Chisato Izumi

Background: Current guidelines classify normal‐flow low‐gradient (LG) aortic stenosis (AS) with left ventricular ejection fraction (LVEF) ≥50% as “moderate.” However, the prognostic impact of LVEF remains incompletely understood across various hemodynamic subtypes of AS. Methods: We analyzed 3363 consecutive patients with severe AS from the CURRENT AS Registry‐2 (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis). Patients were classified into LG AS with normal flow (N=1005), and LG AS with low flow (N=372), and high‐gradient AS (N=1986). Patients were further divided according to baseline LVEF: P P =0.003) with hazards comparable to those with LVEF P =0.59). Conclusions: These findings suggest that LVEF may provide additional prognostic stratification within severe AS phenotypes, particularly in normal‐flow LG AS. Registration: URL: https://center6.umin.ac.jp ; Unique Identifier: UMIN000034169.

BACKGROUND: Cardiac sarcoidosis (CS) may lead to serious outcomes, but large-scale data are lacking because of its rarity, diagnostic uncertainty, and heterogeneous clinical presentations. Actual management and outcomes, including recurrence, are not well understood. This study aimed to clarify the actual management and outcomes of CS from a nationwide large-scale registry. METHODS: This multicenter retrospective registry enrolled 2366 consecutive patients with CS. Of these, 1852 patients newly diagnosed between 2012 and 2021 were analyzed. Patients were stratified into 4 groups: definite CS, probable CS, presumed systemic sarcoidosis, and presumed isolated CS based on diagnostic criteria. The primary end point was a composite of all-cause death, heart failure hospitalization, or fatal ventricular arrhythmic event. The secondary end point was recurrence of CS. RESULTS: Cardiac imaging performance rates were high (cardiac magnetic resonance: 64%, ¹⁸ F-fluorodeoxyglucose positron emission tomography: 82%), and 974 (53%) patients were diagnosed clinically without histological evidence. During a median 5.1-year follow-up, the primary outcome occurred in 519 (28%, 6.4/100 patient-years) patients, and the 4 groups exhibited different clinical presentations and prognoses; definite CS and presumed isolated CS groups showed a high incidence of the primary end point, fatal ventricular arrhythmic event, hospitalization for heart failure, and cardiovascular death. Most patients (89%) received immunosuppressive therapy, but 291 (18%, 4.1/100 patient-years) patients developed recurrence during steroid tapering, with a 5-year recurrence rate of 17.0%. Recurrence was associated with subsequent primary end point (hazard ratio, 1.38 [95% CI, 1.00–1.89]; P =0.048). CONCLUSIONS: This large-scale multicenter registry showed that clinical presentation and prognosis differ depending on the presence or absence of extracardiac lesions and histological evidence; therefore, it is necessary to recognize the characteristics of each phenotype in managing CS.

Background: Female sex has been associated with poor prognosis in hypertrophic cardiomyopathy (HCM), but the factors contributing to this disparity remain insufficiently defined. We aimed to clarify sex differences in clinical characteristics and factors associated with cardiovascular death in Japan. Methods: This multicenter, retrospective observational study of HCM was conducted between January 1, 2006, and December 31, 2018 (REVEAL‐HCM study [Multicenter Registry to Evaluate Risk Factors for Disease Progression, Sudden Cardiac Death and Adverse Clinical Outcomes in Japanese Patients With Hypertrophic Cardiomyopathy]; UMIN000046932). Patients aged ≥16 years with HCM were enrolled. Baseline characteristics and clinical outcomes including cardiovascular death were assessed. Univariable and multivariable Cox proportional hazards models were used to identify factors associated with cardiovascular death. Results: Of 3247 patients (median age, 67 years; 43% women), women were older and more symptomatic at presentation (52% New York Heart Association class II–IV versus 35% in men). Cardiovascular death was more common in women (hazard ratio [HR], 1.37 [95% CI, 1.02–1.82]; P =0.03). In multivariable analysis, older age (per 1‐year increase; HR, 1.04 [95% CI, 1.02–1.06]), advanced New York Heart Association class (HR, 1.99 [95% CI, 1.40–2.82]), history of atrial fibrillation (HR, 1.55 [95% CI, 1.10–2.18]), greater maximal wall thickness indexed to body surface area (per 1‐mm/m ² increase; HR, 1.12 [95% CI, 1.06–1.20]), and apical HCM (HR, 0.53 [95% CI, 0.32–0.88]) were independently associated with cardiovascular death, attenuating the HR for female sex. Conclusions: Sex differences in clinical characteristics and outcomes were observed. The excess cardiovascular death in women with HCM was largely explained by older age, more advanced symptoms, greater indexed wall thickness, and sex‐specific differences in both the prevalence and prognostic impact of apical HCM.

Background: A valve syndrome framework (stable valve syndrome [SVS], progressive valve syndrome [PVS], and acute valve syndrome [AVS]) integrates clinical presentation with objective markers, but its prognostic implications remain incompletely characterized. Methods: Among 3369 consecutive patients with severe aortic stenosis (AS) in the CURRENT AS Registry‐2, we analyzed 2824 patients with natriuretic peptide (NP) and left ventricular ejection fraction (LVEF) data. Patients were classified as SVS (no symptoms with low NP), PVS (mild symptoms and/or mildly elevated NP), or AVS (acute deterioration and/or markedly elevated NP or reduced LVEF), and stratified by initial aortic valve replacement (AVR) and conservative strategies. The primary outcome was a composite of death or heart failure hospitalization. Subgroup analyses further classified patients into five phenotypes: SVS, progressive valve signs without symptoms, progressive valve symptoms, acute valve signs without symptoms, and acute valve symptoms. Results: In the initial AVR stratum, AVS was associated with higher risk for the primary outcome compared with SVS (adjusted HR 2.34, 95% CI 1.19–4.59, P=0.01), whereas PVS was not. In the conservative stratum, SVS demonstrated a very low early event rate (1.0% at 6 months), while AVS and PVS had higher risk than SVS. In the five‐phenotype analysis, patients with progressive valve signs without symptoms underwent AVR at rates comparable to SVS yet had worse outcomes than SVS in the conservative stratum (adjusted HR 1.89, 95% CI 1.18‐3.03, P=0.008). Conclusions: A valve syndrome framework highlights limitations of symptom‐based risk stratification and may refine surveillance and intervention strategies in severe AS.

Background: The long-term prognosis of patients supported by durable left ventricular assist devices (LVAD) while receiving immunosuppressive therapy remains unclear. Underlying conditions such as cardiac sarcoidosis, recurrent myocarditis, or post-organ transplantation may necessitate concomitant immunosuppressive therapy during LVAD support. In particular, patients requiring prolonged immunosuppressive therapy exceeding low-dose corticosteroids represent a clinically challenging population in whom infectious complications and long-term outcomes have not been well characterized. Case summary: We retrospectively reviewed 241 consecutive LVAD recipients (HeartMate II and HeartMate 3) at a single centre (2013–24). Five patients (2.1%) required prolonged immunosuppressive therapy exceeding low-dose corticosteroids. Underlying cardiac conditions included myocarditis (n = 3), cardiac sarcoidosis (n = 1), and dilated cardiomyopathy following liver transplantation (n = 1). The mean duration of immunosuppressive therapy during LVAD support was 2.3 years (0.8–4.5 years). One patient developed LVAD-specific infections including driveline infection. Two underwent successful heart transplantation without perioperative complications. One was tapered to low-dose corticosteroid monotherapy due to a non-device-related infection, and two remained stable on LVAD support. Discussion: This case series underscores the complexity of managing LVAD patients requiring extended immunosuppressive therapy and highlights a unique and underreported patient population. Our findings suggest that successful heart transplantation may be achievable in immunosuppressed LVAD patients when supported by vigilant infection surveillance and individualized treatment strategies. This topic is of increasing clinical importance, particularly in regions where DT indications have recently been expanded.

Background and Aims: Pathological examination is commonly used to diagnose immune checkpoint inhibitor (ICI)-related myocarditis. However, well-organized clinicopathological evidence remains limited. In this study, we aimed to investigate the pathological and clinical characteristics of myocarditis to enhance understanding. Methods: This multicentre retrospective observational study included 38 patients diagnosed with or suspected of having ICI-related myocarditis. Patients were stratified using the pathological grading system proposed by Palaskas et al. Lymphocyte infiltration was assessed using both global and hot-spot (hotspot) methods. Immunohistochemistry was performed for lymphocytes, macrophages, and inflammatory markers, including human leucocyte antigen–DR isotype (HLA-DR), programmed death-ligand 1 (PD-L1), granzyme B, and tenascin C. Results: An increased infiltration of CD3, CD4, CD8-positive T cells, and CD68 and CD163-positive macrophages was observed with higher pathological grades. HLA-DR and tenascin C (clone 4F10) were sensitive markers of inflammation, whereas PD-L1 and tenascin C (clone 4C8) were more specific for high-grade inflammation. Global assessment more accurately predicted myocarditis-related mortality than hotspot assessment, although both methods similarly predicted fulminant myocarditis and major adverse cardiac events. Two patients presented with suspected ICI-mediated non-inflammatory left ventricular dysfunction (NILVD), with minimal myocardial inflammation. Conclusions: Pathological grading using both global and hotspot assessment is valuable for the diagnosis and risk stratification of ICI-related myocarditis. As low-grade inflammation is not uncommon, supplementary markers such as HLA-DR, granzyme B, tenascin C, and PD-L1 may aid diagnosis. Furthermore, ICI-mediated NILVD may encompass cases of low-grade myocarditis.

Background: Superb microvascular imaging (SMI) can visualize low-velocity blood flow vividly without contrast agents. Superb microvascular imaging could be used to evaluate blood flow in the myocardium or cardiac tumours, which have never been assessed using a conventional echocardiographic probe. Evaluating intratumoural blood flow using SMI may provide supportive haemodynamic characterization for the differential diagnosis of cardiac tumours. Case summary: This report describes three cases in which SMI was useful for detecting intratumoural blood flow signals and differential diagnosis of cardiac tumours. Intratumoural blood flow signals were detected in Case 1 (pulmonary artery intimal sarcoma) but not in Case 2 (malignant lymphoma). The patient described in Case 3 had a large intracardiac tumour and was too old and frail to undergo surgery; therefore, based on the SMI findings of abundant intratumoural blood flow signals, cardiac sarcoma was presumed, and best supportive care was selected without performing invasive tests or treatment. Discussion: Rapid differential diagnosis between cardiac sarcoma and malignant lymphoma is important for determining the treatment strategy. Cardiac sarcoma has a poor prognosis and progresses rapidly, whereas cardiac malignant lymphoma can potentially be cured by chemotherapy. Intratumoural blood flow is abundant in patients with cardiac sarcoma but poor in those with malignant lymphoma. Superb microvascular imaging can assist whether blood flow is abundant or poor in a cardiac tumour. Evaluation of intratumoural blood flow using SMI provides supportive haemodynamic characterization for the differential diagnosis of cardiac tumours and may shorten the time to treatment.

BACKGROUND: Mitral regurgitation (MR) is a frequent comorbidity in patients with hypertrophic cardiomyopathy (HCM), which includes distinct subtypes with various characteristics. However, data on the long-term prognostic impact of MR and its progression or regression over time remain limited, particularly across individual HCM subtypes. METHODS: Patients with HCM were retrospectively included from a Japanese multicenter registry and compared by MR severity (moderate or greater versus mild or less) within each subtype: hypertrophic obstructive cardiomyopathy (HOCM), end-stage HCM (ES-HCM), and other HCM (including nonobstructive, midventricular obstruction, and apical HCM). RESULTS: Among 3602 patients (HOCM: n=837; ES-HCM: n=275; other HCM: n=2490), the prevalence of moderate or greater MR was highest in HOCM (36.3%), followed by ES-HCM (21.5%) and other HCM (8.5%). During a median follow-up of 5.3 (interquartile range, 2.1–9.3) years, the cumulative 5-year incidence of all-cause death or heart failure hospitalization was not significantly different between the moderate or greater MR and mild or less MR groups in HOCM (14.6% versus 12.4%; P =0.35) or ES-HCM (60.7% versus 54.7%; P =0.84). After adjustment for clinical covariates, no significant association was observed in either subtype (HOCM: hazard ratio, 1.13 [95% CI, 0.79–1.60], P =0.51; ES-HCM: hazard ratio, 0.84 [95% CI, 0.55–1.28], P =0.42). In contrast, in other HCM, moderate or greater MR was significantly associated with the higher 5-year cumulative incidence of all-cause death or heart failure hospitalization (34.2% versus 13.9%, P P =0.01; P _interaction =0.02). MR severity improved over time in HOCM, showed no clear change in ES-HCM, and worsened in other HCM ( P P _interaction <0.001). CONCLUSIONS: In patients with HCM, moderate or greater MR was not associated with worse outcomes in HOCM or ES-HCM, but had significant prognostic implications in other HCM subtypes, suggesting the need for HCM subtype-specific MR management.

Background: Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM). Validation of the Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS) guidelines for SCD prevention needs to be undertaken in a large cohort of Japanese patients with HCM.Methods and Results: In a subanalysis of the REVEAL-HCM registry comprising 3,611 patients, we enrolled 3,547 patients after excluding 64 patients with missing data required for calculating the HCM Risk-SCD score. The endpoint was a composite of SCD or an equivalent event. During a median 5.8-year follow-up period, SCD events occurred in 247 (7.0%) patients. The 5-year cumulative incidence of SCD events differed significantly between Class 2a and 2b recommendations (6.7% vs. 4.9%, respectively; P=0.006) and between Class 2b and 3 recommendations (4.9% vs. 1.7%, respectively; P<0.001). Excess risk of SCD was also significant for patients with Class 2a and 2b compared with Class 3 recommendations, with hazard ratios of 3.59 (95% confidence interval [CI] 2.40–5.37; P<0.001) and 2.09 (95% CI 1.47–2.97; P<0.001), respectively. The 2018 JCS/JHFS guidelines had an area under the curve of 0.75 (95% CI 0.71–0.80; P<0.001) for discriminating SCD events at 5 years.Conclusions: The 2018 JCS/JHFS guidelines showed good discriminatory performance for SCD risk stratification, particularly among patients with Class 2a recommendations for an implantable cardioverter defibrillator.