Background: B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are key biomarkers used for heart failure (HF) management. Although traditional auscultation lacks objective evaluation, the SSS01-series phonocardiogram enables rapid recording of heart sounds and ECG. We developed a deep-learning model to estimate plasma BNP levels from these non-invasive dynamic physiological signals, with the aim of validating the model’s performance with an external validation dataset and assessing its feasibility for clinical application.

Methods and Results: This multicenter study evaluated the estimated BNP (eBNP) model for predicting plasma BNP levels ≥100 pg/mL using 8 s of heart sound and ECG data. Validation was performed on an external validation dataset of 140 patients, achieving an area under the receiver operating characteristic curve (AUROC) of 0.895, with sensitivity and specificity of 84.3% and 82.9%, respectively. Subgroup analysis of patients with body mass index of 18.5–25 (n=127) showed more substantial predictive capability, with an AUROC of 0.959, sensitivity of 92.5%, and specificity of 84.8%.

Conclusions: The eBNP model demonstrated strong potential for non-invasive and rapid HF screening. Its simplicity and objectivity make it ideally suited for point-of-care testing, offering a promising approach for early HF diagnosis and detection monitoring of HF exacerbations. These findings, validated on datasets independent of training, highlight the model’s robustness across diverse clinical populations.

Background: The aim of this study was to retrain our existing deep learning-based fully automated aortic valve leaflets/root measurement algorithm, using computed tomography (CT) data for root dilatation (RD), and assess its clinical feasibility.

Methods and Results: 67 ECG-gated cardiac CT scans were retrospectively collected from 40 patients with RD to retrain the algorithm. An additional 100 patients’ CT data with aortic stenosis (AS, n=50) and aortic regurgitation (AR) with/without RD (n=50) were collected to evaluate the algorithm. 45 AR patients had RD. The algorithm provided patient-specific 3-dimensional aortic valve/root visualization. The measurements of 100 cases automatically obtained by the algorithm were compared with an expert’s manual measurements. Overall, there was a moderate-to-high correlation, with differences of 6.1–13.4 mm²for the virtual basal ring area, 1.1–2.6 mm for sinus diameter, 0.1–0.6 mm for coronary artery height, 0.2–0.5 mm for geometric height, and 0.9 mm for effective height, except for the sinotubular junction of the AR cases (10.3 mm) with an indefinite borderline over the dilated sinuses, compared with 2.1 mm in AS cases. The measurement time (122 s) per case by the algorithm was significantly shorter than those of the experts (618–1,126 s).

Conclusions: This fully automated algorithm can assist in evaluating aortic valve/root anatomy for planning surgical and transcatheter treatments while saving time and minimizing workload.

Background: Possible etiologies of out-of-hospital cardiac arrest (OHCA), including aortic dissection, ruptured aortic aneurysms, and pulmonary embolism, may be classified as non-cardiac causes. We investigated whether cardiac and non-cardiac OHCAs increased following the Kumamoto earthquake and whether the impact on OHCAs extended to regions far from the epicenter.

Methods and Results: We prospectively analyzed a nationwide registry of patients who experienced OHCAs between January 2013 and December 2019. Data from cases registered in 7 prefectures, including Kumamoto (Kyushu region; n=82,060), in the All-Japan Utstein Registry were analyzed for OHCAs of cardiac and non-cardiac origin. The numbers of OHCAs before and after the Kumamoto earthquake were compared using an interrupted time series analysis. The incidence of both cardiac (rate ratio [RR] 1.22) and non-cardiac (RR 1.27) OHCAs in Kumamoto Prefecture increased after the earthquake. The difference disappeared when the analysis was limited to patients with non-cardiac OHCAs with a clear cause of cardiac arrest. The number of cardiac and non-cardiac OHCAs did not increase in other prefectures within the Kyushu region.

Conclusions: The Kumamoto earthquake led to an increase in the incidence of cardiac and non-cardiac OHCAs. However, this was attenuated by increasing distance from the epicenter. Except for cardiac causes, cases complicated by earthquake-related events may include non-cardiac OHCAs due to vascular diseases that might be overlooked.

Background: This study aimed to identify risk factors associated with the implementation of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with acute myocarditis and to develop a predictive model.

Methods and Results: This retrospective study included 841 patients from 7 hospitals in Korea with biopsy-proven or clinically suspected acute myocarditis. Logistic regression analysis was used to identify the clinical characteristics of patients who required VA-ECMO and to construct a scoring system to predict the implementation of VA-ECMO. Among the study population, 217 (25.8%) patients underwent VA-ECMO. The study population was divided into training (n=621) and testing (n=220) cohorts according to participating center. The final predictive model of VA-ECMO insertion derived from the training cohort included the following: initial mean blood pressure <65 mmHg, cardiac arrest, Glasgow Coma Scale score ≤12, platelet count <100×10³/mL, pulmonary congestion on chest X-ray, QRS interval ≥120 ms, left or right bundle branch block, and left ventricular ejection fraction <40%. Using this predictive model, a β coefficient-weighted Korean Acute Myocarditis (KAM) score was developed. External validation of the predictive model and KAM score using the testing cohort showed excellent discriminant ability (areas under the curve of 0.945 and 0.921, respectively).

Conclusions: A risk scoring system based on simple clinical and laboratory parameters at initial presentation could predict the implementation of VA-ECMO and clinical course in patients with acute myocarditis.

Background: Abdominal aortic aneurysm (AAA) is a vascular disease strongly associated with immune dysregulation and metabolic disturbances. Although lactate metabolism and its associated process, lactylation, have been implicated in various diseases, their specific role in AAA pathogenesis remains poorly understood.

Methods and Results: In this study, we used a multi-faceted approach, integrating single-cell and bulk RNA data analyses, with the objective of elucidating the interrelationship between lactylation and immune response in AAA patients. The result revealed significant heterogeneity in lactylation levels across different immune cell types. Cells with higher lactylation activity exhibited markedly elevated immune response scores. Differential expression and correlation analyses identified 65 lactylation-associated genes, which were further evaluated in the bulk RNA sequencing data to assess their relationship with the immune microenvironment in patients with AAA. Using 113 combinations of machine-learning algorithms, we identified 8 lactylation-related hub genes. The immune infiltration analysis demonstrated that these genes were linked to a multitude of immune cells. The animal experiments corroborated that Tnfsf8, Hist1 h2ag, Cd79b, Cd69, and Bank1 were upregulated in the AAA group, while Rpl36a and Rps29 were downregulated in the AAA group.

Conclusions: This study highlighted a potentially critical link between lactylation and immune dysregulation in AAA, thereby advancing our comprehension of the function of lactylation in AAA.

Background: The pathogenesis of aortic aneurysm (AA) is characterized by chronic inflammation of the aortic wall, the associated accumulation of macrophages, and degradation of the extracellular matrix, including elastin. Colchicine (COL) has long been known for its anti-inflammatory effects, so in this study we investigated its effects on AA.

Methods and Results: In vitro, tumor necrosis factor (TNF)-α-stimulated macrophages and vascular smooth muscle cells (VSMCs) were treated with and without COL for 24 h. Unstimulated cells were used as controls. COL significantly reduced interleukin (IL)-1β, TNF-α, monocyte chemotactic protein (MCP)-1, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-9, and activated caspase-1 in macrophages, and increased lysyl oxdase (Lox) and tissue inhibitor of metalloproteinase (TIMP)-2 expression in VSMCs. In vivo, aged male apolipoprotein E-deficient (ApoE⁻/⁻) mice were infused with angiotensin II (Ang II) for 28 days. The mice received either normal saline (NS) or COL orally. The control group of ApoE⁻/⁻mice did not receive Ang II infusion or treatment. COL significantly suppressed aortic enlargement and reduced AA incidence by preserving elastin and decreasing IL-1β, TNF-α, MCP-1, NLRP3 inflammasome, neutrophil elastase, and myeloperoxidase expression. No significant differences were observed in the enzymatic activities of MMP-2 and MMP-9 between the 2 groups.

Conclusions: The results suggested that COL prevents AA progression in a clinically relevant model and is expected to be a novel preventive agent for AA.

Background: This study evaluated the efficacy of dual antiplatelet therapy (DAPT) on the long-term prognosis of coronary artery bypass grafting (CABG) patients with high inflammatory risk.

Methods and Results: We analyzed 2,409 patients who underwent isolated CABG between January 2001 and December 2017 and had baseline high-sensitivity C-reactive protein (hs-CRP) levels >2.0 mg/L. Patients were divided into 2 groups: those on DAPT for ≥12 months (n=545) and those on single antiplatelet therapy (SAPT; n=1,864). The primary outcome was all-cause death or myocardial infarction (MI) after CABG. Propensity score (PS) matching was used to minimize confounding factors and selection bias. During follow-up, the ≥12-month DAPT group had a significantly lower risk of the primary outcome than the SAPT group (7.5% vs. 13.3%; hazard ratio [HR] 0.42; 95% confidence interval [CI] 0.24–0.72; P=0.002). After PS matching, the incidence of the primary outcome remained lower in the DAPT group (HR 0.36; 95% CI 0.19–0.71; P=0.003). The benefit of prolonged DAPT was consistent across subgroups.

Conclusions: In CABG patients with high inflammatory risk, prolonged DAPT (≥12 months) was associated with significantly lower rates of all-cause death or MI compared with SAPT.

Background: Left heart abnormalities are risk factors for heart failure. However, echocardiography is not always available. Electrocardiograms (ECGs), which are now available from wearable devices, have the potential to detect these abnormalities. Nevertheless, whether a model can detect left heart abnormalities from single Lead I ECG data remains unclear.

Methods and Results: We developed Lead I ECG models to detect low ejection fraction (EF), wall motion abnormality, left ventricular hypertrophy (LVH), left ventricular dilatation, and left atrial dilatation. We used a dataset comprising 229,439 paired sets of ECG and echocardiography data from 8 facilities, and validated the model using external verification with data from 2 facilities. The area under the receiver operating characteristic curves of our model was 0.913 for low EF, 0.832 for wall motion abnormality, 0.797 for LVH, 0.838 for left ventricular dilatation, and 0.802 for left atrial dilatation. In interpretation tests with 12 cardiologists, the accuracy of the model was 78.3% for low EF and 68.3% for LVH. Compared with cardiologists who read the 12-lead ECGs, the model’s performance was superior for LVH and similar for low EF.

Conclusions: From a multicenter study dataset, we developed models to predict left heart abnormalities using Lead I on the ECG. The Lead I ECG models show superior or equivalent performance to cardiologists using 12-lead ECGs.

Background: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version.

Methods and Results: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients (“mimickers”) identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts’ diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating “radiologic findings of pericarditis”, “eosinophilic infiltration or lymphoid follicles”, and “probable diagnosis of extra-PA/-RPF lesions”, improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively.

Conclusions: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

Background: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan’s Intractable Disease Registry.

Methods and Results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations).

Conclusions: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

Background: Abnormal coronary microcirculation is linked to poor patient prognosis, so the aim of the present study was to assess the prognostic relevance of basal microvascular resistance (b-IMR) in patients without functional coronary stenosis.

Methods and Results: Analyses of 226 patients who underwent intracoronary physiological assessment of the left anterior descending artery included primary endpoints of all-cause death and heart failure, as well as secondary endpoints of cardiovascular death and atherosclerotic vascular events. During a median follow-up of 2 years, there were 12 (5.3%) primary and 21 (9.3 %) secondary endpoints. The optimal b-IMR cutoff for the primary endpoints was 47.1 U. Kaplan-Meier curve analysis demonstrated worse event-free survival of the primary endpoints in patients with a b-IMR below the cutoff (χ²=21.178, P<0.001). b-IMR was not significantly associated with the secondary endpoints (P=0.35). A low coronary flow reserve (CFR; <2.5) had prognostic value for both endpoints (primary endpoints: χ²=11.401, P=0.001; secondary endpoints: (χ²=6.015; P=0.014), and high hyperemic microvascular resistance (≥25) was associated only with the secondary endpoints (χ²=4.420; P=0.036). Incorporating b-IMR into a clinical model that included CFR improved the Net Reclassification Index and Integrated Discrimination Improvement for predicting the primary endpoints (P<0.001 and P=0.034, respectively).

Conclusions: b-IMR may be a specific marker of the risk of death and heart failure in patients without functional coronary stenosis.

Background: Proton pump inhibitors (PPIs) reportedly reduce upper gastrointestinal bleeding (UGIB) in patients undergoing percutaneous coronary intervention (PCI). However, whether the benefits of PPIs differ in high-risk subgroups is unknown.

Methods and Results: Among 24,563 patients undergoing first PCI in the CREDO-Kyoto registry Cohort-2 and -3, we evaluated long-term effects of PPI for UGIB, defined as GUSTO moderate/severe bleeding, in several potential high-risk subgroups. In the study population, 45.6% of patients were prescribed PPIs. Over a median 5.6-year follow-up, PPIs were associated with lower adjusted risk of UGIB (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.50–0.80; P<0.001) and a non-significant but numerically lower risk of any gastrointestinal bleeding (HR 0.84; 95% CI 0.71–1.01; P=0.06). PPIs were not associated with a lower risk of GUSTO moderate/severe bleeding (HR 1.04; 95% CI 0.94–1.15; P=0.40) or a higher adjusted risk of myocardial infarction or ischemic stroke (HR 1.00; 95% CI 0.90–1.12; P=0.97), but were associated with higher adjusted mortality risk (HR 1.18; 95% CI 1.09–1.27; P<0.001). The effects of PPIs for UGIB, myocardial infarction or ischemic stroke, and all-cause death were consistent regardless of age, sex, acute coronary syndrome, high bleeding risk, oral anticoagulant use, and type of P2Y₁₂inhibitor.

Conclusions: PPIs were associated with a lower risk of UGIB and a neutral risk of ischemic events regardless of high-risk subgroup.

Background: Resistance exercise is beneficial in patients with lower extremity arterial disease. Muscle-derived exosomes contain many types of signaling molecules, including microRNAs (miRNAs). Here, we tested the hypothesis that exosomal miRNAs secreted by growing muscles promote an angiogenic response in endothelial cells (ECs).

Methods and Results: Skeletal muscle-specific conditional Akt1 transgenic (Akt1-TG) mice, in which skeletal muscle growth can be induced were used as a model of resistance training. Remarkable skeletal muscle growth was observed in mice 2 weeks after gene activation. The protein amount in exosomes secreted by growing muscles did not differ between Akt1-TG and control mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway frequency analysis of 4,665 target genes, identified using an miRNA array miRNAs, revealed a significant increase in Akt and its downstream signaling pathway genes. Among the upregulated miRNAs, miR1, miR133, and miR206 were significantly upregulated in the serum of Akt1-TG mice. miR206 was also increased in insulin-like growth factor (IGF)-1-stimulated hypertrophied myotubes. Exogenous supplementation of exosomal miR206 to human umbilical vein ECs promoted angiogenesis, as assessed using the spheroid assay, and increased the expression of angiogenesis-related transcripts.

Conclusions: Exosomal miR206 is upregulated in the blood of Akt1-TG mice and in IGF-stimulated cultured myotubes. Exogenous supplementation of miR206 promoted an angiogenic response in ECs. Our data suggest that miR206 secreted from growing muscles acts on ECs and promotes angiogenesis.

Background: There are no sex-specific guidelines for chronic aortic regurgitation (AR). This retrospective study examined sex-specific differences and propose treatment criteria from an Asian AR cohort.

Methods and Results: Consecutive 1,305 patients with moderate-severe AR or greater at 3 tertiary centers in Taiwan and Japan (2008–2022) were identified. Study endpoints were aortic valve surgery (AVS), all-cause death (ACD), and cardiovascular death (CVD). The median follow up was 3.9 years (interquartile range 1.3–7.1 years). Compared with men (n=968), women (n=337) were older, had more advanced symptoms, more comorbidities, larger indexed aorta size (iAorta_max) and indexed left ventricular (LV) end-systolic dimension (LVESDi; P<0.001 for all). Symptomatic status was poorly correlated with the degree of LV remodeling in women (P≥0.18). Women received fewer AVS (P≤0.001) and men had better overall 10-year survival (P<0.01). Ten-year post-AVS survival (P=0.9) and the progression of LV remodeling were similar between sexes (P≥0.16). Multivariable determinants of ACD and CVD were age, advanced symptoms, iAorta_max, LV ejection fraction (LVEF), LVESDi, LV end-systolic volume index (LVESVi), and Taiwanese ethnicity (all P<0.05), but not female sex (P≥0.05). AVS was associated with better survival (P<0.01). Adjusted LVEF, LVESDi, LVESVi, and iAorta_maxcut-off values for ACD were 53%, 24.8 mm/m², 44 mL/m², and 25.5 mm/m², respectively, in women and 52%, 23.4 mm/m², 52 mL/m², and 23.2 mm/m², respectively, in men.

Conclusions: Early detection and intervention using sex-specific cut-off values may improve survival in women with AR.

Background: Brugada syndrome is a potential cause of sudden cardiac death (SCD) and is characterized by a distinct ECG, but not all patients with A Brugada ECG develop SCD. In this study we sought to examine if an artificial intelligence (AI) model can predict a previous or future ventricular fibrillation (VF) episode from a Brugada ECG.

Methods and Results: We developed an AI-enabled algorithm using a convolutional neural network. From 157 patients with suspected Brugada syndrome, 2,053 ECGs were obtained, and the dataset was divided into 5 datasets for cross-validation. In the ECG-based evaluation, the precision, recall, and F₁score were 0.79±0.09, 0.73±0.09, and 0.75±0.09, respectively. The average area under the receiver-operating characteristic curve (AUROC) was 0.81±0.09. On per-patient evaluation, the AUROC was 0.80±0.07. This model predicted the presence of VF with a precision of 0.93±0.02, recall of 0.77±0.14, and F₁score of 0.81±0.11. The negative predictive value was 0.94±0.11 while its positive predictive value was 0.44±0.29.

Conclusions: This proof-of-concept study showed that an AI-enabled algorithm can predict the presence of VF with a substantial performance. It implies that the AI model may detect a subtle ECG change that is undetectable by humans.

Background: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).

Methods and Results: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92–139] vs. 142 [121–165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110–157] vs. 142 [123–174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman’s r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76–0.96, P=0.033), whereas HDL-C was not.

Conclusions: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.

Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan.

Methods and Results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001).

Conclusions: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Background: To predict mortality in patients with acute heart failure (AHF), we created and validated an internal clinical risk score, the KICKOFF score, which takes physical and social aspects, in addition to clinical aspects, into account. In this study, we validated the prediction model externally in a different geographic area.

Methods and Results: There were 2 prospective multicenter cohorts (1,117 patients in Osaka Prefecture [KICKOFF registry]; 737 patients in Kochi Prefecture [Kochi YOSACOI study]) that had complete datasets for calculation of the KICKOFF score, which was developed by machine learning incorporating physical and social factors. The outcome measure was all-cause death over a 2-year period. Patients were separated into 3 groups: low risk (scores 0–6), moderate risk (scores 7–11), and high risk (scores 12–19). Kaplan-Meier curves clearly showed the score’s propensity to predict all-cause death, which rose independently in higher-risk groups (P<0.001) in both cohorts. After 2 years, the cumulative incidence of all-cause death was similar in the KICKOFF registry and Kochi YOSACOI study for the low-risk (4.4% vs. 5.3%, respectively), moderate-risk (25.3% vs. 22.3%, respectively), and high-risk (68.1% vs. 58.5%, respectively) groups.

Conclusions: The unique prediction score may be used in different geographic areas in Japan. The score may help doctors estimate the risk of AHF mortality, and provide information for decisions regarding heart failure treatment.

Background: Idiopathic bradyarrhythmia is considered to be due to pathological degeneration of the cardiac conduction system (CCS) during aging. There appears to have been no comprehensive genetic investigations in patients with idiopathic bradyarrhythmia.

Methods and Results: Ten autopsy cases with advanced bradyarrhythmia (6 men and 4 women; age: 70–94 years, 81.5±6.9 years; 5 cases each of sinus node dysfunction [SND] and complete atrioventricular block [CAVB]) were genetically investigated by using whole-exome sequencing. Morphometric analysis of the CCS was performed with sex-, age- and comorbidity-matched control cases. As a result, severe loss of nodal cells and distal atrioventricular conduction system were found in SND and CAVB, respectively. However, the conduction tissue loss was not significant in either the atrioventricular node or the proximal bundle of His in CAVB cases. A total of 13 heterozygous potential variants were found in 3 CAVB and 2 SND cases. Of these 13 variants, 4 were missense in the known progressive cardiac conduction disease-related genes: GATA4 and RYR2. In the remaining 9 variants, 5 were loss-of-function mutation with highly possible pathogenicity.

Conclusions: In addition to degenerative changes of selectively vulnerable areas in the heart during advancing age, the vulnerability of the CCS, which may be associated with “rare variants of small effect,” may also be a contributing factor to the degeneration of CCS, leading to “idiopathic” bradyarrhythmia.

Background: Low-invasive stereotactic body radiation therapy is a novel anti-arrhythmic strategy. The mechanisms underlying its effects against ventricular tachycardia/fibrillation (VT/VF) are gradually becoming clear, whereas those underlying atrial tachycardia/fibrillation (AT/AF) remain unknown. This study investigated the effects of carbon ion beam on gap junction expression and sympathetic innervation.

Methods and Results: Atrial and ventricular tachyarrhythmia models was established in 26 hypercholesterolemic (HC) 3-year-old New Zealand white rabbits; 12 rabbits were irradiated with a single 15-Gy carbon ion beam (targeted heavy ion irradiation [THIR]) and 14 were not (HC group). Eight 3-month-old rabbits (Young) were used as a reference group. In vivo induction frequencies in the Young, HC, and HC+THIR groups were 0%, 9.9%, and 1.2%, respectively, for AT/AF and 0%, 7.8%, and 1.2%, respectively, for VT/VF (P<0.01). The conduction velocity of the atria and ventricles on optical mapping was significantly reduced in the HC group; this was reversed in the HC+THIR group. Connexin-40 immunolabelling in the atria was 66.1–78.7% lower in the HC than Young group; this downregulation was less pronounced in the HC+THIR group (by 23.1–44.4%; P<0.01). Similar results were obtained for ventricular connexin-43. Sympathetic nerve densities in the atria and ventricles increased by 41.9–65.3% in the HC vs. Young group; this increase was reversed in the HC+THIR group.

Conclusions: Heavy ion radiation reduced vulnerability to AT/AF and VT/VF in HC elderly rabbits and improved cardiac conductivity. The results suggest involvement of connexin-40/43 upregulation and suppression of sympathetic nerve sprouting.