Toyoaki Murohara

Background: Durable left ventricular assist devices (LVADs) improve the outcomes of patients with advanced heart failure; however, recurrent hospitalization remains a major burden. The days alive and out of hospital (DAOH) is a patient‐centered metric that reflects both survival and hospitalization burden; however, data using this measure are limited. This study aimed to evaluate both short‐ and long‐term DAOH following durable LVAD implantation. Methods: We analyzed patients who underwent durable LVAD implantation between 2010 and 2023 using the J‐MACS (Japanese Registry for Mechanically Assisted Circulatory Support) registry. DAOH and days lost due to death and hospitalization were evaluated across 3 postimplantation intervals: days 1 to 365 (n=1379), 366 to 730 (n=1136), and 731 to 1095 (n=895). Results: The mean DAOHs were 216, 309, and 303 days during the first, second, and third years, respectively. During days 1 to 365, most days lost were attributable to the initial hospitalization for LVAD implantation, whereas in subsequent periods, other hospitalizations became the main contributors. Older age and impaired renal function were associated with shorter DAOH during the first 365 days. A lower INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile and implantation in the earlier era were consistently associated with shorter DAOH among all 3 time intervals. Infection, particularly pump‐related infection, and neurological dysfunction were the major contributors to hospitalization‐related days lost after discharge from the initial hospitalization among all time intervals. Conclusions: In this nationwide registry analysis, ≈15% of the days remained lost annually after the first year. These findings emphasize the need for improved chronic‐phase management and targeted prevention of key complications to optimize long‐term outcomes following durable LVAD implantation.

Background: Optimal unloading strategies for patients with cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation remain uncertain, particularly when comparing Impella and intra‐aortic balloon pump (IABP). We aimed to compare outcomes of patients receiving Impella or IABP during venoarterial extracorporeal membrane oxygenation and evaluate cause‐specific differences. Methods: In this retrospective cohort study using the nationwide JROAD‐DPC (Japanese Registry of All Cardiac and Vascular Diseases–Diagnosis Procedure Combination) database from 2012 to 2023, patients with cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation and either Impella or IABP were analyzed. Propensity score–based inverse probability of treatment weighting was applied to adjust baseline differences. Results: Among 18 906 patients (Impella, n=1688; IABP, n=17 218), overall in‐hospital mortality was 57.3% with Impella and 67.2% with IABP. Impella use was associated with lower in‐hospital mortality compared with IABP (odds ratio [OR], 0.86 [95% CI, 0.75–0.99]). Cause‐specific analyses showed significantly lower mortality with Impella in heart failure (OR, 0.66 [95% CI, 0.47–0.91]) and arrhythmia (OR, 0.62 [95% CI, 0.42–0.91]). Impella use was also associated with longer hospital stay (median, 22 versus 12 days), longer support duration (7 versus 4 days), and higher total costs (56.1 versus 27.3 thousand USD). Conclusions: In this nationwide cohort, Impella unloading during venoarterial extracorporeal membrane oxygenation was associated with lower in‐hospital mortality than IABP in the overall cohort, particularly in selected causes, at the expense of prolonged hospitalization and higher costs. Further studies are needed to define optimal cause‐specific unloading strategies in cardiogenic shock.

Aortic aneurysms are age-linked aortic dilations that progress silently and carry high mortality rates following rupture. Immune cells are recognized drivers of aneurysm pathogenesis. Clonal hematopoiesis is an age-related expansion of somatically mutated hematopoietic stem cells that reshapes immune function and contributes to diverse age-associated diseases. However, its contribution to aneurysm pathogenesis remains unclear. In this study, targeted ultradeep sequencing of patient specimens revealed a high prevalence of clonal hematopoiesis–associated mutations that correlated with faster aneurysm expansion. Thus, we modeled clonal hematopoiesis by competitively transplanting ten-eleven translocation 2–deficient ( Tet2 -deficient) bone marrow into apoliprotein E–KO ( Apoe -KO) mice and induced aneurysms with angiotensin II. Mice with Tet2 clonal hematopoiesis developed significantly greater aortic dilation than did controls. Interestingly, Tet2 -deficient macrophages adopted an acid phosphatase 5, tartrate resistant (ACP5 ⁺ ), osteoclast-like state and produced more matrix metalloproteinase 9 (MMP9). Both genetic and pharmacological inhibition of osteoclast-like differentiation suppressed the Tet2-mediated aneurysmal growth in vivo. Thus, Tet2-driven clonal hematopoiesis accelerated aortic aneurysm progression through MMP9-producing, osteoclast-like macrophages and therefore represents a tractable therapeutic axis.

Cardiac sympathetic nervous dysfunction is linked to poor prognosis in heart failure with reduced ejection fraction (HFrEF), and patients with HFrEF complicated by type 2 diabetes mellitus (T2DM) represent a particularly high risk. Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations in patients with T2DM, but the mechanisms underlying these benefits are not fully understood; modulation of cardiac sympathetic activity has been proposed as one contributor. The TARGET-HF trial will investigate whether tofogliflozin improves cardiac sympathetic nerve activity, assessed by I-123 metaiodobenzylguanidine (MIBG) scintigraphy, along with other cardiovascular parameters in patients with HFrEF and T2DM. This single-arm prospective interventional study will enroll 50 patients with HFrEF (left ventricular ejection fraction < 40%), T2DM (hemoglobin A1c level, 6.5–10.0%), and estimated glomerular filtration rate ≥ 30mL/min/1.73 m². Participants will receive oral tofogliflozin (20 mg/day) for 24 weeks. The primary endpoint is the change in the heart-to-mediastinum ratio on delayed I-123 MIBG scintigraphy from baseline to 24 weeks. Secondary endpoints include changes in the early heart-to-mediastinum ratio, washout rate, echocardiographic parameters, and various biomarkers related to HF, inflammation, and metabolism. The TARGET-HF trial is the first interventional study to comprehensively evaluate the effects of tofogliflozin on cardiac sympathetic nerve activity using I-123 MIBG scintigraphy in patients with HFrEF and T2DM. By integrating nuclear imaging, echocardiography, and metabolic and biochemical biomarkers, this study aims to clarify the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors. Improved understanding of these mechanisms may refine patient selection and guide targeted therapeutic strategies in HF management. Japan Registry of Clinical Trials; approval number: jRCTs041210022 (February 6, 2021).

Background: Heart failure (HF) is often complicated by frailty. We evaluated the prognostic value of the Frailty Index based on laboratory tests (FI‐lab) and the Clinical Frailty Scale, as well as their combined use, for adults with acute HF. Methods: This study was a post hoc analysis of the POPEYE‐AHF (Prospective Observational Study on Acute Pharmacotherapy and Prognosis in Management of Acute Heart Failure) registry, a prospective observational study evaluating the treatment and characteristics of patients with acute HF. At discharge, 975 patients had available FI‐lab data, while 637 patients had available Clinical Frailty Scale data. The FI‐lab was determined at discharge by the proportion of 21 laboratory items with abnormal results. The outcomes were all‐cause death, HF hospitalization, and the composite of both. Results: At baseline, the median age was 80 years, and 45.0% of the patients with FI‐lab data were women. Multivariable Cox proportional hazards regression revealed that the measured FI‐lab was associated with all outcomes (all‐cause death: hazard ratio [HR], 1.38 [95% CI, 1.15–1.67], P =0.001; HF hospitalization: HR, 1.15 [95% CI, 1.00–1.32], P =0.044; composite outcome: HR, 1.21 [95% CI, 1.08–1.37], P =0.002) after full adjustment. When dividing patients into the high and low FI‐lab subgroups (median cutoff, 0.48), high FI‐lab was associated with all‐cause death (HR, 2.11 [95% CI, 1.31–3.41], P =0.002) and the composite outcome (HR, 1.40 [95% CI, 1.05–1.88], P =0.023). High FI‐lab/high Clinical Frailty Scale was associated with all‐cause death after adjustment (HR, 2.62 [95% CI, 1.38–4.99], P =0.003). Conclusions: FI‐lab identified high‐risk adults with acute HF. The combined use of the Clinical Frailty Scale and FI‐lab identified adults at high risk of all‐cause death.

Background: Heart rate score (HrSc) ≥ 70% reflects chronotropic incompetence and predicts prognosis in patients with cardiac implantable electronic devices (CIEDs) and left ventricular (LV) systolic dysfunction. However, its prognostic value in Japanese patients remains underexplored, and longitudinal changes in HrSc and their contributing factors are poorly characterized. Methods: This post hoc analysis of the Heart Failure Indication and Sudden Cardiac Death Prevention Trial in Japan (HINODE) included 172 patients with CIEDs and LV ejection fraction ≤ 50%. HrSc, defined as the percentage of all atrial‐paced and sensed beats in a single tallest 10 beat/min device histogram bin, was assessed using remote monitoring. Results: At baseline, the median HrSc was 53% (interquartile range, 41%–83%), with 68 (39.5%) patients having HrSc ≥ 70%. During the 2‐year follow‐up, the incidence of all‐cause death or heart failure (HF) events was similar between patients with HrSc ≥ 70% and < 70% (31.1% vs. 29.4%, log‐rank p = 0.862). However, among 142 patients whose follow‐up data were available, HrSc increased from < 70% to ≥ 70% in 13 patients (13%) and decreased from ≥ 70% to < 70% in 19 (9.1%). An increase in HrSc was associated with lower LV ejection fraction, antiarrhythmic drug initiation, increased lower rate limit, and HF events. Conclusion: In the HINODE study, baseline HrSc ≥ 70% was not predictive of 2‐year cardiovascular outcomes. However, HrSc changed in approximately one‐quarter of patients and was associated with clinical and device‐related factors, as well as HF events. HrSc is not a static measure but a dynamic marker that reflects evolving patient conditions and CIED programming.

Background: Advanced heart failure (HF) remains associated with poor outcomes despite contemporary therapies. Right ventricular (RV) dysfunction, a hallmark of advanced HF, is strongly influenced by afterload. We aimed to evaluate whether the combined assessment of the pulmonary artery pulsatility index (PAPi) and pulmonary arterial capacitance (PAC)-and their transitions during acute-phase therapy-provides prognostic stratification in patients with advanced HF. Methods: We conducted a post-hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, including 146 patients with complete hemodynamic data. A bootstrap-based grid search identified prognostic cutoffs: PAPi at 2.67 and PAC at 2.03. The optimal zone was defined as PAPi ≥2.67 and PAC ≥2.03; the suboptimal zone as PAPi suboptimal zone. Following acute-phase therapy, 33 transitioned to the optimal zone, while 94 remained suboptimal . Kaplan–Meier curves demonstrated significant stratification among groups. In Cox regression models using the suboptimal→suboptimal as reference, transition to the suboptimal→optimal was associated with improved prognosis (multivariable hazard ratio 0.300, 95% confidence interval 0.107–0.847, P=0.023). Conclusions: Transitions in PAPi and PAC during acute-phase therapy were associated with subsequent outcomes in advanced HF. Combined assessment of PAPi and PAC may provide a novel therapeutic target for risk stratification and management in this high-risk population.