Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Implantable loop recorders in patients with Brugada syndrome: the BruLoop study.

BACKGROUND AND AIMS: Available data on continuous rhythm monitoring by implantable loop recorders (ILRs) in patients with Brugada syndrome (BrS) are scarce. The aim of this multi-centre study was to evaluate the diagnostic yield and clinical implication of a continuous rhythm monitoring strategy by ILRs in a large cohort of BrS patients and to assess the precise arrhythmic cause of syncopal episodes. METHODS: A total of 370 patients with BrS and ILRs (mean age 43.5 ± 15.9, 33.8% female, 74.1% symptomatic) from 18 international centers were included. Patients were followed with continuous rhythm monitoring for a median follow-up of 3 years. RESULTS: During follow-up, an arrhythmic event was recorded in 30.7% of symptomatic patients [18.6% atrial arrhythmias (AAs), 10.2% bradyarrhythmias (BAs), and 7.3% ventricular arrhythmias (VAs)]. In patients with recurrent syncope, the aetiology was arrhythmic in 22.4% (59.3% BAs, 25.0% VAs, and 15.6% AAs). The ILR led to drug therapy initiation in 11.4%, ablation procedure in 10.9%, implantation of a pacemaker in 2.5%, and a cardioverter-defibrillator in 8%. At multivariate analysis, the presence of symptoms [hazard ratio (HR) 2.5, P = .001] and age >50 years (HR 1.7, P = .016) were independent predictors of arrhythmic events, while inducibility of ventricular fibrillation at the electrophysiological study (HR 9.0, P < .001) was a predictor of VAs. CONCLUSIONS: ILR detects arrhythmic events in nearly 30% of symptomatic BrS patients, leading to appropriate therapy in 70% of them. The most commonly detected arrhythmias are AAs and BAs, while VAs are detected only in 7% of cases. Symptom status can be used to guide ILR implantation.

Atrial fibrillation cycle-length (AF-CL) inside the pulmonary veins predicts paroxysmal AF ablation success- the INDUCE-AF study.

BACKGROUND: A novel method to measure atrial fibrillation cycle length (AF-CL) was recently described, based on the average of 10 consecutive signals (FARS10). FARS10 accurately identified pulmonary vein isolation (PVI)-responders among patients with persistent AF. Whether this method is applicable to patients with paroxysmal AF is unknown. OBJECTIVE: The aim of this study is to evaluate the prognostic value of FARS10 measurements in patients with paroxysmal AF. METHODS AND RESULTS: We enrolled paroxysmal AF patients undergoing PVI in a prospective multicenter study. After AF induction with a standardized protocol, the AF-CL was measured using FARS-10 method. The primary endpoint was AF/AT-recurrence. One-hundred and four patients were included (61 ± 14 years, 25% females). After a mean follow-up of 12 ± 4 months, AF/AT recurrence rate was 20%. The fastest PV CL (fPV-CL) was independently associated with the primary endpoint at multivariate analysis (HR 1.02, p < 0.001). Every 10 ms increase in fPV-CL, AF recurrences increased by 20%. The value of 160 ms was found to be the optimal cut-off (specificity 81%, sensitivity 76%). Patients with fPV-CL < 160 ms experienced lower AF recurrences as compared to patients with fPV-CL > 160 ms (8% vs. 32% at 1 year; HR = 0.17, p < 0.001). Progression to persistent AF was observed in 13% of patients with fPV-CL > 160 ms. CONCLUSION: fPV-CL measured with the FARS-10 method accurately predicts PVI success in paroxysmal AF patients undergoing PVI. Patients with slow PV activity (fPV-CL > 160 ms) experience higher AF recurrence rate after PVI and more frequent progression to persistent AF. In 104 patients with paroxysmal atrial fibrillation (AF) undergoing AF ablation, AF was induced at the beginning of the procedure. Pulmonary vein activity was measured using FARS10 measurement (10 consecutive fastest atrial repetitive similar morphology signals). The value of 160 ms was found to be the best cut-off to discriminate outcomes. At 1-year follow-up, patients with fast veins (< 160 ms) experienced significantly fewer AF recurrences as compared to patients with slow veins (> 160 ms). PV activity measured with FARS10 method accurately discriminates pulmonary vein isolation responders, in patients with paroxysmal AF. ABBREVIATIONS: AF atrial fibrillation, AT atrial tachycardia, CL cycle length, FARS10: 10 consecutive fastest atrial repetitive similar morphology signal, fPV fastest pulmonary vein, HR hazard ratio, ms milliseconds.

Dynamic changes of left atrial substrate over time following pulmonary vein isolation: the Progress-AF study.

AIMS: Little is known about dynamic changes of the left atrial (LA) substrate over time in patients with atrial fibrillation (AF). This study aims to evaluate substrate changes following pulmonary vein isolation (PVI). METHODS AND RESULTS: In our prospective observational study, consecutive patients undergoing first PVI-only and redo ablation were included. High-density maps of the two procedures were compared. Progression or regression was diagnosed if a significant concordant decrease or increase in bipolar voltages in ≥2 segments was observed, respectively. In 28 patients (61.2 ± 9.5 years, 39% female, 53.5% persistent AF), 111.013 voltage points from 56 high-density LA maps (1.982 points/patient) were analysed. Comparing the high-density maps of the first and second procedures, in the progression group (17 patients, 61%), there was a decrease in global (-35%, P < 0.001) and all regional voltages. In the regression group (11 patients, 39%), there was an increase in global (+43%, P < 0.001) and regional voltages. Comparing the progression with the regression group, the area of low-voltage zone (LVZ) increased (+3.5 vs. -4.5 cm2, P < 0.001) and LA activation time prolonged (+8.0 vs. -9.1 ms, P = 0.005). Baseline clinical parameters did not predict progression or regression. In patients with substrate progression, pulmonary veins (PVs) were more frequently isolated (P = 0.02) and the AF pattern at recurrence was more frequently persistent (P = 0.005). CONCLUSION: Our study describes bidirectional dynamic properties of the LA substrate with concordant either progressive or regressive changes. Regression occurs with reduced AF burden after the first procedure, while progression is associated with persistent AF recurrence despite durable PV isolation. The dynamic nature of LA substrate poses questions about LVZ-based ablation strategies.

Variable clinical expression of a Belgian TGFB3 founder variant suggests the presence of a genetic modifier.

Background: TGFB3 variants cause Loeys-Dietz syndrome type 5, a syndromic form of thoracic aortic aneurysm and dissection. The exact disease phenotype is hard to delineate because of few identified cases and highly variable clinical representation. Methodology: We provide the results of a haplotype analysis and a medical record review of clinical features of 27 individuals from 5 different families, originating from the Campine region in Flanders, carrying the NM_003239.5(TGFB3):c.787G>C p.(Asp263His) likely pathogenic variant, dbSNP:rs796051886, ClinVar:203492. The Asp263 residue is essential for integrin binding to the Arg-Gly-Asp (RGD) motif of the TGFß3-cytokine. Results: The haplotype analysis revealed a shared haplotype of minimum 1.92 Mb and maximum 4.14 Mb, suggesting a common founder originating >400 years ago. Variable clinical features included connective tissue manifestations, non-aneurysmal cardiovascular problems such as hypertrophic cardiomyopathy, bicuspid aortic valve, mitral valve disease, and septal defects. Remarkably, only in 4 out of the 27 variant-harboring individuals, significant aortic involvement was observed. In one family, a 31-year-old male presented with type A dissection. In another family, the male proband (65 years) underwent a Bentall procedure because of bicuspid aortic valve insufficiency combined with sinus of Valsalva of 50 mm, while an 80-year-old male relative had an aortic diameter of 43 mm. In a third family, the father of the proband (75 years) presented with ascending aortic aneurysm (44 mm). Conclusion: The low penetrance (15%) of aortic aneurysm/dissection suggests that haploinsufficiency alone by the TGFB3 variant may not result in aneurysm development but that additional factors are required to provoke the aneurysm phenotype.

Gender-Related Differences in Atrial Substrate in Patients with Atrial Fibrillation.

Gender-related differences have been reported in patients who underwent pulmonary vein isolation (PVI). Atrial substrate plays a role in the outcomes after ablation but gender-related differences in atrial substrate have never been described in detail. We sought to analyze gender-related differences in atrial remodeling (spontaneous low-voltage zones [LVZs]) and their clinical relevance after PVI. We conducted a prospective multicenter study, including consecutive patients who underwent first PVI-only atrial fibrillation (AF) ablation. LVZs were analyzed on high-density electroanatomical maps collected with multipolar catheter, before PVI. In total, 262 patients (61 ± 11 years, 31% female, 50% persistent AF) were followed for 28 months. In women, LVZs were larger (10% vs 4% of left atrial surface [p <0.001]) and female gender was independently associated with fourfold higher risk of having advanced (LVZ > 15%) atrial remodeling (odds ratio 4.56, p <0.001). AF recurrence-free survival was not different between men and women (log-rank p = 0.2). Although LVZs were independently associated higher AF recurrences at multivariate analysis (hazard ratio [HR] 1.2, p = 0.038), female gender was not (HR 1.4, p = 0.211). Specifically, the LVZ cutoff to predict outcomes was different in men and women: >5% in men (HR 3.0, p <0.001), >15% in women (HR 2.7, p = 0.02). In conclusion, women have more widespread LVZ in all left atrial regions. Despite more extensive atrial remodeling, the AF recurrence rate is similar in men and women, and LVZs become prognostic in women only at high burden (>15%). LVZs seem to have a different prognostic role in men and women.

Left Bundle Branch Area Defibrillator (LBBAD): A First-in-Human Feasibility Study.

BACKGROUND: Left bundle branch area (LBBA) pacing is a promising pacing technique. LBBA implantable cardioverter-defibrillator (ICD) lead implantation reduces the number of leads in patients with both pacing and ICD indications, reducing cost and potentially increasing safety. LBBA positioning of ICD leads has not previously been described. OBJECTIVES: The goal of this study was to evaluate the safety and feasibility of implanting an LBBA ICD lead. METHODS: This prospective, single-center, feasibility study was conducted in patients with an ICD indication. LBBA ICD lead implantation was attempted. Acute pacing parameters and paced electrocardiography data were collected, and defibrillation testing was performed. RESULTS: LBBA defibrillator (LBBAD) implantation was attempted in 5 patients (mean age 57 ± 16.5 years; 20% female) and achieved in 3 (60%). Mean procedural and fluoroscopy duration were 170.0 ± 17.3 minutes and 28.8 ± 16.1 minutes, respectively. Left bundle capture was achieved in 2 patients (66%) and left septal capture in 1 patient. LBBA pacing exhibited a mean QRS duration and V6 R-wave peak time of 121.3 ± 8.3 milliseconds and 86.1 ± 10.0 milliseconds. In all 3 patients, defibrillation testing was successful with mean time to adequate shock delivery of 8.6 ± 2.6 seconds. Acute LBBA pacing threshold and R-wave amplitudes were 0.80 ± 0.60 V at 0.4 milliseconds and 7.0 ± 2.7 mV. No LBBA lead-related complications occurred. CONCLUSIONS: This first-in-human evaluation showed the feasibility of LBBAD implantation in a small cohort of patients. With current tools, implantation remains complex and time-consuming. Considering the feasibility reported and the potential benefits, further technological development in this field is warranted with evaluation of long-term safety and performance.

Microelectrode voltage mapping for substrate assessment in catheter ablation of ventricular tachycardia: A dual-center experience.

INTRODUCTION: The assessment of the ventricular myocardial substrate critically depends on the size of mapping electrodes, their orientation with respect to wavefront propagation, and interelectrode distance. We conducted a dual-center study to evaluate the impact of microelectrode mapping in patients undergoing catheter ablation (CA) of ventricular tachycardia (VT). METHODS: We included 21 consecutive patients (median age, 68 [12], 95% male) with structural heart disease undergoing CA for electrical storm (n = 14) or recurrent VT (n = 7) using the QDOT Micro catheter and a multipolar catheter (PentaRay, n = 9). The associations of peak-to-peak maximum standard bipolar (BVc ) and minibipolar (PentaRay, BVp ) with microbipolar (BVµMax ) voltages were respectively tested in sinus rhythm with mixed effect models. Furthermore, we compared the features of standard bipolar (BE) and microbipolar (µBE) electrograms in sinus rhythm at sites of termination with radiofrequency energy. RESULTS: BVµMax was moderately associated with both BVc (ß = .85, p < .01) and BVp (ß = .56, p < .01). BVµMax was 0.98 (95% CI: 0.93-1.04, p < .01) mV larger than corresponding BVc , and 0.27 (95% CI: 0.16-0.37, p < .01) mV larger than matching BVp in sinus rhythm, with higher percentage differences in low voltage regions, leading to smaller endocardial dense scar (2.3 [2.7] vs. 12.1 [17] cm2 , p < .01) and border zone (3.2 [7.4] vs. 4.8 [20.1] cm2 , p = .03) regions in microbipolar maps compared to standard bipolar maps. Late potentials areas were nonsignificantly greater in microelectrode maps, compared to standard electrode maps. At sites of VT termination (n = 14), µBE were of higher amplitude (0.9 [0.8] vs. 0.4 [0.2] mV, p < .01), longer duration (117 [66] vs. 74 [38] ms, p < .01), and with greater number of peaks (4 [2] vs. 2 [1], p < .01) in sinus rhythm compared to BE. CONCLUSION: microelectrode mapping is more sensitive than standard bipolar mapping in the identification of viable myocytes in SR, and may facilitate recognition of targets for CA.

Clinical and functional characterisation of a recurrent KCNQ1 variant in the Belgian population.

BACKGROUND: The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant. RESULTS: Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele. CONCLUSIONS: The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.

Anterior mitral line in patients with persistent atrial fibrillation and anterior scar: A multicenter matched comparison-The MiLine study.

BACKGROUND: The benefit of an anterior mitral line (AML) in patients with persistent atrial fibrillation (AF) and anterior atrial scar undergoing ablation has never been investigated. OBJECTIVE: The purpose of this study was to evaluate the outcomes of AML in addition to standard treatment compared to standard treatment alone (no AML) in this subset of patients. METHODS: Patients with persistent AF and anterior low-voltage zone (LVZ) treated with AML in 3 centers were retrospectively enrolled. The patients were matched in 1:1 fashion with patients having persistent AF and anterior LVZ who underwent conventional ablation in the same centers. Matching parameters were age, LVZ burden, and repeated ablation. Primary endpoint was AF/atrial tachycardia (AT) recurrence. RESULTS: One hundred eight-six patients (age 66 ± 9 years; 34% women) were selected and divided into 2 matched groups. Bidirectional conduction block was achieved in 95% of AML. After median follow-up of 2 years, AF/AT recurrence occurred in 29% of the patients in the AML group vs 48% in the no AML group (log-rank P = .024). On Cox regression multivariate analysis, left atrial volume (hazard ratio [HR] 1.03; P = .006) and AML (HR 0.46; P = .003) were significantly associated with the primary endpoint. On univariate logistic regression, lower body mass index, older age, extensive anterior LVZ, and position of the left atrial activation breakthrough away from the AML were associated with first-pass AML block. CONCLUSION: In this retrospective matched analysis of patients with persistent AF and anterior scar, AML in addition to standard treatment was associated with improved AF/AT-free survival compared to standard treatment alone.

Characterization of Atrial Substrate to Predict the Success of Pulmonary Vein Isolation: The Prospective, Multicenter MASH-AF II (Multipolar Atrial Substrate High Density Mapping in Atrial Fibrillation) Study.

Background Left atrial substrate may have mechanistic relevance for ablation of atrial fibrillation (AF). We sought to analyze the relationship between low-voltage zones (LVZs), transition zones, and AF recurrence in patients undergoing pulmonary vein isolation. Methods and Results We conducted a prospective multicenter study on consecutive patients undergoing pulmonary vein isolation-only approach. LVZs and transition zones (0.5-1 mV) were analyzed offline on high-density electroanatomical maps collected before pulmonary vein isolation. Overall, 262 patients (61±11 years, 31% female) with paroxysmal (130 pts) or persistent (132 pts) AF were included. After 28 months of follow-up, 73 (28%) patients experienced recurrence. An extension of more than 5% LVZ in paroxysmal AF and more than 15% in persistent AF was associated with recurrence (hazard ratio [HR], 4.4 [95% CI, 2.0-9.8], P<0.001 and HR, 1.9 [95% CI, 1.1-3.7], P=0.04, respectively). Significant association was found between LVZs and transition zones and between LVZs and left atrial volume index (LAVI) (both P<0.001). Thirty percent of patients had significantly increased LAVI without LVZs. Eight percent of patients had LVZs despite normal LAVI. Older age, female sex, oncological history, and increased AF recurrence characterized the latter subgroup. Conclusions In patients undergoing first pulmonary vein isolation, the impact of LVZs on outcomes occurs with lower burden in paroxysmal than persistent AF, suggesting that not all LVZs have equal prognostic implications. A proportional area of moderately decreased voltages accompanies LVZs, suggesting a continuous substrate instead of the dichotomous division of healthy or diseased tissue. LAVI generally correlates with LVZs, but a small subgroup of patients may present with disproportionate atrial remodeling, despite normal LAVI.

Electrocardiographic phenotype of exercise-induced arrhythmogenic cardiomyopathy: A retrospective observational study.

Introduction: The right ventricle can be susceptible to pathologic alterations with exercise. This can cause changes to the ECG. Our aim was to identify the electrocardiographic phenotype of exercise induced (ExI) arrhythmogenic cardiomyopathy (ACM). Methods: A retrospective analysis of ECGs at rest, peak exercise and 1 min of recovery in four groups of individuals was performed: Arrhythmogenic Cardiomyopathy with genetic confirmation (Gen-ACM; n = 16), (genetically negative) ExI-ACM (n = 15), control endurance athletes (End; n = 16) and sedentary individuals (Sed; n = 16). The occurrence of ventricular arrhythmias (VA) and, at each stage, QRS duration, Terminal Activation Delay (TAD), the ratio of the sum of the QRS durations in the right precordials (V1-V3) over that in the left precordials (V4-V6; R/L duration ratio), the presence of complete RBBB and T-wave inversion (TWI) beyond lead V2 were evaluated. Results: At rest, complete RBBB was exclusively found in Gen-ACM (6%) and ExI-ACM (13%). No epsilon waves were identified. TWI beyond V2 was uniquely present in Gen-ACM (73%) and ExI-ACM (38%; p < 0.001). VA was present in Gen-ACM (88%); ExI-ACM (80%), End (25%) and Sed (19%; p < 0.001). The presence of R/L duration ratio of >1.2 and TAD ≥ 55 ms were not significantly different over the four groups (p = 0.584 and p = 0.218, respectively). At peak exercise the most striking finding was a significant decrease of the R/L duration ratio in individuals with ACM, which was the result of lateral precordial QRS prolongation. Conclusion: ExI-ACM shares important ECG-features with Gen-ACM, suggesting a similar underlying pathogenesis regardless of the presence or absence of desmosomal mutations.

Indications and utility of cardiac genetic testing in athletes.

Sports Cardiology practice commonly involves the evaluation of athletes for genetically determined cardiac conditions that may predispose to malignant arrhythmias, heart failure, and sudden cardiac death. High-level exercise can lead to electrical and structural cardiac remodelling which mimics inherited cardiac conditions (ICCs). Differentiation between 'athlete's heart' and pathology can be challenging and often requires the whole armamentarium of available investigations. Genetic studies over the last 30 years have identified many of the genetic variants that underpin ICCs and technological advances have transformed genetic testing to a more readily available and affordable clinical tool which may aid diagnosis, management, and prognosis. The role of genetic testing in the evaluation and management of athletes with suspected cardiac conditions is often unclear beyond the context of specialist cardio-genetics centres. This document is aimed at physicians, nurses, and allied health professionals involved in the athlete's care. With the expanding role and availability of genetic testing in mind, this document was created to address the needs of the broader sports cardiology community, most of whom work outside specialized cardio-genetics centres, when faced with the evaluation and management of athletes with suspected ICC. The first part of the document provides an overview of basic terminology and principles and offers guidance on the appropriate use of genetic testing in the assessment of such athletes. It outlines key considerations when contemplating genetic testing, highlighting the potential benefits and pitfalls, and offers a roadmap to genetic testing. The second part of the document presents common clinical scenarios in Sports Cardiology practice, outlining the diagnostic, prognostic, and therapeutic implications of genetic testing, including impact on exercise recommendations. The scope of this document does not extend to a comprehensive description of the genetic basis, investigation, or management of ICCs.

Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy.

BACKGROUND: The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives. METHODS: Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant. RESULTS: Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered. CONCLUSIONS: Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk.

A new prediction model for left ventricular systolic function recovery after catheter ablation of atrial fibrillation in patients with heart failure: The ANTWOORD Study.

BACKGROUND: in patients with heart failure (HF) and atrial fibrillation (AF), AF ablation improves left ventricular ejection fraction (LVEF), along with prognosis, in a variable percentage of patients. We aimed to investigate the predictors of LVEF recovery after AF ablation and to develop a prediction model for individualized assessment. METHODS: we conducted an observational, retrospective, single-centre study on 111 consecutive patients with AF and HF with impaired LVEF (<50%) undergoing ablation. Patients were divided into Responder vs. Non-Responder according to the "Universal definition of HF". Clinical predictors were evaluated by multivariate logistic regression analysis and cross-validation technique. Independent predictors were used to build an internally validated prediction model. RESULTS: Responders (54%) had significantly shorter QRS duration and less dilated left atrium. Persistent AF and absence of a known etiology were more frequent among Responders. AF recurrence was similar between the two groups (p = 0.2), but the percentage of patient with persistent AF after ablation was significantly lower among Responders (p < 0.001). Absence of known etiology, presence of persistent AF, left atrial volume index<50 mL/m2, and QRS < 120 msec were independent predictors of LVEF recovery and composed the Score (AUC 0.93;95%CI 0.88-0.98-p < 0.001). Patients with Score ≤ 1 had 90% likelihood of LVEF recovery, compared to 5% in patients with 3-6. CONCLUSIONS: Patients with wide QRS, known HF etiology, dilated left atrium, and paroxysmal AF were less likely to recover LVEF after AF ablation. A new score system based on the above-mentioned parameters adequately predicts LVEF recovery after AF ablation. These results warrant confirmation and prospective validation.

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Morpho-functional comparison of differentiation protocols to create iPSC-derived cardiomyocytes.

Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) offer an attractive platform for cardiovascular research. Patient-specific iPSC-CMs are very useful for studying disease development, and bear potential for disease diagnostics, prognosis evaluation and development of personalized treatment. Several monolayer-based serum-free protocols have been described for the differentiation of iPSCs into cardiomyocytes, but data on their performance are scarce. In this study, we evaluated two protocols that are based on temporal modulation of the Wnt/ß-catenin pathway for iPSC-CM differentiation from four iPSC lines, including two control individuals and two patients carrying an SCN5A mutation. The SCN5A gene encodes the cardiac voltage-gated sodium channel (Nav1.5) and loss-of-function mutations can cause the cardiac arrhythmia Brugada syndrome. We performed molecular characterization of the obtained iPSC-CMs by immunostaining for cardiac specific markers and by expression analysis of selected cardiac structural and ionic channel protein-encoding genes with qPCR. We also investigated cell growth morphology, contractility and survival of the iPSC-CMs after dissociation. Finally, we performed electrophysiological characterization of the cells, focusing on the action potential (AP) and calcium transient (CT) characteristics using patch-clamping and optical imaging, respectively. Based on our comprehensive morpho-functional analysis, we concluded that both tested protocols result in a high percentage of contracting CMs. Moreover, they showed acceptable survival and cell quality after dissociation (>50% of cells with a smooth cell membrane, possible to seal during patch-clamping). Both protocols generated cells presenting with typical iPSC-CM AP and CT characteristics, although one protocol (that involves sequential addition of CHIR99021 and Wnt-C59) rendered iPSC-CMs, which were more accessible for patch-clamp and calcium transient experiments and showed an expression pattern of cardiac-specific markers more similar to this observed in human heart left ventricle samples.

Reproducibility and predictive value of a simple novel method to measure atrial fibrillation cycle length in persistent atrial fibrillation - FARS-AF study.

INTRODUCTION: Different methods are used for atrial fibrillation (AF) cycle length (CL) measurement with variable results. Previous studies of pulmonary vein (PV) CL measurement showed contradictory results on predicting PV isolation (PVI) efficacy. A novel simple method of measuring the average of 10 consecutive Fastest Atrial Repetitive Similar morphology signal (FARS10 )-CL to characterize local atrial activity rate was evaluated prospectively. METHODS: The intra-observer reproducibility of FARS10 -CL and traditional AF-CL measurement of continuously fragmented coronary sinus (CS) signals were tested. We prospectively enrolled 100 consecutive patients (62 ± 10 years, 72% male) undergoing wide antral PVI only ablation for persistent AF, measured PV-FARS10 -CLs, and evaluated long-term outcome. RESULTS: The Kendall area correlation between repeated traditional AF-CL measurements was -0.006 and between repeated FARS10 -CL measurements in the right and left atrial appendages, CS and PVs were 0.944, 0.859, 0.882, 0.675-0.955, respectively. Patients with recurrent atrial tachyarrhythmia had significantly longer fastest PV-FARS10 -CL (172 ± 41 vs. 156 ± 41 ms, p = .047). Patients with high burden of spontaneous low-voltage zone (LVZ) had significantly longer fastest PV-FARS10 -CL. Freedom from recurrent tachyarrhythmia at 24 months was 85% versus 59% in patients with fastest PV-FARS10 -CL ≤ 140 versus >140 ms, p = .0018, respectively. In multivariable analysis fastest PV-FARS10 -CL ≤ 140 ms was the only significant predictor of freedom from recurrent tachyarrhythmia. CONCLUSIONS: FARS10 -CL measurements have a high reproducibility in contrast to traditional AF-CL measurement of continuously fragmented CS signals. Patients with high burden of LVZ have longer fastest PV-FARS10 -CLs. Fastest PV-FARS10 -CL ≤ 140 ms is associated with a high success of wide antral PVI-only ablation approach in persistent AF.