Unusual clinical description of adult with Timothy syndrome, carrier of a new heterozygote mutation of CACNA1C.

CANAC1C encodes for the main cardiac L-type calcium channel and mutations on it lead to a prolonged QT interval in Timothy Syndrome (TS). We provide a new de novo constitutional heterozygote missense variation in CACNA1C in a living adult woman, also carrier of the known c.2146-1G>C heterozygous variation of PKP2 inherited from her father. To our knowledge, this patient is the first to have the two variations in these genes. Theses clinical and molecular findings expand the clinical and molecular spectrum of TS and show the interest of next generation sequencing or whole exome sequencing in rare disorders, atypical or novel phenotype.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Management of atrial fibrillation in patients with rheumatic mitral stenosis.

Atrial fibrillation (AF) is frequent in patients with rheumatic mitral stenosis (MS). Pressure overload leads to marked structural and electrical remodelling of left atrium. The frequency of persistent AF increases with age and paroxysmal, asymptomatic, AF seems even more frequent. The occurrence of AF worsens the haemodynamic tolerance of MS and markedly increases the risk of thromboembolic events. AF has a negative impact on the natural history of MS and on its outcome after commissurotomy. The respective indications of rhythm and rate control should be adapted to patient characteristics, particularly the consequences of MS, and take into account the high risk of recurrence of AF. Oral anticoagulant therapy is mandatory when AF complicates MS, regardless of its severity and CHA2DS2-VASc score. Non-vitamin K antagonists oral anticoagulants are not recommended in moderate-to-severe MS due to the lack of data. Percutaneous mitral commissurotomy does not appear to prevent the occurrence of AF in MS but should be considered as the first-line therapy when AF is associated with severe symptomatic MS, followed by the discussion of cardioversion or ablation. AF ablation should be considered in patients with mitral disease requiring intervention, but the ideal timing and techniques are difficult to determine due to the lack of appropriate specific randomised trials in patients with MS.

High mass (>18g) of late gadolinium enhancement on CMR imaging is associated with major cardiac events on long-term outcome in patients with biopsy-proven extracardiac sarcoidosis.

BACKGROUND: Cardiac involvement is the most important cause of mortality in patients with systemic sarcoidosis. Late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging (CMR) has been shown to be a predictor of major cardiovascular adverse events (MACE) in the setting of systemic sarcoidosis. We sought to evaluate the relationship between LGE mass and adverse long-term outcome in patients with biopsy-proven extracardiac sarcoidosis. METHODS: Between 2001 and 2013, 197 consecutive patients with suspected cardiac sarcoidosis were identified in our institution database. Of them, 56 patients have had biopsy-proven extracardiac sarcoidosis and represented our studied population. Patients were divided into two groups based on LGE mass by a median value (mild LGE<18g, high LGE>18g) for comparison of MACE. RESULTS: Twenty-eight patients had a high mass of LGE. Of them, 15 (54%) experienced MACE (OR=31.15, 95% CI 3.7-262). Except for 1 patient, no patient with mild LGE presented with any MACE during follow-up (median of 32months). Patients with high LGE had lower CMR-derived left (53.6±14.9 vs. 62.2±6.7, p<0.01) and right (49.1±11.5 vs. 56.4±9.2, p<0.05) ventricular ejection fractions. LGE mass of 18g discriminated patients with and without MACE (93% sensitivity, 88% specificity, AUC=0.972). LGE mass was the only independent predictor of MACE on multivariate Cox analysis adjusted (OR=1.7, 95% CI 1.06 to 2.72, p=0.03). CONCLUSION: In biopsy-proven extracardiac sarcoidosis patients, a high mass of LGE >18g was associated with MACE.

Benign vs. malignant inferolateral early repolarization: Focus on the T wave.

BACKGROUND: Inferolateral early repolarization (ER) is highly prevalent and is associated with idiopathic ventricular fibrillation (VF). OBJECTIVE: The purpose of this study was to evaluate the potential role of T-wave parameters to differentiate between malignant and benign ER. METHODS: We compared the ECGs of patients with ER and VF (n = 92) with control subjects with asymptomatic ER (n = 247). We assessed J-wave amplitude, QTc interval, T-wave/R-wave (T/R) ratio in leads II and V5, and presence of low-amplitude T waves (T-wave amplitude <0.1 mV and <10% of R-wave amplitude in lead I, II, or V4-V6). RESULTS: Compared to controls, the VF group had longer QTc intervals (388 ms vs. 377 ms, P = .001), higher J-wave amplitudes (0.23 mV vs. 0.17 mV, P <.001), higher prevalence of low-amplitude T waves (29% vs. 3%, P <.001), and lower T/R ratio (0.18 vs. 0.30, P <.001). Logistic regression analysis demonstrated that QTc interval (odds ratio [OR] per 10 ms: 1.15, 95% confidence interval [CI} 1.02-1.30), maximal J-wave amplitude (OR per 0.1 mV: 1.68, 95% CI 1.23-2.31), lower T/R ratio (OR per 0.1 unit: 0.62, 95% CI 0.47-0.81), presence of low-amplitude T waves (OR 3.53, 95% CI 1.26-9.88). and presence of J waves in the inferior leads (OR 2.58, 95% CI 1.18-5.65) were associated with malignant ER. CONCLUSION: Patients with malignant ER have a higher prevalence of low-amplitude T waves, lower T/R ratio (lead II or V5), and longer QTc interval. The combination of these parameters with J-wave amplitude and distribution of J waves may allow for improved identification of malignant ER.

Microvolt T-wave alternans in short QT syndrome.

BACKGROUND: T-wave alternans (TWA) is an accepted marker of risk for malignant ventricular arrhythmias, for which prognosis value has been established in different populations. Short QT syndrome (SQTS) is a very rare primary electrical disease carrying the risk of ventricular fibrillation. TWA in SQTS has not been evaluated yet. METHODS: Thirteen patients with SQTS (QT = 308 ± 16 ms, QTc = 329 ± 10 ms, heart rate = 69 ± 8 beats/min) underwent microvolt TWA measurement using spectral analysis. TWA testing was performed using Heartwave II (Cambridge Heart™, Inc., Bedford, MA, USA) during bicycle exercice and classified as negative, positive, or indeterminate according to the published standards for clinical interpretation. RESULTS: Twelve patients were male (mean age 23 ± 5 years). Five were asymptomatic, three presented with aborted sudden cardiac death, and five with unexplained syncope. Six patients belonged to two unrelated families, while familial cases of SQTS were present for two other patients. A familial history of sudden death (SD) was present for seven patients. Ventricular fibrillation was inducible in three patients. Four patients were implanted with an implantable cardioverter-defibrillator and one presented with polymorphic ventricular tachycardia during follow-up. TWA was negative in each but one patient (indeterminate). Maximal negative heart rate was 118 ± 12 beats/min. Patients with previous SD displayed significant shorter QT and higher resting heart rate compared to the remaining cases. CONCLUSIONS: TWA testing is negative in 12 of 13 SQTS patients, even in the symptomatic or inducible ones. Measurement of TWA using conventional protocol and criteria for risk stratification in SQTS seems therefore useless.

The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands.

AIMS: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic disorder with a highly malignant clinical course. Exercise-stress test is the first-line approach to diagnose suspected individuals. We sought to elucidate the value of exercise-stress test for predicting mutations and future cardiac events in CPVT-family relatives. METHODS AND RESULTS: The present study included 67 asymptomatic relatives (24 ± 15 years) of 17 genetically positive CPVT probands, who underwent exercise-stress test without any medication and genetic testing. Exercise-stress test, which was considered positive with the induction of ventricular tachycardia or premature ventricular contractions consisting of bigeminy or couplets, was positive in 17 relatives (25%). Genetic analysis disclosed mutations in 16 of these 17 relatives (94%) and in 16 of the 50 relatives (32%) with negative exercise-stress test; the sensitivity and specificity for a positive genotype were 50 and 97%, respectively (P< 0.001). Among 32 mutation carriers, cardiac events occurred in 7 of the 16 relatives with positive and 2 of the 16 relatives with negative exercise-stress test during the follow-up period of 9.6 ± 3.8 years, and four with positive and two with negative stress test were not on regular beta-blocker treatment at these events. In the 16 relatives with positive stress test, those on beta-blocker treatment demonstrated a trend of lower cardiac event rate (Log-rank P= 0.054). CONCLUSION: In asymptomatic relatives of CPVT probands, exercise-stress test can be used as a simple diagnostic tool. Nevertheless, because of the low sensitivity for predicting mutations and future cardiac events in those with negative stress test, genetic analysis should be performed to improve patient management.

Decreased nocturnal standard deviation of averaged NN intervals. An independent marker to identify patients at risk in the Brugada Syndrome.

AIMS: Risk-stratification of asymptomatic Brugada Syndrome (BS) patients remains a key-issue. A typical spontaneous BS-ECG pattern and ventricular tachycardia (VT)/ventricular fibrillation (VF) inducibility are two recognized risk markers. The aim of the study was to identify additional risk markers in asymptomatic BS. METHODS AND RESULTS: We have compared Holter recordings in symptomatic and in asymptomatic patients with BS. Heart rate variability (HRV), QT-interval rate-dependence and ST-segment elevation (ST-SE) were analysed. The study population included 47 BS patients (M=36, mean age=45+/-13 years) with a malignant ventricular arrhythmia in 11 cases, an unexplained syncope in 10 cases and no symptoms in the remaining 26 cases. A typical spontaneous BS-ECG was present in 21 cases and a drug-induced BS-ECG in 26 cases. A downward trend of the time domain variables of HRV was observed. During the nocturnal period, standard deviation (SD) of the 5min averaged NN intervals (SDANN) (46+/-13 vs 57+/-18ms, P=0.02) and ultra low frequency component (3287+/-2312 vs 5030+/-3270 ms(2), P=0.04) were significantly lower in symptomatic versus asymptomatic patients. In contrast, no difference was found in QT-interval rate dependence and in ST-SE. At multivariate logistic regression, VT/VF inducibility, typical spontaneous BS-ECG and a decreased nocturnal SDANN were associated with arrhythmic events (P=0.003). CONCLUSIONS: A decreased nocturnal SDANN was an independent marker of arrhythmic events in these BS patients.

Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.

BACKGROUND: The long-QT and Brugada syndromes are important substrates of malignant ventricular arrhythmia. The feasibility of mapping and ablation of ventricular arrhythmias in these conditions has not been reported. METHODS AND RESULTS: Seven patients (4 men; age, 38+/-7 years; 4 with long-QT and 3 with Brugada syndrome) with episodes of ventricular fibrillation or polymorphic ventricular tachycardia and frequent isolated or repetitive premature beats were studied. These premature beats were observed to trigger ventricular arrhythmias and were localized by mapping the earliest endocardial activity. In 4 patients, premature beats originated from the peripheral right (1 Brugada) or left (3 long-QT) Purkinje conducting system and were associated with variable Purkinje-to-muscle conduction times (30 to 110 ms). In the remaining 3 patients, premature beats originated from the right ventricular outflow tract, being 25 to 40 ms ahead of the QRS. The accuracy of mapping was confirmed by acute elimination of premature beats after 12+/-6 minutes of radiofrequency applications. During a follow-up of 17+/-17 months using ambulatory monitoring and defibrillator memory interrogation, no patients had recurrence of symptomatic ventricular arrhythmia but 1 had persistent premature beats. CONCLUSIONS: Triggers from the Purkinje arborization or the right ventricular outflow tract have a crucial role in initiating ventricular fibrillation associated with the long-QT and Brugada syndromes. These can be eliminated by focal radiofrequency ablation.