J. Paul Mounsey

Coexistence of type I atrial flutter and intra-atrial re-entrant tachycardia in patients with surgically corrected congenital heart disease

OBJECTIVES This study assessed the coexistence of intra-atrial re-entrant tachycardia (IART) and isthmus-dependent atrial flutter (IDAF) in patients presenting with supraventricular tachyarrhythmias after surgical correction of congenital heart disease (CHD). BACKGROUND In patients with CHD, atrial tachyarrhythmias may result from IART or IDAF. The frequency with which IART and IDAF coexist is not well defined. METHODS Both IDAF and IART were diagnosed in 16 consecutive patients using standard criteria and entrainment mapping. Seven patients had classic atrial flutter morphology on surface electrocardiogram (ECG), whereas nine had atypical morphology. RESULTS A total of 24 circuits were identified. Three patients had IDAF only, five had IART only, seven had both, and one had a low right atrial wall tachycardia that could not be entrained. Twenty-two different reentry circuits were ablated. Successful ablation was accomplished in 13 of 14 (93%) IART and 9 of 10 (90%) IDAF circuits. There was one IART recurrence. The slow conduction zone involved the region of the right atriotomy scar in 12 of 14 (86%) IART circuits. No procedural complications and no further recurrences were seen after a mean follow-up of 24 months. CONCLUSIONS Both IDAF and IART are the most common mechanisms of atrial re-entrant tachyarrhythmias in patients with surgically corrected CHD, and they frequently coexist. The surface ECG is a poor tool for identifying patients with coexistent arrhythmias. The majority of IART circuits involve the lateral right atrium and may be successfully ablated by creating a lesion extending to the inferior vena cava.

Phospholemman Inhibition of the Cardiac Na+/Ca2+ Exchanger ROLE OF PHOSPHORYLATION

We have demonstrated previously that phospholemman (PLM), a 15-kDa integral sarcolemmal phosphoprotein, inhibits the cardiac Na+/Ca2+ exchanger (NCX1). In addition, protein kinase A phosphorylates serine 68, whereas protein kinase C phosphorylates both serine 63 and serine 68 of PLM. Using human embryonic kidney 293 cells that are devoid of both endogenous PLM and NCX1, we first demonstrated that the exogenous NCX1 current (INaCa) was increased by phorbol 12-myristate 13-acetate (PMA) but not by forskolin. When co-expressed with NCX1, PLM resulted in: (i) decreases in INaCa, (ii) attenuation of the increase in INaCa by PMA, and (iii) additional reduction in INaCa in cells treated with forskolin. Mutating serine 63 to alanine (S63A) preserved the sensitivity of PLM to forskolin in terms of suppression of INaCa, whereas mutating serine 68 to alanine (S68A) abolished the inhibitory effect of PLM on INaCa. Mutating serine 68 to glutamic acid (phosphomimetic) resulted in additional suppression of INaCa as compared with wild-type PLM. These results suggest that PLM phosphorylated at serine 68 inhibited INaCa. The physiological significance of inhibition of NCX1 by phosphorylated PLM was evaluated in PLM-knock-out (KO) mice. When compared with wild-type myocytes, INaCa was significant larger in PLM-KO myocytes. In addition, the PMA-induced increase in INaCa was significantly higher in PLM-KO myocytes. By contrast, forskolin had no effect on INaCa in wild-type myocytes. We conclude that PLM, when phosphorylated at serine 68, inhibits Na+/Ca2+ exchange in the heart.

Relation of Left Atrial Volume from Three-Dimensional Computed Tomography to Atrial Fibrillation Recurrence Following Ablation

The effect of left atrial (LA) structural remodeling and dilatation on the outcome of ablation of atrial fibrillation (AF) remains unknown. We correlated potential prognostic markers of AF ablation, including LA volume from computed tomography, with AF recurrence after ablation. We studied 73 consecutive patients (52 with paroxysmal AF, 21 with persistent AF) undergoing AF ablation. LA volume was calculated by axial slice summation from 3-dimensional computed tomography. Follow-up was through 12 months, with success of ablation determined by electrocardiography and lack of symptoms (unless symptoms proved not AF by Holter monitor). Overall procedure success was 66% (including 15% repeat ablations, 12% on antiarrhythmics). Pulmonary vein isolation was performed, with additional linear ablation in 44 (60%). Mean LA volume (95% confidence interval) for those with recurrent AF was 119 ml (104 to 135) versus 98 ml (90 to 106) for no recurrence (p = 0.01, rank-sum test). Wide variation in LA volume occurred in the 2 groups, but, of the 15% of patients with very large LA volumes (>135 ml), 82% had recurrent AF. A cutpoint of 135 ml yields 36% sensitivity and 96% specificity for recurrence. In multivariable regression analysis, only LA volume and number of cardiovascular co-morbidities were associated with more recurrence (p = 0.02 and p = 0.03, respectively). In conclusion, LA volume varies greatly in those with and without successful AF ablations, mean LA volume is significantly larger in those with recurrence, and patients with LA volumes >135 ml are very likely to develop recurrent AF.

Placement of transvenous pacemaker and ICD leads across total chronic occlusions

Objective: To establish a method of implantation for device leads across total venous occlusions.

Modulation of Xenopus oocyte-expressed phospholemman-induced ion currents by co-expression of protein kinases

Phospholemman (PLM), the major sarcolemmal substrate for phosphorylation by cAMP-dependent kinase (PKA) protein kinase C (PKC) and NIMA kinase in muscle, induces hyperpolarization-activated anion currents in Xenopus oocytes, most probably by enhancing endogenous oocyte currents. PLM peptides from the cytoplasmic tail are phosphorylated by PKA at S68, by NIMA kinase at S63, and by PKC at both S63 and S68. We have confirmed the phosphorylation sites in the intact protein, and we have investigated the role of phosphorylation in the regulatory activity of PLM using oocyte expression experiments. We found: (1) the cytoplasmic domain is not essential for inducing currents in oocytes; (2) co-expression of PKA increased the amplitude of oocyte currents and the amount of PLM in the oocyte membrane largely, but not exclusively, through phosphorylation of S68; (3) co-expression of PKA had no effect on a PLM mutant in which all putative phosphorylation sites had been inactivated by serine to alanine mutation (SSST 62, 63, 68, 69 AAAA); (4) co-expression of PKC had no effect in this system; (5) co-expression of NIMA kinase increased current amplitude and membrane protein level, but did not require PLM phosphorylation. These findings point to a role for phosphorylation in the function of PLM.

Transient ST elevation after transthoracic cardioversion in patients with hemodynamically unstable ventricular tachyarrhythmia

The significance of ST-segment elevation after resuscitation from arrhythmias not associated with ischemia was examined in a group of patients who received transthoracic shocks for hemodynamically unstable ventricular tachyarrhythmias during electrophysiologic studies. ST-segment elevation was seen in 15.4%, was transient, and was not associated with clinical evidence of myocardial infarction.

Effects of phospholemman expression on swelling-activated ion currents and volume regulation in embryonic kidney cells

Phospholemman (PLM) is a 72-amino-acid phosphoprotein that is a major substrate for cAMP-dependent protein kinase, protein kinase C, and NIMA kinase. In lipid bilayers, PLM forms ion channels selective for Cl−, K+, and taurine. Effluxes of these abundant intracellular osmolytes play an important role in the control of dynamic cell volume changes in many cell types. We measured swelling-activated ion currents and regulatory volume decrease (RVD) in human embryonic kidney cells stably overexpressing canine cardiac PLM. In response to swelling, two clonal cell lines overexpressing PLM had increased swelling-activated ion current densities and faster and more extensive RVD. A third clonal cell line overexpressing mutant PLM showed reduced ion current densities and a diminished RVD response. These results suggest a role for PLM in the regulation of cell volume, perhaps as a modulator of an endogenous swelling-activated signal transduction pathway or possibly by participating directly in swelling-induced osmolyte efflux.

Real-Time Rotational ICE Imaging of the Relationship of the Ablation Catheter Tip and the Esophagus During Atrial Fibrillation Ablation

Introduction: Atrioesophageal fistula is a rare complication of atrial fibrillation (AF) ablation that should be avoided. We investigated whether rotational intracardiac echocardiography (ICE) can help to minimize ablation close to the esophagus.

Characterization of the mitral isthmus for atrial fibrillation ablation using intracardiac ultrasound from within the coronary sinus

BACKGROUND Atrial fibrillation (AF) ablation involving the mitral isthmus and/or the coronary sinus (CS) may result in circumflex artery (Cx) or other collateral structure damage. OBJECTIVE The purpose of this study was to investigate the feasibility of intracardiac echocardiographic (ICE) imaging from within the CS to characterize mitral isthmus anatomy and guide ablation. METHODS A 9-Fr sheath was introduced into the CS of 30 patients before AF ablation. A 9-Fr rotational ICE catheter was then advanced within the sheath to the distal CS adjacent to the lateral left atrial (LA) wall. Serial cross-sectional images to document the relations of the LA, Cx, CS, esophagus, and pericardium were obtained at multiple points within the CS during a pullback to the CS ostium. RESULTS The Cx was identified in 62/150 positions in 25/30 patients. The median (range) of the LA-Cx distance was 3.3 mm (0.7-19.6 mm), and the median CS-Cx distance was 2.0 mm (0.4-9.7 mm). The esophagus was seen in 36/150 positions in 17/30 patients. The median CS-esophagus distance was 4.0 mm (1.4-16.2 mm). The proximity of the Cx and esophagus to the LA and CS varied considerably. The median CS-mitral annulus distance was 11.9 mm (4.1-21.6 mm). After CS cannulation, the ICE imaging took 5 +/- 2 minutes and required 120 +/- 60 seconds of fluoroscopy. CONCLUSIONS Mitral isthmus anatomy can be accurately characterized by rotational ICE imaging from within the CS. There is great variability in the location and proximity of the Cx, CS, esophagus, and pericardium to the LA. Real-time identification of these structures could help to plan ablation strategies and potentially reduce complications.

Effects of age and gene dose on skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase.

Myotonic muscular dystrophy (DM) is characterized by abnormal skeletal muscle Na channel gating and reduced levels of myotonic dystrophy protein kinase (DMPK). Electrophysiological measurements show that mice deficient in Dmpk have reduced Na currents in muscle. We now find that the Na channel expression level is normal in mouse muscle partially or completely deficient in Dmpk. Reduced current amplitudes are not changed by age or gene dose, and the reduction is not due to changes in macroscopic or microscopic gating kinetics. The mechanism of abnormal membrane excitability in DM may in part be silencing of muscle Na channels due to Dmpk deficiency.