Prevalence and predictors of bradyarrhythmias requiring Permanent Pacing in patients with Anderson-Fabry disease.

Introduction: Bradyarrhythmias are an established red flag for storage cardiac conditions including Anderson-Fabry disease (AFD). The prevalence of bradyarrhythmias requiring a pacemaker (PM) and their timing in AFD is unresolved. We evaluated prevalence and predictors of PM requirement in a large AFD cohort, investigating the occurrence of bradyarrhythmias as initial versus late manifestation. Methods: we retrospectively evaluated 82 consecutive AFD patients referred to our multidisciplinary referral centre from 1994 to 2020 with a median follow up of 6.9 years, identifying those requiring pacing. Univariable analysis was performed to identify cardiac features associated with PM implantantion. Results: Five of 82 (6%) AFD patients required PM implantation (5/39, i.e. 13% of those with cardiac involvement), always in the context of advanced cardiomyopathy. In none, bradyarrhythmias were the presenting feature. Indications included sick sinus syndrome in 3 patients, advanced atrio-ventricular block in 2 patients. QRS prolongation during follow up strongly correlated with the onset of bradyarrhythmias. Conclusions: Severe bradyarrhythmias are relatively frequent in patients with AFD cardiomyopathy, but do not represent a mode of presentation, occurring late in the disease course and always in the context of advanced cardiac involvement. Monitoring QRS variations over time may help to identify patients requiring pacing.

Loss of Mitochondrial Ca 2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Since mitochondrial function and ROS formation are regulated by excitation-contraction (EC) coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin ( Taz -KD) compared to wild-type (WT) littermates. Respiratory chain assembly and function, ROS emission, and Ca 2+ uptake were determined in isolated mitochondria. EC coupling was integrated with mitochondrial redox state, ROS, and Ca 2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo . Results: Taz -KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca 2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, partly compensated by accelerated diastolic Ca 2+ decay through preactivated sarcoplasmic reticulum Ca 2+ ATPase (SERCA). Taz deficiency provoked heart-specific loss of mitochondrial Ca 2+ uniporter (MCU) protein that prevented Ca 2+ -induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo , Taz -KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca 2+ export via the mitochondrial Na + /Ca 2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo . Conclusions: Downregulation of MCU, increased myofilament Ca 2+ affinity, and preactivated SERCA provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca 2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel coronavirus disease 2019

Funding Acknowledgements Type of funding sources: None. Background Although long-term use of HCQ and AZT has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Purpose: The aim of this study was to assess the effect of HCQ alone and HCQ + AZT on corrected QT (QTc).Methods: A baseline ECG and on-treatment ECGs were retrospectively collected in COVID-19 patients who received HCQ and/or AZT. Also peak QTc intervals of monotherapy and combination therapy was compared. Results: Of the 155 patients included, 102 (65.8%) were using HCQ, 53 (34.2%) were using HCQ + AZT combination. The use of both HCQ alone and HCQ + AZT combined therapy significantly prolonged the QTc and the QTc interval was significantly longer in patients received combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and in 6 (11.3%) patients in the combined therapy group.Conclusion: Patients who received HCQ for COVID-19 were at high risk of QTc prolongation, and concurrent treatment with AZT was associated with greater changes in QTc. Comparison of baseline characteristics a Characteristic Total (n = 155) Hydroxychloroquine (n = 102) Hydroxychloroquine /Azithromycin (n = 53) P value Length of stay at ward, SD 9.54 ± 4.28 9.64 ± 4.31 9.31 ± 4.25 0.88 Length of stay Intensive care unite,SD 7.92 ± 3.76 7.18 ± 3.18 8.46 ± 4.15 0.29 Radiographic findings of pneumonia 118(76.1%) 76(74.5%) 42(49.2%) 0.32 Mechanically ventilation 16(10.3%) 7(6.9%) 9(17.0%) 0.049 In hospital death 19(12.3%) 10(9.8%) 9(17.0%) 0.15 ECG findings median(IQR) (ms) Baseline QRS duration 91.0(80.0-103.0) 92.5(80.75-105.50) 90.0(80.0-102.5) 0.5 Posttreatment QRS peak 97.0(86.0-109.0) 97.5(88.0-109.25) 95.0(85.5-109) 0.68 ΔQRS 4.0(0.0-9.0) 2.0(0.0-8.25) 5.0(1.0-9.5) 0.14 Baseline QTc duration 407.0(385.0-426.0) 408.0(389.25-427.50) 404.0(384.0-420.0) 0.1 Posttreatment QTc peak 437.0(414.0-460.0) 428.0(412.75-449.25) 456.0(422.0-467.5) <0.001 ΔQTc 27.0(13.0-45.0) 18.0(11.0-30.0) 46.0(40.5-54.5) <0.001 Baseline PR duration 145.50(128.7-160.0) 147.0(135.0-160.0) 144.0(120.0-160.0) 0.53 Posttreatment PR peak 159.0(140.0-170.0) 159.0(141.0-168.50) 156.0(139.5-171.0) 0.97 ΔPR 7.0(1.0-13.0) 5.0(0.0-12.25) 10.0(5.0-15.0) 0.022 QTc peak day 5.0(4.0-5.0) 5.0(4.0-6.0) 4.0(3.0-5.0) 0.022 Drug withdrawl due to QRS prolongation 11(7.1%) 5(4.9%) 6(11.3%) 0.12

Abstract P459: Inversion of T Waves on Admission is Associated With Mortality in Spontaneous Intracerebral Hemorrhage

Introduction: Cardiac dysfunction directly caused by spontaneous intracerebral hemorrhage (ICH) is a poorly understood phenomenon, and its impact on outcome is still uncertain. Aim of this study is to investigate the relationship between electrocardiographic (EKG) abnormalities and mortality in ICH. Methods: This is a retrospective study analyzing EKG patterns on admission in patients admitted with ICH at a tertiary care center over eight-year period. For each patient, demographics, medical history, clinical presentation, EKG on admission and repeated during hospitalization, and head CT at presentation were reviewed. Mortality was noted. Results: A total of 301 ICHs were included in the study. The most prevalent EKG abnormalities were QTc prolongation in 56% of patients (n=168) followed by inversion of T waves (TWI) in 37% of patients (n=110). QTc prolongation was associated with ganglionic location (p=0.03) and intraventricular hemorrhage (IVH) (p=0.01), TWI was associated with ganglionic location (p=0.02), PR prolongation with IVH (p=0.01), while QRS prolongation was associated with lobar location (p<0.01). Volume of ICH, hemispheric laterality, and involvement of insular cortex were not correlated with specific EKG patterns. In a logistic regression model, after correcting for ICH severity and prior cardiac history, presence of TWI was independently associated with mortality (OR: 3.04, CI:1.6-5.8, p<0.01). Adding TWI to ICH score improved its prognostic accuracy (AUC 0.81). Disappearance of TWI during hospitalization did not translate in improvement of survival (p=0.5). Conclusion: Presence of TWI on admission is an independent and unmodifiable factor associated with mortality in ICH. TWI may be implemented as an additional early prognostic tool in clinical practice.

Impact of electrophysiological features acquired after anatomical repair of congenital corrected transposition of the great arteries on late mortality and ventricular dysfunction

OBJECTIVES In patients with anatomically repaired congenitally corrected transposition of the great arteries, the impact of electrophysiological features on postoperative ventricular dysfunction remains less well known. Our goal was to investigate the role of fragmented QRS and QRS duration in mortality and systemic ventricular dysfunction after anatomical repair of corrected transposed great arteries. METHODS Consecutive patients who underwent anatomical repair in our institution from January 2005 to December 2017 were enrolled in this retrospective analysis. Fragmented QRS was defined as ≥1 discontinuous deflections in narrow QRS complexes, and ≥2 in wide QRS complexes, in 2 contiguous electrocardiogram leads. The primary end point was a composite of all-cause mortality and systemic ventricular dysfunction. RESULTS A total of 74 patients were included. Among them, 30, 15 and 29 underwent the Senning arterial switch, the Senning Rastelli and the hemi-Mustard/bidirectional Glenn/Rastelli procedures, respectively. The primary end point occurred in 9 (12.2%) patients and included 7 late deaths and 2 cases of late-onset systemic ventricular dysfunction. Fragmented QRS and QRS prolongation were noted in 19 (25.7%) and 21 (28.4%) patients, respectively. In patients with the primary end point, QRS fragmentation (6/9 vs 10/65; P &lt; 0.001) and QRS prolongation (6/9 vs 15/65; P = 0.013) were noted more frequently than in patients without the primary end point. No statistical differences in these electrocardiogram findings were found among patients treated with 3 surgical strategies. CONCLUSIONS Appearance of QRS fragmentation or QRS prolongation is associated with death or ventricular dysfunction in anatomically repaired corrected transposition of the great arteries. Although there is a trend that QRS fragmentation and QRS prolongation appear more frequently in patients who had the Senning-arterial switch operation, there is no statistically significant difference associated with these electrocardiogram features among varied procedures.

Clinical characterization of the first Belgian SCN5A founder mutation cohort

Aims We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. Methods and results The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. Conclusion The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

Abstract 14843: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Associated Myocarditis

Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p<0.001), QRS prolongation (HR=3.35 [1.00-11.21] p=0.05), LBBB (HR=2.24 [1.13-4.45] p=0.021), and supraventricular arrhythmia (HR=2.03 [1.05-3.91] p=0.035) on presenting EKG. Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.

Abstract 17195: Hydroxychloroquine Associated Electrocardiographic Changes in Patients With COVID-19 Extend Beyond QTc Prolongation and Are Accentuated in Those With Myocardial Injury

Introduction: Hydroxychloroquine (HCQ) is known to cause QTc prolongation, however its association with other ECG changes and how those are related to markers of myocardial injury in COVID-19 patients (pts) are not well described. Hypothesis: To study ECG changes in COVID-19 pts with or without troponin (Tn) elevation >3X normal (Tn +/-), who were or were not treated with HCQ (+/-). Methods: This is an observational study of pts admitted with COVID-19. All had at least 3 ECGs during admission; on day 1, day 2-3 and day 4-6. Pre-admission and final ECGs were included when available. Pts were excluded if they had atrial fibrillation, paced QRS, QRS>120msec, STEMI, or end stage renal disease. QRS, QTc, PR, P wave duration, QRS amplitude and the sum of T wave deflections in both limb and precordial leads were measured. Data were collected on medical history, illness severity, electrolytes, and medications within the 12-hour window of each ECG. Results: A total of 116 pts were included: 85 HCQ+ (40% Tn+) and 31 HCQ- (48% Tn+). There were no differences between the two groups in baseline characteristics, illness severity or mortality. Significant QTc prolongation was noted only in the HCQ+ group (p<0.001) peaking at +13.6 ms on day 5 compared to admission (p<0.01) and was accentuated in the HCQ+/Tn+ group (peak of +23.7 ms, p<0.01). QRS prolongation was seen in the HCQ+ group (p<0.001) peaking at +3.5 ms on day 5, and was accentuated in Tn+ pts peaking at +5.2 ms compared to Tn- pts +2.5 ms (p<0.05, both comparisons). The sum of precordial T-wave amplitude decreased in HCQ+ pts (-2.2 mm on final ECG, p=0.015) but this change was only significant in the Tn+ subgroup (peak of -3.6 mm, p<0.01). Finally, the PR interval was prolonged in the HCQ+ group, peaking at +7.6 ms on day 5 (p<0.01), but was again was more marked in the Tn+ subgroup (peak of +9.6 ms, p<0.05). Conclusions: HCQ related ECG effects extend beyond QTc prolongation. These are most notable in pts with evidence of myocardial injury.

Association of QRS duration changes during ergonovine provocation test with arrhythmic complications

Background Ergonovine is ergoline-derivatives that act at serotonin-receptors (5-HT2receptor). Influence of serotonin and 5-HT2 receptor agonist on cardiomyocytes has been known. Purpose However, there was limited data about the association between QRS duration changes during ergonovine provocation test (EPT) and arrhythmic complications. Methods A total of 182 patients who underwent coronary angiography (CAG) with EPT were consecutively enrolled (mean age; 53.9±10.4 years, 59.3% male) at our hospital from 2018 to 2019. ECGs recorded closest to the time of CAG were carefully reviewed and measured PR interval, QRS duration, QT and QTc intervals. Results 41 (22.5%) patients had arrhythmic events including atrial, and ventricular tachycarrhythmia during follow-up. The patients with QRS prolongations had higher incidences of arrhythmic events compared with those without QRS changes (P=0.025). In univariate analysis, diabetes mellitus (P=0.05), coronary artery spasm (P=0.031) and QRS prolongations (P=0.036) were significantly associated with arrhythmic events. In multivariate analysis, QRS prolongations [OR 2.496 (1.077–5.784), P=0.033] was independent risk factors for arrhythmic events at the long-term follow-up. ROC curve analysis were performed to define cut-off point for arrhythmic events (QRS prolongation during EPT&gt;10.6 msec [sensitivity = 0.972; specificity = 0.943]; AUC=0.632; P=0.015) Conclusion The patients with QRS duration prolongations during Ergonovine provocation test were associated with higher incidence of arrhythmic events, suggesting more intensive medical therapy with close clinical follow-up will be required. Funding Acknowledgement Type of funding source: None