The evolutionarily conserved Hippo pathway plays a pivotal role in governing a variety of biological processes. Heart failure (HF) is a major global health problem with a significant risk of mortality. This review provides a contemporary understanding of the Hippo pathway in regulating different cell types during HF. Through a systematic analysis of each component’s regulatory mechanisms within the Hippo pathway, we elucidate their specific effects on cardiomyocytes, fibroblasts, endothelial cells, and macrophages in response to various cardiac injuries. Insights gleaned from both in vitro and in vivo studies highlight the therapeutic promise of targeting the Hippo pathway to address cardiovascular diseases, particularly HF.

Background: Although the relative apical sparing (RAPS) pattern of left ventricular (LV) longitudinal strain is a hallmark of cardiac amyloidosis, recent studies have raised concerns about its accuracy. The aim of this systematic review was to investigate diagnostic test accuracy (DTA) and prognostic impact of RAPS in cardiac amyloidosis.

Methods and Results: We searched PubMed, Embase, and Scopus for manuscripts that could potentially be used in the DTA arm and prognosis arm. Thirty-seven studies were used for DTA analysis. The pooled sensitivity, specificity, and diagnostic odds ratio were 61% (95% confidence interval [CI] 54–68%), 83% (95% CI 80–86%), and 8.9 (95% CI 6.1–13.1), respectively. These values did not differ regardless of the presence of aortic stenosis, but the diagnostic odds ratio differed significantly among analytical software packages. For the prognosis arm, 6 studies were dichotomously assessed for RAPS, and 5 were assessed quantitatively. The pooled proportion of RAPS was 49% and the pooled estimate of the RAPS ratio was 1.40. Although RAPS was associated with outcome (hazard ratio [HR] 1.87; 95% CI 1.15–3.04; P=0.011), its significance disappeared after trim and fill analysis (HR 1.42; 95% CI 0.85–2.38; P=0.184).

Conclusions: RAPS has a modest DTA with a significant vendor dependency and does not provide robust prognostic information.

Background: High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings.

Methods and Results: This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population.

Conclusions: Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Background: Exercise capacity is related to mortality and morbidity in heart failure (HF) patients. Determinants of exercise capacity in transthyretin cardiac amyloidosis (ATTR-CA) have not been established.

Methods and Results: This single-center study retrospectively evaluated ATTR-CA patients and patients with non-amyloidosis HF with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF) (n=32 and n=51, respectively). In the ATTR-CA group, the median age was 75.5 years (interquartile range [IQR] 71.3–78.8 years), 90.6% were male, and the median left ventricular (LV) ejection fraction was 53.5% (IQR 41.4–65.6%). Cardiopulmonary exercise tests revealed a median peak oxygen consumption and anaerobic threshold of 15.9 (IQR 11.6–17.4) and 10.6 (IQR 8.5–12.0] mL/min/kg, respectively, and ventilatory efficiency (minute ventilation/carbon dioxide production [V̇_E/V̇_CO2] slope) of 35.5 (IQR 32.0–42.5). Among exercise variables, V̇_E/V̇_CO2slope has the greatest prognostic value. Univariate analysis revealed a significant correlation between V̇_E/V̇_CO2slope and age, LV global longitudinal strain, tricuspid annular plain systolic excursion/pulmonary arterial systolic pressure (TAPSE/PASP) ratio, and mixed venous oxygen saturation. In multivariate analyses, the TAPSE/PASP ratio was an independent predictor of V̇_E/V̇_CO2slope (95% confidence interval −44.5, −10.8; P=0.0067). In non-amyloidosis HFpEF/HFmrEF patients, the TAPSE/PASP ratio was not independently correlated with V̇_E/V̇_CO2slope.

Conclusions: Right ventricular–pulmonary artery coupling estimated by the TAPSE/PASP ratio determines exercise capacity in ATTR-CA patients. This highlights the importance of early therapeutic intervention against underappreciated right ventricular dysfunction associated with ATTR-CA.

Background: Cardiac sarcoidosis (CS) may result in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), but its response to guideline-directed medical therapy (GDMT) remains uncertain.

Methods and Results: We investigated 881 patients evaluated for CS to identify those with diagnosed CS, left ventricular ejection fraction (LVEF) ≤40% at diagnosis, and follow-up echocardiogram within 11–24 months. Demographics, LVEF, GDMT as quantified by Kansas City Medical Optimization (KCMO) score, and immunosuppressive treatment were recorded. The primary outcome was a composite of event-free survival (unplanned heart failure hospitalization, left ventricular assist device [LVAD]/heart transplant, or death). Seventy-nine (9%) CS patients met the inclusion criteria (35% female, median age 57 years, mean LVEF 30.9%, median New York Heart Association class II [46%], mean number of GDMT agents 1.7, and mean KCMO score 31.8). Most (87%) were treated with immunosuppressive treatment. At follow-up (median 16 months), the mean number of GDMT agents increased to 2.2 (P=0.02), and the mean KCMO score to 70.1 (P<0.001). Mean LVEF improved to 39.9% (excluding LVAD/transplant; P<0.001) and the change in LVEF was correlated with follow-up KCMO score (P<0.001). The primary outcome occurred in 13 (16%) patients and differed by KCMO score (log-rank P<0.001), but not by immunosuppressive treatment (log-rank P=0.36).

Conclusions: GDMT optimization is associated with better cardiac remodeling and clinical outcomes in CS patients with HFrEF.

Background: Fabry disease is a hereditary metabolic disorder caused by a decrease in or deficiency of the lysosomal enzyme α-galactosidase A. Enzyme replacement therapy or pharmacological chaperone therapy can improve prognosis, especially in patients in the early phase of cardiac involvement. Longitudinal strain (LS) evaluated using speckle tracking echocardiography can detect early contractile dysfunction. However, there have been no reports of LS in Japanese Fabry disease patients.

Methods and Results: We recruited 56 patients with Fabry disease (22 men, 34 women) who were followed up at Jikei University Hospital. Fifty-eight control subjects without overt cardiac diseases were also included in the study. We evaluated LS in each patient, and the values of each of the 17 segments of the left ventricle (LV) were averaged, and global LS (GLS) was also calculated. GLS was significantly worse in Fabry disease patients without LV hypertrophy than in control subjects (−18.5±2.8% vs. −20.4±1.6%; P<0.05). In addition, Fabry disease patients without LV hypertrophy had significantly worse lateral LS (−16.4±5.0% vs. −19.3±1.8%; P<0.05), basal LS (−16.5±3.2% vs. −18.5±1.7%; P<0.05), and mid LS (−18.7±1.7% vs. −20.8±1.6%; P<0.05) than control subjects.

Conclusions: These results suggest that early contractile dysfunction in Fabry disease can be observed using GLS, lateral LS, basal LS, and mid LS, even without LV hypertrophy.

Background: This study evaluated right ventricular (RV) volume, strain, and morphology using cardiac 4-dimensional computed tomography (4D-CT) to detect pulmonary hypertension (PH) in adults with repaired tetralogy of Fallot (TOF) scheduled for transcatheter pulmonary valve implantation (TPVI).

Methods and Results: Using cardiac 4D-CT data, we calculated RV strain in 3 different geometries and RV outflow tract (RVOT) mass in 42 patients with repaired TOF. We compared RV strain and RVOT mass between patients with and without PH. Receiver operating characteristic (ROC) analysis was conducted to evaluate the diagnostic performance of these measurements for identifying PH. Four-chamber (4ch) strain was significantly smaller for patients with (n=10) than without (n=32) PH (8.8±1.7% vs. 11.1±2.4%, respectively; P<0.01), whereas RVOT mass was significantly larger in the PH group (12.5±3.5 vs. 9.2±3.2 cm²; P<0.01). ROC analysis of the diagnostic performance revealed that the respective sensitivity and specificity was 70% and 84% (area under the curve [AUC]=0.784) for 4ch strain of 8.8%; 80% and 69% (AUC=0.766) for RVOT mass of 10.7 cm²; and 80% and 81% (AUC=0.844) for a 4ch strain/RVOT mass ratio of 0.97.

Conclusions: RVOT mass and 4ch strain obtained from cardiac 4D-CT may be helpful for identifying PH in patients with repaired TOF.

Background: Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity. This multicenter nationwide Japanese study evaluated mortality and morbidity after initial surgical palliation for patients with heterotaxy syndrome and determined predictors for mortality and morbidity among patients enrolled in the study.

Methods and Results: The Japanese Congenital Cardiovascular Surgery Database (JCCVSD) collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan. Clinical data on preoperative, operative, and postoperative characteristics and survival data within 30 and 90 days were available from the JCCVSD database. Of the 561 patients with heterotaxy syndrome who underwent any of 8 specific initial cardiovascular surgeries, 45 (8.2%) and 75 (13.4%) had died at 30 and 90 days, respectively. Preoperative emergency transport, type of heterotaxy syndrome, low hospital volume, the repair of total anomalous pulmonary vein connection, and the repair of a common atrioventricular valve were identified as significant predictive factors for operative mortality.

Conclusions: Improvements in some medical circumstances, such as fetal diagnosis and the patient transport system, will be needed to improve outcomes for severely ill patients with heterotaxy syndrome. This study describes early outcomes for the largest number of main cardiovascular surgeries to date in infants with heterotaxy syndrome.

Background: With advances in treatment, the prognosis for pregnancies complicated by pulmonary arterial hypertension (PAH) has been improving. However, PAH-related maternal mortality remains high compared with that due to other cardiovascular diseases. The specifics of PAH-related maternal deaths under advanced medical standards are not well understood.

Methods and Results: We used the maternal death registration system established by the Japan Association of Obstetricians and Gynecologists and reviewed 6 PAH-related maternal deaths from 2010 to 2022. All women were initially diagnosed with PAH during pregnancy or immediately after childbirth. The diagnosis of PAH tended to be delayed because symptoms were not reported to healthcare providers and/or a different disease was diagnosed. Cardiogenic shock occurred antepartum in 1 woman and during delivery or within 7 days after delivery in the other 5 women. Four women were resuscitated and started on extracorporeal membrane oxygenation. Pulmonary vasodilators were initiated in 4 women, with a median duration of 8 days from PAH diagnosis to starting medication. Right heart failure was the most common cause of maternal death, with a median duration of 16 days from PAH diagnosis to maternal death.

Conclusions: All PAH-related maternal deaths occurred in women who were diagnosed with PAH after pregnancy. Diagnosing PAH and initiating pulmonary vasodilators takes considerable time, highlighting the importance of early diagnosis and early treatment.

Background: The number of older people in Japan is increasing more quickly than in other countries; with this aging of society, the number of elderly patients hospitalized for acute heart failure (HF) is also increasing. The treatment and prognosis of acute HF may be changing, but there are insufficient recent data, especially for octogenarian and older patients.

Methods and Results: This study investigated the characteristics and treatment of acute HF patients in Japan. From 2018 to 2020, 1,146 patients from 7 Tokai area hospitals were followed for at least 1 year. The mean age was 78 years. Compared with patients aged <80 years, those aged ≥80 years were more likely to be female (57.4% vs. 34.2%), have a lower body mass index (22.2 vs. 24.9 kg/m²), and have HF with preserved ejection fraction (43.1% vs. 21.4%), and less likely to have HF with reduced ejection fraction (38.9% vs. 61.7%). During hospitalization, 6.5% died. After discharge, patients faced high risks of rehospitalization for HF and death (27.6 and 14.2 per 100 patient-years, respectively). Notably, prescription rates of HF medications have declined over time for all patients, but especially for those aged ≥80 years.

Conclusions: Guideline-directed medical therapy should be provided based on a thorough understanding of an individual’s background rather than withheld simply because of clinical inertia due to a patient’s advanced age.

Background: Guideline-directed medical therapy has become an important component of heart failure (HF) therapy, with sacubitril/valsartan as one of the recommended drugs; however, the real-world prognostic implications of sacubitril/valsartan uptitration are unclear.

Methods and Results: Patients with HF newly initiated on sacubitril/valsartan were registered in a retrospective multicenter study (REVIEW-HF). In all, 995 patients were divided into 3 groups according to the maximum dose achieved: high dose, sacubitril/valsartan 400 mg; intermediate dose, sacubitril/valsartan 200–<400 mg; and low dose, sacubitril/valsartan <200 mg. A total of 397 (39.9%) patients received high-dose sacubitril/valsartan; they had a significantly lower risk of mortality or HF hospitalization than patients in the low-dose (hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.29–0.53; P<0.001) and intermediate-dose (HR 0.64; 95% CI 0.45–0.94; P=0.03) groups. In the multivariable Cox regression model, higher systolic blood pressure and maintained geriatric nutritional risk index were significantly associated with a higher incidence of achieving a high dose of sacubitril/valsartan. Patients who did not receive high-dose sacubitril/valsartan experienced more hypotension during the follow-up period, whereas hyperkalemia, severe renal events, and angioedema did not differ across the achieved dose classifications.

Conclusions: Patients who achieved sacubitril/valsartan uptitration had a better prognosis than those who did not. Before sacubitril/valsartan uptitration, patients need to monitor blood pressure closely to prevent worsening events.

Background: Mitochondrial dysfunction in the heart is associated with the development of heart failure (HF). However, the clinical consequences of mitochondrial structural abnormalities in patients with HF remain unexplored.

Methods and Results: Ninety-one patients with left ventricular (LV) systolic dysfunction who underwent endomyocardial biopsy (EMB) were enrolled in the study. Myocardial specimens were obtained from the right ventricular septum. Specimens were characterized using electron microscopy to assess mitochondrial size, outer membrane disruption, and cristae disorganization. The primary endpoint was a composite of cardiovascular death and unplanned hospitalization for HF. Patients were classified into LV reverse remodeling (LVRR)-positive (n=52; 57.1%) and LVRR-negative (n=39; 42.9%) groups. Cristae disorganization was observed in 21 (23.1%) patients: 6 (11.5%) in the LVRR-positive group and 15 (38.5%) in the LVRR-negative group (P=0.005). During the 1-year post-EMB observation period, 16 patients (17.6%) met the primary endpoint, with 2 (2.2%) cardiovascular deaths and 14 (15.4%) HF hospitalizations. Cristae disorganization (P=0.002) was significantly associated with the endpoints, independent of age (P=0.115), systolic blood pressure (P=0.004), B-type natriuretic peptide level (P=0.042), and mitral regurgitation (P=0.003).

Conclusions: We classified mitochondrial structural abnormalities and showed that cristae disorganization was associated with LVRR and worse prognosis. These findings may affect the management of patients with HF and systolic dysfunction who undergo EMB.

Background: Heart failure (HF) patients with complex care needs often experience exacerbations during the transitional phase as care providers and settings change. Regional collaboration aims to ensure continuity of care; however, its impact on vulnerable patients certified as needing support or care under the Japanese long-term care insurance (LTCI) system remains unclear.

Methods and Results: We implemented a regional collaborative program for HF patients involving 3 pillars of transitional care with general practitioners and nursing care facilities: (1) standardized health monitoring using a patient diary and identification of exacerbation warning signs; (2) standardized information sharing among care providers; and (3) standardized HF management manuals. We evaluated outcomes within 1 year of discharge for patients hospitalized with HF and referred to other facilities for outpatient follow-up in 2017–2018 before program implementation (n=110) and in 2019–2020 after implementation (n=126). Patients with LTCI frequently received non-cardiologist follow up and care services and had a higher risk of all-cause mortality and HF readmission compared with those without LTCI (P<0.05). Program implementation was significantly associated with a greater reduction in HF readmissions among patients with LTCI compared with those without (P<0.05 for interaction), although mortality rates remained unchanged.

Conclusions: A regional collaborative program significantly reduces HF readmissions in HF patients with LTCI who are at high risk of worsening HF.

Background: The effects of myocarditis after mRNA COVID-19 vaccination (mCV) on myocardial tissue, and the association between cardiomyocyte injury and clinical presentation, are not fully understood.

Methods and Results: We retrospectively registered patients clinically diagnosed with myocarditis after the first or second mCV who underwent endomyocardial biopsy or autopsy from 42 participating centers in Japan. We investigated the histological features and their association with clinical presentation based on cardiomyocyte injury. Forty patients who underwent endomyocardial biopsy were included in the study. Of these, 19 (47.5%) showed mild lymphocytic infiltration and interstitial edema without cardiomyocyte injury. The remaining 21 (52.5%) patients showed cardiomyocyte injury accompanied by infiltrating inflammatory cells: 11 with lymphocytic infiltration, 7 with eosinophilic infiltration, and 3 with myocarditis with both lymphocyte and eosinophil infiltration. Compared with patients without cardiomyocyte injury, those with cardiomyocyte injury were clinically characterized by older age, a balanced sex distribution, less frequent chest pain, and a lower left ventricular ejection fraction. Fifteen of 21 (71.4%) patients with cardiomyocyte injury developed fulminant myocarditis, with 13 (86.7%) requiring mechanical circulatory support; in contrast, none of those without cardiomyocyte injury developed fulminant myocarditis (P<0.001).

Conclusions: Our histological examination of patients with myocarditis after mCV revealed varying degrees of cardiomyocyte injury, ranging from pronounced to absent, along with various types of myocarditis. Cardiomyocyte injury was strongly associated with the severity of myocarditis.

Background: Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear.

Methods and Results: HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6–20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline −60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study.

Conclusions: In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

Background: Among patients with functional mitral regurgitation (FMR), responders to transcatheter mitral edge-to-edge repair (TEER) remain unclear. We investigated whether the slope of the preload recruitable stroke work relationship (M_w; calculated as stroke work / [EDV − k × EDV + {1 − k} × LV wall], where EDV is end-diastolic volume, k is a constant, and LV wall is the volume of the left ventricular wall) could predict rehospitalization in FMR patients after TEER.

Methods and Results: M_wwas calculated for 24 FMR patients using echocardiography. The median left ventricular ejection fraction was 27% and the median M_wwas 32. Over a 498-day median follow-up period, 38% of patients were rehospitalized for heart failure, and only M_whad a high area under the curve in time-dependent receiver operating characteristic analysis.

Conclusions: M_wis an effective predictor for rehospitalization in FMR patients after TEER.