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Biomedical subjects

Gil J Gross

Publications and source records attributed to Gil J Gross.

14 recordsLinked to original sources
PubMed2006

IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits.

Bradycardic ventricular electrical remodeling predisposes to lethal tachyarrhythmias. We investigated the early temporal sequence and reversibility of electrical remodeling in a rabbit complete heart block model subjected to bradycardic ventricular pacing for either 2 or 8 days, with a third group of animals undergoing 8 days of bradycardic pacing followed by 8 days of physiological-rate pacing. At specified time points after complete heart block induction and pacing initiation, steady-state QT interval measurements and variability as well as dynamic QT interval adaptation to abrupt heart rate acceleration were assessed in the absence and presence of isoproterenol. Rapidly (I(Kr)) and slowly (I(Ks)) activating delayed rectifier repolarizing K(+) tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes. Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate I(Kr) reduction. I(Ks) downregulation was apparent by day 2 but more profound at day 8. Dynamic QT interval adaptation was impaired under baseline conditions at day 8 but only during isoproterenol administration at day 2. Both in vivo and cellular manifestations of remodeling reverted toward control values after 8 days of physiological-rate pacing. In conclusion, in this bradycardic model, I(Ks) downregulation 1) proceeds more gradually but more extensively than that of I(Kr) and 2) is most prominently associated with impaired dynamic QT interval adaptation to heart rate acceleration. Isoproterenol blunts the dynamic QT interval response in animals with partially downregulated I(Ks), consistent with stress-related phenomena in known I(Ks)-impaired states. Relative early sparing of I(Ks) could explain the delay in the onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.

Adaptation, Physiological↗
PubMed2006

Chronotropic incompetence in young patients with late postoperative atrial flutter: a case-control study.

AIMS: Atrial flutter causes late postoperative morbidity in congenital heart disease (CHD). Sinoatrial node dysfunction is associated with late postoperative atrial flutter, but pacing interventions driven by minimum heart rates (HR) have yielded mixed results. METHODS AND RESULTS: A retrospective case-control study was used to test the hypothesis that late postoperative atrial flutter is associated with chronotropic incompetence in active young CHD patients. Control CHD patients aged < or =18 years without documented supraventricular ectopy (n = 42) were matched with 42 patients (cases) having atrial flutter onset > or =6 months postoperatively. Minimum, average, and maximum non-flutter HRs were obtained from outpatient ambulatory 24 h ECG (Holter) recordings and graded exercise tests. Chronotropic competence was assessed using percentage of age-specific predicted maximum HR achieved, and calculated chronotropic index. Effects of rate-adaptive programming and maximum atrial pacing rates were analysed in 19 permanently paced cases. Least square estimates of minimum HRs were similar in cases and controls (54+/-2 vs. 52+/-2 bpm). Average HRs were lower in cases (75+/-2 vs. 81+/-2 bpm, P=0.02). Cases and controls differed most significantly with respect to percentage of predicted maximum HR achieved (67+/-2 vs. 80+/-2%, P < 0.001). This difference remained highly significant when the data were adjusted for age, sex, permanent pacing, and negatively chronotropic medication usage at the time of testing. Among paced patients, atrial flutter was significantly less likely to be observed in the setting of rate-adaptive pacing [odds ratio (OR) = 0.36; P < 0.05], and the likelihood of detecting atrial flutter decreased relative to the maximum programmed atrial pacing rate (OR 0.87 for every 5% increment in maximum pacing rate relative to maximum predicted HR for age; P < 0.05). CONCLUSION: Late postoperative atrial flutter is associated with chronotropic incompetence in paediatric CHD patients.

Adolescent↗
PubMed2006

Natural history of postoperative heart block in congenital heart disease: implications for pacing intervention.

After half a century of major progress in congenital heart disease management, atrioventricular conduction block continues to complicate 1-3% of surgical procedures. Unless treated with an implanted pacemaker, permanent postoperative heart block is associated with 28-100% mortality. Postoperative heart block often proves to be transient, typically resolving within 10 days of onset. The duration of postoperative heart block is widely used as a key determinant for permanent pacemaker implantation. Current professional pacemaker implantation guidelines are largely based on this criterion. However, available natural history data suggest that other factors, such as residual conduction system injury, likely play a role in increasingly recognized cases of very late postoperative mortality and morbidity in patients who have experienced transient postoperative heart block. As growing numbers of congenital heart disease patients survive into adulthood, and artificial pacemaking capabilities continue to improve, it might be necessary to reconsider and refine currently accepted pacing indications for postoperative heart block.

Cardiac Pacing, Artificial↗
PubMed2006

Right ventricular outflow tract tachycardia in children.

OBJECTIVE: To assess the clinical spectrum of right ventricular outflow tract tachycardia and its management in children. STUDY DESIGN: Five centers identified patients for retrospective review. Patients (age <18 years) demonstrating ventricular tachycardia with an inferior axis and left bundle branch block were included. Patients with structural heart disease, myocarditis, cardiomyopathy, or long QT syndrome were excluded. Demographics, clinical presentation, investigations, and treatment were analyzed. Holter data were used to quantify ectopy. RESULTS: Patients (n = 48) were referred for evaluation of incidental findings (39/48), near syncope or syncope (7/48), or other (2/48). Investigations included magnetic resonance imaging (51%), endomyocardial biopsy (25%), and angiography (23%). Medical treatment was initiated in 26 of the 48 patients. The most common indications for treatment were frequent ectopy and symptoms. Medical treatment (P <.007) and observation alone (P <.02) were both associated with a reduction in ectopy. Symptoms persisted in 3 of 13 patients who were treated medically and in all untreated patients. At follow-up, there were no deaths and no difference in ectopy (P <.46) between patients who were treated medically and patients who were observed. Ablation was attempted in 6 of the 48 patients (successful in 4/6). CONCLUSION: The clinical spectrum and management of right ventricular outflow tract tachycardia in children are diverse. Both medical therapy and observation alone were associated with a reduction in ectopy.

Adolescent↗
PubMed2006

Bradycardia-mediated ventricular electrical remodeling.

Bradycardic states are associated with myocardial electrical remodeling predisposing to potentially lethal ventricular tachydysrhythmias. We used a novel model of complete heart block (CHB) in the rabbit to test the hypothesis that ventricular activation rate is the primary determinant of early bradycardic electrical remodeling. Chronic endocardial right ventricular demand (VVI) pacing was applied at either the near-physiologic rate of 280 beats/min or at the bradycardic rate of 140 beats/min, beginning immediately after transcatheter radiofrequency AV node ablation. A third group of animals underwent sham ablation and served as non-paced, normal sinus rhythm controls. The major finding of this study was that electrical remodeling was established within 8 days of CHB induction in the bradycardic animals, but was not observed in either of the other 2 groups. Bradycardic animals had significant QT interval prolongation and biventricular downregulation of the delayed rectifier K+ currents, IKr and IKs. The Ca2+-independent transient outward K+ current, I(to), and the inwardly rectifying K+ current, I(K1), were unaffected. This paper highlights these findings in the context of a literature-based review of heart rate-dependent remodeling of the mammalian myocardium, summarizing the current state of knowledge and describing future challenges.

Action Potentials↗
PubMed2005

The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient.

Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established. We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased Kv4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I(to,f), and increased susceptibility to arrhythmias. Myocardial Irx5 is expressed in a gradient opposite that of Kv4.2, and Irx5 represses Kv4.2 expression by recruiting mBop, a cardiac transcriptional repressor. Thus, an Irx5 repressor gradient negatively regulates potassium-channel-gene expression in the heart, forming an inverse I(to,f) gradient that ensures coordinated cardiac repolarization while also preventing arrhythmias.

Action Potentials↗
PubMed2005

Transcatheter cryoablation of tachyarrhythmias in children: initial experience from an international registry.

OBJECTIVES: We sought to describe the early pediatric experience of transcatheter cryoablation, and identify whether specific arrhythmia substrates and/or ablation locations were particularly suited to cryoablation. BACKGROUND: Radiofrequency (RF) ablation has become established therapy for pediatric tachyarrhythmias. However, challenges remain in terms of the safety and efficacy of RF ablation in specific locations; new methods may address these issues. METHODS: Prospective data were available for 64 patients age 13 +/- 4 (mean +/- SD) years undergoing cryoablation at 14 centers participating in the Cryocath International Patient Registry. Dysrhythmia duration was 5.0 +/- 4.2 years, with diagnoses of atrioventricular node re-entrant tachycardia (AVNRT) (n=30), anteroseptal (n=11), midseptal (n=5), or other (n=15) accessory pathway (AP) mediated AV re-entry, ventricular tachycardia (VT) (n = 3), and ectopic atrial tachycardia (EAT) (n=2). Two patients had more than one arrhythmia substrate. Transcatheter cryoablation was offered by cardiologist preference after written informed procedural consent of each patient and/or legal guardian. Cryomapping was performed at -30 degrees C and cryoablation was delivered with 4-min applications at -75 degrees C. RESULTS: Acute success was achieved in 45 of 65 (69%) cryoablation patients, with best success rates in AVNRT (83%) and right septal AP (75%), and lower success rates in other AP (43%), VT (66%), and EAT (0%). No device-related adverse events were reported. The success of radiofrequency (RF) ablation applied in 14 cryoablation failures was 4 of 4 for AVNRT patients, 1 of 1 for anteroseptal AP patients, 5 of 6 for other AP patients, 0 of 1 for VT patients, and 0 of 2 for EAT patients. CONCLUSIONS: Transcatheter cryoablation is a safe and well-tolerated alternative to RF ablation in pediatric patients on the basis of our initial experience. Success is highest in AVNRT and in substrates recognized as technically challenging or risky for RF ablation.

Adolescent↗
PubMed2005

Ventricular rate determines early bradycardic electrical remodeling.

OBJECTIVES: The purpose of this study was to isolate chronic ventricular rate as the primary determinant of early bradycardic ventricular electrical remodeling. BACKGROUND: Ventricular repolarization delay predisposing to potentially lethal tachydysrhythmias occurs during chronic bradycardia. Prolonged QT intervals and torsades de pointes are associated with down-regulated ventricular myocyte delayed rectifier potassium (K(+)) currents. METHODS: Transcatheter AV node ablation in rabbits was followed by chronic right ventricular pacing at either 140 bpm (n = 16) or the near-physiologic rate of 280 bpm (n = 9). ECG QT intervals were assessed in vivo at days 0 and 8 of paced AV block. Repolarizing currents in isolated left and right ventricular myocytes were assessed using whole-cell patch clamp technique. RESULTS: Bradycardic rabbits had increased steady-state QT intervals (230 +/- 6 ms vs 206 +/- 7 ms [mean +/- SE], day 8 vs day 0; P < .001). Biventricular myocyte expression of the delayed rectifier K(+) currents I(Kr) and I(Ks) was down-regulated in bradycardic rabbits, with no change in the transient outward current I(to) or inwardly rectifying current I(K1). None of these changes were observed in rabbits paced at 280 bpm. Pause-dependent torsades de pointes was documented in one bradycardic animal on day 8. No heart failure or ventricular hypertrophy was apparent. CONCLUSIONS: Bradycardic ventricular electrical remodeling proceeds independently of structural remodeling, heart failure, or AV synchrony and is prevented by maintenance of near-physiologic ventricular rate.

Animals↗
PubMed2004

Presentation, natural history, and outcome in children and adolescents with double orifice mitral valve.

Forty-six children, aged 2 days to 16 years (median 2.4 years) with double orifice mitral valve (DOMV), were studied. Partial atrioventricular septal defect was the most commonly associated cardiac lesion. Symptoms were related to the degree of mitral insufficiency and/or stenosis when present. Surgical intervention directed at DOMV was required in the minority of patients who underwent repair of associated cardiac lesions. The long-term morbidity attributable to DOMV was low.

Adolescent↗
PubMed2003

Propafenone and its metabolites preferentially inhibit IKr in rabbit ventricular myocytes.

Propafenone is an antiarrhythmic agent with recognized cardiac myocyte repolarizing K+ current inhibitory effects. It has two known electropharmacologically active metabolites, 5-hydroxy- and N-depropylpropafenone, whose K+ current inhibitory effects are less thoroughly elucidated than those of the parent compound. This study characterizes and directly compares the pharmacologic interaction of all three compounds with two key repolarizing K+ currents, the rapidly activating delayed rectifier IKr and the transient outward current Ito, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes. All three agents potently inhibited IKr with IC50 values of 0.80 +/-0.14, 1.88 +/-0.21, and 5.78 +/-1.24 microM for propafenone, 5-hydroxypropafenone, and N-depropylpropafenone, respectively, based on reduction of peak tail current amplitude following repolarization from +50 mV to -30 mV. IKr inhibition was concentration- and weakly voltage-dependent, with a time course from channel activation that was well described by a single exponential model and consistent with open channel block. Propafenone and its 5-hydroxy and N-depropyl metabolites also blocked Ito with IC50 values of 7.27 +/-0.53, 40.29 +/-7.55, and 44.26 +/-5.73 microM, respectively, at +50 mV. No significant drug effects were observed with respect to Ito voltage dependence of steady-state inactivation or time course of recovery from inactivation. The preferential interaction of propafenone and its metabolites with IKr relative to Ito in ventricular myocytes sheds new light on the anti- and proarrhythmic activity of propafenone in vivo.

Animals↗
PubMed2002

Use of an implantable loop recorder in the evaluation of children with congenital heart disease.

BACKGROUND: A recently developed implantable loop recorder (ILR) has been used in adult patients whose syncope remains unexplained in spite of extensive investigations. Syncope in the patient with congenital heart disease presents a diagnostic challenge. We applied this technology to a cohort of pediatric patients. METHODS: We reviewed our experience with an ILR in patients with congenital heart disease with syncope or palpitations after conventional investigations failed to identify a cause for the symptoms. RESULTS: ILRs were implanted in 4 patients with congenital heart disease at 2 centers for investigation of syncope (n = 2), near-syncope (n = 1), and palpitations (n = 1). Implantations were performed at a mean age of 5.9 +/- 0.9 years (4.2 to 7.6 years) and a mean weight of 26.7 +/- 6.6 kg (15.7 to 42.5 kg) with patients under general anesthesia, with no complications. All patients experienced typical symptoms and activated the device appropriately at a median of 86 days (46 to 102) after implantation. Each patient had good-quality data that allowed interpretation of the rhythm. In 2 of 4 cases, a likely cause for the symptoms was identified, with exclusion of more malignant arrhythmic diagnoses in all patients. Escalation of therapy was avoidable in all patients on the basis of the data recorded by the ILR. CONCLUSIONS: Recently developed loop recorder technology can be implanted in the young child without difficulty. The ILR proved to be very useful for excluding malignant arrhythmias as a cause of symptoms in these patients at high risk.

Canada↗
PubMed2002

A novel rabbit model of variably compensated complete heart block.

Complete heart block (CHB) provides a useful substrate for study of bradycardia-dependent ventricular arrhythmias and cardiac function. Existing CHB animal models are limited by surgical recovery time and reliance on intrinsic escape rhythms. We describe a novel closed-chest rabbit model of CHB involving transcatheter radiofrequency (RF) atrioventricular (AV) node ablation and ventricular rate control with chronic transvenous pacing. Permanent CHB was achieved in 34 of 38 attempts overall. Procedural mortality due to cardiac tamponade (n = 2), airway complications (n = 2), and unknown causes (n = 5) occurred in nine animals. Survivors with CHB (n = 28) were maintained for < or = 22 days, during which there were three late deaths related to infection (n = 1) or respiratory distress (n = 2). None of the survivors with CHB showed recovery of AV conduction or pacemaker capture loss during chronic ventricular pacing at about one-half normal sinus rates, and 25 animals surviving to death showed no overt signs of hemodynamic compromise such as lethargy, poor feeding, or respiratory distress. This approach provides a reproducible nonsurgical CHB model with adjustable ventricular rate control.

Animals↗