A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Syncope Due to Iatrogenic Cava Vein Obstruction: Rare Complication of Cardiac Implantable Electronic Device Leads.

A 77-year-old female patient with multiple pacemaker leads experienced hypotension and syncope during right heart catheterization. Imaging studies revealed a stenotic inferior vena cava with superior vena cava obstruction and well-developed retrograde collateral vessels, suggesting that balloon obstruction of the sole venous return site caused low cardiac output leading to syncope.

Novel Compound Heterozygous Variants in Trans-2,3-Enoyl-Coenzyme A Reductase-Like Gene Associated With Catecholaminergic Polymorphic Ventricular Tachycardia.

A 10-year-old female patient experienced syncope while swimming, and electrocardiography revealed polymorphic ventricular tachycardia, leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia. No pathogenic variant was identified in RYR2. Additional comprehensive genetic testing revealed novel compound heterozygous variants in trans-2,3-enoyl-coenzyme A reductase-like gene, which caused a recessive form of catecholaminergic polymorphic ventricular tachycardia.

Right Atrial Septal Lead Enhances the Favorable Effects of the Adaptive Cardiac Resynchronization Therapy Algorithm.

The adaptive cardiac resynchronization therapy (CRT) algorithm provides synchronized left ventricular pacing (sLVP). However, ensuring a high sLVP rate is challenging. We assessed the association between the sLVP rate and pacing sites in the right atrium. We evaluated 71 patients who underwent CRT and in whom the adaptive CRT algorithm was applied (53 men; mean age, 66 ± 14 years; median follow-up period, 301 days; IQR: 212-596 days). The atrial pacing leads were positioned in the right atrial (RA) septum in 17 patients (septal group) and in the RA appendage in 54 patients (RA appendage group), with significantly higher sLVP rates in the septal group compared with the RA appendage group (81% ± 30% vs 63% ± 37%; P = 0.045). In patients with first-degree atrioventricular blocks, the sLVP rates tended to be higher in the septal group. Therefore, RA septal pacing increased sLVP rates in patients undergoing CRT.

Impact of High-Voltage Device Implantation in Elderly Japanese Patients With Heart Failure as Primary Prevention　- Post Hoc Analysis of HINODE.

BACKGROUND: Despite an increased incidence of chronic heart failure (HF) and sudden cardiac death (SCD), the use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) is much lower in Japan than in Western countries. The HF Indication and SCD Prevention Trial Japan (HINODE) prospectively assessed the mortality rate, appropriately treated ventricular arrhythmias (VA), and HF in Japanese patients with a higher risk of HF.Methods and Results: HINODE consisted of ICD, CRT-defibrillator (CRT-D), pacing, and non-device treatment cohorts. This subanalysis evaluated the impact of the implantation of high-voltage devices (HVD; ICD and CRT-D) in 171 Japanese patients. We compared all-cause mortality, VA, and HF events between elderly (age >70 years at study enrollment) and non-elderly HVD recipients. The estimated survival rate through 24 months in the HVD cohort was 85.8% (97.5% lower control limit 77.6%). The risk of all-cause mortality was increased for the elderly vs. non-elderly (hazard ratio [HR] 2.82; 95% confidence interval [CI] 1.01-7.91; P=0.039), but did not differ after excluding ICD patients with CRT-D indication (HR 2.32; 95% CI 0.79-6.78; P=0.11). There were no differences in VA and HF event-free rates between elderly and non-elderly HVD recipients (P=0.73 and P=0.55, respectively). CONCLUSIONS: Although elderly patients may have a higher risk of mortality in general, the benefit of HVD therapy in this group is comparable to that in non-elderly patients.

Effect of adaptive cardiac resynchronization therapy in heart failure patients with pacemaker dependency.

BACKGROUND: An adaptive cardiac resynchronization therapy (aCRT) algorithm allows continuous adjustments of pacing timings of atrioventricular delays by periodic automatic evaluation of electrical conduction. This applies to patients with an atrioventricular block and is effective in cardiac resynchronization therapy (CRT) devices; however, whether this algorithm benefits patients with pacemaker dependency is uncertain. METHODS: This study examined the clinical impact of an aCRT algorithm in patients diagnosed with heart failure with reduced ejection fraction and pacemaker dependency. A total of 359 patients underwent CRT between January 2016 and December 2022. Patients undergoing pacemaker-dependent CRT with the aCRT algorithm function were selected. Sixty-four patients with pacemaker dependency (31 with aCRT algorithm and 33 without) were included. Pacemaker dependency was defined as the absence of spontaneous ventricular activity during the sensing test at VVI 30 bpm or prolonged atrioventricular delay (> 300 ms). The primary endpoint was the composite clinical outcome of all-cause death or hospitalization for heart failure. RESULTS: No significant differences were observed in baseline characteristics between groups. During a median follow-up of 1,067 days (interquartile range 553-1,776 days), aCRT reduced the risk of composite clinical outcomes in patients with pacemaker dependency (log-rank P = 0.028). In addition, using the aCRT algorithm was an independent predictor of the composite clinical outcomes in the multivariate analysis (hazard ratio 0.34, 95% confidence interval: 0.12-0.94, P = 0.038). CONCLUSION: The aCRT algorithm significantly reduced the risk of adverse clinical outcomes in patients with pacemaker dependency. This algorithm may be an important tool for managing such patients.

Evaluation of synchronized left ventricular pacing rate over biventricular pacing in cardiac resynchronization therapy.

BACKGROUND: The adaptive cardiac resynchronization therapy (aCRT) algorithm enables synchronized left ventricular pacing (sLVP) to achieve fusion with intrinsic right ventricular activation. Although sLVP presents benefits over biventricular pacing, the adequate sLVP rate for better clinical outcomes remains unclear. We aimed to assess the association between sLVP rates and clinical outcomes. METHODS: Our study cohort included 271 consecutive patients, who underwent CRT implantation between April 2016 and August 2021. RESULTS: We evaluated 63 patients on whom we applied the aCRT algorithm [48 men, mean age: 64 ±â€¯14 years; median follow-up period: 316 days (interquartile range: 212-809 days)]. At the 6-month follow-up after CRT implantation, the frequency of CRT responders was 71 % (n = 45). The sLVP rate was significantly higher in responders than in non-responders (75 ±â€¯30 % vs. 47 ±â€¯40 %, p = 0.003). Receiver operating characteristics curve analysis revealed that the optimal cut-off value during the sLVP rate was 59.4 % for the prediction of CRT responders (area under the curve, 0.70; sensitivity, 80 %; specificity, 61 %; positive predictive value, 84 %; and negative predictive value, 55 %). Kaplan-Meier analysis demonstrated that the higher-sLVP group (sLVP ≧59.4 %, n = 43) had a better prognosis (cardiac death and heart failure hospitalization) than the lower-sLVP group (sLVP <59.4 %, n = 20) (log-rank p < 0.001). Multivariate Cox hazard analysis revealed that a higher sLVP rate was associated with a good prognosis (p < 0.001). CONCLUSIONS: sLVP was associated with CRT response, and a higher sLVP rate (≧59.4 %) was important for good prognosis in patients with aCRT.

Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

Modified procedures of subcutaneous implantable cardioverter defibrillator implantation for a child with small body size.

Modified procedures of subcutaneous implantable cardioverter defibrillator (S-ICD) implantation for a child with a small body size are presented. This report demonstrates the feasibility of novel diagonal S-ICD lead implantation method.

Local dispersion of repolarization in the occurrence of ventricular fibrillation in Brugada syndrome: Possibility of phase 2 reentry?

To date, there have been no reports of recording epicardial electrograms at the onset of spontaneous ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). In the case of BrS, unipolar and bipolar electrogram recording on the right ventricular epicardium revealed that dispersion of repolarization with delayed potential was associated with spontaneous occurrence of VF. Phase 2 reentry associated with shortening and dispersion of action potential could have been recorded for the first time in BrS. Epicardial unipolar mapping can guide accurate and appropriate ablation for the elimination of arrhythmia substrate in J wave syndrome.

Radiofrequency Catheter Ablation for Atrial Fibrillation Patients on Hemodialysis (From the Kansai Plus Atrial Fibrillation Registry)　- Clinical Impact of Early Recurrence.

BACKGROUND: Catheter ablation (CA) for atrial fibrillation (AF) in patients on hemodialysis (HD) is reported to have a high risk of late recurrence (LR). However, the relationship between early recurrence (ER) within a 90-day blanking period after CA in AF patients and LR in HD patients remains unclear.Methods and Results: Of the 5,010 patients in the Kansai Plus Atrial Fibrillation Registry, 5,009 were included in the present study. Of these patients, 4,942 were not on HD (non-HD group) and 67 were on HD (HD group). HD was an independent risk factor for LR after the initial CA (adjusted hazard ratio 1.6; 95% confidence interval 1.1-2.2; P=0.01). In patients with ER, the rate of sinus rhythm maintenance at 3 years after the initial CA was significantly lower in the HD than non-HD group (11.4% vs. 35.4%, respectively; log-rank P=0.004). However, in patients without ER, there was no significant difference in the rate of sinus rhythm maintenance at 3 years between the HD and non-HD groups (67.7% vs. 74.5%, respectively; log-rank P=0.62). CONCLUSIONS: ER in HD patients was a strong risk factor for LR. However, even HD patients could expect a good outcome without ER after the initial CA.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Implications of ventricular arrhythmia after cardiac resynchronization therapy.

BACKGROUND: Conflicting data are available on whether ventricular arrhythmia (VA) or shock therapy increases mortality. Although cardiac resynchronization therapy (CRT) reduces the risk of VA, little is known about the prognostic value of VA among patients with CRT devices. OBJECTIVES: The purpose of this study was to evaluate the implications of VA as a prognostic marker for CRT. METHODS: We investigated 330 CRT patients within 1 year after CRT device implantation. The primary endpoint was the composite endpoint of all-cause death or hospitalization for heart failure. RESULTS: Forty-three patients had VA events. These patients had a significantly higher risk of the primary endpoint, even among CRT responders (P = .009). Fast VA compared to slow VA was associated with an increased risk of the primary endpoint (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.06-4.34; P = .035). Shock therapy was not associated with a primary endpoint (shock therapy vs antitachycardia pacing: HR 1.49; 95% CI 0.73-3.03; P = .269). The patients with VA had a lower prevalence of response to CRT (23 [53%] vs 202 [70%]; P = .031) and longer left ventricular paced conduction time (174 ± 23 ms vs 143 ± 36 ms; P = .003) than the patients without VA. CONCLUSION: VA occurrence within 1 year was related to paced electrical delay and poor response to CRT. VA could be associated with poor prognosis among CRT patients.

Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Oral anticoagulation after atrial fibrillation catheter ablation: benefits and risks.

BACKGROUND AND AIMS: Few recent large-scale studies have evaluated the risks and benefits of continuing oral anticoagulant (OAC) therapy after catheter ablation (CA) for atrial fibrillation (AF). This study evaluated the status of continuation of OAC therapy and the association between continuation of OAC therapy and thromboembolic and bleeding events according to the CHADS2 score. METHODS: This retrospective study included data from the Japanese nationwide administrative claims database of patients who underwent CA for AF between April 2014 and March 2021. Patients without AF recurrence assessed by administrative data of the treatment modalities were divided into two groups according to continuation of OAC therapy 6 months after the index CA. The primary outcomes were thromboembolism and major bleeding after a landmark period of 6 months. After inverse probability of treatment weighting analysis, the association between OAC continuation and outcomes was determined according to the CHADS2 score. RESULTS: Among 231 374 patients included, 69.7%, 21.6%, and 8.7% had CHADS2 scores of ≤1, 2, and ≥3, respectively. Of these, 71% continued OAC therapy at 6 months. The OAC continuation rate was higher in the high CHADS2 score group than that in the low CHADS2 score group. Among all patients, 2451 patients (0.55 per 100 person-years) had thromboembolism and 2367 (0.53 per 100 person-years) had major bleeding. In the CHADS2 score ≤1 group, the hazard ratio of the continued OAC group was 0.86 [95% confidence interval (CI): 0.74-1.01, P = .06] for thromboembolism and was 1.51 (95% CI: 1.27-1.80, P < .001) for major bleeding. In the CHADS2 score ≥3 group, the hazard ratio of the continued OAC group was 0.61 (95% CI: 0.46-0.82, P = .001) for thromboembolism and was 1.05 (95% CI: 0.71-1.56, P = 0.81) for major bleeding. CONCLUSIONS: This observational study suggests that the benefits and risks of continuing OAC therapy after CA for AF differ based on the patient's CHADS2 score. The risk of major bleeding due to OAC continuation seems to outweigh the risk reduction of thromboembolism in patients with lower thromboembolic risk.

Clinical Significance of Atrial Tachyarrhythmia Duration for Ventricular Arrhythmia in Patients With Cardiac Resynchronization Therapy.

BACKGROUND: Atrial tachyarrhythmias (ATAs) are reportedly associated with ventricular arrhythmias (VAs). However, little is known about the association between ATA duration and the risk of VA. We investigated the relationship between ATA duration and subsequent VA in patients with a cardiac resynchronization therapy defibrillator (CRT-D).Methods and Results: We investigated associations between the longest ATA duration during the first year after cardiac resynchronization therapy (CRT) implantation and VA and VA relevant to ATA (VAATA) in 160 CRT-D patients. ATAs occurred in 63 patients in the first year. During a median follow-up of 925 days from 1 year after CRT implantation, 40 patients experienced 483 VAs. Kaplan-Meier analysis showed a significantly higher risk of VA in patients with than without ATA in the first year (log rank P=0.0057). Hazard ratios (HR) of VA (HR 2.36, 2.10, and 3.04 for ATA >30s, >6 min and >24 h, respectively) and only VAATA (HR 4.50, 5.59, and 11.79 for ATA >30s, >6 min and >24 h, respectively) increased according to the duration of ATA. In multivariate analysis, ATA >24 h was an independent predictor of subsequent VA (HR 2.42; P=0.02). CONCLUSIONS: Patients with ATA >24 h in the first year after CRT had a higher risk of subsequent VA and VAATA. The risk of VA, including VAATA, increased with the longest ATA duration.

Fatal Arrhythmic Risks in Cardiac Sarcoidosis With Mildly Impaired Cardiac Function.

Background: The prognosis and later fatal arrhythmia in cardiac sarcoidosis (CS) with relatively preserved cardiac function were unclear. Objectives: This study aimed to evaluate the prognosis and arrhythmic events in patients with CS and mildly impaired cardiac function. Methods: Data were collected from a nationwide Japanese cohort survey conducted in 57 hospitals (n = 420); 322 patients with CS with left ventricular ejection fraction (LVEF) >35% were investigated. Results: Ventricular tachycardia (VT) manifestation was present in 50 patients (16%) and absent in 272 (84%), of whom 36 (72%) and 46 (17%), respectively, had an implantable cardioverter-defibrillator (ICD). Over a median of 5 years, 23 all-cause deaths and 31 appropriate ICD discharges were observed. In Kaplan-Meier analysis, all-cause death did not differ between patients with and without VT manifestation (P = 0.660), although appropriate ICD therapy was significantly less used in patients without VT manifestation than in those with VT manifestation (P < 0.001). Of the 272 patients without VT manifestation, 18 had ventricular arrhythmic events (VAEs), including 3 sudden cardiac deaths and 15 appropriate ICD discharges. In multivariate analysis, concomitant nonsustained ventricular tachycardia (NSVT) with atrioventricular block (AVB), lower LVEF, abnormal gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography of the heart (Ga/PET), and concomitant NSVT with abnormal Ga/PET at CS diagnosis were independent predictors of VAEs (P = 0.008, P = 0.021, P = 0.049, and P = 0.024, respectively). Conclusions: If concomitant NSVT with AVB, concomitant NSVT with abnormal Ga/PET, or abnormal Ga/PET is observed in patients with CS and mildly impaired cardiac function (LVEF >35%), ICD should be considered as primary prevention.