Autonomic modulation of the electrical substrate in mice haploinsufficient for cardiac sodium channels: a model of the Brugada syndrome.

A murine line haploinsufficient in the cardiac sodium channel has been used to model human Brugada syndrome: a disease causing sudden cardiac death due to lethal ventricular arrhythmias. We explored the effects of cholinergic tone on electrophysiological parameters in wild-type and genetically modified, heterozygous, Scn5a+/- knockout mice. Scn5a+/- ventricular slices showed longer refractory periods than wild-type both at baseline and during isoprenaline challenge. Scn5a+/- hearts also showed lower conduction velocities and increased mean increase in delay than did littermate controls at baseline and blunted responses to isoprenaline challenge. Carbachol exerted limited effects but reversed the effects of isoprenaline with coapplication. Scn5a+/- mice showed a reduction in conduction reserve in that isoprenaline no longer increased conduction velocity, and this was not antagonized by muscarinic agonists.

Pharmacological Modulation of Right Ventricular Endocardial-Epicardial Gradients in Brugada Syndrome.

Background We explored the hypothesis that increased cholinergic tone exerts its proarrhythmic effects in Brugada syndrome (BrS) through increasing dispersion of transmural repolarization in patients with spontaneous and drug-induced BrS. Methods BrS and supraventricular tachycardia patients were studied after deploying an Ensite Array in the right ventricular outflow tract and a Cardima catheter in the great cardiac vein to record endo and epicardial signals, respectively. S1-S2 restitution curves from the right ventricular apex were conducted at baseline and after edrophonium challenge to promote increased cholinergic tone. The local unipolar electrograms were then analyzed to study transmural conduction and repolarization dynamics. Results The study included 8 BrS patients (5 men:3 women; mean age, 56 years) and 8 controls patients with supraventricular tachycardia (5 men:3 women; mean age, 48 years). Electrophysiological studies in controls demonstrated shorter endocardial than epicardial right ventricular activation times (mean difference: 26 ms; P<0.001). In contrast, patients with BrS showed longer endocardial than epicardial activation time (mean difference: -15 ms; P=0.001). BrS hearts, compared with controls, showed significantly larger transmural gradients in their activation recovery intervals (mean intervals, 20.5 versus 3.5 ms; P<0.01), with longer endocardial than epicardial activation recovery intervals. Edrophonium challenge increased such gradients in both controls (to a mean of 16 ms [ P<0.001]) and BrS (to 29.7 ms; P<0.001). However, these were attributable to epicardial and endocardial activation recovery interval prolongations in control and BrS hearts, respectively. Dynamic changes in repolarization gradients were also observed across the BrS right ventricular wall in BrS. Conclusions Differential contributions of conduction and repolarization were identified in BrS which critically modulated transmural dispersion of repolarization with significant cholinergic effects only identified in the patients with BrS. This has important implications for explaining the proarrhythmic effects of increased vagal tone in BrS, as well as evaluating autonomic modulation and epicardial ablation as therapeutic strategies.

Ventricular Arrhythmia after Acute Myocardial Infarction: 'The Perfect Storm'.

Ventricular tachyarrhythmias (VAs) commonly occur early in ischaemia, and remain a common cause of sudden death in acute MI. The thrombolysis and primary percutaneous coronary intervention era has resulted in the modification of the natural history of an infarct and subsequent VA. Presence of VA could independently influence mortality in patients recovering from MI. Appropriate risk assessment and subsequent treatment is warranted in these patients. The prevention and treatment of haemodynamically significant VA in the post-infarct period and of sudden cardiac death remote from the event remain areas of ongoing study.

Dynamic conduction and repolarisation changes in early arrhythmogenic right ventricular cardiomyopathy versus benign outflow tract ectopy demonstrated by high density mapping & paced surface ECG analysis.

AIMS: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy. METHODS: 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol. RESULTS: Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43 ± 20 ms) more than RVOT ectopy patients (36 ± 14 ms, p = 0.03) or Normals (25 ± 16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18 ± 20 ms; RVOT ectopy: 5 ± 14, Normal: 1 ± 18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls. CONCLUSIONS: Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.

Prevalence of J-point elevation in sudden arrhythmic death syndrome families.

OBJECTIVES: The purpose of this study was to assess the prevalence of J-point elevation among the relatives of sudden arrhythmic death syndrome (SADS) probands. BACKGROUND: J-point elevation is now known to be associated with idiopathic ventricular fibrillation. We hypothesized that this early repolarization phenomenon is an inherited trait responsible for a proportion of otherwise unexplained SADS cases. METHODS: Families of SADS probands were evaluated in an inherited arrhythmia clinic. Twelve-lead electrocardiograms were analyzed for J-point elevation defined as >0.1 mV from baseline present in 2 or more of the inferior (II, III, and aVF) or lateral (1, aVL, V(4) to V(6)) leads. Electrocardiographic data were compared with those of 359 controls of a similar age, sex, and ethnic distribution. RESULTS: A total of 363 first-degree relatives from 144 families were evaluated. J-point elevation in the inferolateral leads was present in 23% of relatives and 11% of control subjects (odds ratio: 2.54, 95% confidence interval: 1.66 to 3.90; p < 0.001). CONCLUSIONS: J-point elevation is more prevalent in the relatives of SADS probands than in controls. This indicates that early repolarization is an important potentially inheritable pro-arrhythmic trait or marker of pro-arrhythmia in SADS.