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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., Competing Interests: Competing interests: YSo has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, TOA EIYO, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan and NIPRO; and personal fees from Abiomed, AstraZeneca, Amgen Astellas BioPharma, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Abbott Medical Japan, Boston Scientific Japan, Bayer, Daiichi Sankyo, Novartis, TERUMO, Medtronic and Pfizer Pharmaceuticals. SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical and Actelion Pharmaceuticals; and personal fees from Daiichi Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company and Ono Pharmaceutical. DN has received personal fees from Roche Diagnostics. YSa has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca and Actelion Pharmaceuticals; and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb Co, Biosense Webster, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan and Biotronik., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical and Actelion Pharmaceuticals; and personal fees from Daiichi Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company and Ono Pharmaceutical. DN has received personal fees from Roche Diagnostics. TK has received honoraria from AstraZeneca. YS has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K. and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Co, Biosense Webster, Inc., Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan, and Biotronik. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: FS received modest lecture fees from Actelion Pharmaceuticals, Pfizer and Nippon Boehringer Ingelheim. TO received modest lecture fees from Bristol-Myers Squibb, Daiichi Sankyo Company, Nippon Boehringer Ingelheim and Otsuka Pharmaceutical, as well as significant medical advisory fees from Takeda Pharmaceutical. SH received modest personal fees from Daiichi Sankyo Company, Bayer and Astellas Pharma, as well as a modest grant from Actelion Pharmaceuticals. KY-T received a modest lecture fee from Actelion Pharmaceuticals. YS received significant personal fees from Otsuka Pharmaceutical and Daiichi Sankyo Company, and modest personal fees from Actelion Pharmaceuticals, Ono Pharmaceutical, Astellas Pharma, AstraZeneca, Novartis Pharma, Bayer, Pfizer and TOA EIYO. The other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: YSo has received personal fees from Daiichi-Sankyo, Bayer, Boehringer Ingelheim and Bristol-Myers Squibb. SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, Actelion Pharmaceuticals; and personal fees from Daiichi-Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company and Ono Pharmaceutical. DN has received personal fees from Roche Diagnostics. HM is an endowed chair lecturer supported by Asahi Intecc, Terumo Corporation, Nipro Corporation and Shimadzu Corporation, and has received personal fees from Medtronic Japan, Japan Tobacco, Pfizer Japan, Bayer Yakuhin, Japan Lifeline, Abbott Japan, Nippon Boehringer Ingelheim, Toa Eiyo, Daiichi-Sankyo and Kowa. KO has received personal fees from Bayer. YSa has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, AstraZeneca and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan and Biotronik., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Variations in the incidence of acute myocardial infarction during the week may differ between and within communities, according to lifestyle., Objective: To identify potential triggering factors for acute myocardial infarction by examining variations in incidence in the days of the week within the Osaka area of Japan., Patients: Of 2511 consecutive patients in this region who were admitted to hospital for acute myocardial infarction between April 1998 and March 2001 and consented to take part, 2400 who had a definitely identified time of onset were enrolled., Results: For this group as a whole, no significant difference in incidence was noted between days of the week. However, in subgroup analyses women were shown to have significant variation through the week, peaking on Saturday with a 39% increase in relative risk (p = 0.037); working subjects showed a peak on Monday, with a 26% increase in relative risk (p = 0.038). Stratified analyses showed that in working men there was a prominent Monday peak in the onset of infarction, with a 30% increase in relative risk (p = 0.022), while in working women, there was no significant variation through the week., Conclusions: Earlier findings of a Monday peak linked to increased physical and mental occupational stress are confirmed. There is also an increase in uncertain risk factors on Saturdays for Japanese women, possibly involving a stressful weekend burden for women. Confirmation of this finding in other communities may help identify triggers of acute myocardial infarction and be useful in prevention.