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Background The relationship between general obesity or abdominal obesity (abdominal circumference of ≥85 cm in men and ≥ 90 cm in women) and the heart-to-mediastinum ratio (HMR), a measure of cardiac sympathetic innervation, on cardiac iodine-123-metaiodobenzylguanidine scintigraphy (MIBG) in patients with heart failure with preserved ejection fraction (HFpEF) has not been clarified. Methods A total of 239 HFpEF patients with both MIBG and abdominal circumference data were examined. We divided these patients into those with abdominal obesity and those without it. In the cardiac MIBG study, early phase image was acquired 15–20 min after injection, and late phase image was acquired 3 h after the early phase. A HMR obtained from a low-energy type collimator was converted to that obtained by a medium-energy type collimator. Results Early and late HMRs were significantly lower in those with abdominal obesity, although washout rates were not significantly different. The incidence of patients with early and late HMRs <2.2 was significantly higher in those with abdominal obesity. Multivariate linear regression analysis revealed that abdominal obesity was independently associated with early HMR (standardized β  = −0.253, P  = 0.003) and late HMR (standardized β  = −0.222, P  = 0.010). Multivariate logistic regression analysis revealed that abdominal obesity was independently associated with early (odds ratio [OR] [95% confidence interval {CI}] = 4.25 [2.13, 8.47], P  < 0.001) and late HMR < 2.2 (OR [95% CI] = 2.06 [1.11, 3.83], P  = 0.022). Elevated BMI was not significantly associated with low early and late HMR. The presence of abdominal obesity was significantly associated with low early and late HMR even in patients without elevated BMI values. Conclusion Abdominal obesity, but not general obesity, in HFpEF patients was independently associated with low HMR, suggesting that visceral fat may contribute to decreased cardiac sympathetic activity in patients with HFpEF. Trial registration UMIN000021831.

Coronary artery calcium (CAC) is associated with the presence of coronary artery disease (CAD) and cardiovascular risk factors. However, the relation between cardiovascular risk factors and CAD has not yet been fully elucidated in patients with a zero or low coronary artery calcium score (CACS). The purpose of this study was to evaluate the relation of cardiovascular risk factors and angina status to obstructive CAD according to categorical CACS. A total of 753 patients were enrolled in this study. CAC scoring and coronary computed tomographic angiography (CCTA) were performed with dual-source 64-slice CT scanners. The number of patients with a CACS ≤10 and ≤100 were 358 and 528, respectively. Patients with a higher CACS were older and more frequently male, and had a greater frequency of hypertension, diabetes, and hypercholesterolemia. The prevalence of obstructive CAD increased with the CACS. Among patients with a CACS ≤100, age, male gender, diabetes, hypercholesterolemia, and typical angina pectoris were related to obstructive CAD. The presence of hypercholesterolemia was relatively strongly associated with obstructive CAD (OR 6.67, 95% CI 2.91–15.3, p  < 0.001) on multivariate analysis. Among patients with a CACS ≤10, men, hypercholesterolemia, and typical angina pectoris were significantly more frequent in patients with than in those without obstructive CAD ( p  < 0.01). Our data suggest that neither the absence nor low of coronary calcium burden may reliably exclude obstructive CAD in typical symptomatic male patients with hypercholesterolemia. This result may be useful to interpret the relation of CACS to obstructive CAD.

Objectives: Although renal dysfunction is associated with the presence of atherosclerosis, little is known about the relationship between reduced estimated glomerular filtration rate (eGFR) and the presence of atherosclerosis detected by coronary computed tomographic angiography (CCTA). This study evaluated the relation of eGFR to the presence of coronary plaque and obstructive coronary artery disease (CAD) in patients with a zero or low coronary artery calcium score (CACS). Methods: Coronary artery calcium scoring and CCTA were performed with CT scanners. Serum creatinine was measured before CCTA, and GFR was estimated. A total of 720 patients with a CACS ≤10 were enrolled. Results: Coronary plaque was detected in 118 patients. Of the 118 patients, 36 had a diagnosis of obstructive CAD. The multiple-adjusted odds ratios of presenting with coronary plaque and obstructive CAD were 1.82 (95% CI 1.06-3.12, p = 0.030) and 1.79 (95% CI 0.71-4.49, p = 0.217) for the lowest tertile of eGFR compared with the highest tertile, respectively. Conclusions: Lower eGFR levels were associated with the presence of coronary plaque in patients with a zero or low CACS. However, the association between eGFR and the presence of obstructive CAD was not statistically significant.

ObjectiveOur 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.MethodsThis 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.ResultsOf 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.ConclusionsMachine 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 numberUMIN000021831.

ObjectiveThe 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.MethodsThis 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.ResultsPhenotype 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.ConclusionsDistinctive 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 numberUMIN-CTR ID: UMIN000021831.

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.

BackgroundThe 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.MethodsWe 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).ResultsAmong 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.ConclusionsUse 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.

BackgroundWe 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.MethodsFrom 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.ResultsMedian 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.ConclusionsMore 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.

BackgroundGrowth differentiation factor 15 (GDF15) is a cytokine responding to oxidative stress and inflammation, and it regulates appetite and energy balance. The association between GDF15 and clinical factors and its prognostic value in elderly multimorbid patients with heart failure with preserved ejection fraction (HFpEF) have not been well unknown.MethodsThis exploratory analysis is part of the Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF (UMIN000021831). A predefined subcohort of 212 patients underwent multi-biomarker testing. Of these, we analysed 181 patients with available GDF15 data. The primary endpoint was a composite of all-cause death and hospitalisation for HF.ResultsIn this analysis population, the median age was 81 (75–85) years, with 48% male patients. GDF15 significantly correlated with cardiac burden, anaemia, renal dysfunction and inflammation. Notably, poor nutritional status was significantly associated with GDF15. GDF15 was linked to poor prognosis in this elderly multimorbid cohort with HFpEF (adjusted HR for log-transformed GDF15: 13.67, 95% CI: 2.78 to 67.22, p=0.001). Furthermore, GDF15 added significant incremental value to the MAGGIC risk score (net reclassification improvement=0.4955 (95% CI: 0.1367 to 0.8543), p=0.007; integrated discrimination improvement=0.0278 (95% CI: 0.0013 to 0.0543), p=0.040).ConclusionsGDF15 was associated with anaemia, inflammation, renal dysfunction, cardiac burden and malnutrition. It demonstrated prognostic value in elderly multimorbid HFpEF patients, suggesting its potential role as a complementary marker for the prognostic risk assessment of HFpEF patients.Trial registration numberUMIN-CTR ID: UMIN000021831.

ObjectivesThe 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.SettingA prospective, multicentre observational registry of collaborating hospitals in Osaka, Japan.ParticipantsWe 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 measuresAll-cause mortality and/or re-admission for heart failure were evaluated after discharge.ResultsHigh 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.ConclusionsTime-sensitive prognostic performance of Ed/Ea, an afterload-integrated diastolic index, was observed in older patients with HFpEF.Trial registration numberUMIN000021831.