Acute complications of electrophysiology and pacing procedures: identification and management.

Non-pharmacologic interventional techniques for treatment and management of almost all cardiac arrhythmias have greatly expanded over the past decade. These newer interventional electrophysiologic techniques continue to demonstrate increasing success at achieving their targeted goals, and enhancing the patient's quality of life. However, like all interventional procedures, complications may result. In this article we provide the reader with an overview of the more common and significant adverse events that may follow electrophysiologic and pacing procedures, and how best to recognize and manage these complications. After providing the reader with an overview of the complications inherent to all electrophysiologic procedures, we will detail the adverse events intrinsic to specific therapeutic electrophysiologic interventions (DC cardioversion, pharmacologic-based cardioversion, antitachycardia pacing, and ablation of specific arrhythmias). In the last part of the review, we will delineate complications associated with pacing procedures (pacemaker and defibrillator implantation, biventricular pacing and pacing lead extraction).

Ventricular arrhythmia vulnerability in cardiomyopathic mice with homozygous mutant Myosin-binding protein C gene.

BACKGROUND: Homozygous mutant mice expressing a truncated form of myosin-binding protein C (MyBP-C(t/t)) develop severe dilated cardiomyopathy, whereas the heterozygous mutation (MyBP-C(t/+)) causes mild hypertrophic cardiomyopathy. Adult male MyBP-C(t/t) and MyBP-C(t/+) mice were evaluated for arrhythmia vulnerability with an in vivo electrophysiology study. METHODS AND RESULTS: Surface ECGs were obtained for heart rate, rhythm, and conduction intervals. Atrial, atrioventricular, and ventricular conduction parameters and refractoriness were assessed in 22 MyBP-C(t/t), 10 MyBP-C(t/+), and 17 wild-type MyBP-C(+/+) mice with endocardial pacing and intracardiac electrogram recording. Arrhythmia induction was attempted with standardized programmed stimulation at baseline and with isoproterenol. Heart rate variability and ambient arrhythmia activity were assessed with telemetric ECG monitors. Quantitative histological characterization was performed on serial sections of excised hearts. MyBP-C(t/t) and MyBP-C(t/+) mice have normal ECG intervals and sinus node, atrial, and ventricular conduction and refractoriness. Ventricular tachycardia was reproducibly inducible in 14 of 22 MyBP-C(t/t) mice (64%) during programmed stimulation, compared with 2 of 10 MyBP-C(t/+) mice (20%) and 0 of 17 wild-type controls (P<0.001). Ventricular ectopy was present only in MyBP-C(t/t) mice during ambulatory ECG recordings. There were no differences in heart rate variability parameters. Interstitial fibrosis correlated with genotype but did not predict arrhythmia susceptibility within the MyBP-C(t/t) group. CONCLUSIONS: MyBP-C(t/t) mice, despite prominent histopathology and ventricular dysfunction, exhibit normal conduction and refractoriness, yet are vulnerable to ventricular arrhythmias. Somatic influences between genetically identical mutant mice most likely account for variability in arrhythmia susceptibility. A sarcomeric protein gene mutation leads to a dilated cardiomyopathy and ventricular arrhythmia vulnerability phenotype.

Supraventricular arrhythmias in children and young adults with implantable cardioverter defibrillators.

INTRODUCTION: Rapidly conducted supraventricular tachycardias (SVTs) can lead to inappropriate device therapy in implantable cardioverter defibrillator (ICD) patients. We sought to determine the incidence of SVTs and the occurrence of inappropriate ICD therapy due to SVT in a pediatric and young adult population. METHODS AND RESULTS: We undertook a retrospective review of clinical course, Holter monitoring, and ICD interrogations of patients receiving ICD follow-up at our institution between March 1992 and December 1999. Of 81 new ICD implantations, 54 eligible patients (median age 16.5 years, range 1 to 48) were identified. Implantation indications included syncope and/or spontaneous/inducible ventricular arrhythmia with congenital heart disease (30), long QT syndrome (9), structurally normal heart (ventricular tachycardia/ventricular fibrillation [VT/VF]) (7), and cardiomyopathies (7). Sixteen patients (30%) received a dual-chamber ICD. SVT was recognized in 16 patients, with 12 of 16 having inducible or spontaneous atrial tachycardias. Eighteen patients (33%) received > or =1 appropriate shock(s) for VT/VF; 8 patients (15%) received inappropriate therapy for SVT. Therapies were altered after an inappropriate shock by increasing the detection time or rate and/or increasing beta-blocker dosage. No single-chamber ICD was initially programmed with detection enhancements, such as sudden onset, rate stability, or QRS discriminators. Only one dual-chamber defibrillator was programmed with an atrial discrimination algorithm. Appropriate ICD therapy was not withheld due to detection parameters or SVT discrimination programming. CONCLUSION: SVT in children and young adults with ICDs is common. Inappropriate shocks due to SVT can be curtailed even without dual-chamber devices or specific SVT discrimination algorithms.

Progressive atrioventricular conduction defects and heart failure in mice expressing a mutant Csx/Nkx2.5 homeoprotein.

A DNA nonbinding mutant of the NK2 class homeoprotein Nkx2.5 dominantly inhibits cardiogenesis in Xenopus embryos, causing a small heart to develop or blocking heart formation entirely. Recently, ten heterozygous CSX/NKX2.5 homeoprotein mutations were identified in patients with congenital atrioventricular (AV) conduction defects. All four missense mutations identified in the human homeodomain led to markedly reduced DNA binding. To examine the effect of a DNA binding-impaired mutant of mouse Csx/Nkx2.5 in the embryonic heart, we generated transgenic mice expressing one such allele, I183P, under the beta-myosin heavy chain promoter. Unexpectedly, transgenic mice were born apparently normal, but the accumulation of Csx/Nkx2.5(I183P) mutant protein in the embryo, neonate, and adult myocardium resulted in progressive and profound cardiac conduction defects and heart failure. P-R prolongation observed at 2 weeks of age rapidly progressed into complete AV block as early as 4 weeks of age. Expression of connexins 40 and 43 was dramatically decreased in the transgenic heart, which may contribute to the conduction defects in the transgenic mice. This transgenic mouse model may be useful in the study of the pathogenesis of cardiac dysfunction associated with CSX/NKX2.5 mutations in humans.

Electrophysiological characterization of murine myocardial ischemia and infarction.

BACKGROUND: Genetically altered mice will provide important insights into a wide variety of processes in cardiovascular physiology underlying myocardial infarction (MI). Comprehensive and accurate analyses of cardiac function in murine models require implementation of the most appropriate techniques and experimental protocols. OBJECTIVE: In this study we present in vivo, whole-animal techniques and experimental protocols for detailed electrophysiological characterization in a mouse model of myocardial ischemia and infarction. METHODS: FVB mice underwent open-chest surgery for ligation of the left anterior descending coronary artery or sham-operation. By means of echocardiographic imaging, electrocardiography, intracardiac electrophysiology study, and conscious telemetric ECG recording for heart rate variability (HRV) analysis, we evaluated ischemic and post-infarct cardiovascular morphology and function in mice. RESULTS: Coronary artery ligation resulted in antero-apical infarction of the left ventricular wall. MI mice showed decreased cardiac function by echocardiography, infarct-typical pattern on ECG, and increased arrhythmia vulnerability during electrophysiological study. Electrophysiological properties were determined comprehensively, but were not altered significantly as a consequence of MI. Autonomic nervous system function, measured by indices of HRV, did not appear altered in mice during ischemia or infarction. CONCLUSIONS: Cardiac conduction, refractoriness, and heart rate variability appear to remain preserved in a murine model of myocardial ischemia and infarction. Myocardial infarction may increase vulnerability to inducible ventricular tachycardia and atrial fibrillation, similarly to EPS findings in humans. These data may be of value as a reference for comparison with mutant murine models necessitating ischemia or scar to elicit an identifiable phenotype. The limitations of directly extrapolating murine cardiac electrophysiology data to conditions in humans need to be considered.

Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model.

OBJECTIVES: We sought to study the role of I(KACh) in atrial fibrillation (AF) and the potential electrophysiologic effects of a specific I(KACh) antagonist. BACKGROUND: I(KACh) mediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of I(KACh) in the generation of AF and the electrophysiologic effects of specific I(KACh) blockade have not been studied. METHODS: Adult wild-type (WT) and I(KACh)-deficient knockout (KO) mice were studied in the absence and presence of the muscarinic receptor agonist carbachol. The electrophysiologic features of KO mice were compared with those of WT mice to assess the potential effects of a specific I(KACh) antagonist. RESULTS: Atrial fibrillation lasting for a mean of 5.7+/-11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol. Atrial arrhythmia could not be induced in KO mice. Ventricular tachyarrhythmia could not be induced in either type of mouse. Sinus node recovery times after carbachol and sinus cycle lengths were shorter and ventricular effective refractory periods were greater in KO mice than in WT mice. There was no significant difference between KO and WT mice in AV node function. CONCLUSIONS: Activation of I(KACh) predisposed to AF and lack of I(KACh) prevented AF. It is likely that I(KACh) plays a crucial role in the generation of AF in mice. Specific I(KACh) blockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.

A novel mutation in the SLC19A2 gene in a Tunisian family with thiamine-responsive megaloblastic anaemia, diabetes and deafness syndrome.

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome with diabetes and deafness was found in two patients from a Tunisian kindred. The proband was homozygous for a novel mutation, 287delG, in the high-affinity thiamine transporter gene, SLC19A2. We demonstrated that fibroblasts from this patient exhibited defective thiamine transport. These data confirm that the SLC19A2 gene is the high-affinity thiamine carrier and that this novel mutation is responsible for TRMA syndrome.

Induction of atrial tachycardia and fibrillation in the mouse heart.

BACKGROUND: Atrial tachycardia and fibrillation in humans may be partly consequent to vagal stimulation. Induction of fibrillation in the small heart is considered to be impossible due to lack of a critical mass of > 100-200 mm2. Even with the recent progression of the technology of in vivo and in vitro mouse electrophysiological studies, few reports describe atrial tachycardia or fibrillation in mice. The purpose of this study was to attempt provocation of atrial tachyarrhythmia in mice using transvenous pacing following cholinergic stimulation. METHODS AND RESULTS: In vivo electrophysiology studies were performed in 14 normal mice. A six-lead ECG was recorded from surface limb leads, and an octapolar electrode catheter was inserted via jugular vein cutdown approach for simultaneous atrial and ventricular endocardial recording and pacing. Atrial tachycardia and fibrillation were inducible in one mouse at baseline electrophysiology study and eleven of fourteen mice after carbamyl choline injection. The mean duration of atrial tachycardia was 126 +/- 384 s. The longest episode lasted 35 min and only terminated after atropine injection. Reinduction of atrial tachycardia after administration of atropine was not possible. CONCLUSION: Despite the small mass of the normal mouse atria, sustained atrial tachycardia and fibrillation can be easily and reproducibly inducible with endocardial pacing after cholinergic agonist administration. This finding may contribute to our understanding of the classical theories of arrhythmogenesis and critical substrates necessary for sustaining microreentrant circuits. The techniques of transcatheter parasympathetic agonist-mediated atrial tachycardia induction may be valuable in further murine electrophysiological studies, especially mutant models with potential atrial arrhythmia phenotypes.

Is arrhythmia detection by automatic external defibrillator accurate for children?: sensitivity and specificity of an automatic external defibrillator algorithm in 696 pediatric arrhythmias.

BACKGROUND: Use of automatic external defibrillators (AEDs) in children aged <8 years is not recommended. The purpose of this study was to develop an ECG database of shockable and nonshockable rhythms from a broad age range of pediatric patients and to test the accuracy of the Agilent Heartstream FR2 Patient Analysis System for sensitivity and specificity. METHODS AND RESULTS: Children aged

Electroanatomic mapping of entrained and exit zones in patients with repaired congenital heart disease and intra-atrial reentrant tachycardia.

BACKGROUND: Characterization of reentrant circuits and targeting ablation sites remains difficult for intra-atrial reentrant tachycardias (IART) in congenital heart disease (CHD). METHODS AND RESULTS: Electroanatomic mapping and entrainment pacing were performed before successful ablation of 18 IART circuits in 15 patients with CHD. Principal features of IART circuits were atrial septal defect (4 patients), atriotomy (3 patients), other atrial scar (3 patients), crista terminalis (3 patients), and right atrioventricular valve (5 patients). A median of 176 sites (range, 96 to 317 sites) was mapped for activation and 13 sites (range, 9 to 28 sites) for entrainment response. Postpacing intervals within 20 ms of tachycardia cycle length and stimulus-to-P-wave intervals of 0 to 90 ms (exit zones) were mapped to atrial surfaces generated by electroanatomic mapping. Criteria for entrainment were met over a median of 21 cm2 of atrial surface (range, 2 to 75 cm2), 19% (range, 1% to 81%) of total area tested. Using integrated data, relations between activation sequence and protected corridor of conduction could be inferred for 16 of 17 LARTs. Successful ablation was achieved at a site distant from the putative protected corridor in 9 of 18 (50%) circuits. CONCLUSIONS: The right atrium in CHD supports a variety of IART mechanisms. Fusion of activation and entrainment data provided insight into specific IART mechanisms relevant to ablation.

Comparison of two murine models of familial hypertrophic cardiomyopathy.

Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(403/+) or a cardiac MyBP-C mutation (MyBP-C(t/+)) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(403/+) mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C(t/+) hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C(t/+) mice are not as likely to have inducible ventricular tachycardia as alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(403/+) mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C(t/+) mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Cardiomyopathy in Irx4-deficient mice is preceded by abnormal ventricular gene expression.

To define the role of Irx4, a member of the Iroquois family of homeobox transcription factors in mammalian heart development and function, we disrupted the murine Irx4 gene. Cardiac morphology in Irx4-deficient mice (designated Irx4(Delta ex2/Delta ex2)) was normal during embryogenesis and in early postnatal life. Adult Irx4(Delta ex2/Delta ex2) mice developed a cardiomyopathy characterized by cardiac hypertrophy and impaired contractile function. Prior to the development of cardiomyopathy, Irx4(Delta ex2/Delta ex2) hearts had abnormal ventricular gene expression: Irx4-deficient embryos exhibited reduced ventricular expression of the basic helix-loop-helix transcription factor eHand (Hand1), increased Irx2 expression, and ventricular induction of an atrial chamber-specific transgene. In neonatal hearts, ventricular expression of atrial natriuretic factor and alpha-skeletal actin was markedly increased. Several weeks subsequent to these changes in embryonic and neonatal gene expression, increased expression of hypertrophic markers BNP and beta-myosin heavy chain accompanied adult-onset cardiac hypertrophy. Cardiac expression of Irx1, Irx2, and Irx5 may partially compensate for loss of Irx4 function. We conclude that Irx4 is not sufficient for ventricular chamber formation but is required for the establishment of some components of a ventricle-specific gene expression program. In the absence of genes under the control of Irx4, ventricular function deteriorates and cardiomyopathy ensues.

Minimally invasive cardioverter defibrillator implantation for children: an animal model and pediatric case report.

The smaller venous capacitance in infants and small children may hamper transvenous ICD lead implantation, and epicardial approaches require thoracotomy and have associated complications. The study evaluated the feasibility and performance of subcutaneous arrays and active can ICDs without transvenous shocking coils or epicardial patches. An immature and mature pig were anesthetized and ventilated. A pacing lead was inserted in the right ventricle for fibrillation induction and rate sensing. Subcutaneous arrays were positioned in the right and left chest walls. An ICD emulator was placed in abdominal and prepectoral pockets. Fluoroscopic images were acquired for each electrical vector configuration (array --> can, can --> array, array --> array, array + array --> can). Ventricular fibrillation was induced and DFT testing performed. Defibrillation was achieved in all ten trials in the immature piglet, with DFT < or = 9 J, regardless of vector configuration. Using a single subcutaneous array and active can, the shock impedance ranged from 28-36 ohms. With two arrays, shocking impedance fell to 15-22 ohms. In the adult pig, defibrillation was not accomplished with maximum energy of 40 J, using all vector configurations. Using data garnered from these experiments, this technique was then successfully performed in a 2-year-old child with VT and repaired congenital heart disease, needing an ICD. This study demonstrates the feasibility of leadless ICD implantation in an immature animal and successful implementation in a small child. A single subcutaneous array and active can resulted in excellent implant characteristics and DFTs with a minimally invasive approach. Defibrillation was not possible in a larger animal, possibly due to maximal available energy. This may be of value for small children requiring ICD implantation.

In vivo electrophysiologic studies in endothelial nitric oxide synthase (eNOS)-deficient mice.

INTRODUCTION: Endothelial nitric oxide synthase (eNOS) mediates attenuation of the L-type calcium channel and modulates myocyte contractility. Arrhythmogenic afterdepolarizations are seen in vitro in ouabain-treated isolated myocytes from eNOS-deficient mice. The aim of these studies was to characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice and their potential susceptibility to cardiac conduction abnormalities and inducible arrhythmias. METHODS AND RESULTS: Surface ECG and in vivo intracardiac EP studies were performed in 27 mice lacking the eNOS gene and 21 wild-type littermate control mice. Baseline studies were performed in 10 eNOS-deficient mice and 10 wild-type controls. Subsequently, 17 eNOS-deficient mice and 11 wild-type controls were pretreated with digoxin, and ECG and EP testing were repeated. Data analysis revealed no significant differences in ECG intervals or cardiac conduction parameters, except sinus cycle length was higher in eNOS-deficient mice than wild-type mice (P < 0.01). After digoxin pretreatment, 7 of 17 eNOS-deficient mice had inducible ventricular tachycardia and 2 others had frequent ventricular premature beats, compared with only 3 of 11 wild-type mice with inducible ventricular tachycardia. In addition, 2 digoxin-treated eNOS-deficient mice and 1 wild-type mouse had inducible nonsustained atrial fibrillation. CONCLUSION: Mice with a homozygous targeted disruption of the eNOS gene have slower heart rates but no other distinguishable EP characteristics under basal sedated conditions. Partial inhibition of the Na+/K+ ATPase pump with digoxin administration increases ventricular ectopic activity in eNOS-/- mice, a phenotype analogous to afterdepolarizations seen in vitro in this eNOS-deficient mouse model.

Estimation of atrial response to entrainment pacing using electrograms recorded from remote sites.

INTRODUCTION: Assessing the entrainment response by measuring postpacing intervals (PPIs) at the pacing site facilitates localization of reentrant circuits, but may be technically difficult. METHODS AND RESULTS: There were 269 right atrial sites entrained in 21 circuits in congenital heart patients left atrial (LA) electrograms were recorded. Entrainment response was measured by two methods: (1) PPI-tachycardia cycle length, and (2) the difference in latencies between the stimulus artifact and the pacing site electrogram, referenced to the LA electrogram. PPI also was measured from the LA as an index of antidromic activation. Among 43 pacing sites with antidromic LA activation, half showed a discrepancy 225 msec between methods 1 and 2. At the other 226 sites, agreement between the two methods was high (mean discrepancy -3+/-8 msec, r = 0.975, 0 sites with discrepancy 225 msec). Correcting all sites by LA antidromicity reduced the mean discrepancy to +1+/-6 msec and improved correlation (r = 0.988). CONCLUSION: LA electrograms can be used to estimate right atrial entrainment response, if antidromic activation of the LA is recognized and taken into account.

A targeted disruption in connexin40 leads to distinct atrioventricular conduction defects.

INTRODUCTION: Gap junctions consist of connexin (Cx) proteins that enable electrical coupling of adjacent cells and propagation of action potentials. Cx40 is solely expressed in the atrium and His-Purkinje system. The purpose of this study was to evaluate atrioventricular (AV) conduction in mice with a homozygous deletion of Connexin40 (Cx40(-/-)). METHODS: Surface ECGs, intracardiac electrophysiology (EP) studies, and ambulatory telemetry were performed in Cx40(-/-) mutant mice and wild-type (WT) controls. Atrioventricular (AV) conduction parameters and arrhythmia inducibility were evaluated using programmed stimulation. Analysis of heart rate variability was based on results of ambulatory monitoring. RESULTS: Significant findings included prolonged measures of AV refractoriness and conduction in connexin40-deficient mice, including longer PR, AH, and HV intervals, increased AV refractory periods, and increased AV Wenckebach and 2:1 block cycle lengths. Connexin40-deficient mice also had an increased incidence of inducible ventricular tachycardia, decreased basal heart rates, and increased heart rate variability. CONCLUSION: A homozygous disruption of Cx40 results in prolonged AV conduction parameters due to abnormal electrical coupling in the specialized conduction system, which may also predispose to arrhythmia vulnerability.

Early ECG abnormalities associated with transcatheter closure of atrial septal defects using the Amplatzer septal occluder.

UNLABELLED: Conduction abnormalities and arrhythmias may occur in patients following secundum atrial septal defect (ASD) closure using the Amplatzer septal occluder (ASO). Therefore, the aim of this study was to prospectively perform ambulatory ECG monitoring to assess the electrocardiographic effects of transcatheter closure (TCC) of ASD using the ASO device. From 5/97 to 3/99, 41 patients with secundum ASD, underwent TCC using the ASO device at a median age of 9.2[emsp4 ]y. (0.5-87[emsp4 ]y.) and median weight of 34[emsp4 ]kg (5. 6-88[emsp4 ]kg.). Ambulatory Holter monitoring was performed pre- and immediately post TCC. Holter analysis included heart rate (HR), ECG intervals, supraventricular ectopy (SVE), ventricular ectopy (VE), and AV block. No change in baseline rhythm was noted in 37 patients (90%). Changes in AV conduction occurred in 3 patients (7%), including intermittent second degree AV block type II, and complete AV dissociation post closure. SVE was noted in 26 patients (63%) post closure, ranging from 5-2207 supraventricular premature beats (SVPB), including 9 patients (23%) with non-sustained supraventricular tachycardia (SVT), 3 of whom had short runs of SVT prior to closure. A significant increase in post-closure number of SVPB per hour (p=0.047) was noted. No significant difference was noted in PR interval, ventricular premature beats per hour, or QRS duration. CONCLUSIONS: Based on ambulatory ECG analysis, TCC of ASD with the ASO device is associated with an acute increase in SVE and a small risk of AV conduction abnormalities, including complete heart block. Long term follow-up studies will be necessary to determine late arrhythmia prevalence and relative frequency compared with standard surgical ASD repair.

Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha(3)-isoform in hearts.

To understand why the adult human heart expresses three isoforms of the sodium pump, we generated transgenic mice (TGM) with 2.3- to 5. 5-fold overexpression of the human alpha(3)-isoform of Na-K-ATPase in the heart. Hearts from the TGM had increased maximal Na-K-ATPase activity and ouabain affinity compared with control hearts, even though the density of Na-K-ATPase pump sites (of all isoforms) was similar to that of control mice. In perfused hearts, contractility both at baseline and in the presence of ouabain tended to be greater in TGM than in controls. Surface electrocardiograms in anesthetized TGM had a steeper dependence of Q-T on sinus cycle length, and Q-T intervals measured during atrial pacing were significantly longer in TGM. Q-T dispersion during sinus rhythm also tended to be longer in TGM. Thus TGM overexpressing human alpha(3)-isoform have several of the phenotypical features of human long Q-T syndrome, despite the absence of previously described mutations in Na(+) or K(+) channels.