High Risk of Sustained Ventricular Arrhythmia Recurrence After Acute Myocarditis.

Acute myocarditis is associated with cardiac arrhythmia in 25% of cases; a third of these arrhythmias are ventricular tachycardia (VT) or ventricular fibrillation (VF). The implantation of a cardiac defibrillator (ICD) following sustained ventricular arrhythmia remains controversial in these patients. We sought to assess the risk of major arrhythmic ventricular events (MAEs) over time in patients implanted with an ICD following sustained VT/VF in the acute phase of myocarditis compared to those implanted for VT/VF occurring on myocarditis sequelae. Our retrospective observational study included patients implanted with an ICD following VT/VF during acute myocarditis or VT/VF on myocarditis sequelae, from 2007 to 2017, in 15 French university hospitals. Over a median follow-up period of 3 years, MAE occurred in 11 (39%) patients of the acute myocarditis group and 24 (60%) patients of the myocarditis sequelae group. Kaplan-Meier MAE rate estimates at one and three years of follow-up were 19% and 45% in the acute group, and 43% and 64% in the sequelae group. Patients who experienced sustained ventricular arrhythmias during acute myocarditis had a very high risk of VT/VF recurrence during follow-up. These results show that the risk of MAE recurrence remains high after resolution of the acute episode.

Atrial premature activity detected after an ischaemic stroke unveils atrial myopathy.

BACKGROUND: Recent publications suggest that left atrial (LA) myopathy is a potential source of thromboembolism, independent of atrial fibrillation. AIMS: We sought to investigate whether the presence of atrial premature activity after an ischaemic stroke is associated with LA remodelling and dysfunction, and might be a surrogate marker of LA myopathy. METHODS: After an ischaemic stroke or a transient ischaemic attack, patients without known atrial fibrillation or overt heart disease were included prospectively in the study. All patients had a standard workup, including ambulatory Holter electrocardiogram monitoring and transthoracic echocardiography. In some patients, transoesophageal echocardiography was also performed. Anatomical and functional LA remodelling were assessed using minimal and maximal volumes and LA emptying fraction in two-dimensional and three-dimensional echocardiography. Patients were separated into two groups according to the burden of atrial premature complexes (APCs), measured by Holter electrocardiography. RESULTS: Among 148 eligible patients recruited from October 2015 to May 2016, 93 were included in the group with non-frequent APCs (nf-APC:<100 APCs/24hours) and 43 in the group with frequent APCs (f-APC:>100 APCs/24hours). Twelve patients had paroxysmal atrial fibrillation, and were not included in the statistical analysis. Maximal and minimal indexed LA volumes were significantly higher in the f-APC group than in the nf-APC group (P<0.01). LA emptying fraction was worse in the f-APC group than in the nf-APC group. In addition, LA appendage emptying velocity was impaired in the f-APC group, and was correlated with LA remodelling variables, especially LA emptying fraction (r=0.621). CONCLUSIONS: After an ischaemic stroke or a transient ischaemic attack, excessive APCs are associated with LA remodelling. Thus, LA dilatation and dysfunction reflect early LA myopathy, which might itself be responsible for cardioembolic stroke.

Flecainide is a safe and effective treatment for pre-excited atrial fibrillation rapidly conducted to the ventricle in pregnant women: a case series.

BACKGROUND: Pregnancy is associated with an increased incidence of cardiac arrhythmias likely due to hormonal, haemodynamic, and autonomic changes. Yet, there is little data available regarding the efficacy and safety of anti-arrhythmic agents to prevent pre-excited atrial fibrillation (AF) in pregnant women. CASE SUMMARY: We report on three pregnant women who developed AF rapidly conducted to the ventricle through an overt accessory pathway as the first manifestation of Wolff-Parkinson-White syndrome. DISCUSSION: All patients were treated with flecainide with neither arrhythmias recurrence nor adverse events of the treatment. Mechanisms of action and clinical efficacy of flecainide are discussed.

Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is a common arrhythmia for which the genetic studies mainly focused on the genes involved in electrical remodeling, rather than left atrial muscle remodeling. To identify rare variants involved in atrial myopathy using mutational screening, a high-throughput next-generation sequencing (NGS) workflow was developed based on a custom AmpliSeq™ panel of 55 genes potentially involved in atrial myopathy. This workflow was applied to a cohort of 94 patients with AF, 76 with atrial dilatation and 18 without. Bioinformatic analyses used NextGENe® software and in silico tools for variant interpretation. The AmpliSeq custom-made panel efficiently explored 96.58% of the targeted sequences. Based on in silico analysis, 11 potentially pathogenic missense variants were identified that were not previously associated with AF. These variants were located in genes involved in atrial tissue structural remodeling. Three patients were also carriers of potential variants in prevalent arrhythmia-causing genes, usually associated with AF. Most of the variants were found in patients with atrial dilatation (n=9, 82%). This NGS approach was a sensitive and specific method that identified 11 potentially pathogenic variants, which are likely to play roles in the predisposition to left atrial myopathy. Functional studies are needed to confirm their pathogenicity.

First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease with an estimated prevalence of 1/500. More than 40 genes have been reported to cause HCM. Among them, CSRP3 is usually included on HCM gene panels used for molecular diagnosis by next-generation sequencing (NGS). To provide new insights into the pathophysiology of hypertrophic cardiomyopathy, a NGS workflow based on a panel of 48 cardiomyopathies-causing genes was analyzed on a cohort of 542 HCM patients. As expected, this molecular approach led to identify most pathogenic or likely pathogenic variants into prevalent HCM-causing genes: MYBPC3 (123/542; 22.7%), MYH7 (48/542; 8.9%), TNNT2 (12/542; 2.2%), and TNNI3 (10/542; 1.8%). Among MYBPC3 variants, 96 led to a premature stop codon (78%). More surprisingly, our molecular study led also to detect, for the first time, homozygous CSRP3 truncating variants in two unrelated HCM probands. Meta-analysis of rare previously reported CSRP3 variants on HCM probands using ACMG guidelines indicate that only one variation (p.Cys58Gly) could be considered as likely pathogen. By combining meta-analysis results and identification of two unrelated HCM patients with homozygous CSRP3 truncating variants, we suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM (OMIM 612124).

Delayed diagnosis of Brugada syndrome in a patient with aborted sudden cardiac death and initial negative flecainide challenge.

A negative flecainide challenge does not rule out Brugada syndrome even in the presence of nonfatal cardiac arrest as the first manifestation of the disease. This should prompt clinicians to ensure long-term ECG follow-up and consider repeating a drug test with another sodium channel blocker.

Additional coronary sinus shocking lead as rescue therapy after multiple internal and external defibrillation failures.

High defibrillation threshold (DFT) and defibrillation failure can lead to intractable ventricular arrhythmias. Additional coronary sinus coil is an effective strategy to achieve marked reduction in DFT. However, physicians should retain this might prevent future coronary sinus lead placement in case the patient would develop complete left bundle branch block.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes Provide In Vivo Biological Pacemaker Function.

BACKGROUND: Although multiple approaches have been used to create biological pacemakers in animal models, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have not been investigated for this purpose. We now report pacemaker function of iPSC-CMs in a canine model. METHODS AND RESULTS: Embryoid bodies were derived from human keratinocytes, their action potential characteristics determined, and their gene expression profiles and markers of differentiation identified. Atrioventricular blocked dogs were immunosuppressed, instrumented with VVI pacemakers, and injected subepicardially into the anterobasal left ventricle with 40 to 75 rhythmically contracting embryoid bodies (totaling 1.3-2×106 cells). ECG and 24-hour Holter monitoring were performed biweekly. After 4 to 13 weeks, epinephrine (1 µg kg-1 min-1) was infused, and the heart removed for histological or electrophysiological study. iPSC-CMs largely lost the markers of pluripotency, became positive for cardiac-specific markers. and manifested If-dependent automaticity. Epicardial pacing of the injection site identified matching beats arising from that site by week 1 after implantation. By week 4, 20% of beats were electronically paced, 60% to 80% of beats were matching, and mean and maximal biological pacemaker rates were 45 and 75 beats per minute. Maximum night and day rates of matching beats were 53±6.9 and 69±10.4 beats per minute, respectively, at 4 weeks. Epinephrine increased rate of matching beats from 35±4.3 to 65±4.0 beats per minute. Incubation of embryoid bodies with the vital dye, Dil, revealed the persistence of injected cells at the site of administration. CONCLUSIONS: iPSC-CMs can integrate into host myocardium and create a biological pacemaker. Although this is a promising development, rate and rhythm of the iPSC-CMs pacemakers remain to be optimized.

Increased Late Sodium Current Contributes to the Electrophysiological Effects of Chronic, but Not Acute, Dofetilide Administration.

BACKGROUND: Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. METHODS AND RESULTS: We continuously infused dofetilide (6-9 µg/kg bolus+6-9 µg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. CONCLUSIONS: Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome.

Interventricular dispersion in repolarization causes bifid T waves in dogs with dofetilide-induced long QT syndrome.

BACKGROUND: Long QT2 (LQT2) syndrome is characterized by bifid (or notched) T waves, whose mechanism is not understood. OBJECTIVE: The purpose of this study was to test whether increased interventricular dispersion of repolarization induces bifid T waves. METHODS: We simultaneously recorded surface ECG and unipolar electrograms at baseline and after dofetilide in a canine model of dofetilide-induced LQT2 (6 male mongrel dogs). Standard ECG variables, T-wave duration, and moments of peaks of bifid T waves (Tp1 and Tp2) were correlated with moments of local repolarization. Epicardial electrograms were recorded over the left ventricular (LV) and right ventricular (RV) anterior walls (11 × 11 electrode grid, 5-mm interelectrode distance). In 5 of the 6 hearts, we also recorded intramural unipolar electrograms (n = 4-7 needles per heart). In each unipolar recording, we determined activation time, repolarization time (RTs), and activation-recovery interval. In addition, we studied RT response to heart rate changes. RESULTS: Dofetilide prolonged QT and QTc, induced bifid T waves in 4 of 6 animals, and prolonged RT heterogeneously in LV and RV, resulting in increased interventricular and LV intraventricular RT dispersion. Dofetilide did not induce a disparate response in activation-recovery interval across the transmural axis. Dofetilide-induced separation of RT across the RV-LV interface concurred with the moments of T-wave peaks. Dofetilide-induced steepening of restitution slopes was larger in LV than RV. CONCLUSION: Dofetilide-induced bifid T waves result from interventricular RT dispersion.

Stem cell-based biological pacemakers from proof of principle to therapy: a review.

Electronic pacemakers are the standard therapy for bradycardia-related symptoms but have shortcomings. Over the past 15 years, experimental evidence has demonstrated that gene and cell-based therapies can create a biological pacemaker. Recently, physiologically acceptable rates have been reported with an adenovirus-based approach. However, adenovirus-based protein expression does not last more than 4 weeks, which limits its clinical applicability. Cell-based platforms are potential candidates for longer expression. Currently there are two cell-based approaches being tested: (i) mesenchymal stem cells used as a suitcase for delivering pacemaker genes and (ii) pluripotent stem cells differentiated down a cardiac lineage with endogenous pacemaker activity. This review examines the current achievements in engineering a biological pacemaker, defines the patient population for whom this device would be useful and identifies the challenges still ahead before cell therapy can replace current electronic devices.

In-hospital heart rate turbulence and microvolt T-wave alternans abnormalities for prediction of early life-threatening ventricular arrhythmia after acute myocardial infarction.

BACKGROUND: In the setting of primary prevention, most implantable cardiac defibrillators (ICD) are implanted more than 6 months after acute myocardial infarction (AMI). Abnormal heart rate turbulence (HRT) and T-wave alternans (TWA) are predictors of long-term sudden cardiac death (SCD). We intended to assess the predictive value of HRT and TWA for early post-AMI SCD and life-threatening ventricular arrhythmias (VA). METHODS: One hundred ninety-nine consecutive patients with AMI were prospectively included (age 61.7 years, LV ejection fraction 45%). One hundred eighty-three patients (92%) underwent percutaneous coronary intervention. We assessed HRT using turbulence slope (TS), turbulence onset (TO), and TWA on channels 1 and 2 (TWA1 and TWA2) using the modified moving average method. Predictive performance for SCD/VA was assessed by area under the receiver operating curve characteristic (ROC-AUC). RESULTS: Within 6 months after AMI, 2 patients (1%) developed life-threatening VA and 3 (1.5%) experienced SCD. TO and TWA1 had poor ROC-AUC (both 0.64) whereas TS and TWA2 failed to show any predictive performance (ROC-AUC 0.48 and 0.57, respectively). When combining TO and TWA1, ROC-AUC increased to 0.80. Importantly, when considering the subset of patients with a LV ejection fraction ≤40%, the combined variable of TO and TWA1 remained strongly predictive of a short-term event (ROC-AUC 0.86). CONCLUSIONS: Combined assessment of HRT and TWA showed a high predictive performance for SCD or life-threatening VA within 6 months after AMI. This combined Holter ECG index could be useful to identify high-risk patients who might benefit from early ICD implantation.

Periatrial epicardial fat is associated with markers of endothelial dysfunction in patients with atrial fibrillation.

BACKGROUND: Epicardial adipose tissue (EAT) is associated to atrial fibrillation (AF) burden and outcome after AF ablation. We intended to determine whether global or local EAT is associated with systemic and/or left atrial (LA) inflammation and markers of endothelial dysfunction in AF patients. METHODS AND RESULTS: Total, atrial, and ventricular EAT volume (EAT total, EAT atrial, EAT ventricular) were measured by multislice cardiac CT in 49 patients with paroxysmal (PAF, n=25) or persistent AF (PeF, n=24). Periatrial epicardial fat thickness at the esophagus (LA-ESO) and thoracic aorta (LA-ThA) were also measured. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), soluble intercellular adhesion molecule 1 (sICAM-1), transforming growth factor-ß1 (TGF-ß1), and von Willebrand Factor (vWF) levels were measured in peripheral and LA blood samples obtained during catheterization during AF ablation. Patients with PeF had higher EAT atrial (P<0.05) and LA-ESO (P=0.04) than patients with PAF. VEGF, IL-8, and TGF-ß1 were not associated with EAT. In contrast, after adjusting for LA volume and body mass index, higher LA-ThA was significantly associated with higher sICAM-1 and vWF levels, both in peripheral blood (P<0.05) and in LA (P<0.05). Similar results were found with LA-ESO. Body mass index, EAT total and EAT ventricular were not associated with sICAM-1 and vWF. CONCLUSIONS: Periatrial epicardial fat showed a significant positive association with increased levels of sICAM-1 and vWF, which are biomarkers of endothelial dysfunction. No such associations were found when considering body mass index or EAT total. These results suggest that local EAT rather than regional or total adiposity may modulate endothelial dysfunction in patients with AF.

Persistent abnormal intraventricular conduction after myocarditis revealed by recurrent syncopes.

A 24-year-old male was admitted to our hospital for recurrent syncopes. Several ECG showed paroxysmal second degree atrioventricular block with the QRS axis changing between conducted beats and escape beats. Transvenous cardiac pacing was performed until permanent recapture of atrioventricular conduction (day 4). At day 7, the CMRI showed extensive subepicardial enhancement highly consistent with acute myocarditis. A second CMRI was performed 3months later showing complete regression of subepicardial enhancement despite persistent RBBB and left posterior fascicular block. Although there was no ECG available before the event, the likelihood of a causal relationship between ECG findings and the myocardial disease is high. When it happens, a long follow-up should be advised.