Lethal Arrhythmic Events Research Articles

Novel electric predictors of lethal arrhythmic event in patients with hypertrophic cardiomyopathy

Abstract Background Little is known regarding the association between electrical markers and lethal arrhythmic events (LAE) in patients with hypertrophic cardiomyopathy (HCM). This study aimed to identify the electrical predictors of LAE in adult patients with HCM. Methods This study was a retrospective analysis of patients with HCM at a single center from 1998 to 2021. LAE was defined as a composite outcome of (1) sustained ventricular arrhythmia, (2) aborted sudden cardiac death (SCD), (3) implantable cardioverter defibrillator (ICD) implantation, and (4) appropriate ICD shock. A 12-lead electrocardiography was performed at the time of diagnosis. Results A total of 611 patients with HCM were analyzed, and 48 (7.8%) experienced LAE. Patients who experienced LAE were diagnosed at a younger age and more frequently had history of ventricular arrhythmia, new-onset atrial fibrillation (AF) or non-sustained ventricular tachycardia. New-onset AF, an increase in the QTc interval, and the absence of massive LVH were associated with LAE risk. In addition to conventional markers of HCM Risk-SCD, consideration of the QTc interval and massive LVH on electrocardiography improved the prediction of LAE (area under curve 0.682 to 0.740). Further inclusion of new-onset AF, history of ventricular arrhythmia, HCM type, and left ventricular mass index improved the predictability to 0.867. Conclusion An increase in the QTc interval, the absence of a massive LVH pattern on electrocardiography (ECG), and new-onset AF were independently associated with an increased risk of LAE. Comprehensive stratification using electrical markers improves the prediction of LAE when combined with conventional markers.

Evaluating corticosteroid treatment strategies for cardiac sarcoidosis: analysis of the nationwide claims-based JROAD-DPC dataset

Abstract Background Corticosteroid-based immunosuppressive therapy is the cornerstone of treatment for cardiac sarcoidosis (CS), aimed at preventing severe adverse events including death, heart failure and lethal arrhythmic events. Nevertheless, data on the optimal initial dosing, appropriate tapering schedules, suitable maintenance dosages, and the recurrence rates among patients are insufficient. Purpose This study sought to scrutinize real-world data on corticosteroid therapy regimen for CS and to reassess optimal treatment protocols. Methods From the Japanese Diagnosis Procedure Combination database, 6,282 patients with hospitalized CS were identified between 2012 and 2022. Among them, 3,067 CS patients who were initiated on corticosteroid therapy during hospitalization were analyzed. We examined the baseline patient characteristics and treatment strategies for corticosteroid therapy, including starting dose, tapering period, maintenance dose, and their correlation with the onset of adverse events. Results The cohort had a mean age was 63±11 years, and 1,256 patients (41.0 %) were female. The starting dose of corticosteroids was 30.3±6.9 mg, with 88.6% of patients receiving a dose of ≧30 mg/day. The doses of corticosteroids at 30, 60, 90, 120, 150 and 180 days post-discharge were 21.4±9.8, 15.7±6.9, 12.2±5.7, 10.4±5.0, 9.3±4.5 and 9.0±4.6 mg, respectively. By day 180, 83.7% of the patients were maintained on ≦10 mg/day. However, 17.1 % of patients required an increase in corticosteroid dosage during the tapering course, primarily due to exacerbation of sarcoidosis. When analyzing only the group without corticosteroid escalation up to 180 days post-discharge, the average corticosteroid dose was 8.7±3.8 mg, with 95.3% of patients on ≦10 mg/day. We observed 965 re-hospitalization (31.5 %) during follow-up, with 58.8% of these patients having corticosteroid escalation to ≧30 mg, and 12.8% of patients received second-line immunosuppressive therapy, such as methotrexate. Conclusion The majority of CS patients were initiated on a corticosteroid regimen of 30 mg/day, which was subsequently tapered to below 10 mg/day by day 180. However, non-negligible number of patients experienced clinical events or relapse, underscoring the necessity for vigilant follow-up during corticosteroid therapy.Figure

Cardiac sympathetic activity and lethal arrhythmic events: insight into bell-shaped relationship between 123I-meta-iodobenzylguanidine activity and event rates

Background123I-meta-iodobenzylguanidine (mIBG) has been applied to patients with chronic heart failure (CHF). However, the relationship between 123I-mIBG activity and lethal arrhythmic events (ArE) is not well defined. This study aimed to determine this relationship in Japanese and European cohorts.ResultsWe calculated heart-to-mediastinum (H/M) count ratios and washout rates (WRs) of 827 patients using planar 123I-mIBG imaging. We defined ArEs as sudden cardiac death, arrhythmic death, and potentially lethal events such as sustained ventricular tachycardia, cardiac arrest with resuscitation, and appropriate implantable cardioverter defibrillator (ICD) discharge, either from a single ICD or as part of a cardiac resynchronization therapy device (CRTD). We analyzed the incidence of ArE with respect to H/M ratios, WRs and New York Heart Association (NYHA) functional classes among Japanese (J; n = 581) and European (E; n = 246) cohorts. We also simulated ArE rates versus H/M ratios under specific conditions using a machine-learning model incorporating 13 clinical variables. Consecutive patients with CHF were selected in group J, whereas group E comprised candidates for cardiac electronic devices. Groups J and E mostly comprised patients with NYHA functional classes I/II (95%) and II/III (91%), respectively, and 21% and 72% were respectively implanted with ICD/CRTD devices. The ArE rate increased with lower H/M ratios in group J, but the relationship was bell-shaped, with a high ArE rate within the intermediate H/M range, in group E. This bell-shaped curve was also evident in patients with NYHA classes II/III in the combined J and E groups, particularly in those with a high (> 15%) mIBG WR and with ischemic, but not in those with non-ischemic etiologies. Machine learning-based prediction of ArE risk aligned with these findings, indicating a bell-shaped curve in NYHA class II/III but not in class I.ConclusionsThe relationship between cardiac 123I-mIBG activity and lethal arrhythmic events is influenced by the background of patients. The bell-shaped relationship in NYHA classes II/III, high WR, and ischemic etiology likely aids in identifying patients at high risk for ArEs.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Cardiac SARS-CoV-2 Infection, Involvement of Cytokines in Postmortem Immunohistochemical Study.

In the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, significant attention was given to pulmonary manifestations. However, cardiac involvement is increasingly recognized as a critical factor influencing the prognosis, leading to myocardial damage, heart failure, acute coronary syndromes, potentially lethal arrhythmic events, and sudden cardiac death. Despite these findings, there is a lack of studies detailing the necroscopic, macroscopic, and microscopic cardiac changes associated with SARS-CoV-2. This study aimed to investigate the presence of SARS-CoV-2 viral proteins in cardiac tissue using immunohistochemical techniques to assess viral tropism. The analysis of cardiac tissue samples from deceased subjects, in different stages of conservation, confirmed to be positive for SARS-CoV-2 via reverse transcriptase-polymerase chain reaction (RT-PCR), showed immunopositivity for the SARS-CoV-2-NP viral antigen in 33% of cases. Notably, the presence of leukocyte infiltrates sufficient for diagnosing lymphocytic myocarditis was not observed. The central proinflammatory cytokines involved in the pathogenetic mechanism of coronavirus disease 19 (COVID-19) were researched using the immunohistochemical method. A significant increase in cytokine expression was detected, indicating myocardial involvement and dysfunction during SARS-CoV-2 infection. These findings suggest that the immunohistochemical detection of SARS-CoV-2 viral antigens and inflammatory cytokine expression in cardiac tissue could be crucial for a proper forensic assessment of the cause of death, even in sudden cardiac death.

Calmodulinopathy in Japanese Children - Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

Characteristics, clinical presentation and treatment in older patients with cardiac sarcoidosis

Abstract Background Patients with cardiac sarcoidosis have high risks of heart failure and lethal arrhythmic events, and often require comprehensive therapies including medications for heart failure, anti-arrhythmic drugs, and immunosuppressive therapy in addition to implantable device therapies. However, controversy exist whether these treatments should be applied to the elderly patients. Purpose The aim of this study was to investigate whether older age affects treatment strategy in patients with cardiac sarcoidosis. Methods A total of 4,566 patients with hospitalized cardiac sarcoidosis were identified from the Japanese diagnosis procedure combination database from 2012 to 2020. Among them, we analyzed 1,946 patients who were initiated corticosteroid therapy during the hospitalization. Patients’ characteristics and treatment including starting dose of corticosteroid therapy were compared between patients aged ≧ 70 years and those with < 70 years. Results A mean age was 63±11 years, and 1,256 patients (64.5 %) were female. Older patients (age ≧ 70 years , n = 599 [30.8%]) had lower BMIs (22.4±3.7 vs 23.1±4.1 kg/m2, p = 0.001), and higher prescription rates of diuretics (268 [44.7 %] vs 488 [36.2%], p<0.001) , calcium channel broker (162 [27.1%] vs 195 [14.5%], p<0.001), anti-diabetes drugs (204 [34.1%] vs 344 [25.5%], p<0.001), statin (252 [42.1%] vs 461 [34.2%], p = 0.001), anti-coagulant therapy (322 [53.8%] vs 658 [48.9%], p = 0.050), and anti-platelet therapy (119 [19.9%] vs 106 [7.9%], p<0.001). There were no significant differences regarding beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, mineralocorticoid receptor antagonists, SGLT-2 inhibitors, amiodarone, and immunosuppressive therapies except for corticosteroids. The starting dose of corticosteroids were significantly lower in the older group (37 vs 46 mg/day, p<0.001). In addition, older patients were associated with a higher risk of hospitalization due to acute decompensated heart failure (53 [8.9%] vs 78 [5.8%], p = 0.014), while patients with age <70 years had a higher risk of fatal ventricular arrhythmia (11 [1.8%] vs 49 [3.6 %], p = 0.033). Thirty days mortality and the prevalence of cardiac resynchronization therapy were similar between both groups (5 vs 3, p = 0.064; 2 [2.4%] vs 71 [3.8%], p = 0.768, respectively). Conclusion Older patients with cardiac sarcoidosis tended to be treated with lower doses of corticosteroids, and were more likely to admit due to heart failure exacerbation, while the risks of arrhythmic events were higher in the younger group.

Late ventricular potential for risk prediction of sudden cardiac death risk: a valuable tool or an unnecessary step?

Abstract Background/Introduction Signal-averaged electrocardiography (SA-ECG) is a high-resolution electrocardiography that can detect late ventricular potential, which known to be a noninvasive tool for risk stratification of sudden cardiac death (SCD) by predicting reentrant ventricular tachyarrhythmia. There is a paucity of data with SA-ECG on SCD survivors without structural heart disease, whereas majority of previous studies had been focused on post myocardial infarction survivors. Purpose This study assessed the clinical utility of SA-ECG as a risk stratification modality for lethal arrhythmic event in patients at risk of SCD without definite structural heart disease. Methods Total 629 patients who experienced or had potential risk of SCD were studied with SA-ECG. Among them, 48 patients who were found to have significant structural heart disease were excluded, except arrhythmogenic right ventricular cardiomyopathy. Major arrhythmic event (MAE) was defined as composite of all-cause death, aborted SCD, and sustained VT during any time either before visit of clinic or during follow up period. Syncope and non-sustained VT was defined as non-major arrhythmic event. SA-ECG was defined positive when fulfilling three or more criterion: (1) unfiltered QRS duration ≥114ms, (2) filtered QRS duration ≥114ms, (3) duration of terminal QRS <40uV exceeding 40ms, and (4) root mean square voltage in the terminal 40ms of ≤20ms. Results Among total 581 patients, 145 patients with positive SA-ECG showed higher incidence of MAE compared to patients with negative SA-ECG (21.4% vs. 6.7%, OR 3.816 [95% CI 2.208–6.597], p<0.001, Table). As the number of positive SA-ECG criteria increases, incidence of MAE tended to increase sequentially, which was markedly noted from 2 positive to 3 positive criteria (10.7% to 20.8%, p<0.001, Figure). In particular, patient with inherited arrhythmia showed higher rate of positive late potential compared to those with non-inherited arrhythmia (51.0% vs. 19.3%, p<0.001). Conclusion This study showed that at least 3 out of 4 diagnostic criteria in SA-ECG can independently predict lethal arrhythmic events and the positive late potential was associated with lethal arrhythmic event that leads to SCD, suggesting risk prediction for SCD using SA-ECG in patients even without structural heart disease including inherited arrhythmias. Funding Acknowledgement Type of funding sources: None.

Different prognosis of ARVC patients between DSG2 and PKP2 variant carriers

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. In Europe and North America, pathogenic variants in PKP2 were identified in most of the ARVC patients. On the other hand, we have reported that the genetic backgrounds of ARVC in Japanese were different from those in European; pathogenic variants in DSG2 were predominant in Japanese. Genotype-phenotype correlations, however, have not been clarified yet. Purpose In this study, we aimed to examine whether the genotype affect the phenotype and outcome in Japanese ARVC patients. Methods and results This study included 167 Japanese ARVC patients who received genetic testing (128 males [77%]). Their median age at diagnosis was 44 [24–55] years old and median follow-up duration was 10 [4–21] years. We found 90 patients with pathogenic variants: 52 in DSG2 (31%), 30 in PKP2 (18%), 3 in DSP (1.8%), 1 in DSC (0.6%), 1 in JUP (0.6%) and 3 in DES (1.8%). The age of the first sustained ventricular arrhythmia (SVT) were older in the patients with DSG2 than those with PKP2 variants (48±15 years vs. 35±15 years, P=0.008) but younger in DSG2 variant carriers at the first hospitalization for heart failure (41 [22–61] years vs. 67 [61–74] years, P=0.03). The left ventricular ejection fractions of DSG2 variant carriers were significantly lower at diagnosis than that of PKP2 (52 [41–60] % vs. 61 [56–66] %, P=0.002). Kaplan-Meier survival curve for lethal arrhythmic events including SVT, ventricular fibrillation and sudden death revealed that the event rate of DSG2 variant carriers was significantly lower than that of PKP2 (log-rank test, P=0.02) (Fig. 1). Among 11 patients who had both SVT and hospitalizations for HF, 7 PKP2 variant carriers had SVT first, then, hospitalized for HF (48 [35–53] years and 67 [55–71] years, P=0.02). Contrary, the clinical course of 4 DSG2 variants carriers were different from those with PKP2 (54 [40–68] years for SVT and 65 [56–70, P=0.1] years for HF) (Fig. 2). Conclusion The patients with DSG2, which is the major causative gene for ARVC in Japanese, show different phenotype and outcome from those with PKP2. We should examine the effect of variants on the prognosis of ARVC patients in more large population including various ethnics. Funding Acknowledgement Type of funding sources: None.

External validation study of the 2014 European Society of Cardiology Guidelines in relation to 2020 ACC/AHA guidelines on sudden cardiac death prevention in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Strategies for reliable selection of high-risk hypertrophic cardiomyopathy (HCM) patients for prevention of sudden cardiac death (SCD) with implantable cardioverter-defibrillators (ICDs) are still debated. Purpose Assess the sensitivity of sudden death risk strategies (2014 ESC SCD 5-year risk score and 2020 ACC/AHA risk factor strategy) in predicting lethal arrhythmic events (LAE), appropriate ICD shocks, SCD or out of hospital cardiac arrest among a cohort of HCM patients Methods Sixty-five patients (42±17 y) with a clinical diagnosis of HCM were enrolled in our institution from 1990 to 2021. Among them, 28 patients (43%) underwent a genetic test and a pathogenic/likely pathogenic sarcomeric variant was detected in 23 cases (82%). Patients were managed according to the best available treatment strategy for HCM in the different clinical eras. Results Of the 65 patients, 28 cases (43%) received an ICD, including 23 for primary and 5 for secondary prevention. During a follow-up period of 15 years (median, 15 [6, 21], range 1 to 33 years, 1014 patients/year), a total of 10 LAE were observed (0.98%/year). According to ESC SCD 5-year Risk Score, 7 (10%) were at high risk, 14 (22%) at intermediate to high risk, and 44 (68%) at low risk. Median SCD 5-year risk score of 3.5% ± 2.1. ACC/AHA risk factors categorized patients as 35 (54%) at high risk, 24 (37%) at intermediate to high risk, and 6 (9%) at low risk. A total of 4 (2.8%) patients experiencing SCD events were misclassified as low-risk patients by the ESC SCD Risk Score, whereas none by the ACC/AHA model. Of the 7 patients categorized as high risk by the ESC SCD Risk Score, 2 (29%) experienced a LAE, whereas of the 35 patients at high risk by the ACC/AHA, 9 (26%) suffered a LAE. No difference in the area under the curve was showed for the 2020 ACC/AHA SCD risk stratification strategies with respect to 2014 ESC SCD 5-year-risk score (0.72; 95% CI 0.60–0.83, 0.66; 95% CI 0.49–0.84, p =0.55). Conclusions In this HCM cohort followed up over an extended period of more than 15 years, LAE remained relatively low (0.98%/year). SCD risk stratification recommended by the 2014 ESC SCD 5 year risk score did not showed a better discrimination than that of 2020 ACC/AHA stratifications, despite the latter proved to be more sensible in the identification of the low risk patients. More than half of our cohort was classified with a recommendation by the 2020 ACC/AHA for an ICD implantation. A larger multicenter, independent, and prospective study with long-term follow-up is warranted to better elucidate these results.

School-based routine screenings of electrocardiograms for the diagnosis of long QT syndrome.

School-based routine screenings of electrocardiograms (ECGs) have been performed upon admission to primary school (PS), junior high school (JHS), and high school (HS) in Japan. Though ECGs with prolonged QT intervals are occasionally found, the role of regular ECG screening tests in identifying long QT syndrome (LQTS) remains to be determined. We investigated the usefulness of the ECG screenings by comparing the results of genetic tests between students who showed QT-prolongation in the screenings and patients with LQTS. We genetically screened 341 students (106 PS, 173 JHS, and 62 HS). Of these, 230 subjects showed QT-prolongation during regular screenings (S-S group), and the other 111 patients were clinically consulted with suspected LQTS by paediatricians (C-C group). Genotype-phenotype relationships were compared between the two groups. The positive rates in the genetic tests were comparable among the two groups; however, symptomatic subjects were significantly fewer in the S-S group than the C-C group (3% vs. 70%). Compared to the genotype-negative subjects, the positive subjects showed significantly longer QTc (P < 0.0001) and more frequently presented LQTS risk scores with ≥3.5 points (P < 0.0001). Lethal arrhythmic events (LAE) occurred only in the C-C group; 18 subjects experienced LAE and 83% of them were found to carry variant(s) in the LQTS-related genes. The school-based ECG screenings are effective in identifying young patients with LQTS who require genetic analysis. If individuals are screened at a younger age, we can identify patients at risk earlier and provide preventative treatments.

Prognostic Relevance of a Score for Identifying Diastolic Dysfunction according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging Recommendations in Patients with Hypertrophic Cardiomyopathy

In hypertrophic cardiomyopathy (HCM), one of the main pathophysiological features is diastolic dysfunction. According to the 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) recommendations, diastolic function is assessed with echocardiographic variables. However, the association between the ASE/EACVI recommendations and the outcome in patients with HCM remains unclear. We evaluated the prognostic implications of the ASE/EACVI recommendations in patients with HCM. This study included 290 patients with HCM. We evaluated four variables for identifying diastolic dysfunction using the following abnormal cutoff values: septal e' < 7cm/sec, septal E/e' ratio > 15, left atrial volume index > 34mL/m2, and peak tricuspid regurgitation velocity > 2.8m/sec. A score was developed in which one point was designated for each abnormal echo parameter of diastolic function. We divided patients into two groups with an ASE/EACVI score of 3 as the cutoff value. The primary endpoint was the combination of HCM-related adverse outcomes (combination of sudden death or potentially lethal arrhythmic events, heart failure-related death, and heart failure hospitalization). The prevalence of an ASE/EACVI score ≥3 was 37.2%. Over a median follow-up of 9.7 (6.9-12.9) years, 26 (24.1%) patients with an ASE/EACVI score ≥3 and 25 (13.7%) patients with an ASE/EACVI score <3 experienced a combination of HCM-related adverse outcomes. Patients with an ASE/EACVI score ≥3 had a significantly higher incidence of the combined endpoint than those with an ASE/EACVI score <3 (log-rank, P=.010). An ASE/EACVI score ≥3 was an independent determinant of the combined endpoint in multivariate analysis (adjusted hazard ratio=1.92; 95% CI, 1.05-3.49; P=.033). The score for identifying diastolic dysfunction by following ASE/EACVI recommendations may be associated with an adverse outcome in patients with HCM.

Abstract 9177: Prognostic Value of Chronic Kidney Disease and Cardiac Sympathetic Dysfunction Assessed by 123 I-metaiodobenzylguanidine Scintigraphy for Lethal Arrhythmic Events in Chronic Heart Failure

Introduction: Clinical implication of chronic kidney disease (CKD) and cardiac sympathetic nerve activity (CSNA) for lethal arrhythmic events has not been fully elucidated in patients with chronic heart failure (CHF). Hypothesis: The combination of CKD and abnormal CSNA, assessed by 123 I-metaiodobenzylguanidine ( 123 I-MIBG) scintigraphy, may provide useful prognostic information for the incidence of lethal arrhythmic events. Methods: We studied 165 consecutive hospitalized CHF patients without dialysis. In a clinically stable condition, cardiac 123 I-MIBG scintigraphy was performed. CKD was defined as estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73m 2 , and abnormal CSNA was defined as late heart to mediastinum ratio &lt;1.6. We then investigated the incidence of lethal arrhythmic events (sustained ventricular arrhythmia, appropriate implantable cardioverter-defibrillator therapy, or sudden cardiac death). Results: During a median follow-up of 5.3 years, lethal arrhythmic events were observed in 40 patients (24.2%). The patients were divided into 4 groups according to the presence of CKD and CSNA abnormality: non-CKD/ normal CSNA ( n = 52), CKD/ normal CSNA ( n = 39), non-CKD/ abnormal CSNA ( n = 33), and CKD/ abnormal CSNA ( n = 41).The Kaplan-Meier analysis showed that CKD/ abnormal CSNA had the highest event rate (log-rank p = 0.004). In addition, the multivariable Cox proportional hazard analysis after the adjustment of multiple confounders showed that CKD/ abnormal CSNA was an independent predictor for lethal arrhythmic events compared to non-CKD/ normal CSNA (HR, 4.667, p = 0.006). However, the other two groups did not show significant differences compared to non-CKD/ normal CSNA. Conclusions: The combination of CKD and abnormal CSNA, assessed by cardiac 123 I-MIBG scintigraphy, had a significant prognostic value for the incidence of lethal arrhythmic events in patients with CHF.

Protocolo diagnóstico de las canalopatías

Channelopathies are a set of anomalies that affect cellular ion channels. Although they can be acquired, those which are most cardiologically relevant are of genetic origin. They affect certain channels of the myocytes or the specific cardiac conduction system. Although their prevalence may not be very high, their clinical repercussions are very important, because most of them are associated with the onset of polymorphic ventricular tachycardias and sudden death, many times in children and young adults. The baseline ECG has a key diagnostic role as it is the phenotypic/electrical expression of the affected channels, giving rise on many occasions to anomalies in the J point, ST segment, T wave, or QT interval. The diagnosis of the affected genes is another key element in its management, given the possible familial repercussions. Therapeutic management can be both primary, for preventing lethal arrhythmic events, and secondary, if the patient has survived one. For many, an implantable automatic defibrillator is a first-line indication.

Predictive impacts of chronic kidney disease and cardiac sympathetic nervous activity on lethal arrhythmic events in chronic heart failure.

BackgroundThe clinical implications of chronic kidney disease (CKD) and cardiac sympathetic nervous activity (CSNA) regarding lethal arrhythmic events have not yet been fully elucidated in patients with chronic heart failure (CHF). We hypothesized that the combination of CKD and abnormal CSNA, assessed by 123I‐metaiodobenzylguanidine (123I‐MIBG) scintigraphy, may provide useful prognostic information for lethal arrhythmic events.MethodsWe studied 165 consecutive hospitalized CHF patients without dialysis. Cardiac 123I‐MIBG scintigraphy was performed in a clinically stable condition, and abnormal CSNA was defined as a late heart‐to‐mediastinum ratio of <1.6. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m2. We then investigated the incidence of lethal arrhythmic events (sustained ventricular tachyarrhythmia, appropriate implantable cardioverter‐defibrillator therapy, or sudden cardiac death).ResultsDuring a median follow‐up of 5.3 years, lethal arrhythmic events were observed in 40 patients (24.2%). The patients were divided into four groups according to the presence of CKD and CSNA abnormality: non‐CKD/normal CSNA (n = 52), CKD/normal CSNA (n = 39), non‐CKD/abnormal CSNA (n = 33), and CKD/abnormal CSNA (n = 41). Kaplan–Meier analysis showed that CKD/abnormal CSNA had the highest event rate (log‐rank p = .004). Additionally, the Cox proportional hazard analysis revealed that CKD/abnormal CSNA was a predictor for lethal arrhythmic events compared with non‐CKD/normal CSNA (hazard ratio, 5.368, p = .001). However, the other two groups did not show significant differences compared with the non‐CKD/normal CSNA group.ConclusionsThe combination of CKD and abnormal CSNA, assessed by 123I‐MIBG scintigraphy, had a high predictive value for lethal arrhythmic events in patients with CHF.

Early onset of heart failure in Japanese ARVC patients with pathogenic desmosomal gene variants

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. Although there are a lot of reports regarding to European ARVC patients, the ones in Asian are a few, and the characteristics of Asian ARVC have been still unclear. We have reported that the genetic backgrounds in Japanese ARVC patients were different from those in European ones. In this study, we aimed to examine the phenotype and outcome of Japanese ARVC patients with specific genetic backgrounds. Methods and results This study included 104 Japanese ARVC patients who were diagnosed as definite in the 2010 Task Force Criteria for ARVC and received genetic analysis (79 males [76%]; median age at diagnosis, 40 years [IQR 22–53 years].) Fifty-seven patients carried variants in desmosomal genes classified as pathogenic based on ACMG guideline: 30 in DSG2 (29%), 22 in PKP2 (21%), 2 in DSC2 (2%) and 3 in DSP (3%). The median age of diagnosis was significantly younger in the patients with the pathogenic variants than in those without (37 years [IQR 21–49 years] vs. 46 years [IQR 34–58 years], P=0.01). During a median follow-up of 9.3 years (IQR 3.5–20.9 years), 10 patients died and 2 were received heart transplantation. Sixty-two suffered lethal arrhythmic events including cardiopulmonary arrest, ventricular fibrillation, sustained ventricular tachycardia and appropriate shocks by implantable cardioverter defibrillator. Twenty-two were hospitalized for heart failure. There was no difference in these events rate between the two groups. However, survival analysis revealed that patients with pathogenic variants hospitalized for heart failure significantly earlier in their life than those without (P=0.04, log-rank test, Figure 1). Conclusions The Japanese ARVC patients with pathogenic variants in desmosomal genes are diagnosed and hospitalize for heart failure at younger age than those without. These findings have not been reported in other ethnics. Our study warns that we should be cautious for not only the prevention of lethal arrhythmic events but also the progress of the heart failure in Japanese ARVC patients with pathogenic variants. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Japan Agency for Medical Research and Development Figure 1

Functionally validated SCN5A variants allow interpretation of pathogenicity and prediction of lethal events in Brugada syndrome.

The prognostic value of genetic variants for predicting lethal arrhythmic events (LAEs) in Brugada syndrome (BrS) remains controversial. We investigated whether the functional curation of SCN5A variations improves prognostic predictability. Using a heterologous expression system and whole-cell patch clamping, we functionally characterized 22 variants of unknown significance (VUSs) among 55 SCN5A mutations previously curated using in silico prediction algorithms in the Japanese BrS registry (n = 415). According to the loss-of-function (LOF) properties, SCN5A mutation carriers (n = 60) were divided into two groups: LOF-SCN5A mutations and non-LOF SCN5A variations. Functionally proven LOF-SCN5A mutation carriers (n = 45) showed significantly severer electrocardiographic conduction abnormalities and worse prognosis associated with earlier manifestations of LAEs (7.9%/year) than in silico algorithm-predicted SCN5A carriers (5.1%/year) or all BrS probands (2.5%/year). Notably, non-LOF SCN5A variation carriers (n = 15) exhibited no LAEs during the follow-up period. Multivariate analysis demonstrated that only LOF-SCN5A mutations and a history of aborted cardiac arrest were significant predictors of LAEs. Gene-based association studies using whole-exome sequencing data on another independent SCN5A mutation-negative BrS cohort (n = 288) showed no significant enrichment of rare variants in 16985 genes including 22 non-SCN5A BrS-associated genes as compared with controls (n = 372). Furthermore, rare variations of non-SCN5A BrS-associated genes did not affect LAE-free survival curves. In vitro functional validation is key to classifying the pathogenicity of SCN5A VUSs and for risk stratification of genetic predictors of LAEs. Functionally proven LOF-SCN5A mutations are genetic burdens of sudden death in BrS, but evidence for other BrS-associated genes is elusive.

Calmodulinopathy in inherited arrhythmia syndromes.

Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that controls and regulates key cellular functions. In all vertebrates, three CaM genes located on separate chromosomes encode an identical 149 amino acid protein, implying an extraordinarily high level of evolutionary importance and suggesting that CaM mutations would be possibly fatal. Inherited arrhythmia syndromes comprise a spectrum of primary electrical disorders caused by mutations in genes encoding ion channels or associated proteins leading to various cardiac arrhythmias, unexplained syncope, and sudden cardiac death. CaM mutations have emerged as an independent entity among inherited arrhythmia syndromes, referred to as calmodulinopathies. The most common clinical presentation associated with calmodulinopathy is congenital long QT syndrome, followed by catecholaminergic polymorphic ventricular tachycardia, both of which significantly increase the possibility of repeated syncope, lethal arrhythmic events, and sudden cardiac death, especially in young individuals. Here, we aim to give an overview of biochemical and structural characteristics of CaM and progress toward updating current known CaM mutations and associated clinical phenotypes. We also review the possible mechanisms underlying calmodulinopathy, based on several key in vitro studies. We expect that further experimental studies are needed to explore the complexity of calmodulinopathy.

Effect of Renal Dysfunction on Risk of Sudden Cardiac Death in Patients With Hypertrophic Cardiomyopathy

Renal dysfunction is a known risk of sudden cardiac death in patients with ischemic heart disease. However, the association between renal dysfunction and sudden death in hypertrophic cardiomyopathy (HC) patients remains unknown. This study investigated the significance of an impaired renal function for the sudden death risk in a cohort of patients with HC. We included 450 patients with HC (mean age 52.9 years, 65.1% men). The estimated glomerular filtration rate (eGFR) was evaluated at the time of the initial evaluation. Renal dysfunction was defined as an eGFR <60 ml/min/1.73 m2. Renal dysfunction was found in 171 patients (38.0%) at the time of enrollment. Over a median (IQR) follow-up period of 8.8 (5.0 to 12.5) years, 56 patients (12.4%) experienced the combined end point of sudden death or potentially lethal arrhythmic events, including 20 with sudden death (4.4%), 11 resuscitated after a cardiac arrest, and 25 with appropriate implantable defibrillator shocks. Patients with renal dysfunction were at a significantly higher risk of sudden death (Log-rank p = 0.034) and the combined end point (Log-rank p <0.001) than patients without renal dysfunction. After adjusting for the highly imbalanced baseline variables, the eGFR remained as an independent correlate of the combined end point (adjusted hazard ratio: 1.24 per 10 ml/min decline in the eGFR; 95% confidence interval 1.04 to 1.47; p = 0.013). In conclusion, an impaired renal function may be associated with an incremental risk of sudden death or potentially lethal arrhythmic events in patients with HC.

Remote monitoring can predict lethal arrhythmic events through time-domain analysis of heart rate variability in patients with implantable cardioverter defibrillator

Abstract Background We prospectively collected device and heart rate data, i.e. heart rate variability (HRV), through remote monitoring (RM) of patients with implantable cardioverter defibrillator (ICD). Several studies have demonstrated usefulness of RM in implanted device patients, however, reports concerning the predictors of lethal ventricular arrhythmias are limited. Purpose The objective was to identify the predictors of lethal arrhythmic events (VT/VF). Methods Thirty-three patients (mean age: 50 years) with ICDs [with functionality of HRV analysis] were divided into 2 groups [VT/VF(+), VT/VF(−)]. Clinical, device (ventricular lead impedance; amplitude of ventricular electrogram), and HRV data were compared between the 2 groups. As the index of time-domain HRV analysis, NN intervals-index (SDNNi) was calculated for every 5 minutes, and the mean, maximum, and minimum SDNNi during the 24-hour period were used. Results During the observation period (median 12 months), 10 patients experienced VT/VF events. In HRV data, the mean, max, and min SDNNi were higher in VT/VF(+) than VT/VF(−) group (132.9±9.3 v.s. 93.5±6.1, p=0.0013; 214.6±10.6 v.s. 167.0±7.0, p=0.0007; 71.2±7.5 v.s. 43.9±4.9, p=0.0047). The other parameters did not exhibit significant difference. On logistic regression analysis, the mean SDNNi of 100.1, max SDNNi of 185.0 and min SDNNi of 52.0 as cut-off values for prediction of VT/VF event demonstrated significant receiver operating characteristics (ROC) curves (AUC=0.86, p=0.0007; AUC=0.84, p=0.0005; AUC=0.78, p=0.0030). Furthermore, in cases of VT/VF(+) group, the max ΔSDNNi, i.e., difference from baseline SDNNi, and min ΔSDNNi in 7 and 28 days preceding VT/VF events exhibited time course changes in comparison with baseline values. They were significant predictors of VT/VF events (max ΔSDNNi cut-off: 46.8, AUC=0.91, p=0.0002; min ΔSDNNi cut-off: −42.4, AUC=0.88, p=0.0014). Conclusion Time-domain analysis of HRV through RM may help identify patients at high risk of lethal arrhythmic events, and predict occurrence of such arrhythmic events. Funding Acknowledgement Type of funding source: None