BACKGROUND: Severe right ventricular (RV) dilatation and exercise intolerance are considered indications for pulmonary valve replacement in surgically repaired tetralogy of Fallot (rTOF). METHODS AND RESULTS: Cardiopulmo...BACKGROUND: Severe right ventricular (RV) dilatation and exercise intolerance are considered indications for pulmonary valve replacement in surgically repaired tetralogy of Fallot (rTOF). METHODS AND RESULTS: Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) were performed in rTOF patients with pulmonary insufficiency (PI). Oxygen pulse (OP), calculated as oxygen consumption (V̇O)/heart rate, was used as a surrogate of stroke volume (SV). Correlations between CPET and CMR measures were investigated. In all, 37 patients (mean [±SD] age 17±5 years; 14 males) were examined. Peak V̇O/kg was approximately 70% of predicted value. The pulmonary regurgitant fraction (PRF) was 28.3±13.4%. Body surface area (BSA)-indexed RV end-diastolic volume (RVEDVi) and RVSV (RVSVi) were 127±28 and 65±16 mL/m, respectively. RV and left ventricular (LV) ejection fractions were 50.3±7.8% and 59.1±6.1%, respectively. A strong positive correlation was noted between RV end-diastolic volume and RVSV (P<0.0001), RVSV and LVSV (P<0.0001), and RVEDVi and peak OP/BSA (P=0.0004). Larger RVEDVi was correlated with better exercise performance, whereas smaller RVEDVi was correlated with worse exercise performance. RVEDVi was larger in male than female rTOF patients despite comparable PRF, RVSVi, LVEDVi, and BSA-indexed LVSV. CONCLUSIONS: A smaller RV was associated with worse exercise performance, indicating exercise intolerance is independent of RV dilatation in young rTOF with PI and represents a unique pathological entity responsible for reduced exercise performance.
BACKGROUND: This study aimed to identify the most influential factors affecting severe respiratory failure requiring respiratory assist devices (RADs), including mechanical ventilation and non-invasive positive pressure...BACKGROUND: This study aimed to identify the most influential factors affecting severe respiratory failure requiring respiratory assist devices (RADs), including mechanical ventilation and non-invasive positive pressure ventilation, in patients with uncomplicated acute Stanford Type B aortic dissection (TBAD). METHODS AND RESULTS: Ninety-seven patients were retrospectively analyzed and categorized into RAD (n=15) and non-RAD (n=82) groups. The mean (±SD) time to RAD initiation was 2.1±1.2 days, with a PaOto fraction of inspired oxygen (FiO) ratio of 116±53 at initiation. Compared with the non-RAD group, patients in the RAD group were younger (56.8±13.6 vs. 70.2±12.1 years; P<0.001), had higher body mass index (27.2±7.0 vs. 23.4±3.9 kg/m; P=0.003), more frequently had a completely patent false lumen (47% vs. 11%; P<0.001), and showed significantly higher white blood cell (WBC) counts the day after admission (12,580±2,899 vs. 9,589±2,917/μL; P<0.001). Multivariable logistic regression identified a WBC count ≥11,100/μL on the day after admission as an independent predictor of RAD requirement (odds ratio 6.17; 95% confidence interval 1.71-25.74; P=0.007). Structural equation modeling further supported the central role of an elevated WBC count (regression coefficient=0.184; P<0.05). CONCLUSIONS: An elevated WBC count appears to be the most influential factor associated with respiratory failure requiring RAD in patients with uncomplicated acute TBAD.
BACKGROUND: The benefits of adding aspirin to warfarin and warfarin treatment intensity for Japanese patients with mechanical valve replacement (MeVR) are unclear. METHODS AND RESULTS: This multicenter non-randomized obs...BACKGROUND: The benefits of adding aspirin to warfarin and warfarin treatment intensity for Japanese patients with mechanical valve replacement (MeVR) are unclear. METHODS AND RESULTS: This multicenter non-randomized observational study recruited 158 Japanese patients who underwent MeVR in 11 university hospitals in Kyushu and Okinawa; 74 patients were allocated to the warfarin (W) group and 84 were allocated to the warfarin plus aspirin (W+A) group. Patients were followed for a mean (±SD) of 5.0±1.9 years. The primary and secondary endpoints were mainly atherosclerotic/thrombotic and bleeding events, respectively. There was no difference in the incidence of the primary endpoint between the W and W+A groups (14% vs. 22%, respectively; P=0.13). Univariate analysis revealed a higher incidence of the secondary endpoint in the W+A than W group (35% vs. 22%; P=0.032), but the difference was not significant in multivariate analysis. For the entire cohort, the postoperative mean international normalized ratio of prothrombin time (PT-INR) was relatively low (2.1±0.3). There were no differences in the incidence of events between PT-INR <2.0 and 2.0-3.0 (primary endpoint: 21% vs. 16%, respectively [P=0.41]; secondary endpoints: 33% vs. 26%, respectively [P=0.19]). CONCLUSIONS: Adding aspirin to warfarin treatment was not superior to warfarin alone, and relatively weak warfarin treatment (PT-INR <2.0) was not necessarily associated with an increased number of events (vs. PT-INR 2.0-3.0) in Japanese patients who underwent MeVR.
BACKGROUND: The quantitative flow ratio (QFR), an angiography-based index for the assessment of coronary functional stenosis, correlates well with fractional flow reserve (FFR). In this study we explored the clinical sig...BACKGROUND: The quantitative flow ratio (QFR), an angiography-based index for the assessment of coronary functional stenosis, correlates well with fractional flow reserve (FFR). In this study we explored the clinical significance of the difference between these values, calculated by subtracting FFR from QFR (delta QFR-FFR), in patients undergoing FFR-guided elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: This retrospective analysis included patients with chronic coronary syndrome who underwent FFR-guided PCI and comprehensive coronary functional assessments, including QFR. Patients were divided into tertiles based on pre-PCI delta QFR-FFR. We compared clinical and physiological characteristics and major adverse cardiovascular events (MACE; a composite of cardiac death, myocardial infarction, stroke, and heart failure requiring admission) among the 3 groups, and evaluated delta QFR-FFR as a predictor of MACE. Among 301 patients, lower delta QFR-FFR was associated with a lower QFR pullback pressure gradient, a higher index of microcirculatory resistance, lower microvascular resistance reserve, and reduced post-PCI coronary flow reserve, whereas post-PCI FFR was similar across tertiles. MACE occurred more frequently in patients with delta QFR-FFR less than -0.060 (log-rank P=0.006). Cox regression analysis identified lower delta QFR-FFR as an independent predictor of MACE. CONCLUSIONS: Pre-PCI delta QFR-FFR correlates with microvascular dysfunction and diffuse disease patterns. A lower delta QFR-FFR predicted an increased risk of MACE after FFR-guided revascularization, highlighting its potential clinical significance as a risk stratification tool.
BACKGROUND: Improved prognosis of pulmonary arterial hypertension (PAH) has been reported from specialized facilities, though nationwide patient access to both specialized centers and initial treatment regimen in Japan r...BACKGROUND: Improved prognosis of pulmonary arterial hypertension (PAH) has been reported from specialized facilities, though nationwide patient access to both specialized centers and initial treatment regimen in Japan remains unclear. METHODS AND RESULTS: The study group comprised patients with PAH defined as having disease-specific ICD-10 code, administration of medications and diagnostic testing between 2012 and 2023 in the National Database of Health Insurance Claims. Among 13,228 patients across the country, 30.7% accessed Japan Pulmonary Hypertension Registry facilities and 23.7% were initiated with disease-specific combination therapy, though numbers varied across regions. CONCLUSIONS: Regional disparities in access to disease-specific specialized treatment for PAH need to be addressed.
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an unmet clinical need and a serious problem worldwide because of the limited therapeutic options. Moreover, the precise mechanisms of its onset or pr...BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an unmet clinical need and a serious problem worldwide because of the limited therapeutic options. Moreover, the precise mechanisms of its onset or progression remain unknown. The important role of cardiac lymphatic vessels has recently received attention, so we investigated the kinetics and role of cardiac lymphatic vessels in the setting of HFpEF and tested the therapeutic potential for therapeutic lymphangiogenesis against HFpEF. METHODS AND RESULTS: We observed the kinetics of cardiac lymphatic vessels in HFpEF induced by a 2-hit model (with a high-fat diet [HFD]+L-NAME) in wild-type mice. Cardiac lymphatic rarefaction was observed in a series of HFpEF progression. Additionally, we verified that inhibition of lymphangiogenesis aggravates cardiac remodeling and dysfunction in the HFpEF model. VCAM1-positive cardiac fibroblasts (VCFs) augmented lymphatic vessel formation and progression in the heart and the lymphangiogenic effect of VCFs were partly mediated by VEGF-C-VEGFR3 signaling, based on cellular experiments using lymphatic endothelial cells. We verified that therapeutic lymphangiogenesis with VCF implantation could ameliorate cardiac remodeling and dysfunction in HFpEF. CONCLUSIONS: Cardiac lymphatic vessels play an important role in remodeling and function in HFpEF progression. Moreover, lymphangiogenesis could be a novel therapeutic target for HFpEF.
Yamabe S, Kayama K, Tsuruta Y
… +14 more, Kawada Y, Mizoguchi T, Yokoi M, Mori K, Ito T, Matsui K, Kitada S, Goto T, Yasuda M, Kimura H, Koyama S, Shinohara T, Itatani K, Seo Y
BACKGROUND: In repaired tetralogy of Fallot (TOF) and related diseases, reoperation for pulmonary regurgitation (PR) may be delayed unless marked right ventricular (RV) enlargement is present. METHODS AND RESULTS: 32 pat...BACKGROUND: In repaired tetralogy of Fallot (TOF) and related diseases, reoperation for pulmonary regurgitation (PR) may be delayed unless marked right ventricular (RV) enlargement is present. METHODS AND RESULTS: 32 patients with significant PR post-repair underwent catheterization and 4D flow MRI for reoperation evaluation. The Non-severe RV Dilation group (n=20) did not meet the surgical volume criteria, whereas the Severe RV Dilation group (n=12) did. The Non-severe RV Dilation group had higher biventricular filling pressures. The RV-Energy loss index in both groups was high. CONCLUSIONS: Diastolic dysfunction could serve as a therapeutic target in PR patients with heterogeneous etiologies.
BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a major complication of type 2 diabetes mellitus (T2DM), but the roles of arterial stiffness and right atrial (RA) function in CAN remain unclear. METHODS AND RESU...BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a major complication of type 2 diabetes mellitus (T2DM), but the roles of arterial stiffness and right atrial (RA) function in CAN remain unclear. METHODS AND RESULTS: In 120 patients with T2DM, we assessed short-term heart rate variability (CVR-R), cardio-ankle vascular index (CAVI), and two-dimensional speckle-tracking echocardiography (2DSTE). CAN was defined as CVR-R <2%. Multivariable analysis showed that higher CAVI and lower RA function composite scores were independently associated with CAN. CONCLUSIONS: Both increased arterial stiffness and impaired RA function characterized CAN, indicating a key cardiovascular interaction. Combined CAVI and RA strain assessment may aid early detection.
Cardiac conduction is a central determinant of normal rhythm and arrhythmia susceptibility. Although arrhythmias have traditionally been attributed to abnormal automaticity, triggered activity, and re-entry, emerging evi...Cardiac conduction is a central determinant of normal rhythm and arrhythmia susceptibility. Although arrhythmias have traditionally been attributed to abnormal automaticity, triggered activity, and re-entry, emerging evidence indicates that conduction abnormalities integrate structural, electrical, and immune-derived signals into a common arrhythmogenic substrate. This review summarizes multiscale mechanisms of impulse propagation, with an emphasis on gap junction-mediated coupling. Connexin 43 (Cx43), the principal ventricular connexin, maintains intercellular current flow through phosphorylation-dependent localization at intercalated discs; its remodeling leads to conduction slowing, heterogeneous propagation, and reentrant vulnerability. Recent studies have revealed that cardiac resident macrophages preserve ventricular conduction by promoting Cx43 phosphorylation via amphiregulin-epidermal growth factor receptor signaling. Loss of this macrophage-derived pathway causes Cx43 disorganization, atrioventricular block, ventricular fibrillation, and sudden death during cardiac stress, establishing an immune-electrical interface essential for conduction stability. This review further highlights conduction abnormalities in human disease, differences between mice and humans, and insights derived from electrocardiography and advanced computational modeling. Simulations linking molecular alterations to organ-level activation patterns provide a mechanistic bridge between cellular coupling, Purkinje network integrity, fibrosis distribution, and clinical electrophysiology. Together, these findings position conduction as a dynamic, regulated property of the ventricular myocardium and suggest that targeting gap junction and immune pathways may enable future conduction-based precision cardiology.
BACKGROUND: Ischemic heart disease remains the leading cause of death worldwide, and although early coronary revascularization is essential, it can paradoxically induce additional myocardial damage known as ischemia-repe...BACKGROUND: Ischemic heart disease remains the leading cause of death worldwide, and although early coronary revascularization is essential, it can paradoxically induce additional myocardial damage known as ischemia-reperfusion (I/R) injury, driven in part by excessive generation of reactive oxygen species (ROS). This study evaluated the cardioprotective potential of resorcimoline (RML), a newly developed free radical scavenger, in mitigating ROS-mediated myocardial injury in a preclinical setting. METHODS AND RESULTS: ROS production was induced in primary cardiomyocytes through hypoxia, angiotensin II, or hydrogen peroxide treatment. The antioxidant effects of RML were assessed by cytosolic and mitochondrial ROS assays. Cell viability and cytotoxicity were evaluated by metabolic activity and lactate dehydrogenase release assays. In vivo, myocardial I/R injury was induced in rats by transient coronary artery ligation followed by reperfusion. RML significantly reduced intracellular and mitochondrial ROS levels and improved cardiomyocyte viability in vitro. Consistently, in vivo DHE staining demonstrated that RML suppressed myocardial ROS accumulation, decreased infarct size, lowered serum troponin I, reduced apoptosis, and preserved left ventricular function, whereas these protective effects were not observed without reperfusion. CONCLUSIONS: RML exerts cardioprotective effects by scavenging ROS and mitigating downstream oxidative damage in both in vitro and in vivo models of myocardial I/R injury, suggesting promise as a therapeutic agent against reperfusion-induced myocardial injury.
BACKGROUND: Congenital heart disease involving outflow tract (OFT) malformations remains a major clinical challenge, particularly in 22q11.2 deletion syndrome. Although folic acid (FA) reduces the incidence of neural tub...BACKGROUND: Congenital heart disease involving outflow tract (OFT) malformations remains a major clinical challenge, particularly in 22q11.2 deletion syndrome. Although folic acid (FA) reduces the incidence of neural tube defects, its mechanistic role in cardiac OFT development is not fully understood. METHODS AND RESULTS: Using Tbx1 hypomorphic mice as a model of 22q11.2 deletion syndrome, we investigated the effects of maternal FA supplementation on cardiac development. Pregnant dams received FA through diet or intraperitoneal injection and embryonic cardiac morphology was assessed at E15.5 and E18.5. Maternal FA administration significantly improved the persistent truncus arteriosus (PTA) phenotype, with 60% of Tbx1 embryos exhibiting a partially septated PTA (Van Praagh type A1) vs. complete PTA (type A2) in controls. Neural crest cell (NCC) migration from the neural tube into the OFT was enhanced. GFP lineage tracing confirmed the presence of increased NCCs in the OFT and reduced ectopic neuronal differentiation. Single-cell RNA-sequencing and immunohistochemistry revealed activation of the Notch and Midkine signaling pathways in NCCs following FA treatment. CONCLUSIONS: Maternal FA supplementation improved cardiac OFT malformations in Tbx1 embryos by enhancing NCC migration and fate specification, possibly mediated by Notch and Midkine signaling activation. Our findings provide mechanistic insights into the observed reduction in congenital heart defects with FA and suggest its potential as a minimally invasive prenatal intervention.
Catheter ablation has become the cornerstone therapy for cardiac arrhythmias, supported by continuous technological innovation. Since the introduction of radiofrequency (RF) ablation in the 1980s, remarkable progress, su...Catheter ablation has become the cornerstone therapy for cardiac arrhythmias, supported by continuous technological innovation. Since the introduction of radiofrequency (RF) ablation in the 1980s, remarkable progress, such as open irrigation, contact force sensing, local impedance monitoring, and index-guided ablation, has significantly improved procedural safety, reproducibility, and efficacy. In atrial fibrillation ablation, pulmonary vein isolation remains the fundamental strategy, and advances in RF technology have contributed to durable lesion formation and reduced complications. Although new non-thermal energy sources such as pulsed-field ablation (PFA) have recently emerged, RF ablation continues to play a central role in clinical practice. Its ability to provide precise lesion control and adaptability across a wide range of arrhythmia substrates, including supraventricular and ventricular tachycardias, remains unmatched. Furthermore, recent developments such as dual-energy catheters capable of delivering both RFA and PFA suggest a complementary future for both modalities. RF ablation has evolved in pursuit of greater safety and efficiency through sustained technological advancement. These innovations have improved lesion predictability and procedural outcomes, and RF ablation will remain an indispensable component of arrhythmia management in the coming era of energy diversification.
Renal denervation is a catheter-based therapy that interrupts renal sympathetic traffic and lowers blood pressure through durable neuromodulation. Contemporary catheter-based systems deliver energy to the periadventitial...Renal denervation is a catheter-based therapy that interrupts renal sympathetic traffic and lowers blood pressure through durable neuromodulation. Contemporary catheter-based systems deliver energy to the periadventitial space with an acceptable safety profile. Across blinded placebo-controlled trials in off-medication and on-medication settings, renal denervation achieves greater reductions in ambulatory and office blood pressure than placebo, with a uniform 24-h effect that includes night-time and early-morning periods. Long-term follow-up data from randomized programs and large registries show sustained separation in blood pressure between renal denervation and control groups, preserved renal function, and low re-intervention rates over several years, with select cohorts approaching a decade. This review summarizes the mechanism and target anatomy of renal denervation, key features and results of placebo-controlled trials, and practical considerations for integrating the procedure with contemporary pharmacologic therapy in patients with uncontrolled hypertension.