Faculty Bibliography

BACKGROUND: There are little data on the appropriate endpoint for slow pathway ablation that balances acceptable procedural times, recurrence rates, and complication rates. This study compared recurrence rates of three commonly utilized endpoints of slow pathway ablation for atrioventricular nodal reentrant tachycardia (AVNRT). METHODS: We performed a meta-analysis of AVNRT slow pathway ablation cohorts by searching electronic databases, the Internet, and conference proceedings. Inclusion criteria were age >18 years, >20 human subjects per study, primary AVNRT ablation, English language publication, and >1 month of follow-up. Data were analyzed with a fixed-effects model using Comprehensive Meta-Analysis software version 2.2.046 (Biostat, Englewood, NJ, USA). RESULTS: We included 10 studies encompassing 1,204 patients with a mean age of 41-53 years. Endpoints were complete slow pathway ablation, residual jump only, and single remaining echo beat. Pooled estimates revealed 28 of 641 patients (4.4%) with complete slow pathway ablation, 13 of 192 patients (6.8%) with a residual jump only, and 24 of 371 patients (6.5%) with one echo had recurrences. With uniform isoproterenol use after ablation, there was no significant difference in recurrence rates among the endpoints. However, when isoproterenol was utilized after ablation only if needed to induce AVNRT before ablation, a significantly higher recurrence rate occurred in patients with a residual jump (P = 0.002), a single echo (P = 0.003), or the combined group of a residual jump and/or one echo (P = 0.001). CONCLUSIONS: Isoproterenol should be used routinely after slow pathway modification, when a residual jump and/or single echo remain

Introduction: Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias. We hypothesized that SCS may reduce susceptibility to tachypacing (TP) induced atrial fibrillation (AF). Methods: Spinal cord leads (Octrode, St. Jude Medical) were implanted in the upper thoracic spine (T1-T5) of canines and connected to pulse generators (EonC, St. Jude Medical). The AV node was ablated and atrial effective refractory period (AERP) was measured at baseline and with SCS (n=10). In separate animals the AV node was ablated and endocardial RA and RV pacing leads were connected to dual chamber pacemakers for ambulatory AF induction. Custom firmware provided continuous 30s periods of atrial TP followed by 6s sense windows. TP was interrupted by detection of AF (atrial rate >250 bpm) and resumed upon return to sinus rhythm. AF Index was defined as the fraction of time the animal did not receive TP relative to the total allowable TP time. The effect of SCS delivered intermittently for 6 hr/day (SCS ON; n=3) on AF index was followed for 8 weeks and compared to control (SCS OFF; n=3). Results: Right (p=0.002) and left (p=0.009) AERP were significantly longer during SCS (168+/-15.1, 168+/-14.8 ms) compared to baseline (130+/-8.7, 152+/-10.3 ms). AF Index was significantly decreased in the SCS ON compared to SCS OFF (p<0.0001). AF Index was >70% in the SCS OFF group and <5% in the SCS ON animals starting at week 3 (Figure). Conclusions: These data demonstrate that SCS prolongs AERP and prevents TP-induced AE (Graph presented)

Introduction: The Medtronic Fidelis lead family is associated with an unacceptable incidence of premature lead failure. Multiple studies have attempted to identify risk factors for lead failure and include younger age, better ejection fraction, and non-cephalic access. We hypothesized that other factors leading to potential increased forces on the lead including right-sided implantation or subpectoral positioning may be associated with premature lead failure. Methods: We reviewed the implant data from our group and identified 220 patients who received a Medtronic 6949 (dual coil) or 6931 (single coil) Fidelis lead. Implant data including age, sex, venous access site, implant side, implant location, lead length, and number of venous leads was reviewed. Hospital, Pacemaker Clinic, and Medtronic registration database were reviewed for evidence of lead failure, replacement, or abandonment. Data was evaluated in a univariate and multivariate analysis. Results: Of the 220 Fidelis leads implanted, 9 (4%) were noted to develop malfunction. This presented as inappropriate shocks from sensed noise, or elevated impedance measurements. Of the above noted implant features, only right-sided (vs. left-sided) implant, and subpectoral implant (vs. prepectoral) were found in uni- and multivariate analysis to be predictive of lead failure. Of 13 right-sided lead implants, 4 (30.7%) fractured (p<0.001). Of 14 subpectoral implants, 3 (21%) had lead failure (p<0.001). Conclusions: We have identified both right sided implantation and subpectoral generator positioning as factors associated with premature lead malfunction in the Fidelis lead family. Clinical decisions regarding patient management should incorporate these findings in regard to lead replacement in high risk patients

BACKGROUND: PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. METHODS AND RESULTS: Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible alpha-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (Tg(OFF(E-8 weeks))) or at different time points during life (Tg(OFF(4-16 weeks)), Tg(OFF(8-20 weeks)), and Tg(OFF(>20 weeks))). One group never received tetracycline, expressing transgene throughout life (Tg(ON)). Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction. CONCLUSIONS: Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease. Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration. Taken together, these data provide insight into mechanisms of cardiac PRKAG2 disease and suggest that glycogen-storage cardiomyopathy can be modulated by lowering glycogen content in the heart

Pacemaker cells in the heart generate periodic electrical signals that are conducted to the working myocardium via the specialized conduction system. Effective cell-to-cell communication is critical for rapid, uniform conduction of cardiac action potentials-- a prerequisite for effective, synchronized cardiac contraction. Local circuit currents form the basis of the depolarization wave front in the working myocardium. These currents flow from cell to cell via gap junction channels. In this chapter, we trace the path of the action potential from its generation in the sinus node to propagation through the working myocardium, with a detailed discussion of the role of gap junctions. First, we review the transmembrane ionic currents and the basic principles of conduction of the action potential to the working myocardium via the specialized tissues of the heart. Next, we consider the relative contribution of cell geometry, size, and gap junction conductance. These factors are examined in terms of their source-to-sink relationships. Lastly, we will discuss new insights into the importance of gap junctions in cardiac conduction in health and disease which have been gained from high resolution optical mapping in connexin-deficient mice

Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM

Ventricular tachycardia is a common heart rhythm disorder and a frequent cause of sudden cardiac death. Aberrant cell-cell coupling through gap junction channels, a process termed gap junction remodeling, is observed in many of the major forms of human heart disease and is associated with increased arrhythmic risk in both humans and in animal models. Genetically engineered mice with cardiac-restricted knockout of Connexin43, the major cardiac gap junctional protein, uniformly develop sudden cardiac death, although a detailed electrophysiological understanding of their profound arrhythmic propensity is unclear. Using voltage-sensitive dyes and high resolution optical mapping techniques, we found that uncoupling of the ventricular myocardium results in ectopic sites of ventricular activation. Our data indicate that this behavior reflects alterations in source-sink relationships and paradoxical conduction across normally quiescent Purkinje-ventricular muscle junctions. The aberrant activation profiles are associated with wavefront collisions, which in the setting of slow conduction may account for the highly arrhythmogenic behavior of Connexin43-deficient hearts. Thus, the extent of gap junction remodeling in diseased myocardium is a critical determinant of cardiac excitation patterns and arrhythmia susceptibility