Françoise Hidden-Lucet

Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

AIMS Five desmosomal genes have been recently implicated in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) but the clinical impact of genetics remains poorly understood. We wanted to address the potential impact of genotyping. METHODS AND RESULTS Direct sequencing of the five genes (JUP, DSP, PKP2, DSG2, and DSC2) was performed in 135 unrelated patients with ARVD/C. We identified 41 different disease-causing mutations, including 28 novel ones, in 62 patients (46%). In addition, a genetic variant of unknown significance was identified in nine additional patients (7%). Distribution of genes was 31% (PKP2), 10% (DSG2), 4.5% (DSP), 1.5% (DSC2), and 0% (JUP). The presence of desmosomal mutations was not associated with familial context but was associated with young age, symptoms, electrical substrate, and extensive structural damage. When compared with other genes, DSG2 mutations were associated with more frequent left ventricular involvement (P = 0.006). Finally, complex genetic status with multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (P = 0.047). CONCLUSION This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.

Long-term efficacy of low doses of quinidine on malignant arrhythmias in Brugada syndrome with an implantable cardioverter-defibrillator: A case series and literature review

BACKGROUND To prevent the recurrence of ventricular arrhythmias (VA) in Brugada syndrome (BrS), only quinidine has been consistently reported to have a beneficial effect. Recommended doses are ≥ 1 g/d. The efficacy of lower doses of quinidine has been suggested on the basis of a few isolated experiences. OBJECTIVES To describe the efficacy and safety of doses ≤ 600 mg/d of quinidine after cardioverter-defibrillator implantation in BrS at 2 referral centers and to compare those results with a comprehensive review of the literature. METHODS In a retrospective analysis of medical records from the 2 centers, 6 men with BrS who received ≤ 600 mg/d of quinidine sulfate or hydroquinidine after cardioverter-defibrillator implantation were identified. Quinidine was initiated after arrhythmic syncope or appropriate shocks, including arrhythmic storm in 4. A literature search was performed to find previous cases with symptomatic BrS reported as having received ≤ 600 mg/d of quinidine. RESULTS Quinidine prevented recurrence of VA in all patients from our series without side effects during a median follow-up of 4 years (from 2 to 8 years). In the literature review, 14 additional adults were found. With the exception of 3, quinidine effectively suppressed arrhythmic events in all of them. Four subjects who discontinued the medication experienced VA recurrence, successfully treated by restarting quinidine. CONCLUSIONS Low doses of quinidine were well tolerated and effective to prevent the recurrence of VA, including arrhythmic storm, in subjects with BrS with an implantable cardioverter-defibrillator. Effectiveness of quinidine or hydroquinidine in doses ≤ 600 mg/d is 85%.

Expert consensus document: Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

Effects of cardiac resynchronization therapy on echocardiographic indices, functional capacity, and clinical outcomes of patients with a systemic right ventricle

AIMS Surgically (SC) or congenitally corrected (CC) transposition of the great arteries (TGA), associated with a systemic right ventricle (RV), is often complicated by heart failure. This retrospective study assessed the functional and mechanical effects of cardiac resynchronization therapy (CRT) in patients presenting with TGA. METHODS AND RESULTS Seven patients with SC (n = 5) or CC (n = 2) TGA (mean age 24.6 +/- 12 years), a failing systemic RV, and intraventricular dyssynchrony, underwent implantation of a CRT-P. Permanent pacemakers were previously implanted in five patients. The leads were implanted by a combined transvenous and epicardial approach in the five patients with SC TGA. Echocardiography, including tissue Doppler imaging and cardiopulmonary exercise testing were performed before and during CRT. Since, in all patients, ventricular dyssynchrony was due to delayed septal wall contraction, the interventricular septum and RV free wall were stimulated synchronously, with a view to resynchronize a maximum amount of myocardium. After 19.4 +/- 8.1 months of CRT, mean QRS duration decreased from 160 +/- 31 to 120 +/- 28 ms (P = 0.03), intraventricular delay from 104 +/- 27 to 14 +/- 15 ms (P = 0.01), New York Heart Association functional class from 3.0 to 1.57 (P = 0.01), and peak oxygen consumption increased from 13.8 +/- 2.5 to 22.8 +/- 6.7 mL/kg/min (P = 0.03). One patient died suddenly at 23 months of follow-up. CONCLUSIONS CRT was technically feasible and associated with improvements in cardiac mechanical function and clinical status in patients with TGA, failing systemic RV, and intraventricular dyssynchrony.

Causes-of-death analysis of patients with cardiac resynchronization therapy: an analysis of the CeRtiTuDe cohort study

Aims The choice of resynchronization therapy between with (CRT-D) and without (CRT-P) a defibrillator remains a contentious issue. Cause-of-death analysis among CRT-P, compared with CRT-D, patients could help evaluate the extent to which CRT-P patients would have additionally benefited from a defibrillator in a daily clinical practice. Methods and results A total of 1705 consecutive patients implanted with a CRT (CRT-P: 535 and CRT-D: 1170) between 2008 and 2010 were enrolled in CeRtiTuDe, a multicentric prospective follow-up cohort study, with specific adjudication for causes of death at 2 years. Patients with CRT-P compared with CRT-D were older (P < 0.0001), less often male (P < 0.0001), more symptomatic (P = 0.0005), with less coronary artery disease (P = 0.003), wider QRS (P = 0.002), more atrial fibrillation (P < 0.0001), and more co-morbidities (P = 0.04). At 2-year follow-up, the annual overall mortality rate was 83.80 [95% confidence interval (CI) 73.41–94.19] per 1000 person-years. The crude mortality rate among CRT-P patients was double compared with CRT-D (relative risk 2.01, 95% CI 1.56–2.58). In a Cox proportional hazards regression analysis, CRT-P remained associated with increased mortality (hazard ratio 1.54, 95% CI 1.07–2.21, P = 0.0209), although other potential confounders may persist. By cause-of-death analysis, 95% of the excess mortality among CRT-P subjects was related to an increase in non-sudden death. Conclusion When compared with CRT-D patients, excess mortality in CRT-P recipients was mainly due to non-sudden death. Our findings suggest that CRT-P patients, as currently selected in routine clinical practice, would not potentially benefit with the addition of a defibrillator.

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.

Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening.

BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2. OBJECTIVE We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. METHODS We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations. RESULTS We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available. CONCLUSION In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.

Effects of inadvertent atrioventricular block on clinical outcomes during cryoablation of the slow pathway in the treatment of atrioventricular nodal re-entrant tachycardia

AIMS The study aimed at evaluating the long-term effects of transient atrioventricular (AV) block on clinical outcomes during atrioventricular nodal re-entrant tachycardia (AVNRT) cryoablation. METHODS AND RESULTS In 150 consecutive patients (39 +/- 14 years, ineffective anti-arrhythmic drugs 1.9 +/- 1.3), slow-pathway cryoablation for AVNRT was performed. A 7 Fr 6 mm-tip cryocatheter was used. After successful cryomapping (-30 degrees C), defined as jump abolition or AV nodal refractory period prolongation, cryoablation (-80 degrees C for 4 min) was applied if no AV block occurred. Atrioventricular nodal re-entrant tachycardia inducibility was checked after 30 min. Acute success (AVNRT non-inducibility) was achieved in 142 patients (95%). Overall, after a follow-up of 18 +/- 10 months, 118 of 150 patients (79%) were recurrence-free (including 2 patients for whom the procedure was unsuccessful). Among successful procedures, 116 of 142 (82%) patients were recurrence-free. During cryoablation, inadvertent transient AV block of varying degrees occurred in 34 patients (22.7%), namely, increased PR in 17 patients and a 2nd-3rd AV block in the remaining 17. In 24 patients, AV block occurred at the last effective site (increased PR in 13 patients and a 2nd-3rd AV block in 11). In the study population as a whole, univariate predictors of recurrence in the follow-up were AVNRT inducibility (P < 0.001), increased PR at the last effective site (P < 0.001), residual jump (P < 0.02), and small Kochs triangle (X-ray distance < 11 mm between the His and coronary sinus ostium catheters; P < 0.02). Atrioventricular nodal re-entrant tachycardia inducibility (P < 0.03), increased PR (P < 0.01), and small Kochs triangle (P< 0.04) were independently significant. For attempts at the last effective site, 3 groups of patients were compared: 13 patients with increased PR duration (Group A), 11 with a 2nd-3rd AV block (Group B), and 126 without AV block (Group C). Cryo-application time was 277 +/- 203 s in Group A, 75 +/- 87 s in Group B, and 253 +/- 135 s in Group C (A vs. B, P < 0.01; B vs. C, P < 0.001; and C vs. A, P= NS). There was no statistical difference among groups in the atriogram/ventriculogram amplitude ratio at the site of the last attempt, unsuccessful acute procedure, small Kochs triangle, and residual jump. Actuarial incidence of recurrence-free status at 12 months was 38% in A, 82% in B, and 82% in C (A vs. B, P < 0.05; B vs. C, P = NS; and C vs. A, P < 0.001). CONCLUSION All AV blocks occurring during cryoablation were transient, confirming the safety of this method. An increased PR duration at the last effective site is associated with a higher recurrence rate, whereas a 2nd-3rd degree AV block has a recurrence rate similar to that of patients without AV block despite a shorter cryo-application time at the last site.

A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation

BACKGROUND Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias. OBJECTIVE To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. METHODS Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. RESULTS The mutant channel expressed alone caused a 70% reduction in inward sodium current (INa) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of INa were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2, a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in INa at the atrial potential. CONCLUSION We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.

Brugada ECG pattern: a physiopathological prospective study based on clinical, electrophysiological, angiographic, and genetic findings

Introduction: Brugada syndrome (BrS) is considered a primary electrical disease. However, morphological abnormalities have been reported and localized arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) may mimic its phenotype, raising the question of an overlap between these two conditions and making difficult the therapeutic management of patients with borderline forms. The main objective of this study was to assess prospectively the prevalence of BrS and ARVD/C on the basis of international criteria, in patients with BrS-ECG and normal echocardiography, looking for a potential overlap between the two pathologies. The secondary objectives were to describe and quantify angiographic structural alterations, hemodynamics, electrophysiology, and genetics in the setting of BrS-ECG. Materials and Methods: Hundred and fourteen consecutive patients matched in age underwent prospectively cardiac catheterization and quantitative biventricular contrast angiography to rule out a structural heart disease. Fifty-one patients with a BrS-ECG (BrS group, 7 F, 44 M, 43 ± 11 y) had a spontaneous or ajmaline-induced BrS coved type ECG. For angiographic comparison, 49 patients with localized ARVD/C but without ST segment elevation in the right precordial leads (14 F, 35 M, 39 ± 13 y) were also studied. They fulfilled international ESC/WHF 2000 criteria and presented angiographic localized forms, mainly confined to hypokinetic anteroapical zone (characterized by trabecular dysarray and hypertrophy), and/or diaphragmatic wall, thus resulting in RV normal volumes and preserved systolic function. These two populations were also compared with 14 control patients (7 F, 7 M, 38 ± 16 y). Among BrS group, we identified three main angiographic phenotypes: BrS group I = patients with normal RV (n = 15, 29%); BrS group II = patients with segmental RV wall motion abnormalities but no structural arguments for ARVD/C (n = 26, 51%); BrS group III = patients with localized abnormalities suggestive of focal ARVD/C (n = 10, 20%). Results: Among BrS group, 34/51 patients (67%) fulfilled BrS HRS/EHRA 2005 criteria. Nineteen (37%) were symptomatic for aborted sudden death, agonal nocturnal respiration or syncope. Ventricular stimulation was positive in 14 patients (28%). Angiography showed RV abnormalities in 36/51 patients (71%) of BrS group (BrS groups II and III). Late potentials were present in 73% (100% sensitivity and NPV for an angiographic ARVD/C, but poor specificity and PPV, both 37%). In BrS group III, 8/10 patients (16% of BrS patients) finally fulfilled international ESC/WHF 2000 ARVD/C criteria and 5/10 (10% of BrS patients) fulfilled BrS diagnostic criteria. An overlap was observed in 4 patients (8% of BrS patients) who fulfilled both ARVD/C and BrS criteria. Among the 45 genotyped patients, only one presented a SCN5A mutation, whereas a TRPM4 mutation was found in another patient. Both belonged to BrS group II. MOG1 gene analysis was negative for all patients, as were PKP2, DSP, DSG2, and DSC2 analyzes performed in BrS group III. Conclusions: Seventy-one percent of patients with a BrS-ECG had abnormal RV wall motion and 16 had structural alterations corresponding to localized (anteroapical and/or diaphragmatic) ARVD/C. Moreover, 8% of BrS-ECG patients fulfilled both BrS and ARVD/C criteria. Our results support the hypothesis of an overlap between BrS and localized forms of ARVD/C. Conversely, genetic screening was poorly contributive for both diseases in the present series.