Background
Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. ...SCN5A‐E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype–phenotype relationship in a large family carrying SCN5A‐E1784K and SCN5A‐H558R polymorphism.
Methods and Results
Clinical work‐up, follow‐up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A‐E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A‐H558R did not significantly alter the phenotype of SCN5A‐E1784K carriers. Fourteen SCN5A‐E1784K patients underwent implantable cardioverter‐defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow‐up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A‐E1784K and SCN5A‐H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole‐cell patch‐clamp techniques. Co‐expression of SCN5A‐E1784K and SCN5A‐WT reduced INa,P to 70.03% of WT, shifted steady‐state inactivation by −11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A‐E1784K was co‐expressed with SCN5A‐H558R.
Conclusions
We demonstrate a strong genotype‐phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A‐E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.
Background Short QT syndrome ( SQTS ) is a rare inheritable disease associated with sudden cardiac death. Data on long-term outcomes of families with SQTS are limited. Methods and Results Seventeen ...patients with SQTS in 7 independent families (48% men; median age, 42.4 years; corrected QT interval, 324.9±40.8 ms) were followed up for 13.5±2.5 years. A history of sudden cardiac death was documented in 71% of families. A large number of them showed sudden cardiac deaths at a younger age, with a predominance of men (67%). Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter. An SQTS -related gene was found in 76% of the patients as follows: KCNH 2 ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6. Five patients (29%) received an implantable cardioverter-defibrillator and 5 patients received long-term prophylaxis with hydroquinidine. During follow-up, 1 patient received an appropriate implantable cardioverter-defibrillator shock attributable to ventricular fibrillation. The patient received no further implantable cardioverter-defibrillator shocks after treatment with hydroquinidine. Conclusions The risk of sudden cardiac death in SQTS families is high. However, after appropriate risk assessment and individualized treatment options (hydroquinidine and/or implantable cardioverter-defibrillator), the long-term outcome is relatively benign when patients are seen at a reference center.
Short QT syndrome (SQTS) is associated with sudden cardiac arrest. There are limited data on the impact of antiarrhythmic drugs on the outcome of SQTS.
We studied data that describe the clinical ...outcome of 62 SQTS patients treated with antiarrhythmic drugs, who were recruited from a pool of patients diagnosed in our institution and also from known databases after a systematic search of the published literature.
Sixty-two SQTS patients treated with antiarrhythmic drugs were followed up over a median timeframe of 5.6 years (interquartile range 1.6-7.7 years). Six patients, in particular, received multiple drugs as a combination. Of the 55 patients treated with hydroquinidine (HQ), long-term prophylaxis was documented in 41 patients. Fourteen patients stopped treatment due to the following reasons: gastrointestinal intolerance (n = 4), poor compliance (n = 8), and no QTc prolongation (n = 2). Of the 41 patients treated with HQ, the QTc interval increased from 313.5 ± 17.2 to 380.1 ± 21.2 ms. Thirteen of the 41 patients suffered from at least one or more ventricular tachyarrhythmias (VAs) before HQ initiation. VAs are reduced in incidence after HQ treatment (13/41: 31% versus 3/41: 7.3%, p < 0.001).
HQ increases the corrected QT interval and prevents VAs in the majority of the patients in this cohort. HQ is safe for use in SQTS patients, particularly due to its low rate of side effects. Other antiarrhythmic drugs might be useful, but the data justifying their use are sparse.
Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes.
To identify and characterize variations in SCN1Bb associated with Brugada syndrome ...(BrS) and sudden infant death syndrome (SIDS).
All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques.
Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3.
Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.
Short QT syndrome (SQTS) is a rare syndrome and affects different types of genes. However, data on differences of clinical profile and outcome of different SQTS types are sparse.
We conducted a ...pooled analysis of 110 SQTS patients. Patients have been diagnosed between 2000 and 2017 at our institution (n = 12) and revealed using a literature review (n = 98). 29 studies were identified by analysing systematic data bases (PubMed, Web of Science, Cochrane Libary, Cinahl).
67 patients with genotype positive SQTS origin and 43 patients with genotype negative origin were found. A significant difference is documented between the sex with a higher predominance of male in genotype negative SQTS patients and predominance of females in genotype positive SQTS patients (male 52% versus 84%, female 45% versus 14%; p = 0.0016). No relevant difference of their median age (genotype positive 27 ± 19 versus genotype negative 29 ± 15; p = 0.48) was found. Asymptomatic patients and patients reporting symptoms such as syncope, sudden cardiac death, atrial flutter and ventricular fibrillation documented in both groups were similar except atrial fibrillation (genotype positive 19% versus genotype negative 0%; p = 0.0055). The QTc interval was not significantly different in both groups (genotype positive 315 ± 32 versus genotype negative 320 ± 19; p = 0.30). The treatments (medical treatment and ICD implantation) in both groups were comparable. Electrophysiology studies were not significantly higher documented in patients with genotype positive and negative origin (24% versus 9%; p = 0.075). Events at follow up such as VT, VF, and SCD were not higher presented in patients with genotype positive (13% versus 9%) (p = 0.25). 54% of genotype positive SQTS patients showed SQTS 1 followed by STQS 2 (21%) and SQTS 3 (10%).
The long-term risk of a malignant arrhythmic event is not higher in patients with genotype positive. However, patients with genotype positive present themselves more often with AF with a female predominance. Also, other events at follow up such as syncope, atrial flutter and palpitation were not significantly higher (9% versus 0%; p = 0.079).
PURPOSE OF REVIEWSudden cardiac death in patients without structural heart disease remains a challenge in diagnostics and risk stratification. Genetically determined arrhythmias are a potential cause ...for a primary electrical disease. A recently discovered primary electrical disease is discussed.
RECENT FINDINGSThe inherited short QT syndrome is a recently recognized genetic condition, which is associated with atrial fibrillation, syncope and/or sudden cardiac death. Attention has been focused on diagnostic ECG features, the identification of underlying mutations and mechanisms of arrhythmogenesis.
SUMMARYThe short QT syndrome is clinically associated with atrial fibrillation, syncope and sudden cardiac death. A shortened QT interval (QTc <360 ms) and reduced ventricular refractory period together with an increased dispersion of repolarization constitute the potential substrate for reentry and life-threatening ventricular tachyarrhythmia. To date, gain-of-function mutations in KCNH2, KCNQ1, KCNJ2, encoding potassium channels and loss-of-function mutations in CACNA1C and CACNB2b, encoding L-type calcium channel subunits have been identified. The therapy of choice is the implantable cardioverter defibrillator in symptomatic patients. Quinidine has been shown to prolong the QT interval and to normalize the effective refractory periods of the atrium and ventricle in patients with short QT-1 syndrome.
The arrhythmogenic potential of short QT intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-interval prolongation is a known risk factor for ventricular ...tachyarrhythmias. However, reports on drug-induced QT-interval shortening are rare and proarrhythmic effects remain unclear.
Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT intervals in patients with difficult-to-treat epilepsies.
Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and T(peak)-T(end) intervals were analyzed before and during rufinamide treatment.
The mean QT interval shortened significantly following rufinamide administration (QT interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). T(peak)-T(end) intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed.
QTc-interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations notwithstanding, the ability of rufinamide to significantly shorten the QT interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.
Background: Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial ...fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS.
Methods and Results:
Pinacidil, an IK‐ATP channel opener, was administered in increasing concentrations (50–100 μM) in 48 Langendorff‐perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the IKr blocker sotalol (100 μM) and the class I antiarrhythmic drugs flecainide (2 μM) and quinidine (0.5 μM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with sotalol and flecainide. Moreover, quinidine, in contrast to sotalol and flecainide, reduced dispersion of repolarization.
Conclusion: Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.
Introduction: Inappropriate implantable cardioverter defibrillator (ICD) therapy carries a low but relevant risk of ventricular proarrhythmia. In the present case, the extremely rare event of a fatal ...arrhythmia caused by inappropriate therapy is reported. Dislodgement of the ventricular lead to the level of the tricuspid annulus led to additional sensing of the atrial signal during sinus tachycardia. Spuriously, ventricular fibrillation was sensed and induced inappropriate ICD shocks. The fourth inappropriate shock caused ventricular fibrillation, which was subsequently undersensed by the dislodged lead due to low ventricular amplitudes. The ICD started antibradycardic pacing during ventricular fibrillation. After initial successful resuscitation, the patient died 1 week later due to severe hypoxic brain damage. Although not preventable in the present case, it underlines the necessity of immediate interrogation of the ICD after ICD therapy and deactivation of the ICD in the setting of a dislodged endocardial lead and intensive care monitoring of the patient until revision.
Myocardial fibrosis is frequently identified in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to investigate the role of myocardial fibrosis detected by late ...gadolinium-enhancement (LGE) cardiovascular magnetic resonance (CMR) as a potential arrhythmogenic substrate in HCM. We hypothesized that the extent of LGE might be associated with the inducibility of ventricular tachyarrhythmias (VT) during programmed ventricular stimulation (PVS).
We evaluated retrospectively LGE CMR of 76 consecutive HCM patients, of which 43 presented with one or more risk factors for sudden cardiac death (SCD) and were therefore clinically classified as high-risk patients. Of these 43 patients, 38 additionally underwent an electrophysiological testing (EP). CMR indices and the extent of LGE, given as the % of LV mass with LGE were correlated with the presence of risk factors for SCD and the results of EP.
High-risk patients had a significant higher prevalence of LGE than low-risk patients (29/43 67% versus 14/33 47%; p = 0.03). Also the % of LV mass with LGE was significantly higher in high-risk patients than in low-risk patients (14% versus 3%, p = 0.001, respectively). Of the 38 high- risk patients, 12 had inducible VT during EP. LV function, volumes and mass were comparable in patients with and without inducible VT. However, the % of LV mass with LGE was significantly higher in patients with inducible VT compared to those without (22% versus 10%, p = 0.03). The prevalence of LGE was, however, comparable between HCM patients with and those without inducible VT (10/12 83% versus 15/26 58%; p = 0.12). In the univariate analysis the % of LV mass with LGE and the septal wall thickness were significantly associated with the high-risk group (p = 0.001 and 0.004, respectively). Multivariate analysis demonstrated that the extent of LGE was the only independent predictor of the risk group (p = 0.03).
The extent of LGE in HCM patients correlated with risk factors of SCD and the likelihood of inducible VT. Furthermore, LGE extent was the only independent predictor of the risk group. This supports the hypothesis that the extent of fibrosis may serve as potential arrhythmogenic substrate for the occurrence of VT, especially in patients with clinical risk factors for SCD.
PDF
