David D. Spragg

Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy

Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (>20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by >40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (P<0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (P<0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (P=0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF.

Regional alterations in protein expression in the dyssynchronous failing heart.

Background—Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results—Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial–paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions—LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.

Complications of Catheter Ablation for Atrial Fibrillation: Incidence and Predictors

Introduction: Pulmonary vein (PV) isolation by catheter ablation is an increasingly used strategy to treat atrial fibrillation (AF). Complication rates from AF ablation reported in different case series vary widely. We conducted a retrospective analysis of 641 consecutive ablation procedures to assess complication rates, temporal trends, and clinical predictors of adverse outcomes.

Optimal Left Ventricular Endocardial Pacing Sites for Cardiac Resynchronization Therapy in Patients With Ischemic Cardiomyopathy

OBJECTIVES We sought to investigate the impact of left ventricular (LV) pacing site on mechanical response to cardiac resynchronization therapy (CRT) in patients with ischemic cardiomyopathy (ICM). BACKGROUND CRT reduces morbidity and mortality in patients with dyssynchronous LV failure; however, variability in response, particularly in ICM patients, poses ongoing challenges. Endocardial biventricular (BiV) stimulation may provide more flexibility in LV site selection and yield more natural transmural activation patterns. Whether this applies to ICM and whether optimal LV endocardial pacing locations vary among ICM patients remain unknown. METHODS Peak rate of LV pressure increase (dP/dt(max)) was measured at baseline, during VDD pacing at the right ventricular apex, and during BiV pacing from the right ventricular apex and 51 +/- 14 different LV endocardial sites in patients with ICM (n = 11). Seven patients already had an epicardial LV lead (CRT) in place, allowing comparison of epicardial BiV stimulation with that using an endocardial site directly transmural to the CRT-coronary sinus lead tip. Electroanatomic 3-dimensional maps with color-coded dP/dt(max) response defined optimal pacing regions delivering >or=85% of maximal increase in dP/dt(max). RESULTS Endocardial BiV pacing improved dP/dt(max) over right ventricular apex pacing in all patients (mean increase 241 +/- 38 mm Hg/s; p < 0.0001). In patients with pre-existing CRT leads, LV endocardial versus epicardial pacing at transmural sites yielded equivalent dP/dt(max) values. However, dP/dt(max) at the best endocardial site exceeded that achieved with the pre-implanted CRT device (mean increase 111 +/- 25 mm Hg/s; p = 0.004). An average of approximately 2 optimal endocardial sites were identified for each patient, located at the extreme basal lateral wall (8 of 11 patients) and other regions (9 of 11). Standard mid-LV free wall pacing yielded suboptimal LV function in 73% of patients. Optimal pacing sites were typically located in LV territories remote (9.3 +/- 3.6 cm) from the infarct zone. CONCLUSIONS CRT delivered at best LV endocardial sites is more effective than via pre-implanted coronary sinus lead pacing. The location of optimal LV endocardial pacing varies among patients with ICM, and individual tailoring may improve CRT efficacy in such patients.

Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation

Background: Although it is well recognized that recovery of pulmonary vein (PV) conduction is common among patients who fail atrial fibrillation (AF) ablation, little is known about the precise time course of recurrence.

Long‐Term Safety and Efficacy of Circumferential Ablation with Pulmonary Vein Isolation

Background: Each of the two main approaches to catheter ablation of atrial fibrillation (AF, segmental and circumferential) is associated with moderate long‐term efficacy.

Dual Antiplatelet Therapy and Heparin “Bridging” Significantly Increase the Risk of Bleeding Complications After Pacemaker or Implantable Cardioverter-Defibrillator Device Implantation

OBJECTIVES This study was designed to assess the risk of significant bleeding complications in patients receiving antiplatelet or anticoagulation medications at the time of implantable cardioverter-defibrillator (ICD) device implantation. BACKGROUND Periprocedural management of antiplatelet or anticoagulation therapy at the time of device implantation remains controversial. METHODS We performed a retrospective chart review of bleeding complications in all patients undergoing ICD or pacemaker implantation from August 2004 to August 2007. Aspirin or clopidogrel use was defined as taken within 5 days of the procedure. A significant bleeding complication was defined as need for pocket exploration or blood transfusion; hematoma requiring pressure dressing or change in anticoagulation therapy; or prolonged hospitalization. RESULTS Of the 1,388 device implantations, 71 had bleeding complications (5.1%). Compared with controls not taking antiplatelet agents (n = 255), the combination of aspirin and clopidogrel (n = 139) significantly increased bleeding risk (7.2% vs. 1.6%; p = 0.004). In patients taking aspirin alone (n = 536), bleeding risk was marginally higher than it was for patients taking no antiplatelet agents (3.9% vs. 1.6%, p = 0.078). The use of periprocedural heparin (n = 154) markedly increased risk of bleeding when compared with holding warfarin until the international normalized ratio (INR) was normal (n = 258; 14.3% vs. 4.3%; p < 0.001) and compared with patients receiving no anticoagulation therapy (14.3% vs.1.6%; p < 0.0001). There was no statistical difference in bleeding risk between patients continued on warfarin with an INR > or =1.5 (n = 46) and patients who had warfarin withheld until the INR was normal (n = 258; 6.5% vs. 4.3%; p = 0.50). CONCLUSIONS Dual antiplatelet therapy and periprocedural heparin significantly increase the risk of bleeding complications at the time of pacemaker or ICD implantation.

Initial experience with magnetic resonance imaging of atrial scar and co-registration with electroanatomic voltage mapping during atrial fibrillation: Success and limitations

BACKGROUND Ablation for atrial fibrillation (AF) frequently requires multiple procedures to achieve durable restoration of sinus rhythm. Early studies have suggested that delayed enhancement magnetic resonance imaging (DE-MRI) of the left atrium (LA) can assist in performing repeat ablation procedures. OBJECTIVE The purpose of this study was to investigate the utility of DE-MRI in delineating regions of LA low voltage and PV reconnection sites in patients undergoing repeat PV isolation for recurrent AF. METHODS We enrolled 10 patients undergoing repeat ablation for AF recurrence to undergo preprocedural DE-MRI of the LA in conjunction with high-density voltage mapping (>100 sites) of the LA during the ablation procedure. LA wall regions with hyperenhancement were segmented from DE-MRI images and retrospectively co-registered with the electroanatomic LA map. The association between scar on DE-MRI images and low-voltage regions of the LA was assessed, as was the association between scar gaps and electrogram-determined PV reconnection sites. RESULTS Ten patients underwent successful DE-MRI imaging and repeat AF ablation without complication. In all 10 patients, the majority of PVs were found to have regained electrical continuity with the LA (30/37 PVs electrically active); all patients underwent successful reisolation of all PVs using standard ablation techniques. There was a significant association between scar identified by DE-MRI and low-voltage regions of the LA (-0.7±0.1 mV in scar regions; generalized estimating equations model clustered by patient, P<.001). However, there was no association between scar gaps and PV reconnection sites. CONCLUSION We demonstrate the co-registration of DE-MRI scar imaging and electroanatomic LA mapping, with agreement between regions of scar on DE-MRI and low voltage by mapping. However, at our center, this technique did not provide accurate information on the location of PV reconnection sites in patients undergoing repeat ablation for AF.

A Prospective Study Evaluating the Role of Obesity and Obstructive Sleep Apnea for Outcomes After Catheter Ablation of Atrial Fibrillation

Effect of Obesity and OSA on Outcomes Post AF Ablation. Background: Obesity and obstructive sleep apnea (OSA) have a strong association with atrial fibrillation (AF). The purpose of this study was to prospectively determine the effects of obesity, assessed by the body mass index (BMI) and OSA on the efficacy of catheter ablation of AF.

End-Stage Renal Disease Predicts Complications in Pacemaker and ICD Implants

End‐Stage Renal Disease Predicts Complications in Pacemaker and ICD Implants. Introduction: Patients with chronic kidney disease (CKD) have increased morbidity following invasive procedures. We hypothesized that patients with CKD have higher complication rates following device implantation than patients with normal renal function.