Congenital Short QT Syndrome

Long QT intervals in the ECG have long been associated with sudden cardiac death. The congenital long QT syndrome was first described in individuals with structurally normal hearts in 1957.1 Little was known about the significance of a short QT interval. In 1993, after analyzing 6693 consecutive Holter recordings Algra et al concluded that an increased risk of sudden death was present not only in patients with long QT interval, but also in patients with short QT interval (<400 ms).2 Because this was a retrospective analysis, further evaluation of the data was not possible. It was not until 2000 that a short-QT syndrome (SQTS) was proposed as a new inherited clinical syndrome by Gussak et al.3 The initial report was of two siblings and their mother all of whom displayed persistently short QT interval. The youngest was a 17 year old female presenting with several episodes of paroxysmal atrial fibrillation requiring electrical cardioversion.3 Her QT interval measured 280 msec at a heart rate of 69. Her 21 year old brother displayed a QT interval of 272 msec at a heart rate of 58, whereas the 51 year old mother showed a QT of 260 msec at a heart rate of 74. The authors also noted similar ECG findings in another unrelated 37 year old patient associated with sudden cardiac death

Drug-induced spatial dispersion of repolarization

Spatial dispersion of repolarization in the form of transmural, trans-septal and apico-basal dispersion of repolarization creates voltage gradients that inscribe the J wave and T wave of the ECG. Amplification of this spatial dispersion of repolarization (SDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited or acquired ion channelopathies giving rise to the long QT, short QT and Brugada syndromes (BrS). This review focuses on the role of spatial dispersion of repolarization in drug-induced arrhythmogenesis associated with the long QT and BrS. In the long QT syndrome, drug-induced amplification of SDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the BrS, it is thought to be due to selective abbreviation of the APD of right ventricular epicardium. Among the challenges ahead is the identification of a means to quantitate SDR non-invasively. This review also discusses the value of the interval between the peak and end of the T wave (Tpeak-Tend, Tp-Te) as an index of SDR and transmural dispersion of repolarization, in particular. (Cardiol J 2008; 15: 100-121

Abnormal Repolarization as the Basis for Late Potentials and Fractionated Electrograms Recorded From Epicardium in Experimental Models of Brugada Syndrome

ObjectivesThe aim of this study was to test the hypothesis that late potentials and fractionated electrogram activity are due to delayed depolarization within the anterior aspects of right ventricular (RV) epicardium in experimental models of Brugada syndrome (BrS).BackgroundClinical reports have demonstrated late potentials on signal-averaged electrocardiography (ECG) recorded in patients with BrS. Recent studies report the appearance of late potentials and fractionated activity on bipolar electrograms recorded in the epicardium of the RV outflow tract in patients with BrS.MethodsAction potential and bipolar electrograms were recorded at epicardial and endocardial sites of coronary-perfused canine RV wedge preparations, together with a pseudo-ECG. The transient outward potassium current agonist NS5806 (5 μM) and the Ca2+-channel blocker verapamil (2 μM) were used to pharmacologically mimic the BrS genetic defect.ResultsFractionated electrical activity was observed in RV epicardium, but not in endocardium, as a consequence of heterogeneities in the appearance of the second upstroke of the epicardial action potential, and discrete high-frequency spikes developed as a result of concealed phase 2 re-entry. In no case did we observe primary conduction delay as the cause of the BrS ECG phenotype or of late potential or fractionated electrogram activity. Quinidine (10 μM) and the phosphodiesterase-3 inhibitors cilostazol (10 μM) and milrinone (2.5 μM) restored electrical homogeneity, thus abolishing all late potentials and fractionated electrical activity.ConclusionsThese data point to an alternative pathophysiological basis for late potentials and fractionated electrical activity recorded in the right ventricle in the setting of BrS. We demonstrate an association of such activity with abnormal repolarization and not with abnormal depolarization or structural abnormalities

Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome

AbstractOBJECTIVESTo define the cellular mechanisms responsible for the development of life-threatening arrhythmias in response to sympathetic activity in the congenital and acquired long QT syndromes (LQTS).METHODSTransmembrane action potentials (AP) from epicardial (EPI), M and endocardial (ENDO) cells and a transmural electrocardiogram were simultaneously recorded from an arterially perfused wedge of canine left ventricle. We examined the effect of beta-adrenergic agonists and antagonists on action potential duration (APD90), transmural dispersion of repolarization (TDR) and the development of Torsade de Pointes (TdP) in models of LQT1, LQT2 and LQT3 forms of LQTS.RESULTSIKsblock with chromanol 293B (LQT1) homogeneously prolonged APD90of the three cell types without increasing TDR. Addition of isoproterenol prolonged QT and APD90of M but abbreviated that of EPI and ENDO, causing a persistent increase in TDR; Torsade de Pointes developed or could be induced only in the presence of isoproterenol. IKrblock with d-sotalol (LQT2) and augmentation of late INawith ATX-II (LQT3) prolonged APD90of M more than EPI and ENDO, causing increases in QT and TDR. TdP developed in the absence of isoproterenol. In LQT2 isoproterenol initially prolonged, then abbreviated, the APD90of M but always abbreviated EPI, thus transiently increasing TDR and the incidence of TdP. In LQT3, isoproterenol always abbreviated APD90of the three cell types, causing a persistent decrease in TDR and suppression of TdP. The arrhythmogenic as well as protective actions of isoproterenol were reversed by propranolol.CONCLUSIONSOur data suggest that beta-adrenergic stimulation induces TdP by increasing transmural dispersion of repolarization in LQT1 and LQT2 but suppresses TdP by decreasing dispersion in LQT3. The data indicate that beta-blockers are protective in LQT1 and LQT2 but may facilitate TdP in LQT3

J-wave syndromes: Brugada and early repolarization syndromes.

A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada syndrome and early repolarization syndromes. Brugada syndrome and early repolarization syndromes differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J-wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these 2 inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, and molecular, ionic, cellular, and genetic mechanisms underlying these 2 fascinating syndromes that have captured the interest and attention of the cardiology community in recent years

Przestrzenna dyspersja okresu repolaryzacji wywołana działaniem leków

Przestrzenna dyspersja okresu repolaryzacji pod postacią przezściennej, przezprzegrodowej oraz koniuszkowo-podstawnej dyspersji okresu repolaryzacji powoduje powstanie gradientu napięcia, który jest odpowiedzialny za powstawanie załamka T oraz fali J w zapisie elektrokardiograficznym. Amplifikacja przestrzennej dyspersji okresu repolaryzacji leży u patofizjologicznych podstaw rozwoju zagrażających życiu arytmii komorowych związanych z wrodzonymi bądź nabytymi kanałopatiami odpowiedzialnymi za zespół długiego QT, zespół krótkiego QT oraz zespół Brugadów (BrS). W niniejszej pracy skupiono się głównie na roli przestrzennej dyspersji okresu repolaryzacji w arytmogenezie indukowanych działaniem leków zespołu długiego QT oraz zespołu Brugadów. W przypadku zespołu długiego QT wywołana przez leki amplifikacja procesu przestrzennej dyspersji okresu repolaryzacji jest często wtórna do preferencyjnego wydłużenia czasu trwania potencjału czynnościowego komórek M. Z kolei w przypadku BrS powszechnie uważa się, że jest on wywołany selektywnym skróceniem czasu trwania potencjału czynnościowego w komórkach podnasierdziowych leżących w obrębie prawej komory. Jednym z najważniejszych wyzwań związanych z tą tematyką jest próba identyfikacji sposobów i metod ilościowej oceny stopnia przestrzennej dyspersji okresu repolaryzacji w sposób nieinwazyjny. W niniejszym opracowaniu poruszono także zagadnienie znaczenia różnicy czasu pomiędzy szczytem a końcem załamka T (T peak-T end) jako wykładnika procesu przestrzennej (a także przezściennej) dyspersji okresu repolaryzacji mięśniówki komór

Brugada syndrome: 12 years of progression.

Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease.</p

Tissue-specific effects of acetylcholine in the canine heart

Acetylcholine (ACh) release from the vagus nerve slows heart rate and atrioventricular conduction. ACh stimulates a variety of receptors and channels, including an inward rectifying current [ACh-dependent K(+) current (I(K,ACh))]. The effect of ACh in the ventricle is still debated. We compared the effect of ACh on action potentials in canine atria, Purkinje, and ventricular tissue as well as on ionic currents in isolated cells. Action potentials were recorded from ventricular slices, Purkinje fibers, and arterially perfused atrial preparations. Whole cell currents were recorded under voltage-clamp conditions, and unloaded cell shortening was determined on isolated cells. The effect of ACh (1–10 μM) as well as ACh plus tertiapin, an I(K,ACh)-specific toxin, was tested. In atrial tissue, ACh hyperpolarized the membrane potential and shortened the action potential duration (APD). In Purkinje and ventricular tissues, no significant effect of ACh was observed. Addition of ACh to atrial cells activated a large inward rectifying current (from −3.5 ± 0.7 to −23.7 ± 4.7 pA/pF) that was abolished by tertiapin. This current was not observed in other cell types. A small inhibition of Ca(2+) current (I(Ca)) was observed in the atria, endocardium, and epicardium after ACh. I(Ca) inhibition increased at faster pacing rates. At a basic cycle length of 400 ms, ACh (1 μM) reduced I(Ca) to 68% of control. In conclusion, I(K,ACh) is highly expressed in atria and is negligible/absent in Purkinje, endocardial, and epicardial cells. In all cardiac tissues, ACh caused rate-dependent inhibition of I(Ca.

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, p &lt; 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, p = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-SCN5A variants, which may be pathogenic in some ancestries but only disease-predisposing in others