Genetic Burden of TNNI3K in Diagnostic Testing of Patients With Dilated Cardiomyopathy and Supraventricular Arrhythmias

BACKGROUND: Genetic variants in TNNI3K (troponin-I interacting kinase) have previously been associated with dilated cardiomyopathy (DCM), cardiac conduction disease, and supraventricular tachycardias. However, the link between TNNI3K variants and these cardiac phenotypes shows a lack of consensus concerning phenotype and protein function. METHODS: We describe a systematic retrospective study of a cohort of patients undergoing genetic testing for cardiac arrhythmias and cardiomyopathy including TNNI3K. We further performed burden testing of TNNI3K in the UK Biobank. For 2 novel TNNI3K variants, we tested cosegregation. TNNI3K kinase function was estimated by TNNI3K autophosphorylation assays.RESULTS: We demonstrate enrichment of rare coding TNNI3K variants in DCM patients in the Amsterdam cohort. In the UK Biobank, we observed an association between TNNI3K missense (but not loss-of-function) variants and DCM and atrial fibrillation. Furthermore, we demonstrate genetic segregation for 2 rare variants, TNNI3K-p.Ile512Thr and TNNI3K-p.His592Tyr, with phenotypes consisting of DCM, cardiac conduction disease, and supraventricular tachycardia, together with increased autophosphorylation. In contrast, TNNI3K-p.Arg556_Asn590del, a likely benign variant, demonstrated depleted autophosphorylation. CONCLUSIONS: Our findings demonstrate an increased burden of rare coding TNNI3K variants in cardiac patients with DCM. Furthermore, we present 2 novel likely pathogenic TNNI3K variants with increased autophosphorylation, suggesting that enhanced autophosphorylation is likely to drive pathogenicity.</p

ECG Quantification of Myocardial Scar Does Not Differ between Primary and Secondary Prevention ICD Recipients with Ischemic Heart Disease

Background: Myocardial scar is an anatomic substrate for potentially lethal arrhythmias. Recent study showed that higher QRS-estimated scar size using the Selvester QRS score was associated with increased arrhythmogenesis during electrophysiologic testing. Therefore, QRS scoring might play a potential role in risk stratification before implantable cardioverter defibrillator (ICD) implantation. In this study, we tested the hypothesis that QRS scores among ICD recipients for secondary prevention are higher than QRS scores in primary prevention patients. Methods and Results: From the hospital database, 100 consecutive patients with ischemic heart disease and prior ICD implantation were selected. Twelve-lead electrocardiograms (ECGs) had been obtained before implantation. ECGs were scored following the 32-points Selvester QRS scoring system and corrected for underlying conduction defects and/or hypertrophy. Ninety-three ECGs were suitable for scoring; seven ECGs were rejected because of noise, missing leads, excessive ventricular extrasystoles, or ventricular pacing. No statistically significant difference in QRS score was found between the primary [6.90 (standard deviation [SD] 3.94), n = 63] and secondary prevention group [6.17 (SD 4.50) (P = 0.260), n = 30]. Left ventricular ejection fraction (LVEF) was significantly higher in the secondary prevention group [31% (SD 13.5) vs 24% (SD 11.7) (P = 0.015)]. When patients with LVEF ≥35% were excluded, QRS scores were still comparable, namely 7.02 (SD 4.04) in the primary prevention group (n = 52) and 6.28 (SD 4.24) in the secondary (P = 0.510) (n = 18). Conclusion: We found no significant difference in QRS score between the ischemic primary and secondary prevention groups. Therefore, a role of the Selvester QRS score as a risk stratifier remains unlikely. (PACE 2010; 33:192–197

Scar tissue and microvolt T-wave alternans

Microvolt T-wave alternans (MTWA) is an electrocardiographic marker for predicting sudden cardiac death. In this study, we aimed to study the relation between MTWA and scar assessed with cardiac magnetic resonance imaging (CMR) in patients with ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM). Sixty-eight patients with positive or negative MTWA and analysable CMR examination were included. Using CMR and the delayed enhancement technique, left ventricular ejection fraction (LVEF), volumes, wall motion and scar characteristics were assessed. Overall, positive MTWA (n = 40) was related to male gender (p = 0.04), lower LVEF (p = 0.04) and increased left ventricular end-diastolic volume (LVEDV) (p < 0.01). After multivariate analysis, male gender (p = 0.01) and lower LVEF remained significant (p = 0.02). Scar characteristics (presence, transmurality, and scar score) were not related to MTWA (all p > 0.5). In the patients with ICM (n = 40) scar was detected in 38. Positive MTWA (n = 18) was related to higher LVEDV (p = 0.05). In patients with DCM (n = 28), scar was detected in 11. Trends were found between positive MTWA (n = 15) and male gender (p = 0.10), lower LVEF (p = 0.10), and higher LVEDV (p = 0.09). In both subgroups, the presence, transmurality or extent of scar was not related to MTWA (all p > 0.45). In this small study, neither in patients with ICM or DCM a relation was found between the occurrence of MTWA and the presence, transmurality or extent of myocardial scar. Overall there was a significant relation between heart failure remodeling parameters and positive MTWA

Implantable cardioverter-defibrillators have reduced the incidence of resuscitation for out-of-hospital cardiac arrest caused by lethal arrhythmias

Background-Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline. Methods and Results-Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005-2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995-1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005-2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995-1997 to 17.4/100 000 in 2005-2008 (P<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (P<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005-2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence. Conclusions-The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA

Dutch outcome in implantable cardioverterdefibrillator therapy: Implantable cardioverter-defibrillator–related complications in a contemporary primary prevention cohort

BACKGROUND: One third of primary prevention implantable cardioverter-defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. METHODS AND RESULTS: Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverterdefibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter-defibrillator. During a follow-up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead-related (n=47) and pocket-related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. CONCLUSIONS: One in 13 patients experiences at least one major implantable cardioverter-defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits

Low 30-Day Mortality After Atrial Fibrillation Ablation: Results From the Netherlands Heart Registration

This study presents the 30-day mortality of patients who underwent atrial fibrillation (AF) ablation between 2013 - 2020 and were registered in the Netherlands Heart Registration. In total, 30,197/30,238 (99.9%) patients were analyzed. Fifteen (0.05%) died within 30 days. Nine deaths were considered procedurally related, four were considered non-procedural related, and in two patients the cause of death was unknown