The development of life-saving pharmacotherapies such as the sodium-glucose cotransporter-2 inhibitors has changed heart failure with preserved ejection fraction (HFpEF) into a treatable disease. This paradigm shift in treatment has made the diagnosis of HFpEF more important. However, HFpEF is underdiagnosed in primary and secondary/tertiary care settings due to its diagnostic difficulties. Particularly, HFpEF is often missed in patients with obesity or atrial fibrillation. This review describes the reasons for the difficulty in diagnosing HFpEF and proposes a 5-step approach to identifying HFpEF in patients with unexplained dyspnea. Primary care physicians play a key role in the early identification of HFpEF in the community. We also discuss potential approaches to enhancing community referral and thus improving the rate of HFpEF diagnosis.

Background: Right ventricular dysfunction (RVD), driven by right ventricular (RV) afterload, is prognostic in patients with heart failure with preserved ejection fraction (HFpEF). Hemodynamic phenotyping based on RVD and RV afterload may provide useful information for the management of HFpEF. This study investigated the prognostic impacts of the pulmonary artery pulsatility index (PAPi) and pulmonary arterial capacitance (PAC) in patients with HFpEF.

Methods and Results: A retrospective cohort of 246 HFpEF patients who underwent right heart catheterization was analyzed. Patients were divided into 4 groups according to the median PAPi and PAC values. The primary endpoint was a composite of all-cause death or heart failure-related hospitalization over a median follow-up of 4.1 years. Kaplan-Meier analysis showed significant stratification of event-free survival among the groups (log-rank P=0.003). Multivariate Cox proportional analysis revealed that patients with low PAPi and PAC exhibited worse outcomes than those with the high PAPi and PAC (hazard ratio 3.205; 95% confidence interval [CI] 1.401–7.330; P=0.006). Incorporating PAPi and PAC values into the MAGGIC risk score improved the C-index from 0.671 to 0.720 (∆C-index 0.050; 95% CI 0.004–0.095; P=0.032).

Conclusions: A combination of PAPi and PAC improved prognostic ability in patients with HFpEF. Future investigations into treatments for these new hemodynamic phenotypes may improve clinical outcomes of patients with HFpEF.

Background: Few studies have examined the characteristics of heart failure (HF) patients with cachexia using the Asian Working Group for Cachexia (AWGC) 2023 criteria. This study assessed the characteristics and clinical impact of cachexia in older adults with HF.

Methods and Results: Results of laboratory measurements, echocardiography, physical function, depression, nutritional status, and the prevalence of cachexia, frailty, and sarcopenia were assessed in older adults (≥65 years) with HF in a stable condition just before discharge. After discharge, all participants were prospectively followed for adverse clinical events. Patients were classified based on the presence or absence of cachexia, and their frailty, sarcopenia, and clinical outcomes were compared. The prevalence of cachexia diagnosed by AWGC 2023 and Evans criteria was 24.7% and 12.9%, respectively. Among HF patients with cachexia, 71.6% had frailty and 86.7% had sarcopenia. Patients with cachexia had significantly poorer physical function and nutrition than those without. Cox proportional hazards analysis identified cachexia as an independent predictor of all-cause and cardiovascular death.

Conclusions: Cachexia in older adults with HF is strongly associated with poor physical function, malnutrition, and adverse clinical outcomes. Early identification and management of cachexia may help improve the prognosis in this population.

Background: The effects of sacubitril/valsartan (angiotensin receptor–neprilysin inhibitor [ARNI]) on myocardial tissue in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% remain unclear.

Methods and Results: Sixty-four HF outpatients with LVEF <50% were randomized to ARNI (switching from an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker [ACEi/ARB] to ARNI) or control (continuing with ACEi/ARB). Left ventricular (LV) structure and myocardial tissue, including changes in LV extracellular volume fraction (ECV), were evaluated before and after the 9-month program using cardiac magnetic resonance imaging. The primary endpoint was changes in ECV. Secondary endpoints were changes in LVEF, LV volume and mass, and extra- and intracellular mass. Fifty-nine patients completed the 9-month intervention. ARNI decreased systolic blood pressure from the first month. The ARNI group showed significant reductions in LV volume, LV mass, and extra- and intracellular mass from baseline to 9 months, but there was no change in LVEF, or in ECV (31.6±5.0% vs. 31.9±5.0%, respectively; P=0.795). In the control group, there was no change in systolic blood pressure, LV volume, LV mass, ECV, or extra- and intracellular mass. There was no significant difference in the change in ECV between the ARNI and control groups (0.3±5.1% vs. 1.2±4.1%, respectively; P=0.461), whereas the change in extracellular mass was greater in the ARNI group (P=0.025).

Conclusions: ARNI reduced LV volume and mass, resulting from decreases in both extra- and intracellular mass, without changing ECV. This suggests ARNI has potential to improve LV tissue characteristics in HF patients with LVEF <50%.

Background: Adherence to contemporary guideline-directed medical therapy (GDMT) and its association with incident outpatient worsening heart failure (WHF) events after discharge in hospitalized patients with heart failure (HF) remain unclear.

Methods and Results: The PRE-UPFRONT-HF study was a retrospective multicenter observational registry of patients hospitalized for HF between June 2022 and March 2023 with a left ventricular ejection fraction <50%. Data on medications at admission, discharge, and 6 months after admission were collected. Outpatient WHF was defined as intravenous diuretic therapy and/or intensification of oral diuretics in outpatient settings (e.g., without hospitalization). Less than half the 442 patients registered were on all 4 GDMT medications (β-blockers, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) at discharge and 6 months after admission. Better GDMT implementation, defined by a simple GDMT score above the median, was significantly associated with a lower incidence of composite outcomes of death, HF hospitalization, and WHF (P<0.001), as well as outpatient WHF events alone (P=0.035), which remained significant even after adjusting for covariates. In addition, outpatient WHF was associated with subsequent worse prognoses, including mortality (hazard ratio 6.52; P<0.001).

Conclusions: GDMT implementation during hospitalization for HF is suboptimal, even in the contemporary era. Patients with better GDMT implementation at discharge had a lower incidence of outpatient WHF, which was associated with subsequent mortality.

Background: Changes in left ventricular (LV) remodeling, especially in relation to the duration of therapy, are poorly understood in patients with hypertrophic non-obstructive cardiomyopathy (HNCM).

Methods and Results: This study included 254 consecutive patients with HNCM. Patients were divided into 3 groups according to the length of chronic cibenzoline therapy (CCT): Group I (n=104), CCT ≥10 years; Group II (n=85), 5 years≤CCT<10 years; and Group III (n=65), 1 year ≤CCT<5 years. SV1+RV5 and the maximum depth of precordial negative T waves were measured on electrocardiograms (ECG). In addition to routine echocardiographic indices, we measured the distance between the mitral valve and the apex (i.e., the “LV long distance” [LVLD]). After CCT, ECG indices and LV wall thicknesses were decreased in all 3 groups. LV dimensions and LV fractional shortening were preserved, and did not differ significantly among the groups. Left atrial dimension and the E/A ratio also did not differ among the groups, whereas the E/early diastolic annular velocity (Ea) ratio was decreased in Groups I and II. After CCT, LVLD was increased in all groups (all P<0.0001). These improvements were greater in Group I than in Groups II and III.

Conclusions: CCT preserved LV systolic function and reduced LV hypertrophy in patients with HNCM. The E/Ea ratio was improved in Groups I and II. Thus, CCT aids in treating patients with HNCM.

Background: Transcatheter atrial septal defect (ASD) closure is the first treatment option for secundum ASD, but parameters for optimal device selection have not been established. We compared outcomes between occluders with a wire frame and metal mesh devices.

Methods and Results: This study included secundum ASD patients implanted with a wire frame occluder (GORE^®CARDIOFORM ASD occluder [GCA]; W.L. Gore & Associates) or metal mesh devices (Amplatzer septal occluder device [Abbott] and Occlutech Figulla Flex II device [Occlutech]). The presence of residual shunt and B-type natriuretic peptide (BNP) levels after implantation were compared. Of the 970 patients with either GCA (n=48) or a metal mesh device (n=922; control), 42 patients from each group were analyzed after propensity score matching. The prevalence of residual shunt was significantly lower in the GCA group 1 day and 1 month after implantation (P<0.001 and P=0.017, respectively), whereas there was no significant difference between the 2 groups 6 months later (P=0.088). BNP levels at 1 month were significantly higher in the GCA group (ratio of change 1.36; 95% confidence interval [CI] 1.01–1.83), but did not differ significantly between the 2 groups at 6 months (ratio of change 1.04; 95% CI 0.65–1.65).

Conclusions: Patients implanted with a wire frame occluder had a lower prevalence of residual shunt and a greater increase in BNP levels in the early period after implantation.

Background: This study investigated current trends in transcatheter atrial septal defect (ASD) closure among adult patients, with an emphasis on device and size selection, as well as acute complications.

Methods and Results: This study used the Japanese Structural Heart Disease (J-SHD) registry database, which is a prospective nationwide multicenter registry. In all, 1,921 patients who underwent transcatheter ASD closure between 2019 and 2022 were analyzed in this study. The specifics of the procedures, including device type, size selection, and acute complications, were assessed. The mean (±SD) age of participants was 57±18 years, with 37.6% being male. Aortic rim deficiency was observed in most patients (50.3%). The prevalence of aortic rim deficiency was 32.5% for the Amplatzer^®Septal Occluder (ASO), 65.6% for the Occlutech^®Figulla Flex II Septal Occluder (FSO), and 57.8% for the GORE^®CARDIOFORM ASD Occluder. In patients in whom the ASO or FSO was used, device size was 2–3 and 5–6 mm larger than defect size, respectively. Device migration was observed in 8 (0.4%) patients, and occurred regardless of device oversizing or undersizing relative to defect size.

Conclusions: This study reports the trends in clinical features, device and size selection, and acute complications in adult patients who underwent transcatheter ASD closure.

Background: Adult congenital heart disease (ACHD) patients often require additional interventions or surgeries in adulthood, presenting new clinical challenges. However, clinical research on the current status and outcomes of cardiac procedures in ACHD patients remains limited.

Methods and Results: We analyzed the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database between April 2013 and March 2021. Patients with ACHD (aged >15 years) who underwent major cardiac surgery and transcatheter procedures were included. We assessed clinical background, treatment, length of hospital stay, and in-hospital mortality. In all, 22,490 patients with ACHD (median age 56 years [interquartile range 36–69 years], 51.1% female) were enrolled. Emergency hospitalizations and in-hospital deaths were observed in 3.7% and 1.1% of cases, respectively. Congenital heart operations with high in-hospital mortality (>5.0%) included aortic arch repair, systemic-to-pulmonary artery shunts, cardiac tumor resection, coronary artery bypass grafting, 3-valve replacement, and ventricular assist device implantation. Although stent graft procedures had the highest in-hospital mortality rate (2.6%), other transcatheter procedures, such as transcatheter patent ductus arteriosus closure, atrial septal defect closure, and catheter ablation, had in-hospital mortality rates of <1.0%.

Conclusions: This study provides fundamental insights into the current clinical characteristics and outcomes associated with procedures in patients with ACHD. The in-hospital mortality rates for both cardiac surgery and transcatheter procedures in Japanese ACHD patients were low, demonstrating acceptable outcomes.

Background: The EMPA-REG OUTCOME trial confirmed empagliflozin reduced mortality and heart failure hospitalization risk. These findings raised the possibility that empagliflozin may modulate cardiac autonomic function in patients with type 2 diabetes (T2D).

Methods and Results: The EMPYREAN study was a prospective randomized open-label assessor-blinded multicenter investigation of patients with T2D without prior antidiabetic therapy with sodium-glucose cotransporter 2 or dipeptidyl peptidase 4 inhibitors. Electrocardiographic monitoring was performed at study onset and after 12 and 24 weeks of treatment. Heart rate variability was analyzed using the MemCalc method. The primary endpoint was the change in the low frequency (LF; 0.04–0.15 Hz)/high frequency (HF; 0.15–0.4 Hz) ratio from baseline to 24 weeks. In all, 113 patients were randomized. The median age in the empagliflozin and sitagliptin groups was 60 and 63 years, respectively. There were no significant differences in serial changes in the LF/HF ratio (0.52, 95% confidence interval [CI] −0.15 to 1.19, P=0.126) or HF (16.13, 95% CI −11.58 to 43.84, P=0.251) between the 2 groups. In time domain analysis, serial changes in root mean square successive difference (1.90, 95% CI −0.56 to 4.38, P=0.12) and percent of difference between adjacent normal RR intervals >50 ms (1.04, 95% CI −0.32 to 2.41, P=0.13) were not significantly different.

Conclusions: The effects of empagliflozin and sitagliptin on autonomic nerve activity did not differ significantly in patients with T2D.

Background: An N-terminal pro B-type natriuretic peptide (NT-proBNP) level above 125 pg/mL has been suggested as a universal marker for heart failure (HF). Furthermore, the Japanese Heart Failure Society (JHFS) advises follow-up when NT-proBNP exceeds 55 pg/mL, even if it remains below 125 pg/mL, for early HF detection. However, evidence supporting these thresholds remains limited.

Methods and Results: This prospective study, part of the Toon Health Study, included 573 participants with NT-proBNP levels below 125 pg/mL. Pre-HF progression was defined as reaching NT-proBNP levels of 125 pg/mL or higher after 5 years. The median age of the 573 participants was 61 years, and 70% were female. After 5 years, 53 (9.2%) participants developed pre-HF. Higher baseline NT-proBNP was associated with increased progression to pre-HF. A receiver operating characteristic curve identified 52.4 pg/mL NT-proBNP as the optimal threshold for predicting pre-HF progression, with an area under the curve of 0.78.

Conclusions: Even if NT-proBNP levels are below 125 pg/mL, especially when exceeding 52.4 pg/mL, close monitoring may be needed due to the risk of future pre-HF. These findings could support the JHFS’s recommendation.

Background: Idiopathic pericarditis generally has a favorable prognosis, but contemporary data on treatment patterns and outcomes remain limited.

Methods and Results: Using a nationwide Japanese database, we analyzed 8,020 pericarditis patients hospitalized between April 2016 and March 2021, and identified 3,963 (49%) patients with idiopathic pericarditis after excluding those with infectious, autoimmune or other causes. During the study period, the median age increased from 62 to 68 years (P_trend<0.001), and prescription rates of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, and the simultaneous administration of NSAIDs and colchicine increased over time (from 65.9 to 72.6% [P=0.049], from 17.4 to 44.3% [P<0.001], and from 8.0 to 22.7% [P<0.001], respectively). The mean incidence of in-hospital death and rehospitalization for recurrence was 1.4% and 5.7%, respectively; neither changed over time. The mean length of hospitalization increased from 8 to 10 days and the cost of hospitalization increased from JPY 417,000 to JPY 525,000. Multivariable analysis showed that age and steroid use were significant predictors of in-hospital death, whereas cardiac tamponade was not (adjusted odds ratio 1.32; 95% confidence interval 0.56–3.14).

Conclusions: Among hospitalized patients with idiopathic pericarditis, prescription rates of medications recommended by European Society of Cardiology guidelines have increased, although the concurrent use of NSAIDs and colchicine remains uncommon; there have been no changes in the incidence of in-hospital death. Prospective studies, including outpatients, are needed to clarify the prognosis and recurrence rate of idiopathic pericarditis.

Background: Vericiguat, an oral soluble guanylate cyclase stimulator, is a novel therapeutic agent for patients with heart failure with reduced ejection fraction; however, the detailed cardioprotective mechanism remains unclear. We aimed to explore the mechanism of the effect of vericiguat on the myocardium, particularly focusing on oxidative stress, using in vivo and in vitro experiments.

Methods and Results: Male 8-week-old mice were divided into a control group, angiotensin II (AngII) infusion group, and AngII infusion with low- or high-dose vericiguat treatment group. After 14 days of treatment, vericiguat did not affect the systolic or diastolic blood pressure increase caused by AngII infusion. AngII-induced cardiac hypertrophy and fibrosis in the left ventricle (LV) were significantly ameliorated by high-dose vericiguat treatment. AngII-induced O₂⁻overproduction and upregulation of messenger RNA levels of Nppa, Nppb, Myh7, Col1a1, Col3A1, and Tgfb1 in the LV were significantly attenuated by vericiguat in a dose-dependent manner. Incubation of neonatal rat cardiomyocytes using vericiguat and AngII revealed that preceding incubation with vericiguat directly reduced AngII-induced cardiomyocyte O₂⁻production and cardiac hypertrophy-associated gene expression. In addition, AngII-induced phosphorylation of ERK 1/2 or p38 MAPK was significantly attenuated by the incubation with vericiguat.

Conclusions: Our study demonstrated that vericiguat suppresses myocardial oxidative stress via the regulation of ERK 1/2 or p38 MAPK signaling, leading to antihypertrophic/fibrotic effects.

Background: Intravascular lithotripsy (IVL) is currently recommended for heavily calcified coronary lesions with an optical coherence tomography (OCT)- or intravascular ultrasound (IVUS)-based calcium score of 3 or 4.

Methods and Results: We retrospectively assessed both calcium scores for the same lesions, which had a heavily calcified coronary lesion requiring plaque modification. Among 52 lesions, the mean OCT-based calcium score was 3.96, whereas the mean IVUS-based calcium score was 2.15 (P<0.001).

Conclusions: This comparative study revealed a significant discrepancy between IVUS- and OCT-based calcium scores in heavily calcified coronary lesions, which may influence treatment strategies, including use of IVL.