = 0.013).Conclusions The index of LA overload for prognosis may differ according to the different endpoints in elderly patients with HFpEF.

DOI： 10.1002/ehf2.13865

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PURPOSE: A four-parameter risk model that included cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging and readily available clinical parameters was recently developed for prediction of 2-year cardiac mortality risk in patients with chronic heart failure. We sought to validate the ability of this risk model to predict post-discharge clinical outcomes in patients with acute decompensated heart failure (ADHF) and to compare its prognostic value with that of the Acute Decompensated Heart Failure National Registry (ADHERE) and Get With The Guidelines-Heart Failure (GWTG-HF) risk scores. METHODS: We studied 407 consecutive patients who were admitted for ADHF and survived to discharge, with definitive 2-year outcomes (death or survival). Cardiac MIBG imaging was performed just before discharge. The 2-year cardiac mortality risk was calculated using four parameters, namely age, left ventricular ejection fraction, New York Heart Association functional class, and cardiac MIBG heart-to-mediastinum ratio on delayed images. Patients were stratified into three groups based on the 2-year cardiac mortality risk: low- (< 4%), intermediate- (4-12%), and high-risk (> 12%) groups. The ADHERE and GWTG-HF risk scores were also calculated. RESULTS: There was a significant difference in the incidence of cardiac death among the three groups stratified using the 2-year cardiac mortality risk model (p < 0.0001). The 2-year cardiac mortality risk model had a higher C-statistic (0.732) for the prediction of cardiac mortality than the ADHERE and GWTG-HF risk scores. CONCLUSION: The 2-year MIBG-based cardiac mortality risk model is useful for predicting post-discharge clinical outcomes in patients with ADHF. TRIAL REGISTRATION NUMBER: UMIN000015246, 25 September 2014.

DOI： 10.1007/s00259-021-05663-y

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OBJECTIVES: The authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) single-photon emission computed tomography (SPECT) imaging in patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). BACKGROUND: Cardiac sympathetic nerve dysfunction assessed by 123I-MIBG imaging is associated with poor outcomes in chronic HF patients with reduced left ventricular ejection fraction (HFrEF). However, no information is available on the prognostic vale of cardiac 123I-MIBG SPECT imaging in patients with HFpEF. METHODS: We studied 148 patients admitted for acute decompensated HF (ADHF) with nonischemic HFpEF and who underwent cardiac 123I-MIBG imaging at discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (H/M) was measured on the delayed planar image (late H/M). SPECT analysis of the delayed image was conducted, and the tracer uptake in all 17 regions on the polar map was scored on a 5-point scale by comparison with a sex-matched normal control database. The total defect score (TDS) was calculated by summing the score of each of the 17 segments. The primary endpoint was the association between TDS and cardiac events (the composite of emergent HF hospitalization and cardiac death). RESULTS: During a mean follow-up period of 2.4 ± 1.6 years, 61 patients experienced cardiac events. TDS was significantly associated with cardiac events after multivariate Cox adjustment (P < 0.0001). Patients with high TDS levels had a significantly greater risk of cardiac events than those with middle or low TDS levels (63% vs 40% vs 20%, respectively; P < 0.0001; HR: 4.69; 95% CI: 2.29 to 9.61; and HR: 2.46; 95% CI: 1.14 to 5.29). C-statistic of TDS was 0.730 (95% CI: 0.651 to 0.799), which was significantly higher than that of late H/M (0.607; 95% CI: 0.524 to 0.686; P = 0.0228). CONCLUSIONS: Cardiac 123I-MIBG SPECT imaging provided useful prognostic information in nonischemic ADHF patients with HFpEF. (Clinical Trial: Osaka Prefectural Acute Heart Failure Syndrome Registry [OPAR]: UMIN000015246).

DOI： 10.1016/j.jcmg.2021.08.003

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AIMS: The prognostic value of serum chloride level has been reported primarily in patients with heart failure with reduced ejection fraction, and hence, there is limited evidence in patients of heart failure with preserved ejection fraction (HFpEF). This study was conducted to clarify the relationship between serum chloride level and clinical outcomes in patients with HFpEF with acute decompensated heart failure (ADHF). METHODS AND RESULTS: Patient data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, a prospective multicentre observational registry for ADHF-HFpEF in Osaka. The data of 870 patients were analysed after excluding patients with in-hospital death, missing follow-up data, missing data of serum chloride level, or on chronic dialysis therapy. The primary endpoint of this study was all-cause mortality. At discharge, right ventricular systolic dysfunction was significantly associated with the lowest tertile of serum chloride level after multivariable adjustment (P = 0.0257). During a mean follow-up period of 1.8 ± 1.0 years, 186 patients died. Cox multivariable analysis showed that serum chloride level at discharge (P = 0.0017) was independently associated with all-cause mortality after multivariable adjustment of major confounders, whereas serum sodium level was no longer significant (P = 0.6761). Kaplan-Meier survival curve analysis revealed a significantly increased risk of mortality stratified by the tertile of serum chloride level [29% vs. 19% vs. 16%, P = 0.0002; hazard ratio (HR): 2.09 (95% confidence interval, CI: 1.31 to 3.34), HR: 1.03 (95% CI: 0.65 to 1.64)]. CONCLUSIONS: Serum chloride level was useful for the prediction of poor outcome in ADHF patients with preserved ejection fraction.

DOI： 10.1002/ehf2.13840

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Aims The effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE-I and/or ARB (ACE-I/ARB) and frailty on prognosis in patients with HFpEF. In the present study, we examined the association between ACE-I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty.Methods and results We examined the association between the use of ACE-I/ARB and prognosis according to the presence [Clinical Frailty Scale (CFS) >= 5] or absence (CFS <= 4) of frailty in patients with HFpEF in a post hoc analysis of registry data. Primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission. Of 1059 patients, median age was 83 years and 45% were male. Kaplan-Meier analysis showed that the risk of composite endpoint (log-rank P = 0.001) and all-cause death (log-rank P = 0.005) in patients with ACE-I/ARB was lower in those with CFS >= 5, but similar between patients with and without ACE-I/ARB in patients with CFS <= 4 (composite endpoint: log-rank P = 0.830; all-cause death: log-rank P = 0.192). In a multivariable Cox proportional hazards model, use of ACE-I/ARB was significantly associated with lower risk of the composite endpoint [hazard ratio (HR) = 0.52, 95% confidence interval (CI) = 0.33-0.83, P = 0.005] and heart failure admission (HR = 0.45, 95% CI = 0.25-0.83, P = 0.010) in patients with CFS >= 5, but not in patients with CFS <= 4 (composite endpoint: HR = 1.41, 95% CI = 0.99-2.02, P = 0.059; heart failure admission: HR = 1.43, 95% CI = 0.94-2.18, P = 0.091). The association between ACE-I or ARB and prognosis did not significantly differ by CFS (CFS <= 4: log-rank P = 0.562; CFS >= 5: log-rank P = 0.100, for with ACE-I vs. ARB, respectively). Adjusted HRs for CFS 1-4 were higher than 1.0 but were <1.0 at CFS 5.Conclusions In patients with HFpEF, use of ACE-I/ARB was associated with better prognosis in patients with frailty as assessed with the CFS, but not in those without frailty.

DOI： 10.1002/ehf2.13873

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AIMS: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected. CONCLUSION: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

DOI： 10.1093/ehjcvp/pvaa132

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BACKGROUND: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: This study aimed to investigate the prognostic value of echocardiographic markers of congestion that can be applied to both AF and patients without AF with HFpEF. METHODS: We conducted a multicenter study of 505 patients with HFpEF admitted to hospitals for acute decompensated heart failure. The ratio of early diastolic transmitral flow velocity to mitral annulus velocity (E/e'), the tricuspid regurgitation peak velocity, and the collapsibility of the inferior vena cava were obtained at discharge. Congestion was determined by echocardiography if any one of E/e' ≥14 (E/e' ≥11 for AF), tricuspid regurgitation peak velocity ≥2.8 m/s, or inferior vena cava collapsibility <50% was positive. We classified patients into grade A, grade B, and grade C according to the number of positive congestion indices. The primary endpoint was the composite of cardiovascular death and heart failure hospitalization. RESULTS: During the follow-up period (median: 373 days), 162 (32%) patients experienced the primary endpoint. Grade C patients had a higher risk for the primary endpoint than grade A (HR: 2.98; 95% CI: 1.97-4.52) and grade B patients (HR: 1.92; 95% CI: 1.29-2.86) (log-rank P < 0.0001). Echocardiographic congestion grade improved the predictive value when added to the age, sex, New York Heart Association functional class, and N-terminal pro-B-type natriuretic peptide, not only in sinus rhythm (Uno C-statistic: 0.670 vs 0.655) but in AF (Uno C-statistic: 0.667 vs 0.639). CONCLUSIONS: Echocardiographic congestion grade has prognostic value in patients with HFpEF with and without AF.

DOI： 10.1016/j.jacasi.2021.10.012

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BACKGROUND: Although diastolic dysfunction is important pathophysiology in heart failure with preserved ejection fraction (HFpEF), its prognostic impact in HFpEF patients, including those with atrial fibrillation (AF), remains to be elucidated.Methods and Results:We included the data for 863 patients (321 patients with AF) registered in a prospective multicenter observational study of patients with HFpEF. Patients were divided into 3 groups according to the 2016 ASE/EACVI recommendations. The primary endpoint was a composite of all-cause death or HF rehospitalization. Median age was 83 years, and 55.5% were female. 196 (22.7%) were classified with normal diastolic function (ND), 253 (29.3%) with indeterminate (ID) and 414 (48.0%) with diastolic dysfunction (DD). The primary endpoint occurred more frequently in patients with DD than in those with ND or ID (log-rank P<0.001 for DD vs. ND, and log-rank P=0.007 for DD vs. ID, respectively). Taking ND as the reference, multivariable Cox regression analysis revealed that DD (hazard ratio (HR): 1.57, 95% confidence interval (CI):1.06-2.32, P=0.024) was independently associated with the composite endpoint, whereas ID (HR: 1.28, 95% CI: 0.84-1.95, P=0.255) was not. DD was associated with the composite endpoint in both patients with and without AF. CONCLUSIONS: HFpEF patients classified with DD using the 2016 ASE/EACVI recommendations had worse clinical outcomes than those with ND or ID. DD may be considered a prognostic marker in patients with HFpEF regardless of AF.

DOI： 10.1253/circj.CJ-21-0300

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Background Although the prognostic importance of pulmonary arterial capacitance (PAC; stroke volume/pulmonary arterial pulse pressure) has been elucidated in heart failure with reduced ejection fraction, whether its significance in patients suffering from heart failure with preserved ejection fraction is not known. We aimed to examine the association of PAC with outcomes in inpatients with heart failure with preserved ejection fraction. Methods and Results We prospectively studied 705 patients (median age, 83 years; 55% women) registered in PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction). We investigated the association of echocardiographic PAC at discharge with the primary end point of all-cause death or heart failure rehospitalization with a mean follow-up of 384 days. We further tested the acceptability of the prognostic significance of PAC in a subgroup of patients (167/705 patients; median age, 81 years; 53% women) in whom PAC was assessed by right heart catheterization. The median echocardiographic PAC was 2.52 mL/mm Hg, with a quartile range of 1.78 to 3.32 mL/mm Hg. Univariable and multivariable Cox regression testing revealed that echocardiographic PAC was associated with the primary end point (unadjusted hazard ratio, 0.82; 95% CI, 0.72-0.92; P=0.001; adjusted hazard ratio, 0.86; 95% CI, 0.74-0.99; P=0.035, respectively). Univariable Cox regression testing revealed that PAC assessed by right heart catheterization (median calculated PAC, 2.82 mL/mm Hg) was also associated with the primary end point (unadjusted HR, 0.70; 95% CI, 0.52-0.91; P=0.005). Conclusions A prospective cohort study revealed that impaired PAC diagnosed with both echocardiography and right heart catheterization was associated with adverse outcomes in inpatients with heart failure with preserved ejection fraction. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.

DOI： 10.1161/JAHA.121.023043

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AIMS: At present, the clinical significance of admission hyperglycaemia in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. This study was designed to evaluate the relationship between admission hyperglycaemia and clinical outcome in HFpEF patients, especially in non-diabetic patients. METHODS AND RESULTS: We enrolled 486 non-diabetic HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure from the PURSUIT-HFpEF registry, a prospective, multicentre observational study. We divided non-diabetic patients into two groups, an admission hyperglycaemia group whose blood glucose on admission was ≥7.0 mmol/L (148 patients) and a normoglycaemic group whose blood glucose on admission was <7.0 mmol/L (338 patients). The primary endpoint was all-cause mortality, and the secondary endpoints were heart failure death and other causes of cardiac death. During a mean follow-up period of 400 ± 335 days, all-cause mortality was 69 patients. Twenty-five patients suffered cardiac death. All-cause mortality (P = 0.002), cardiac death (P = 0.009), and heart failure death (P = 0.001) were significantly more frequent in the admission hyperglycaemia group than in the normoglycaemic group. Admission hyperglycaemia was independently and significantly associated with all-cause mortality and cardiac death (HR 2.01, 95% CI 1.20-3.34, P = 0.008 and HR 3.03, 95% CI 1.35-6.96, P = 0.007, respectively). CONCLUSIONS: Non-diabetic HFpEF patients with admission hyperglycaemia when hospitalized for heart failure had poorer clinical outcomes than normoglycaemic patients.

DOI： 10.1002/ehf2.13501

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The obesity paradox states higher body mass index (BMI) is associated with better outcomes than normal weight in patients with heart failure with preserved ejection fraction (HFpEF). However, underweight was defined by BMI < 18.5 kg/m2, and results have been inconclusive, in part due to small number of participants. The number of underweight patients with HFpEF is higher in Asian than in Western countries. In this study, we aim to determine the prognostic impact of underweight in patients with HFpEF in Asian population.We enrolled 846 consecutive patients from the PURSUIT-HFpEF registry. We then divided them into three groups by BMI, namely, underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 23), and overweight (23 ≤ BMI). The underweight group consisted of 187 patients (22%). Over a mean follow-up of 407 days, 105 deaths were reported as all-cause mortality. On multivariable Cox analysis, the underweight group was determined to be significantly associated with higher risk of all-cause mortality than the normal and overweight groups (Hazard ratios [HR]: 2.33; 95% confidence intervals [CI]: 1.45-3.75, P < 0.001; HR: 3.54; 95% CI: 1.99-6.29, P < 0.001, respectively), after adjustment for age, sex, vital signs, and comorbidities.Underweight is a useful predictor of poor prognosis in patients with HFpEF in Asian population.

DOI： 10.1536/ihj.21-195

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OBJECTIVE: The semiquantitative urine dipstick test is a simple and convenient method that is available in the smallest community-based healthcare clinics. We sought to clarify the prognostic significance of dipstick proteinuria in patients with heart failure (HF) with preserved ejection fraction (HFpEF). DESIGN: A Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) registry. PARTICIPANTS AND SETTING: We assessed 851 discharged-alive patients in the PURSUIT-HFpEF registry who were initially hospitalised due to an acute decompensated HFpEF (EF≥50%) and elevated N-terminal-pro-brain natriuretic peptide (≥400 ng/L) at Osaka University Hospital and other 30 affiliated hospitals in the Kansai region of Japan. Patients received a urine dipstick test, and were divided into two groups according to the absence or presence of proteinuria. A trace or more of dipstick proteinuria was defined as the presence of proteinuria. MAIN OUTCOME MEASURES: A composite of cardiac death or HF rehospitalisation. RESULTS: Median age was 83 years and 473 patients (55.6%) were female. Five hundred and two patients (59%) were proteinuria (-) and 349 patients (41%) were proteinuria (+). The composite endpoint and HF rehospitalisation occurred more often in proteinuria (+) individuals than proteinuria (-) individuals (log-rank p=0.006 and p=0.007, respectively); but cardiac death did not (log-rank p=0.139). Multivariable Cox regression analysis showed that the presence of proteinuria was associated with the composite endpoint (HR: 1.47, 95% CI 1.07 to 2.01, p=0.016), and HF rehospitalisation (HR: 1.48, 95% CI 1.07 to 2.05, p=0.020), but not with cardiac death (HR: 1.52, 95% CI 0.83 to 2.76, p=0.172). CONCLUSIONS: Dipstick proteinuria may be a prognostic marker in patients with HFpEF. Evaluation of proteinuria by a urine dipstick test may be a simple but useful method for risk stratification in HFpEF. UMIN-CTR ID: UMIN000021831.

DOI： 10.1136/bmjopen-2021-049371

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AIMS: Frailty is associated with prognosis of cardiovascular diseases. However, the significance of frailty in patients with heart failure with preserved ejection fraction (HFpEF) remains to be elucidated. The purpose of this study was to examine the prognostic significance of the Clinical Frailty Scale (CFS) in real-world patients with HFpEF using data from a prospective multicentre observational study of patients with HFpEF (PURSUIT-HFpEF study). METHOD AND RESULTS: We classified 842 patients with HFpEF enrolled in the PURSUIT-HFpEF study into two groups using CFS. The registry enrolled patients hospitalized with a diagnosis of decompensated heart failure. Median age was 82 [interquartile range: 77, 87], and 45% of the patients were male. Of 842 patients, 406 were classified as high CFS (CFS ≥ 4, 48%) and 436 as low CFS (CFS ≤ 3, 52%). The primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission. Patients with high CFS were older (85 vs. 79 years, P < 0.001), predominantly female (65% vs. 46%, P < 0.001) and more likely to have New York Heart Association (NYHA) ≥ 2 (75% vs. 53%, P < 0.001) and a higher level of NT-proBNP (1360 vs 838 pg/mL, P < 0.001) than those with low CFS. Patients with high CFS had a significantly greater risk of composite endpoint (Kaplan-Meier estimated 1-year event rate 39% vs. 23%, log-rank P < 0.001), all-cause mortality (Kaplan-Meier estimated 1-year event rate 17% vs. 7%, log-rank P < 0.001) and heart failure admission (Kaplan-Meier estimated 1-year event rate 28% vs. 19%, log-rank P = 0.002) than those with low CFS. Multivariable Cox regression analysis revealed that high CFS was significantly associated with composite endpoint (adjusted HR 1.92, 95% CI 1.35-2.73, P < 0.001), all-cause mortality (adjusted HR 2.54, 95% CI 1.39-4.66, P = 0.003) and heart failure admission (adjusted HR 1.55, 95% CI 1.03-2.32, P = 0.035) even after adjustment for covariates. Moreover, change in CFS grade was also significantly associated with composite endpoint (adjusted HR 1.23, 95% CI 1.11-1.36, P < 0.001), all-cause mortality (adjusted HR 1.32, 95% CI 1.13-1.55, P = 0.001) and heart failure admission (adjusted HR 1.15, 95% CI 1.02-1.30, P = 0.021). CONCLUSIONS: Frailty assessed by the CFS was associated with poor prognosis in patients with HFpEF.

DOI： 10.1002/ehf2.13482

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AIMS: The prognostic importance of admission systolic blood pressure (SBP) in heart failure with preserved ejection fraction (HFpEF) is elusive. We aimed to clarify the pathophysiological differences between patients categorized with admission SBP among HFpEF patients. METHODS AND RESULTS: We studied 1008 inpatients from PURSUIT-HFpEF, a multicentre prospective observational registry. We classified patients as having elevated (>140 mmHg), preserved (90-140 mmHg), or low (<90 mmHg) admission SBP. Most cases had elevated (n = 584) or preserved (n = 420) SBP; the four cases with low SBP were excluded. Univariable Cox regression testing revealed that preserved SBP patients had a higher risk of a composite of cardiac death and heart failure re-hospitalization [hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.14-1.92, P = 0.0035] than elevated SBP patients. In multivariable Cox regression models, while prior heart failure hospitalization (HR 1.36, 95% CI 1.01-2.84, P = 0.0453), atrial fibrillation (HR 1.82, 95% CI 1.10-2.99, P = 0.0209), and N-terminal pro-B-type natriuretic peptide (HR 1.94, 95% CI 1.10-3.43, P = 0.0229) at discharge were significantly associated with adverse outcomes in elevated SBP patients, N-terminal pro-B-type natriuretic peptide (HR 2.06, 95% CI 1.04-4.07, P = 0.0373) and right ventricular-pulmonary artery uncoupling reflected by the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio (HR 0.19, 95% CI 0.05-0.65, P = 0.0075) at discharge were significant prognostic factors in preserved SBP patients. CONCLUSIONS: Patients with preserved admission SBP had significant higher risks for adverse outcomes than those with elevated SBP in HFpEF. Tricuspid annular plane systolic excursion/pulmonary artery systolic pressure was the distinctive prognostic factor between the two groups.

DOI： 10.1002/ehf2.13420

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AIMS: The impacts of high density lipoprotein cholesterol (HDL-C) as an anti-inflammatory and C reactive protein (CRP) as inflammatory properties on the pathogenesis of heart failure were reported. At present, the clinical significance of the HDL-C/CRP ratio in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. METHODS AND RESULTS: We examined the data on 796 consecutive HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure from the PURSUIT-HFpEF registry, a prospective, multicentre observational study. We calculated the HDL/CRP ratios and evaluated the relationship between the values and clinical outcomes, including degree of cardiac function. The mean follow-up duration was 420 ± 346 days. All-cause death occurred in 118 patients, of which 51 were cardiac deaths. HDL/CRP ≤ 4.05 was independently and significantly associated with all-cause death (odds ratio = 1.84, 95% CI: 1.06-3.20, P = 0.023), and HDL/CRP ≤ 3.14 was associated with cardiac death by multivariate Cox proportional hazard analysis (odds ratio = 2.86, 95% CI: 1.36-6.01, P = 0.003). HDL-C/CRP ratio significantly correlated with the product of the left atrial volume and left ventricular mass index as well as the tricuspid annular plane systolic excursion by multiple regression analysis (standardized beta-coefficient = -0.085, P = 0.034 and standardized beta-coefficient = 0.081, P = 0.044, respectively). CONCLUSIONS: HDL-C/CRP ratio was a useful marker for predicting all-cause death and cardiac death and correlated with left ventricular diastolic function and right ventricular systolic function in HFpEF patients.

DOI： 10.1002/ehf2.13350

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BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

DOI： 10.1186/s12872-021-02098-z

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AIMS: Heart failure (HF) readmissions with preserved ejection fraction (HFpEF) are increasing in the elderly, which is a major socioeconomic problem. We investigated the clinical impact of HF readmissions (HFR) on octogenarians with HFpEF. METHODS AND RESULTS: We enrolled consecutive octogenarians (≥80 years old) from June 2016 to February 2020 in PURSUIT-HFpEF registry. We divided them into HFR group readmitted for HF during the follow-up period and non-HF readmission (non-HFR) group. We evaluated the impact of HFR on all-cause mortality, cardiac death, and quality of life (QOL). Additionally, we evaluated the factors at discharge correlated with HFR. HFR group comprised 116 patients (21.4%). Among all-cause deaths, 40 patients suffered cardiac deaths (48.2%). The Kaplan-Meier analysis revealed a similar prognosis between HFR and non-HFR groups as well as similar incidences of HF deaths. The QOL scores had significantly deteriorated by 1 year later in the HFR group (0.71 ± 0.19 vs. 0.59 ± 0.21, P < 0.001), while it was similar at 1 year in the non-HFR group. In the multivariate analysis, diabetes mellitus (DM) (P = 0.019), N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels ≥ 1611 pg/mL (P < 0.001), and serum albumin level ≤ 3.7 g/dL (P = 0.011) were useful markers for HFR in octogenarians. CONCLUSIONS: In octogenarians with HFpEF, HF readmission was not directly correlated with the prognosis but was well correlated with the QOL. Close follow-up is essential to decrease HFR of octogenarians with HFpEF with DM, high NT-pro BNP (≥1611 pg/mL) and low albumin (≤3.7 g/dL) levels at discharge.

DOI： 10.1002/ehf2.13293

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AIMS: The HFA-PEFF score is a part of the stepwise diagnostic algorithm of heart failure with preserved ejection fraction (HFpEF). We aimed to evaluate the prognostic significance of the HFA-PEFF score on the clinical outcomes in patients with HFpEF. METHODS AND RESULTS: The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study is a prospective, multicentre, observational study in which collaborating hospitals in Osaka record clinical, echocardiographic, and outcome data of patients with acute decompensated heart failure with preserved left ventricular ejection fraction (≥50%) [UMIN-CTR ID: UMIN000021831]. Acute decompensated heart failure was diagnosed on the basis of the following criteria: (i) clinical symptoms and signs according to the Framingham Heart Study criteria; and (ii) serum N-terminal pro-B-type natriuretic peptide level of ≥400 pg/mL or brain natriuretic peptide level of ≥100 pg/mL. The HFA-PEFF score has functional, morphological, and biomarker domains. We evaluated the prognostic significance of the HFA-PEFF score (calculated based on the data at hospital discharge) on post-discharge clinical outcomes in this cohort. The primary endpoint of the present study was a composite of all-cause death and heart failure readmission. Between June 2016 and December 2019, 871 patients were enrolled from 26 hospitals (mean follow-up duration 399 ± 349 days). A total of 804 patients were finally analysed after excluding patients with scores of 0 (N = 5) and 1 (N = 15) from 824 patients with available HFA-PEFF score based on the echocardiographic and laboratory data at discharge. According to the laboratory and echocardiographic data at the time of discharge, 487 patients (59.1%) were diagnosed as HFpEF (HFA-PEFF score ≥ 5) while 317 patients (38.5%) had intermediate score. Kaplan-Meier analysis divided by the HFA-PEFF score [low, score 2-5 (N = 494) vs. high, score 6 (N = 310)] indicated that the HFA-PEFF score successfully stratified the patients for the primary endpoint (log-rank test P < 0.001). Cox proportional hazard model showed that the HFA-PEFF score was significantly associated with the primary endpoint (high score with reference to low score, adjusted hazard ratio 1.446, 95% confidence interval [1.099-1.902], P = 0.008). CONCLUSION: The HFA-PEFF score at discharge was significantly associated with the post-discharge clinical outcomes in acute decompensated heart failure patients with preserved ejection fraction. This study suggested clinical usefulness of the HFA-PEFF score not only as a diagnostic tool but also a practical prognostic tool.

DOI： 10.1002/ehf2.13302

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AIMS: Co-morbidities are associated with poor clinical outcomes in patients with chronic heart failure, while cardiac iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging provides prognostic information in such patients. We sought to prospectively investigate the incremental prognostic value of cardiac MIBG imaging over the co-morbid burden, in patients admitted for acute decompensated heart failure (ADHF). METHODS AND RESULTS: In 433 consecutive ADHF patients with survival to discharge, we measured the co-morbidity using age-adjusted Charlson co-morbidity index (ACCI), commonly employed to evaluate a weighted and scored co-morbid condition, adding additional points for age. In cardiac MIBG imaging, the cardiac MIBG heart-to-mediastinum ratio (late HMR) was measured on the delayed image. Over a follow-up period of 2.9 ± 1.5 years, 160 patients had a cardiac event (a composite of cardiac death and unplanned hospitalization for worsening heart failure). Patients with high ACCI (≥6: median value) had a significantly greater risk of a cardiac event. In multivariate Cox analysis, the ACCI and late HMR were significantly and independently associated with a cardiac event. In both high and low ACCI subgroups (ACCI ≥ 6 and <6, respectively), patients with low late HMR had a significantly greater risk of a cardiac event (high ACCI: 51% vs. 34% P = 0.0026, adjusted HR 1.74 [1.21-2.51]; low ACCI: 34% vs. 17%, P = 0.0228, adjusted HR 2.19 [1.10-4.37]). CONCLUSIONS: Cardiac MIBG imaging could provide additional prognostic information over ACCI, which was also promoted to be a useful risk model, in patients admitted for ADHF.

DOI： 10.1002/ehf2.13173

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BACKGROUND: Estimated plasma volume status (ePVS) is a well-validated prognostic indicator in heart failure. However, it remains unclear whether ePVS has prognostic significance in patients with acute myocardial infarction (AMI). Moreover, there is no available information on its additive effect with the Global Registry of Acute Coronary Events (GRACE) risk score in AMI patients. METHODS: Data were obtained from the Osaka Acute Coronary Insufficiency Study (OACIS) registry database. Patients whose data were available for ePVS derived from Hakim's formula and the GRACE risk score were studied. The primary endpoints were in-hospital and 5-year mortality. RESULTS: Of 3930 patients, 206 and 200 patients died during hospitalization and 5 years after discharge, respectively. After adjustment, ePVS remained an independent predictor of in-hospital death (OR:1.02, 95% CI: 1.00-1.04, p = 0.036), and 5-year mortality(HR:1.03, 95% CI: 1.01-1.04, p < 0.001). An additive effect of ePVS with the GRACE risk score was observed in predicting the 5-year mortality with an area under the receiver operating characteristic curve (AUC) from 0.744 to 0.763 (p = 0.026), but not in-hospital mortality (the AUC changed from 0.875 to 0.875, p = 0.529). The incremental predictive value of combining ePVS and the GRACE risk score for 5-year mortality was significantly improved, as shown by the net reclassification improvement (NRI:0.378, p < 0.001) and integrated discrimination improvement (IDI:0.014, p < 0.001). CONCLUSIONS: In patients with AMI, ePVS independently predicted in-hospital and long-term mortality. In addition, ePVS had an additive effect with the GRACE risk score on long-term mortality. Therefore, ePVS may be useful for identifying high-risk subjects for intensive treatment.

DOI： 10.1016/j.ijcha.2021.100748

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AIMS: Cardiohepatic interactions have been a focus of attention in heart failure (HF). The model for end-stage liver disease excluding international normalized ratio (MELD-XI) score has been shown to be useful for predicting poor outcomes in patients with acute decompensated HF (ADHF). Furthermore, the fibrosis-4 (FIB-4) index, a simple marker to assess liver fibrosis, predicts adverse prognoses in patients with HF as well. However, there is little information available on the prognostic significance of the combination of the MELD-XI score and FIB-4 index in patients with ADHF and its association with left ventricular ejection fraction (LVEF) subgroup. METHODS AND RESULTS: We prospectively studied 466 consecutive patients who were admitted for ADHF [HF with reduced LVEF (LVEF < 40%): n = 164, HF with mid-range LVEF (40% ≤ LVEF < 50%): n = 104, and HF with preserved LVEF (LVEF ≥ 50%): n = 198]. We calculated the MELD-XI score and FIB-4 indices at discharge. The primary endpoint was all-cause death (ACD). During the mean follow-up period of 2.8 years, 143 patients had ACD. In the multivariate Cox analysis, the MELD-XI score and FIB-4 index were independently associated with ACD. Patients were stratified into the following three groups according to the median value of MELD-XI score (=11) and FIB-4 index (=2.13): Group 1 had both a low MELD-XI score and a low FIB-4 index; Group 2 had either a high MELD-XI score (MELD-XI score ≥11) or a high FIB-4 index (FIB-4 index ≥2.13); and Group 3 had both a high MELD-XI score and a high FIB-4 index. Kaplan-Meier analysis revealed that Group 2 and Group 3 had a significantly greater risk of ACD than Group 1 [Group 2 vs. Group 1: adjusted hazard ratio, 2.48 (95% confidence interval: 1.75-3.53), P < 0.0001; Group 3 vs. Group 1: adjusted hazard ratio, 7.03 (95% confidence interval: 3.95-13.7), P < 0.0001]. In addition, the patients with both a higher MELD-XI score and FIB-4 index showed a significantly higher risk of ACD also in the patients with HF with reduced LVEF, HF with mid-range LVEF, and HF with preserved LVEF (all P < 0.0001). CONCLUSIONS: The combination of MELD-XI score and FIB-4 index may be useful for stratifying patients at risk for ACD in patients with ADHF, irrespective of LVEF.

DOI： 10.1002/ehf2.13195

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The American Society of Echocardiography and/or the European Association of Cardiovascular Imaging recommend a conventional algorithm for estimating left ventricular (LV) filling pressure in heart failure. However, several patients are classed as "indeterminate" due to their LV filling pressures being impossible to calculate. We investigated whether our new echocardiographic algorithm can predict clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF). We enrolled 754 consecutive patients from the PURSUIT-HFpEF registry. We used the new algorithm to divide them into 2 groups; a normal LV filling pressure group (N group) and a high LV filling pressure group (H group). The H group consisted of 342 patients. Over a mean follow-up of 342 days, 185 patients reached the primary composite end point (157 readmissions for worsening heart failure and 43 cardiovascular deaths). In a multivariable Cox analysis, being in the H group was significantly associated with an increased rate of cardiac events compared with the N group (hazard ratio: 1.71; 95% confidence interval: 1.17 to 2.50, p = 0.006). There were 56 patients (7%) who were assigned to "indeterminate" with the conventional algorithm. Using the new algorithm, we reclassified 16 patients (29%) into the H group and 40 patients (71%) into the N group. The Kaplan-Meier curves showed the reclassified H group had a significantly higher incidence of cardiac events than those assigned to the N group (p < 0.01). In conclusion, the present study demonstrated LV filling pressure assessed by our algorithm can predict clinical outcomes in patients with HFpEF.

DOI： 10.1016/j.amjcard.2020.12.035

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BACKGROUND: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure. METHODS: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula. RESULTS: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups. CONCLUSIONS: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.

DOI： 10.1161/CIRCHEARTFAILURE.120.007048

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Background The female preponderance in heart failure with preserved ejection fraction (HFpEF) is a distinguishing feature of this disorder, but the association of sex with degree of diastolic dysfunction and clinical outcomes among individuals with HFpEF remains unclear. Methods and Results We conducted a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF [Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction]: UMIN000021831). Between 2016 and 2019, 871 patients were enrolled from 26 hospitals (follow-up: 399±349 days). We investigated sex-related differences in diastolic dysfunction and postdischarge clinical outcomes in patients with HFpEF. The echocardiographic end point was diastolic dysfunction according to American Society of Echocardiography/European Association of Cardiovascular Imaging criteria. The clinical end point was a composite of all-cause death and heart failure readmission. Women accounted for 55.2% (481 patients) of the overall cohort. Compared with men, women were older and had lower prevalence rates of hypertension, coronary artery disease, and chronic kidney disease. Women had diastolic dysfunction more frequently than men (52.8% versus 32.0%, P<0.001). The incidence of the clinical end point did not differ between women and men (women 36.1/100 person-years versus men 30.5/100 person-years, P=0.336). Female sex was independently associated with the echocardiographic end point (adjusted odds ratio, 2.839; 95% CI, 1.884-4.278; P<0.001) and the clinical end point (adjusted hazard ratio, 1.538; 95% CI, 1.143-2.070; P=0.004). Conclusions Female sex was independently associated with the presence of diastolic dysfunction and worse clinical outcomes in a cohort of elderly patients with HFpEF. Our results suggest that a sex-specific approach is key to investigating the pathophysiology of HFpEF. Registration URL: https://upload.umin.ac.jp; Unique identifier: UMIN000021831.

DOI： 10.1161/JAHA.120.018574

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AIMS: Cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging provides prognostic information in patients with chronic heart failure (HF). However, there is little information available on the prognostic role of cardiac 123I-MIBG imaging in patients admitted for acute decompensated heart failure (ADHF), especially relating to reduced ejection fraction [HFrEF; left ventricular ejection fraction (LVEF) < 40%], mid-range ejection fraction (HFmrEF; 40% ≤ LVEF < 50%) and preserved ejection fraction (HFpEF; LVEF ≥ 50%). METHODS AND RESULTS: We studied 349 patients admitted for ADHF and discharged with survival. Cardiac 123I-MIBG imaging, echocardiography, and venous blood sampling were performed just before discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (late H/M) was measured on the chest anterior view images obtained at 200 min after the isotope injection. The endpoint was cardiac events defined as unplanned HF hospitalization and cardiac death. During a follow-up period of 2.1 ± 1.4 years, 128 patients had cardiac events (45/127 in HFrEF, 28/78 in HFmrEF, and 55/144 in HFpEF). On multivariable Cox analysis, late H/M was significantly associated with cardiac events in overall cohort (P = 0.0038), and in subgroup analysis of each LVEF subgroup (P = 0.0235 in HFrEF, P = 0.0119 in HFmEF and P = 0.0311 in HFpEF). Kaplan-Meier analysis showed that patients with low late H/M (defined by median) had significantly greater risk of cardiac events in overall cohort (49% vs. 25% P < 0.0001) and in each LVEF subgroup (HFrEF: 48% vs. 23% P = 0.0061, HFmrEF: 51% vs. 21% P = 0.0068 and HFpEF: 50% vs. 26% P = 0.0026). CONCLUSION: Cardiac sympathetic nerve dysfunction was associated with poor outcome in ADHF patients irrespective of HFrEF, HFmrEF, or HFpEF.

DOI： 10.1093/ehjci/jeaa025

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OBJECTS: We aimed to clarify the differences in the of the ratio of diastolic elastance (Ed) to arterial elastance (Ea), [Ed/Ea=(E/e')/(0.9×systolic blood pressure)], anafterload-integrateddiastolic index that reflects left atrial pressure overload, on prognosis between patients with heart failure with preserved ejection fraction (HFpEF) with and without atrial fibrillation (AF). METHODS: We studied 552 HFpEF patients hospitalized for acute decompensated heart failure (sinus rhythm/AF:352/200).Blood testing and transthoracic echocardiography were performed before discharge. Primary endpoint was all-cause mortality after discharge. RESULTS: During a median follow-up of 508 days, 88 patients (sinus rhythm/AF: 54/34) had all-cause mortality. In the subgroup with sinus rhythm, but not AF, Ed/Ea was significantly higher in patients with than without all-cause mortality. In a multivariate Cox hazard analysis, Ed/Ea was significantly associated with all-cause mortality independent of N-terminal pro-brain natriuretic peptide level in patients with sinus rhythm, but not with AF. CONCLUSIONS: Ed/Ea providedlesser important information for predicting all-cause mortality in HFpEF patients with AF than with sinus rhythm. The prognostic risk factors may differ between elderly HFpEF patients with and without AF.

DOI： 10.4022/jafib.2469

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© 2020, The Author(s). The index for a target that can lead to improved prognoses and more reliable therapy in each heterogeneous patient with heart failure with preserved ejection fraction (HFpEF) remains to be defined. We examined the heterogeneity in the cardiac performance of patients with HFpEF by clarifying the relationship between the indices of left atrial (LA) volume (LAV) overload and pressure overload with echocardiography. We enrolled patients with HFpEF (N = 105) who underwent transthoracic echocardiography during stable sinus rhythm. Relative LAV overload was evaluated using the LAV index or stroke volume (SV)/LAV ratio. Relative LA pressure overload was estimated using E/e’ or the afterload-integrated index of left ventricular (LV) diastolic function: diastolic elastance (Ed)/arterial elastance (Ea) ratio = (E/e’)/(0.9 × systolic blood pressure). The logarithmic value of the N-terminal pro-brain natriuretic peptide was associated with SV/LAV (r = −0.214, p = 0.033). The pulmonary capillary wedge pressure was positively correlated to Ed/Ea (r = 0.403, p = 0.005). SV/LAV was negatively correlated to Ed/Ea (r = −0.292, p = 0.002), with no observed between-sex differences. The correlations between the LAV index and E/e’ and Ed/Ea and between SV/LAV and E/e’ were less prominent than the abovementioned relationships. SV/LAV and Ed/Ea, showing relative LAV and LA pressure respectively, were significantly but modestly correlated in patients with HFpEF. There may be considerable scatter in the relationships between these indices, which could possibly affect the selection of medications or efforts to improve the prognoses of patients with HFpEF.

DOI： 10.1038/s41598-019-56581-x

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OBJECTIVE: During follow-up time, the value of prognostic factors may change, especially in the elderly patients, and the altered extent may affect the prognosis. We aimed to clarify the significance of the ratio of diastolic elastance (Ed) to arterial elastance (Ea), (Ed/Ea=(E/e')/(0.9×systolic blood pressure)), an afterload-integrated diastolic index, in relation to follow-up periods and other laboratory factors, on the prognosis of elderly patients with heart failure with preserved ejection fraction (HFpEF). METHODS: We studied 552 HFpEF patients hospitalised for acute decompensated heart failure (men/women: 255/297). Blood testing and transthoracic echocardiography were performed before discharge. The primary endpoint was all-cause mortality. RESULTS: During a median follow-up of 508 days, 88 patients (men/women: 39/49) had all-cause mortality. During the first year after discharge, Ed/Ea (p=0.045) was an independent prognostic factor in association with albumin (p<0.001) and N-terminal pro-brain natriuretic peptide (NT-proBNP, p=0.005) levels after adjusting for age and sex in the multivariate Cox hazard analysis. However, at 1 to 3 years after discharge, no other significant prognostic factors, except for albumin level (p=0.046), were detected. In the subgroup analysis, albumin, but not NT-proBNP level, showed a significant interaction with Ed/Ea for prognosis (p=0.047). CONCLUSION: The prognostic significance of a haemodynamic parameter such as Ed/Ea may be valid only during a short-term period, but that of albumin was persisting during the entire follow-up period in the elderly patients. The clinical significance of prognostic factors in HFpEF patients may differ according to the follow-up period.

DOI： 10.1136/openhrt-2020-001469

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BACKGROUND: Recent accumulating evidence reveals that the right ventricular (RV)-pulmonary artery (PA) uncoupling is associated with poor outcome in patients with heart failure (HF), RV dysfunction, and pulmonary hypertension. However, the prognostic utility of RV-PA uncoupling in HF with preserved ejection fraction (HFpEF) remains elusive. In this study, we aim to investigate the associations of RV-PA uncoupling with outcomes of HFpEF inpatients. METHODS: We prospectively studied 655 patients, registered in PURSUIT-HFpEF (The Prospective Multicenter Obervational Study of Patients with Heart Failure with Preserved Ejection Fraction), a multicenter observational study of Japanese HFpEF inpatients. We assigned registered patients based on the determined value of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure ratio that can predict primary outcome as an indicator of RV-PA uncoupling. RESULTS: Univariable Cox regression testing revealed that RV-PA uncoupling was associated with the primary endpoint of all-cause death, HF rehospitalization, and cerebrovascular events (hazard ratio [HR] 1.77 [95% CI, 1.34-2.32], P<0.0001) and the secondary endpoints of all-cause death and HF rehospitalization (HR 2.75 [95% CI, 1.77-4.33], P<0.0001, HR 1.63 [95% CI, 1.18-2.26], P=0.0036, respectively). Multivariable analysis also showed that RV-PA uncoupling was significantly associated with primary endpoint and all-cause death independent of age, sex, atrial fibrillation, renal dysfunction, elevated E/e', and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) (HR 1.38 [95% CI, 1.01-1.88], P=0.0413, HR 1.85 [95% CI, 1.14-3.01], P=0.0129, respectively). CONCLUSIONS: Prospective study of a hospitalized cohort revealed that RV-PA uncoupling was independently associated with adverse outcomes in acute decompensated patients with HFpEF. Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.

DOI： 10.1161/CIRCIMAGING.120.011430

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BACKGROUND: AdreView myocardial imaging for risk evaluation in heart failure (ADMIRE-HF) risk score is a novel risk score to predict serious arrhythmic risk in chronic heart failure patients with reduced ejection fraction (HFrEF). Moreover, early repolarization pattern (ERP) has been shown to be associated with an increased risk of sudden cardiac death (SCD) in HFrEF patients. We sought to investigate the prognostic value of combining ADMIRE-HF risk score and ERP to predict SCD in HFrEF patients. METHODS: We studied 90 HFrEF outpatients with LVEF< 40% in our prospective cohort study. In cardiac MIBG imaging, the heart-to-mediastinum (H/M) ratio was measured on the delayed planar image. ADMIRE-HF risk score was derived from the sum of the point values of LVEF, H/M ratio, and systolic blood pressure. We also assessed ERP on the standard electrocardiogram. RESULTS: During a median follow-up of 7.5(4.5-12.0) years, 22 patients had SCD. At multivariate Cox analysis, ADMIRE-HF risk score and ERP were independently associated with SCD. Patients with both intermediate/high ADMIRE-HF score and ERP had a higher SCD risk than those with either and none of them. CONCLUSION: The combination of ADMIRE-HF risk score and ERP would provide the incremental prognostic information for predicting SCD in HFrEF patients.

DOI： 10.1007/s12350-019-01639-6

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AIMS: Acute decompensated heart failure (ADHF) is generally treated by decongestion using diuretic therapy. However, the use of loop diuretics is associated with increased cardiac sympathetic nerve activity (CSNA). We aimed to evaluate the effect of adjunctive tolvaptan therapy on CSNA in ADHF patients with preserved left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We enrolled 51 consecutive ADHF patients with LVEF ≥45%. Patients were randomly assigned to receive either tolvaptan add-on (n = 25) or conventional diuretic therapy (n = 26). Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed after stabilisation of heart failure symptoms, and the cardiac MIBG heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated. There were no significant differences in the body weight change and total urine volume during 2 days after randomisation or in the HMR on delayed image (HMR(d)) and WR between the tolvaptan and conventional groups. After stratification based on the median change in body weight, the patients with higher weight reduction had a significantly lower HMR(d) (P = 0.0128) and tended to have a higher WR (P = 0.0786) in the conventional group, whereas the cardiac MIBG imaging results were not influenced by body weight reduction in the tolvaptan group. CONCLUSIONS: Adjunctive tolvaptan therapy may provide rapid decongestion without a harmful effect on CSNA in ADHF patients with preserved LVEF.

DOI： 10.1002/ehf2.12690

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BACKGROUND: Cardiac sympathetic nerve activity (CSNA) and epicardial adipose tissue (EAT) are known to be major determinants in the progression of atrial fibrillation (AF). OBJECTIVE: The aim was to investigate the relationship between the combination of CSNA and EAT, and AF recurrence (AFR) following 3 months after the index catheter ablation (CA) in patients without heart failure (HF). METHODS AND RESULTS: Sixty-four paroxysmal AF patients without HF were studied. Cardiac metaiodobenzylguanidine (MIBG) scintigraphy was performed at baseline and 3 months post-ablation. In MIBG imaging, the MIBG washout rate (WR) was calculated. The volumes of the total EAT and periatrial EAT surrounding the left atrium were measured by computed tomography before CA, and the periatrial to total EAT volume ratio (P/T) was obtained. During the follow-up period of 11 ± 4 months, AFR was observed in 14 patients. The WR change from baseline to 3 months after CA (dWR) and P/T were significantly greater in patients with than without AFR. Greater dWR and P/T determined by ROC curve analysis were independently associated with AFR. Patients with both greater dWR (≥6.9%) and P/T (≥17.1%) had a higher risk of AFR than those with either and none of them. Periatrial EAT volume showed a significant correlation with the baseline WR. CONCLUSIONS: The combination of dWR and P/T was associated with AFR in patients without HF. Thus, both of CSNA and EAT might be related to development of AF.

DOI： 10.1016/j.ijcard.2019.11.092

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Background Malnutrition is one of the most important comorbidities in patients with heart failure with preserved ejection fraction. We recently reported the prognostic significance of serum cholinesterase level and superior predictive power of cholinesterase level to other objective nutritional indices such as the controlling nutritional status score, prognostic nutritional index, and geriatric nutritional risk index in patients with acute decompensated heart failure. The aim of this study was to clarify the prognostic role of cholinesterase in patients with heart failure with preserved ejection fraction/acute decompensated heart failure and investigate incremental cholinesterase value. Methods and Results We prospectively studied 274 consecutive patients from the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients with Heart Failure With Preserved Ejection Fraction) study. During a follow-up period of 1.2±0.6 years, 56 patients reached the composite end points (cardiovascular death and readmission for worsening heart failure). In the multivariable Cox analysis, cholinesterase level was significantly associated with the composite end points after adjustment for major confounders. A Kaplan-Meier analysis revealed that patients with low cholinesterase levels (stratified by tertile) had significantly greater risk of reaching the composite end points than those with middle or high cholinesterase levels (P=0.0025). Cholinesterase level showed the best C-statistics (0.703) for prediction of the composite end points among the objective nutritional indices. C-statistics of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score for prediction of the composite end points were improved when cholinesterase level was added (C-statistics, from 0.601 to 0.705; P=0.0408). Conclusions Cholinesterase was a useful prognostic marker for prediction of adverse outcome in patients with heart failure with preserved ejection fraction/acute decompensated heart failure.

DOI： 10.1161/JAHA.119.014100

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BACKGROUND: Cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with heart failure (HF). Recent studies showed that the highest rate of ventricular tachyarrhythmias (VTs) is seen in HF patients with an intermediate decrease in MIBG uptake, rather than in those with the lowest values. However, prolonged QRS duration (QRSd) has been shown to be associated with VTs in HF patients. This study assessed the prognostic value of the combination of an intermediate decrease in MIBG uptake and prolonged QRSd for predicting VTs in patients with implantable cardioverter defibrillators (ICDs) in relation to the presence of heart failure (HF). METHODS AND RESULTS: A total of 196 outpatients with ICDs (age: 64 ± 14 years, male: 81%, left ventricular ejection fraction [LVEF]: 49% ± 16%) were prospectively enrolled; 135 had HF (NYHA class: 2.0 ± 0.6). At entry, cardiac MIBG imaging was performed, and QRSd was measured on standard 12‑lead electrocardiography. An intermediate decrease in the heart-to-mediastinum ratio on the delayed planar image (ID-H/M) was defined as 1.40-1.89. During the 3.3 ± 2.2-year follow-up, 59 patients had appropriate ICD discharges (ATx) for VTs. On multivariate Cox analysis, ID-H/M and prolonged QRSd (≥147 ms) were significantly and independently associated with ATx. In both patients with and without HF, ATx were significantly more frequent in patients with ID-H/M and/or prolonged QRSd than in those with neither (with HF: 40% vs. 14%, p = 0.020; without HF: 43% vs. 10%, p = 0.0028). CONCLUSIONS: The combination of ID-H/M and prolonged QRSd provided more prognostic information for predicting VTs in ICD patients, with and without HF.

DOI： 10.1016/j.ijcard.2019.07.068

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Background: Congestion is one of the main predictors of poor outcome in patients with heart failure (HF); thus, a simple tool to evaluate plasma volume (PV), which can be used for risk stratification of HF patients, is necessary. We sought to compare the prognostic values of commonly used formulas for the estimation of PV and relative PV status (PVS) in patients admitted with acute decompensated HF (ADHF). Methods and Results: We analyzed 384 consecutive ADHF patients who survived to discharge. The PV was calculated by 3 commonly used formulas (Strauss, Kaplan, and Hakim), and the relative PVS was calculated using the Hakim formula at both admission and discharge. The primary endpoint was a composite of all-cause mortality and hospitalization for worsening HF. The secondary endpoints were pump failure death (PFD) and sudden cardiac death (SCD). During a median follow-up of 743 days, 175 patients reached the primary endpoint, 28 patients had PFD, and 20 patients had SCD. Multivariate Cox analysis revealed that among the PV indices, only the PVS values at admission and discharge were independent predictors of the primary endpoint. In addition, the PVS values at admission and discharge were independent predictors of PFD and SCD in the multivariate analysis. Conclusions: Among the indices of PV, the calculated PVS may be the most useful for predicting prognosis in ADHF patients.

DOI： 10.1253/circrep.CR-19-0039

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BACKGROUND: Nutritional status is associated with poor outcomes in patients with heart failure. Serum cholinesterase (CHE) concentration, a marker of malnutrition, was reported to be a prognostic factor in patients with chronic heart failure. The geriatric nutritional risk index (GNRI), the controlling nutritional status (CONUT) score, and the prognostic nutritional index (PNI) are established objective nutritional indices. OBJECTIVE: The aim of this study was to clarify the prognostic significance of CHE concentration and to compare it with other well-established objective nutritional indices in patients with acute decompensated heart failure (ADHF). METHODS: We prospectively enrolled 371 consecutive patients admitted for ADHF with survival discharge. Laboratory data including CHE and the objective nutritional indices were obtained at discharge. The primary endpoint of this study was all-cause mortality. RESULTS: During a mean ± SD follow-up period of 2.5 ± 1.4 y, 112 patients died. CHE concentration was significantly associated with all-cause mortality independently of GNRI, CONUT score, or PNI, after adjustment for major confounders including other nutritional indices, such as age, sex, systolic blood pressure, BMI, left ventricular ejection fraction, history of hypertension, diabetes mellitus, dyslipidemia, prior heart failure hospitalization, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, β-blocker use, statin use, hemoglobin, sodium, blood urea nitrogen, albumin, C-reactive protein, and brain natriuretic peptide concentrations via multivariable Cox analysis. Kaplan-Meier analysis revealed that the risk of all-cause mortality significantly increased in accordance with CHE stratum [lowest tertile: 53%, adjusted HR: 6.92; 95% CI: 3.87, 12.36, compared with middle tertile: 28%, adjusted HR: 2.72; 95% CI: 1.45, 5.11, compared with highest tertile: 11%, adjusted HR: 1.0 (reference), P < 0.0001]. CHE showed the best area under the curve value (0.745) for the prediction of all-cause mortality compared with the other objective nutritional indices. Net reclassification improvement afforded by adding CHE to the fully adjusted multivariable model was statistically significant for all-cause mortality (0.330; 95% CI: 0.112, 0.549, P = 0.0030). CONCLUSION: CHE is a simple, strong prognostic marker for the prediction of all-cause mortality in patients with ADHF.

DOI： 10.1093/ajcn/nqz103

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BACKGROUND: The sympathetic nervous system provides an important trigger for major arrhythmic events through regional heterogeneity of sympathetic activity, which could be evaluated by SPECT imaging as the regional MIBG washout rate (WR). There is little information available on the prognostic value of regional WR in SPECT imaging for the prediction of sudden cardiac death (SCD) in patients with chronic heart failure (CHF). METHODS: We studied 73 CHF outpatients with LVEF < 40%. At study entry, the regional WR was measured in 17 segments on the polar map. We defined abnormal regional WR as both the regional WR range (maximum - minimum regional WR) and maximum regional WR > mean value + 2SD obtained in 15 normal controls. RESULTS: During a mean follow-up of 7.5 ± 4.1 years, 15 of 73 patients had SCD. The abnormal regional WR and abnormal global WR on planar images were significantly and independently associated with SCD. Patients with both the abnormal regional WR and global WR had a significantly higher risk of SCD than those with none of these criteria. CONCLUSIONS: The analysis of regional MIBG WR on SPECT imaging provides additional prognostic value to global WR on planar images for SCD prediction in CHF patients.

DOI： 10.1007/s12350-017-0913-0

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© 2018 Wiley Periodicals, Inc. Background: We previously reported that an index of afterload-related left ventricular diastolic function, operant diastolic elastance (Ed)/effective arterial elastance (Ea) = E/e’/(0.9 × systolic blood pressure), was significantly higher in elderly hypertensive women. We aimed to determine sex-related differences in the E/e’-related indices for left ventricular diastolic function and their related factors during admission in patients with heart failure with preserved ejection fraction (HFpEF). Hypothesis: Elderly HFpEF women exhibit severe left ventricular diastolic dysfunction associated with different left atrioventricular volume ratio. Methods: We divided 267 patients with HFpEF (men/women, 116/151) into two groups by age (≥75 years, n = 212; <75 years, n = 55). We examined the alterations of E/e’, E/e’/stroke volume index = Ed, and Ed/Ea, and cardiac structure during admission. Results: Ed and Ea were significantly higher in women than in men, at admission, especially in patients ≥75 years. Before discharge, not only Ed and Ea but also Ed/Ea was significantly higher in women than in men, especially in patients ≥75 years. Elderly female patients had larger left atrial than left ventricular volume. Conclusions: Higher afterload-related left ventricular diastolic elastance, Ed/Ea, in association with higher arterial elastance, Ea, accompanied by left atrioventricular volume mismatch was observed in elderly HFpEF women.

DOI： 10.1002/clc.23073

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BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

DOI： 10.1007/s10557-018-6799-5

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BACKGROUND: Although hyponatremia predicts morbidity and mortality in acute decompensated heart failure (ADHF), hypochloremia is also independently associated with poor prognosis in ADHF. Little is known, however, about the prognostic value of serial change in serum chloride during hospitalization in ADHF patients.Methods and Results:We prospectively studied 208 ADHF survivors after discharge and divided them into 4 groups according to serum chloride on admission and at discharge: (1) persistent hypochloremia group (n=12), hypochloremia both on admission and at discharge; (2) progressive hypochloremia group (n=42), development of hypochloremia after admission; (3) improved hypochloremia group (n=14), hypochloremia only on admission; and (4) no hypochloremia group, no hypochloremia during hospitalization (n=140). During a mean follow-up period of 1.86±0.76 years, 20 of 208 patients had heart failure death (HFD). In a model adjusted for hyponatremia, hypochloremia both on admission and at discharge was still significantly associated with HFD. Hyponatremia, however, was not significantly associated with HFD after adjustment for hypochloremia. Patients with persistent hypochloremia (HR, 9.13; 95% CI: 2.56-32.55) and with progressive hypochloremia (HR, 4.65; 95% CI: 1.61-13.4) had a significantly greater risk of HFD than those without hypochloremia during hospitalization. CONCLUSIONS: Both persistent hypochloremia and progressive hypochloremia during hospitalization are associated with HFD in ADHF patients.

DOI： 10.1253/circj.CJ-17-0938

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BACKGROUND: Eplerenone is reported to reduce the development of atrial fibrillation (AF). The aim of this study was to clarify the mechanism of eplerenone for AF prevention from the viewpoint of P wave morphology, which is reported to correlate with atrial fibrosis. METHODS: Thirty-five patients with hypertension, who were randomized to receive eplerenone (n = 16) or amlodipine (n = 19) for 1 year, were evaluated. P wave signal-averaged electrocardiography was recorded at baseline and 1 year after entry, and P wave duration (Ad) and P wave dispersion (P-disp) were obtained. Serum levels of intact procollagen type I N-terminal propeptide (PINP) and N-terminal procollagen-III peptide (PIIIP) were also measured. RESULTS: There were no significant differences in baseline clinical characteristics including Ad, P-disp, and the decrease in blood pressure at 1-year follow-up between the two groups. Ad and P-disp (mean ± standard deviation) significantly increased in patients on amlodipine after 1 year (140 ± 21 ms to 139 ± 19 ms vs 132 ± 10 ms to 136 ± 12 ms, P < 0.01 and 14 ± 7 ms to 9 ± 4 ms vs 12 ± 5 to 16 ± 8, P < 0.01, respectively). PINP was significantly more decreased in patients with eplerenone than amlodipine (56.6 ± 30.4 μg/mL to 46.6 ± 19.4 μg/mL vs 41.5 ± 16.2 μg/L to 48.7 ± 21.3 μg/L, P < 0.01). Percent changes of Ad, P-disp, PINP, and PIIIP were significantly smaller in patients with eplerenone than amlodipine (0.0 ± 4.7% vs 3.2 ± 4.4%, P < 0.05, - 28.6 ± 31.0% vs 46.3 ± 73.0%, P < 0.01, - 5.6 ± 38.1% vs 22.7 ± 42.7%, P < 0.05, and - 9.2 ± 25.1% vs 7.4 ± 19.0%, P < 0.05, respectively). CONCLUSIONS: Eplerenone reduced the increase of Ad and P-disp with a decrease of PINP and PIIIP, which might translate into reduction of atrial fibrosis. This study showed that eplerenone may be useful as upstream therapy for AF in patients with hypertension.

DOI： 10.1111/pace.13169

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BACKGROUND: Although the mainstay of treatment for acute decompensated heart failure (ADHF) is decongestion by diuretic therapy, it is often associated with worsening renal function (WRF). The effect of tolvaptan, a selective V2 receptor antagonist, on WRF in ADHF patients with preserved left ventricular ejection fraction (LVEF) is unknown.Methods and Results:We enrolled 50 consecutive ADHF patients whose LVEF on admission was ≥45%. Patients were randomly assigned to either tolvaptan add-on (n=26) or conventional diuretic therapy (n=24). The primary endpoint was the incidence of WRF, defined as an increase in serum creatinine (Cr) ≥0.3 mg/dL or 50% above baseline within 48 h of randomization. There was no significant difference between the 2 groups in the change in body weight or the total urine volume during 48 h. However, the change in Cr (∆Cr) at 24 and 48 h after randomization and the incidence of WRF (12% vs. 42%, P=0.0236) were significantly lower, and the fractional excretion of urea (FEUN) at 24 and 48 h after randomization was significantly higher in the tolvaptan group. There was an inverse correlation between ∆Cr and FEUN at 48 h after randomization. CONCLUSIONS: Tolvaptan can alleviate congestion with a significantly lower risk of WRF in ADHF patients with preserved LVEF, presumably through maintenance of renal perfusion.

DOI： 10.1253/circj.CJ-16-1122

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The CHADS2 score is useful in stratifying the risk of ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (AF). However, it remains unclear whether the CHADS2 score could predict stroke or TIA in chronic heart failure (CHF) patients without AF. Recently, the new stroke risk score was proposed from 2 contemporary heart failure trials. We evaluated the prognostic power of the CHADS2 score for stroke or TIA in CHF patients without AF in comparison to the "stroke risk score". We retrospectively studied 127 CHF patients [left ventricular ejection fraction (LVEF) <40 %] without AF, who had been enrolled in our previous prospective cohort study. The primary endpoint was the incidence of stroke or TIA. The mean baseline CHADS2 score was 2.1 ± 1.0. During the follow-up period of 8.4 ± 5.1 years, stroke or TIA occurred in 21 of 127 patients. At multivariate Cox analysis, CHADS2 score (C-index 0.794), but not "stroke risk score" (C-index 0.625), was significantly and independently associated with stroke or TIA. The incidence of stroke or TIA appeared to increase in relation to the CHADS2 score [low (=1), 0 per 100 person-years; intermediate (=2), 1.6 per 100 person-years; high (≥3), 4.7 per 100 person-years; p = 0.04]. CHADS2 score could stratify the risk of ischemic stroke in CHF patients with the absence of AF, with greater prognostic power than the "stroke risk score".

DOI： 10.1007/s00380-016-0861-7

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Liver dysfunction has a prognostic impact on the outcomes of patients with advanced heart failure (HF). The model for end-stage liver disease (MELD) score is a robust system for rating liver dysfunction, and a high score has been shown to be associated with a poor prognosis in ambulatory patients with HF. In addition, cardiac metaiodobenzylguanidine (MIBG) imaging provides prognostic information in patients with chronic HF (CHF). However, the long-term predictive value of combining the MELD score and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac MIBG imaging provides additional prognostic value to the MELD score in patients with mild-to-moderate CHF, we studied 109 CHF outpatients (New York Heart Association: 2.0 ± 0.6) with left ventricular ejection fraction <40%. At enrollment, an MELD score was obtained, and the heart-to-mediastinal ratio on delayed imaging and MIBG washout rate (WR) were measured using cardiac MIBG scintigraphy. During a follow-up period of 7.5 ± 4.2 years, 36 of 109 patients experienced cardiac death (CD). On multivariate Cox analysis, MELD score and WR were significantly independently associated with CD, although heart-to-mediastinal ratio showed an association with CD only on univariate Cox analysis. Patients with abnormal WR (>27%) had a significantly greater risk of CD than those with normal WR in both those with high MELD scores (≥10; hazard ratio 4.0 [1.2 to 13.6]) and with low MELD scores (<10; hazard ratio 6.4 [1.7 to 23.2]). In conclusion, cardiac MIBG imaging would provide additional prognostic information to the MELD score in patients with mild-to-moderate CHF.

DOI： 10.1016/j.amjcard.2016.03.047

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BACKGROUND: Ambulatory electrocardiogram (ECG)-based T-wave alternans (TWA) quantified by the modified moving average method (MMA) can be used to identify patients at risk for sudden cardiac death. However, there is no information available on ambulatory ECG-based TWA as quantified by the frequency domain (FD) method to identify patients with an implantable cardioverter defibrillator (ICD) who are at high risk for ventricular tachyarrhythmias. Further, there are few data regarding the comparison of clinical utility of FD-TWA with MMA-TWA, heart rate variability (HRV), and heart rate turbulence (HRT). METHODS AND RESULTS: In 41 patients with ICD, of whom 14 patients had a past history of at least one appropriate ICD discharge, FD-TWA, MMA-TWA, HRV, and HRT were analyzed from 24-hour Holter ECG monitoring recordings. Only positive results of FD-TWA and abnormal HRV (standard deviation of all normal-to-normal intervals ≤111 ms) were significantly more frequently observed in patients with than without appropriate ICD discharge. Patients with FD-TWA positive had a significantly higher risk of appropriate ICD discharge than those with FD-TWA negative (50% vs 16%; odds ratio, 5.3 [95% confidence interval, 1.2-23.7], P = 0.02). When FD-TWA and HRV were combined, the specificity (93% vs 59%, P = 0.003) and predictive accuracy (83% vs 66%, P = 0.07) for the identification of patients with appropriate ICD discharge were greater than those for FD-TWA only. CONCLUSION: The ambulatory ECG-based FD-TWA might be useful to detect patients with ICD who are at high risk for ventricular tachyarrhythmias, and the combination of FD-TWA and HRV might improve the ability to detect such high-risk patients.

DOI： 10.1111/pace.12747

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AIMS: Right ventricular (RV) systolic dysfunction has been shown to be an independent predictor of clinical outcome in patients with chronic heart failure (CHF), and cardiac metaiodobenzylguanidine (MIBG) imaging also provides prognostic information. We aimed to evaluate the long-term predictive value of combining RV systolic dysfunction and abnormal findings of cardiac MIBG imaging on outcome in CHF patients. METHODS AND RESULTS: We enrolled 63 CHF outpatients with left ventricular ejection fraction (EF) <40% in a prospective cohort study. At entry, RVEF was measured by radionuclide angiography. Furthermore, cardiac MIBG imaging was performed, and the cardiac MIBG washout rate (WR) was calculated. Reduced RVEF was defined as ≤37%, and abnormal WR was defined as >27%. The study endpoint was unplanned hospitalization for worsening heart failure (WHF) and cardiac death. During a follow-up period of 8.9 ± 4.3 years, 19 of 63 patients had unplanned hospitalization for WHF, and 19 of 63 patients had cardiac death. In multivariate analysis, both WR and RVEF were independent predictors of unplanned WHF hospitalization, while WR was also an independent predictor of cardiac death. A risk-stratification model based on independent predictors of unplanned WHF hospitalization separated the patients into those with low (absence of the predictors), intermediate (one of the predictors), and high (two or more of the predictors) risk of unplanned WHF hospitalization (P < 0.0001) or cardiac death (P = 0.0113). CONCLUSIONS: Cardiac MIBG imaging provides incremental value when it is used along with RV systolic dysfunction to predict clinical outcome in patients with CHF.

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Patients with chronic heart failure (CHF) at risk of sudden cardiac death (SCD) are often treated with implantable cardiac defibrillators (ICDs). However, current criteria for device use that is based largely on left ventricular ejection fraction (LVEF) lead to many patients receiving ICDs that never deliver therapy. It is of clinical significance to identify patients who do not require ICDs. Although cardiac I-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information about CHF, whether it can identify patients with CHF who do not require an ICD remains unclear. We studied 81 patients with CHF and LVEF <35%, assessed by cardiac MIBG imaging at enrollment. The heart-to-mediastinal ratio (H/M) in delayed images and washout rates were divided into 6 grades from 0 to 5, according to the degree of deviation from control values. The study patients were classified into 3 groups: low (1 to 4), intermediate (5 to 7), and high (8 to 10), according to the MIBG scores defined as the sum of the H/M and washout rate scores. Sixteen patients died of SCD during a follow-up period. Patients with low MIBG score had a significantly lower risk of SCD than those with intermediate and high scores (low [n = 19], 0%; intermediate [n = 37], 19%; high [n = 25], 36%; p = 0.001). The positive predictive value of low MIBG score for identifying patients without SCD was 100%. In conclusion, the MIBG score can identify patients with CHF and LVEF <35% who have low risk of developing SCD.

DOI： 10.1016/j.amjcard.2015.02.058

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BACKGROUND: Cardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen lysine-rich leukemia (ELL), a co-activator of MR, in this pathway. METHODS AND RESULTS: The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [(3)H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of H2O2, as an oxidative stress but not in the absence of H2O2. H2O2 increased the ELL expression levels and MR-bound ELL. ELL expression levels and MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of [(3)H]proline incorporation in the presence of H2O2 after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts. CONCLUSION: Glucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure.

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BACKGROUND: Endovascular aortic repair (EVAR) is performed in patients with thoracic or abdominal aortic aneurysm because it is less invasive than conventional open repair. However, the effects of EVAR on vascular and cardiac function remain to be clarified. METHODS AND RESULTS: We studied the effects of EVAR on several outcome variables in 40 consecutive patients undergoing EVAR for abdominal and/or thoracic aneurysm with preserved ejection fraction. Echocardiography and brachial-ankle pulse wave velocity (baPWV) data were collected before, 1 week, and 1 year after EVAR. Although no changes in blood pressure were found, baPWV, left ventricular mass index (LVMI), and left atrial volume index were significantly elevated at both post-op time periods after EVAR compared with baseline data. The changes in LVMI correlated with those in baPWV (R=0.32, P<0.05). Among the 22 patients who were successfully followed up, 13 showed deterioration in exercise tolerance 1 year after EVAR. Diastolic wall strain, an index for LV distensibility, was lower at baseline in patients with worsening exercise tolerance than in those with unchanged tolerance. CONCLUSIONS:  EVAR increased vascular stiffness and induced LV hypertrophy and diastolic dysfunction without a corresponding elevation of blood pressure in the acute and chronic phases. In addition, low LV distensibility at baseline was associated with the impairment of exercise tolerance. EVAR-induced stiffness of arteries leads to limited clinical symptoms.

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Although the mouse heart failure (HF) model of hypertensive heart disease (HHD) is useful to investigate the pathophysiology and new therapeutic targets for HHD, the model using simple experimental procedures and stable phenotypes has not been established. This study aimed to develop a novel mouse HF model of HHD by combining salt loading and uninephrectomy with ANG II infusion. Eight-week-old C57BL/6 male mice were treated with ANG II infusion (AT), ANG II infusion and uninephrectomy (AN), ANG II infusion and salt loading (AS), or ANG II infusion, uninephrectomy, and salt loading (ANS). Systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was found in AT, AN, AS, and ANS mice, and there were no significant differences in those parameters between the four groups. At 6 wk after the procedures, only ANS mice showed significant decreases in LV fractional shortening and increases in lung weight with a high incidence. This phenotype was reproducible, and there were few perioperative or early deaths in the experimental procedures. Severe LV fibrosis was found in ANS mice. Oxidative stress was enhanced and small GTPase Rac1 activity was upregulated in the hearts of ANS mice. After the addition of salt loading and uninephrectomy to the ANG II infusion mouse model, cardiac function was significantly impaired, and mice developed HF. This might be a novel and useful mouse HF model to study the transition from compensated LV hypertrophy to HF in HHD.

DOI： 10.1152/ajpheart.00349.2013

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BACKGROUND: Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. METHODS AND RESULTS: An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. CONCLUSION: Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

DOI： 10.1371/journal.pone.0068893

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OBJECTIVES: Prognosis of heart failure with preserved ejection fraction (HFpEF) remains poor because of unknown pathophysiology and unestablished therapeutic strategy. This study aimed to identify a potential therapeutic intervention for HFpEF through metabolomics-based analysis. METHODS AND RESULTS: Metabolomics with capillary electrophoresis time-of-flight mass spectrometry was performed using plasma of Dahl salt-sensitive rats fed high-salt diet, a model of hypertensive HFpEF, and showed decreased free-carnitine levels. Reassessment with enzymatic cycling method revealed the decreased plasma and left-ventricular free-carnitine levels in the HFpEF model. Urinary free-carnitine excretion was increased, and the expression of organic cation/carnitine transporter 2, which transports free-carnitine into cells, was down-regulated in the left ventricle (LV) and kidney in the HFpEF model. L-Carnitine was administered to the hypertensive HFpEF model. L-Carnitine treatment restored left-ventricular free-carnitine levels, attenuated left-ventricular fibrosis and stiffening, prevented pulmonary congestion, and improved survival in the HFpEF model independent of the antihypertensive effects, accompanied with increased expression of fatty acid desaturase (FADS) 1/2, rate-limiting enzymes in forming arachidonic acid, and enhanced production of arachidonic acid, a precursor of prostacyclin, and prostacyclin in the LV. In cultured cardiac fibroblasts, L-carnitine attenuated the angiotensin II-induced collagen production with increased FADS1/2 expression and enhanced production of arachidonic acid and prostacyclin. L-Carnitine-induced increase of arachidonic acid was canceled by knock-down of FADS1 or FADS2 in cultured cardiac fibroblasts. Serum free-carnitine levels were decreased in HFpEF patients. CONCLUSIONS: L-carnitine supplementation attenuates cardiac fibrosis by increasing prostacyclin production through arachidonic acid pathway, and may be a promising therapeutic option for HFpEF.

DOI： 10.1097/HJH.0b013e3283569c5a

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AIMS: Left ventricular (LV) fibrosis and stiffening play crucial roles in the development of heart failure with preserved ejection fraction (HFPEF). Plasma level of digitalis-like factors (DLFs) is increased in patients with hypertension, a principal underlying cardiovascular disease of HFPEF. Digitalis-like factors inhibit ion-pumping function of Na(+)/K(+)-ATPase and activate the Ca(2+) entry mode of Na(+)/Ca(2+) exchanger (NCX). Digitalis-like factors are known to promote collagen production in fibroblasts. The aim of this study was to explore whether the pharmacological inhibition of the NCX entry mode is effective in the prevention of LV fibrosis and in the development of HFPEF. METHODS AND RESULTS: (i) Dahl salt-sensitive rats fed 8% NaCl diet from age 6 weeks served as hypertensive HFPEF model. In this model, 24 h urine excretion of DLFs was greater than that in the age-matched control at compensatory hypertrophic and heart failure stages. (ii) Continuous administration of ouabain for 14 weeks developed LV fibrosis without affecting blood pressure in Sprague-Dawley rats. (iii) Ouabain elevated intracellular Ca(2+) concentration through the entry of extracellular Ca(2+), increased the phosphorylation level of p42/44 mitogen-activated protein kinases, and enhanced (3)H-proline incorporation in cardiac fibroblast; and SEA0400, the inhibitor of the NCX entry mode, suppressed these effects. (iv) In the HFPEF model, administration of SEA0400 at subdepressor dose improved the survival rate in association with the attenuation of LV fibrosis and stiffening. CONCLUSION: Digitalis-like factors and the subsequently activated NCX entry mode may play an important role in the development of hypertensive HFPEF, and the blockade of the NCX entry mode may be a new therapeutic strategy for this phenotype of heart failure.

DOI： 10.1093/eurheartj/ehr106

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BACKGROUND: Diabetic retinopathy (DR) is an independent predictor of heart failure (HF) in patients with diabetes mellitus (DM). However, it is unclear how DR is related to the development of HF. We hypothesized that DR is associated with left ventricular (LV) diastolic dysfunction, which is well recognized to subsequently result in HF. METHODS AND RESULTS: Data were collected in 63 consecutive patients with DM and LV ejection fraction (EF) ≥50%. Patients were excluded if they had HF diagnosed according to the modified Framingham criteria. Doppler echocardiographic indices including peak early-diastolic mitral annular movement velocity (E') were obtained in each patient.We also assessed the diastolic index of echocardiographic color kinesis (CK-DI), which proportionally decreases with LV relaxation abnormality independently of LV filling pressure, as recently published. The DM patients were divided into groups without (DM-N; n = 30) and with (DM-DR; n = 33) DR. Age, gender, LV end-diastolic dimension, EF, E/A ratio of the transmitral flow velocity curves, E', and E/E' were not different between DM-N and DM-DR. However, CK-DI was significantly lower in DM-DR than DM-N. CONCLUSIONS: DR is associated with LV diastolic dysfunction, and this may at least in part explain the increased incidence of HF in DM patients with DR.

DOI： 10.1016/j.cardfail.2011.03.007

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AIMS: The prevalence of heart failure with preserved ejection fraction (HFpEF) has increased in the past two decades, and diabetes mellitus (DM) is frequently associated with HFpEF. Although it has been demonstrated that left ventricular (LV) diastolic and vascular functional abnormalities are generally observed in HFpEF, it remains to be clinically elucidated how an asymptomatic stage progresses to symptomatic HFpEF in DM patients. We aimed to identify risk factors associated with incident HFpEF in DM patients and to evaluate the contribution of LV relaxation and compliance to the development of HFpEF. METHODS AND RESULTS: The study included 544 consecutive Japanese DM patients with ejection fraction ≥50%. Patients with coronary artery disease or serum creatinine ≥2.0 mg/dL were excluded. Multiple logistic regression analysis revealed that obesity, female gender, anaemia, and impaired LV compliance were independently associated with the prevalence of HFpEF, and that age, LV mass index, an index of LV relaxation, estimated glomerular filtration rate, and history of hypertension were not. There was no difference in haemoglobin A1c or brachial-ankle pulse wave velocity between the DM patients with and without HFpEF. CONCLUSIONS: This study suggests that exacerbation of LV compliance impairment, rather than of relaxation abnormality or vascular stiffening, plays a crucial role in the induction of HFpEF in DM patients regardless of the severity of DM and renal dysfunction. Anaemia and obesity may also contribute to the transition from asymptomatic stage to symptomatic HFpEF even without further progression of LV diastolic dysfunction.

DOI： 10.1093/eurjhf/hfr019

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The Seattle Heart Failure Model (SHFM) is a validated prediction model that estimates the mortality in patients with chronic heart failure (CHF) using commonly obtained information, including clinical data, laboratory test results, medication use, and device implantation. In addition, cardiac iodine-123 meta-iodobenzylguanidine (MIBG) imaging provides prognostic information for patients with CHF. However, the long-term predictive value of combining the SHFM and cardiac MIBG imaging in patients with CHF has not been elucidated. To prospectively investigate whether cardiac iodine-123 MIBG imaging provides additional prognostic value to the SHFM in patients with CHF, we studied 106 outpatients with CHF who had radionuclide left ventricular ejection fraction < 40% (30 ± 8%). The SHFM score was obtained at enrollment, and the cardiac MIBG washout rate (WR) was calculated from anterior chest images obtained at 20 and 200 minutes after isotope injection. During a mean follow-up of 6.8 ± 3.5 years (range 0 to 13), 32 of 106 patients died from cardiac causes. A multivariate Cox analysis revealed that the WR (p = 0.0002) and SHFM score (p = 0.0091) were independent predictors of cardiac death. Kaplan-Meier analysis showed that patients with an abnormal WR (> 27%) had a significantly greater risk of cardiac death than did those with a normal WR for both those with a SHFM score of ≥ 1 (relative risk 3.3, 95% confidence interval 1.2 to 9.7, p = 0.01) and a SHFM score of ≤ 0 (relative risk 3.4, 95% confidence interval 1.2 to 9.6, p = 0.004). In conclusion, the cardiac MIBG WR provided additional prognostic information to the SHFM score for patients with CHF.

DOI： 10.1016/j.amjcard.2010.12.019

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BACKGROUND: Systolic abnormality, as well as diastolic dysfunction, is observed in patients with heart failure with preserved ejection fraction (HFPEF). However, the role of these 2 conditions in the transition from asymptomatic diastolic dysfunction to symptomatic heart failure remains unclear. We recently demonstrated that diastolic wall strain (DWS) inversely correlates to the myocardial stiffness constant. METHODS AND RESULTS: This study consisted of 127 subjects: 52 consecutive HFPEF patients (HFPEF group), 50 asymptomatic hypertensive patients with ejection fraction ≥50% whose age, gender and left ventricular (LV) mass index matched those of the HFPEF group (HT group) and 25 normal volunteers (Normal group). The tissue Doppler-derived peak systolic and early diastolic velocities of the mitral annulus were significantly decreased in groups HFPEF and HT than in group Normal, but were not significantly different between groups HFPEF and HT. DWS was significantly lower in group HFPEF than in group HT. CONCLUSIONS: The transition from asymptomatic diastolic dysfunction stage to HFPEF stage is not attributed to progression of systolic abnormality, and exacerbation of LV distensibility rather than relaxation plays a crucial role in the development of HFPEF.

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This paper describes an elasticity sensing system for left ventricle of small laboratory animal. We first show the basic concept of the proposed method, where a ring shaped specimen is dilated by a balloon type probe using a pressure based control, and the elasticity of the specimen is estimated by using the stress and strain information. We introduce a dual cylinder model for approximating the strengths of the specimen's material and the balloon. Based on this model, we can derive Young's modulus of the specimen. After explaining the developed experimental system, we show a couple of experimental results using rats and mice, where HFPEF (Heart Failure Preserved Ejection Fraction) group can be distinguished from a normal group.

DOI： 10.1109/IEMBS.2011.6090202

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The beneficial effects of beta-blocker therapy on the clinical outcomes of heart failure with reduced ejection fraction (HFREF) are attributed to the improvement in ejection fraction (EF) and left ventricular (LV) reverse remodeling. Previous studies only reported the beta-blocker therapy-induced improvement of diastolic function accompanied by the increase in EF in HFREF patients. This retrospective study aimed to elucidate whether beta-blocker therapy improves diastolic function even without an increase in EF. Out of the consecutive 11,830 echocardiographic reports, HFREF patients without an increase in EF following long-term beta-blocker therapy comprised the study subjects (n=19). During the mean follow-up of 17 months, beta-blocker therapy significantly decreased peak mitral E-wave velocity (70±25-50±18 cm/s, p<0.01) and ratio of peak mitral E- to A-wave velocities (E/A ratio) (1.4±0.8-0.9±0.4, p<0.05), prolonged deceleration time of the mitral E-wave velocity (DcT) (167±54-206±61 ms, p<0.05), and improved New York Heart Association functional class (2.3±0.7-1.8±0.4, p<0.01) without changes in LV volume. Because DcT and E/A ratio are well known to correlate with LV filling pressures in patients with reduced EF, our results indicate a reduction in LV filling pressures without changes in LV volume, suggesting a reduction in LV stiffness. Thus, long-term beta-blocker therapy is likely to improve diastolic function even without a concomitant increase in EF in HFREF patients, which may be also responsible for the beta-blocker-induced improvement of their symptoms of heart failure.

DOI： 10.1016/j.jjcc.2010.04.001

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OBJECTIVES: We prospectively compared the predictive value of cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging for sudden cardiac death (SCD) with that of the signal-averaged electrocardiogram (SAECG), heart rate variability (HRV), and QT dispersion in patients with chronic heart failure (CHF). BACKGROUND: Cardiac MIBG imaging predicts prognosis of CHF patients. However, the long-term predictive value of MIBG imaging for SCD in this population remains to be elucidated. METHODS: At entry, cardiac MIBG imaging, SAECG, 24-h Holter monitoring, and standard 12-lead electrocardiography (ECG) were performed in 106 consecutive stable CHF outpatients with a radionuclide left ventricular ejection fraction (LVEF) <40%. The cardiac MIBG washout rate (WR) was obtained from MIBG imaging. Furthermore, the time and frequency domain HRV parameters were calculated from 24-h Holter recordings, and QT dispersion was measured from the 12-lead ECG. RESULTS: During a follow-up period of 65 +/- 31 months, 18 of 106 patients died suddenly. A multivariate Cox analysis revealed that WR and LVEF were significantly and independently associated with SCD, whereas the SAECG, HRV parameters, or QT dispersion were not. Patients with an abnormal WR (>27%) had a significantly higher risk of SCD (adjusted hazard ratio: 4.79, 95% confidence interval: 1.55 to 14.76). Even when confined to the patients with LVEF >35%, SCD was significantly more frequently observed in the patients with than without an abnormal WR (p = 0.02). CONCLUSIONS: Cardiac MIBG WR, but not SAECG, HRV, or QT dispersion, is a powerful predictor of SCD in patients with mild-to-moderate CHF, independently of LVEF.

DOI： 10.1016/j.jacc.2008.10.025

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OBJECTIVE: To evaluate the usefulness of cardiac iodine-123 (123I) metaiodobenzylguanidine (MIBG) imaging as a predictor of sudden death in patients with chronic heart failure (CHF). DESIGN AND SETTING: Prospective cohort study in a tertiary referral centre. PATIENTS: 97 outpatients with CHF with a radionuclide left ventricular ejection fraction <40% (mean (SD) 29% (7.5%)). INTERVENTIONS: At study entry, cardiac I-123 MIBG imaging was performed. The cardiac MIBG heart-to-mediastinum ratio (H/M) and washout rate (WR) were obtained from MIBG imaging. MAIN OUTCOME MEASURES: Patients were assigned to two groups based upon 27% of WR, which was the mean (2SD) control WR. 48 of 97 patients with CHF had abnormal WR (> or =27%), whereas the remaining 49 patients had normal WR (<27%). All the study patients were then followed up. RESULTS: During the mean (SD) follow-up period of 65 (29) months, 12 (25%) patients in the abnormal WR group and 2 (4%) patients in the normal WR group died suddenly. Kaplan-Meier analysis revealed that sudden death was more often observed in patients with abnormal WR than those with normal WR (p = 0.001). On Cox regression analysis, MIBG WR, H/M on the delayed image and H/M on the early image were significantly associated with sudden death. CONCLUSION: Cardiac MIBG imaging would be useful for predicting sudden death in patients with CHF.

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In the case of an emergency coronary procedure where the risk of contrast-induced nephropathy is especially high, there are few reliable methods to attenuate renal injury. We examined the efficacy of sodium bicarbonate for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure. We enrolled 59 patients who were scheduled to undergo an emergency coronary angiography or intervention. These patients were randomized to receive a 154-mEq/L infusion of sodium bicarbonate (n = 30) or sodium chloride (n = 29), as a bolus of 3 ml/kg/hour for 1 hour before the administration of contrast, followed by an infusion of 1 ml/kg/hour for 6 hours during and after the procedure. In the sodium bicarbonate group, serum creatinine concentration remained unchanged within 2 days of contrast administration (1.31 +/- 0.52 to 1.31 +/- 0.59 mg/dl), whereas it increased in the sodium chloride group (1.32 +/- 0.65 to 1.52 +/- 0.92 mg/dl, p = 0.01). The incidence of contrast-induced nephropathy (an increase >0.5 mg/dl or >25% in serum creatinine concentration within 2 days of contrast) was significantly lower in the sodium bicarbonate group than in the sodium chloride group (7% vs 35%, p = 0.01, risk ratio 0.19, 95% confidence interval 0.046 to 0.80). In conclusion, hydration with sodium bicarbonate is more effective than with sodium chloride for the prevention of contrast-induced nephropathy in patients undergoing an emergency coronary procedure.

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BACKGROUND: Statins have pleiotropic effects, such as improvement in endothelial function and antiinflammatory, antiproliferative, and antioxidative effects, that should be beneficial for patients with chronic heart failure (CHF). The aim of this study was to investigate the long-term effect of statins on neurohumoral activation and cardiac function in patients with CHF. METHODS: We enrolled 38 outpatients with mild to moderate CHF and radionuclide left ventricular ejection fraction (LVEF) <40%. These patients were randomly assigned to receive atorvastatin (10 mg/d) or conventional treatment for heart failure and were prospectively followed up for at least 3 years. At entry, we measured plasma concentrations of brain natriuretic peptides (BNPs) and left ventricular end-diastolic dimension and LVEF by echocardiography; thereafter, these measurements were repeated at least every 6 months. The primary end point was defined as the improvement in cardiac function and BNP. RESULTS: There were no significant differences in age, sex, New York Heart Association class, left ventricular end-diastolic dimension, LVEF, and serum cholesterol level at entry between patients with (n = 19) and without atorvastatin (control, n = 19). After a follow-up period of 31 +/- 14 months, BNP (median [25th, 75th percentile]) significantly decreased in the atorvastatin group (84 [36, 186] to 55 [37, 91] pg/mL, P = .02) but not in the control group. Left ventricular end-diastolic dimension significantly decreased (67.1 [59.9, 70.8] to 61.1 [58, 63.9] mm, P = .02), and LVEF also significantly increased in the atorvastatin group (33.3% +/- 7.4% to 39.1% +/- 12.1%, P = .01) but not in the control group. CONCLUSION: Long-term atorvastatin therapy decreases neurohumoral activation and improves cardiac function in patients with mild to moderate CHF.

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Statins have pleiotropic effects such as anti-inflammatory and vascular protective effects that would be beneficial for patients with chronic heart failure. This report describes a patient with idiopathic dilated cardiomyopathy and a long-standing history of heart failure that was treated with atorvastatin in addition to conventional therapy that included beta-blockers. Atorvastatin therapy for 12 months was associated with an improvement in cardiac function and improved left ventricular remodeling and peak oxygen consumption. This result suggests that statin therapy may be a potential novel treatment strategy for patients with chronic heart failure.

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To prospectively evaluate the prognostic significance of spatial dispersion of QRS duration (S-QRSd) on a signal-averaged electrocardiogram in patients with chronic heart failure (CHF), we studied 114 consecutive stable outpatients with radionuclide left ventricular ejection fraction <40%. Cardiac and sudden deaths were significantly more often observed in patients with than without abnormal S-QRSd. S-QRSd is a powerful prognostic marker of the mortality in patients with mild to moderate CHF.

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DOI： 10.1016/S0735-1097(15)60984-6

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