Methods and Results— Among 32 family members, 5 were initially diagnosed with atrioventricular block after age 30; 4 were studied, 3 of whom later developed dilated cardiomyopathy. We found a heterozygous single-nucleotide mutation resulting in an amino acid substitution (A1180V) in all studied patients and in 6 other younger unaffected members but not in 200 control chromosomes. When expressed with the β1 subunit, the mutated channels exhibited a –4.5-mV shift of inactivation with slower recovery leading to a rate-dependent Na⁺ current reduction and a moderate increase in late Na⁺ current. Clinical study revealed that although QRS duration decreased with increasing heart rate in noncarrier family members, this change was blunted in unaffected carriers whose ECG and heart function were normal. Resting corrected QT interval of unaffected carriers was significantly longer than that of noncarriers, even though it was still within the normal range.

Conclusions— A1180V expresses a mild Na⁺ channel phenotype in vitro and a corresponding clinical phenotype in unaffected mutation carriers, implying that A1180V caused structural heart disease in affected carriers by disturbing Na⁺ influx and, hence, cellular Na⁺ homeostasis. The high penetrance of A1180V suggests this phenotype as a high risk factor for dilated cardiomyopathy with preceding atrioventricular block.

Methods and Results— CHF was induced in dogs by ventricular tachypacing (240 bpm x2 weeks). Cellular Ca²⁺-handling properties and expression/phosphorylation status of key Ca²⁺ handling and myofilament proteins were assessed in control and CHF atria. CHF decreased cell shortening but increased left atrial diastolic intracellular Ca²⁺ concentration ([Ca²⁺]_i), [Ca²⁺]_i transient amplitude, and sarcoplasmic reticulum (SR) Ca²⁺ load (caffeine-induced [Ca²⁺]_i release). SR Ca²⁺ overload was associated with spontaneous Ca²⁺ transient events and triggered ectopic activity, which was suppressed by the inhibition of SR Ca²⁺ release (ryanodine) or Na⁺/Ca²⁺ exchange. Mechanisms underlying abnormal SR Ca²⁺ handling were then studied. CHF increased atrial action potential duration and action potential voltage clamp showed that CHF-like action potentials enhance Ca²⁺_i loading. CHF increased calmodulin-dependent protein kinase II phosphorylation of phospholamban by 120%, potentially enhancing SR Ca²⁺ uptake by reducing phospholamban inhibition of SR Ca²⁺ ATPase, but it did not affect phosphorylation of SR Ca²⁺-release channels (RyR2). Total RyR2 and calsequestrin (main SR Ca²⁺-binding protein) expression were significantly reduced, by 65% and 15%, potentially contributing to SR dysfunction. CHF decreased expression of total and protein kinase A–phosphorylated myosin-binding protein C (a key contractile filament regulator) by 27% and 74%, potentially accounting for decreased contractility despite increased Ca²⁺ transients. Complex phosphorylation changes were explained by enhanced calmodulin-dependent protein kinase II expression and function and type-1 protein-phosphatase activity but downregulated regulatory protein kinase A subunits.

Conclusions— CHF causes profound changes in Ca²⁺-handling and -regulatory proteins that produce atrial fibrillation–promoting atrial cardiomyocyte Ca²⁺-handling abnormalities, arrhythmogenic triggered activity, and contractile dysfunction.

Methods and Results— We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81±2 bpm versus 66±2 bpm in healthy subjects [HS], P<0.01). Head-up tilt to 40° induced a greater rise in heart rate in patients with POTS (+24±4 bpm versus +13±2 bpm in HS, P<0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29±3 bursts/min in patients with POTS and +13±2 bursts/min in HS, P<0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS.

Conclusion— Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.

Methods and Results— Twelve dogs underwent evaluation using a newly developed Carto-based 3D ultrasound system. After fiducial clip markers were percutaneously implanted at critical locations in each cardiac chamber, 3D ultrasound geometries, derived from a family of 2D intracardiac echocardiographic images, were constructed. Point-source error of 3D ultrasound-derived geometries, assessed by actual real-time 2D intracardiac echocardiographic clip sites, was 2.1±1.1 mm for atrial and 2.4±1.2 mm for ventricular sites. These errors were significantly less than the variance on CartoMerge computed tomographic images (atria: 3.3±1.6 mm; ventricles: 4.8±2.0 mm; P<0.001 for both). Target ablation at each clip, guided only by 3D ultrasound-derived geometry, resulted in lesions within 1.1±1.1 mm of the actual clips. Pulmonary vein ablation guided by 3D ultrasound-derived geometry resulted in circumferential ablative lesions. Mapping in 15 patients produced modestly smaller 3D ultrasound versus electroanatomic map left atrial volumes (98±24 cm³ versus 109±25 cm³, P<0.05). Three-dimensional ultrasound-guided pulmonary vein isolation and linear ablation in these patients were successfully performed with confirmation of pulmonary vein entrance/exit block.

Conclusions— These data demonstrate that 3D ultrasound images seamlessly yield anatomically accurate chamber geometries. Image volumes from the ultrasound system are more accurate than possible with CartoMerge computed tomographic imaging. This clinical study also demonstrates the initial feasibility of this guidance system for ablation in patients with atrial fibrillation.

Methods and Results— The first 100 consecutive patients (58.8±11.2 years old, 80 male) who underwent single-ring isolation for atrial fibrillation (66 intermittent, 18 persistent, 16 long-standing persistent) were followed up for 9.1±4.5 months. Recurrences were diagnosed by clinical symptoms and Holter monitoring. Patients with recurrences of sustained atrial arrhythmia >3 months after the procedure were offered a repeat procedure and were studied to determine the mechanisms of recurrence. Forty-six patients (46%) experienced sustained postprocedural atrial arrhythmias (35 had atrial fibrillation, and 34 had atrial flutter). Of these, 34 required a second procedure 7.0±3.1 months after their initial procedure. Reconnection of the posterior left atrium was seen in all patients with atrial fibrillation. Atrial flutter was most commonly due to mitral isthmus-dependent macroreentry (n=8, cycle length 368±116 ms) or macroreentry through 2 gaps in the ring of lesions (n=6, cycle length 328±115 ms). Posterior left atrium reisolation was achieved at the second procedure in all patients. Atrial flutter was successfully ablated and rendered noninducible in all patients. Six months after their last procedure, the Kaplan-Meier estimate of freedom from recurrence for all 100 patients was 81±5%.

Conclusions— Atrial fibrillation and atrial flutter recurrence is common after single-ring isolation. Reconnection of the posterior left atrium and macroreentry are the common mechanisms. Repeat ablation results in satisfactory short-term outcomes.

Methods and Results— In 85 patients with long-lasting persistent AF (age=59±10 years), RFA was directed at CFAEs in the LA and coronary sinus until AF terminated (19) or all identified LA CFAEs were eliminated. Sixty-six patients who remained in AF were randomly assigned to cardioversion and no further RFA (n=33) or to RFA of RA CFAEs (n=33). RA sites consisted of the crista terminalis (69%), septum (38%), superior vena cava (28%), coronary sinus ostium (22%), and the base of the appendage (31%). AF terminated in 1 (3%) of 33 patients during RA RFA. At 17±6 months after a single ablation procedure, 74% of the patients in whom AF terminated during LA RFA were in sinus rhythm. Rates of freedom from AF were similar in the patients randomized to no RFA in the RA (24%) and those randomized to RFA of RA CFAEs (30%, P=0.8). The ablation procedure was repeated in 26 patients (31%) for AF (n=22) or atrial flutter (n=4). At 16±7 months after the final procedure, 89% of the patients in whom AF terminated during LA RFA were in sinus rhythm. Among the randomized patients, the proportion of patients who remained in sinus rhythm was similar in patients who did not undergo RFA of RA CFAEs (52%) and those who did (58%, P=0.6).

Conclusion— After RFA of CFAEs in the LA and coronary sinus, ablation of CFAEs in the RA provides little or no increment in efficacy among patients with long-lasting persistent AF.

Methods and Results— All study patients developed AT after ablation for atrial fibrillation. The approach to AT ablation consisted of 4 steps: use of a 20-pole penta-array catheter to map the chamber rapidly during the rhythm of interest, analysis of the patterns of atrial activation to identify wave fronts of electric propagation, targeted entrainment at putative channels, and catheter ablation at these "isthmuses." All ablations were performed with irrigated radiofrequency ablation catheters. Forty-one ATs were identified in 17 patients (2.4±1.6 ATs per patient). Using the multielectrode catheter in conjunction with the Ensite NavX system, we created activation maps of 33 of 41 ATs (81%) (mean cycle length, 284±71 seconds) with a mean of 365±108 points per map and an average mapping time of 8±3 minutes. Of the 33 mapped ATs, 7 terminated either spontaneously or during entrainment maneuvers. Radiofrequency energy was used to attempt ablation of 26 ATs; 25 of 26 of the ATs (96%) were terminated successfully by ablation or catheter pressure.

Conclusions— This study demonstrates a strategy for rapidly defining and eliminating the scar-related ATs typically encountered after ablation of atrial fibrillation.

Methods and Results— Among 290 consecutive patients who underwent ablation for VT or symptomatic premature ventricular complexes (PVCs) based on a focal mechanism, 7 patients were found to have an ablation site at the base of the posterior papillary muscle in the LV. All patients had normal LV systolic function and a normal baseline electrocardiogram. The electrocardiogram during VT or PVCs demonstrated a right bundle-branch block and superior-axis QRS morphology in all patients. VT was not inducible by programmed atrial or ventricular stimulation. In 2 patients with sustained VT, overdrive pacing neither terminated VT nor demonstrated any criterion for transient entrainment. Activation mapping localized the earliest site of activation to the base of the posterior papillary muscle in all patients. When Purkinje potentials were recorded at the site of successful ablation, these potentials preceded local ventricular muscle potentials during sinus rhythm. During VT or PVCs, however, the ventricular muscle potential always preceded the Purkinje potentials. After recurrence of VT or PVCs with standard radiofrequency ablation, irrigated ablation was successful in eliminating the arrhythmia in all patients. Over a mean follow-up period of 9 months, all patients have been free of PVCs and VT.

Conclusion— We present a distinct syndrome of VT arising from the base of the posterior papillary muscle in the LV by a nonreentrant mechanism. Ablation can be challenging, and irrigated ablation may be necessary for long-term success.

Methods and Results— Twelve patients with outflow tract ventricular arrhythmia originating above the semilunar valves with discrete arterial potentials were studied. The clinical characteristics, properties of the arterial potentials, electrophysiological evaluation and ablation, and short- and long-term outcomes were reviewed. Of the twelve patients, 8 (67%) were women. The patients’ average age was 41±14 years. The average ejection fraction was 0.52±0.16 (range: 0.16 to 0.75). Contact mapping in the great artery demonstrated discrete near-field electrograms that were separate from far-field ventricular electrograms in all patients (8 above the pulmonary valve and in 4 the aortic valve). One or more of the following electrophysiological characteristics, supportive of an arrhythmogenic substrate, were observed in 10 of 12 patients: (1) A fixed or reproducibly variable pattern of discrete potential–ventricular arrhythmia relationship was present at baseline or during pacing; (2) the discrete potential–ventricular electrogram relationship during sinus rhythm was the reverse of that during the ventricular arrhythmia; (3) during sustained ventricular tachycardia, spontaneous variation of the ventricular (V-V) cycle length was preceded by a similar variation of arterial spike potential–spike potential cycle length; and (4) ablation guided by the discrete arterial potential successfully eliminated the clinical arrhythmia. Ablation was successful in these patients. In the remaining 2 patients, the potentials were believed to be bystanders. Over 10±4 months (range: 5 to 32 months) of follow-up, there have been no recurrences of the premature ventricular complex or ventricular arrhythmia.

Conclusions— Discrete potentials are present in the great arteries of a select group of patients with outflow tract ventricular tachycardia originating above the semilunar valves. When an arrhythmogenic relationship can be demonstrated, discrete potentials are useful in guiding ablation within the great vessels, despite significant anatomic complexity.

Methods and Results— Single cells were isolated from samples of rabbit PV_m, central and peripheral sinoatrial node, crista terminalis, and left and right atria. Detailed morphology of cells was assessed and intracellular calcium concentrations measured with the use of Fluo-3. Cells from the PV_m were smaller than atrial cells and showed large elevations in diastolic calcium during activation at physiological rates, a feature the PV_m cells shared with cells from the sinoatrial node. Unstimulated spontaneous activity was observed in a minority of cells from the PV_m, but numerous cells from this region showed spontaneous activity for a brief period immediately subsequent to stimulation at physiological rates. This was not observed in atrial cells. Assessment of calcium removal pathways showed sarcolemmal calcium extrusion in cells from the PV_m to have a high reliance on "slow" extrusion pathways to maintain intracellular calcium homeostasis because of a low expression of sodium–calcium exchanger.

Conclusions— We conclude that cells from the PV_m share some features with cells from the sinoatrial node but also have distinctly unique features that predispose them to the development of spontaneous activity.