Yuki Iwasaki

Mechanisms of Atrial Tachyarrhythmias Associated With Coronary Artery Occlusion in a Chronic Canine Model

Background— Coronary artery disease predisposes to atrial fibrillation (AF), but the effects of chronic atrial ischemia/infarction on AF-related substrates are unknown. Methods and Results— Regional right atrial myocardial infarction (MI) was created in 40 dogs by ligating an artery that supplies the right atrial free wall and not the ventricles; 35 sham dogs with the same artery isolated but not ligated were controls. Dogs were observed 8 days after MI and subjected to open-chest study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca2+ imaging on day 8. Holter ECGs showed more spontaneous atrial ectopy in MI dogs (eg, 662±281 on day 7 versus 34±25 ectopic complexes per day at baseline; 52±21 versus 1±1 atrial tachycardia episodes per day). Triggered activity was increased in MI border zone cells, which had faster decay of caffeine-evoked Ca2+ transients and enhanced (by ≈73%) Na+-Ca2+ exchange current. Spontaneous Ca2+ sparks (confocal microscopy) occurred under &bgr;-adrenergic stimulation in more MI dog cells (66±9%) than in control cells (29±4%; P<0.01). Burst pacing induced long-lasting AF in MI dogs (1146±259 versus 30±14 seconds in shams). Increased border zone conduction heterogeneity was confirmed by both bipolar electrode mapping in vivo and optical mapping. Optical mapping demonstrated stable border zone reentry in all 9 MI preparations but in none of 6 shams. Border zone tissue showed increased fibrous tissue content. Conclusions— Chronic atrial ischemia/infarction creates substrates for both spontaneous ectopy (Ca2+-release events, increased Na+-Ca2+ exchange current) and sustained reentry (conduction abnormalities that anchor reentry). Thus, chronic atrial infarction in dogs promotes both AF triggers and the substrate for AF maintenance. These results provide novel insights into potential AF mechanisms in patients with coronary artery disease.

Thrombomodulin and Tissue Factor Pathway Inhibitor in Endocardium of Rapidly Paced Rat Atria

Background—Atrial fibrillation (AF) is well known as one of the cardiogenic causes for thromboembolism. Although decreased flow and hypercoagulable state of the blood in the fibrillating atrium have been emphasized as the underlying mechanisms, endocardial dysfunction in maintaining the local coagulation balance could also contribute to the thrombogenesis in AF. Methods and Results—The paroxysmal AF model was created by rapid atrial pacing in anesthetized rats. To test the hypothesis that AF induces local coagulation imbalance by disturbing the atrial endocardial function, the gene expression of intrinsic anticoagulant factors, thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI), were determined by means of ribonuclease protection assay, Western blotting, and immunohistochemistry. Rapid atrial pacing for 8 hours significantly decreased TM and TFPI mRNA levels in the left atrium but not in the ventricle, leading to the downregulation of their immunoreactive proteins. Immunohistochemical analysis revealed that TM and TFPI were expressed predominantly in the endocardial cells of the normal atrium, presumably preventing local blood coagulation, and that rapid atrial pacing induced the loss of TM and TFPI expression in the endocardium, leading to deficiency in anticoagulant barriers between the atria and the blood. Conclusions—Rapid atrial pacing acutely downregulated the gene expression of TM and TFPI in the atrial endocardium, thereby inducing local coagulation imbalance on the internal surface of the atrial cavity. These results would support the validity of supplement of anticoagulant molecules deficient in AF.

Circadian variation of cardiac K^+ channel gene expression

Background—Many cardiac arrhythmias have their own characteristic circadian variations. Because the expression of many genes, including clock genes, is regulated variably during a day, circadian variations of ion channel gene expression, if any, could contribute to the fluctuating alterations of cardiac electrophysiological characteristics and subsequent arrhythmogenesis. Methods and Results—To examine whether cardiac K+ channel gene expression shows a circadian rhythm, we analyzed the mRNA levels of 8 Kv and 6 Kir channels in rat hearts every 3 hours throughout 1 day. Among these channels, Kv1.5 and Kv4.2 genes showed significant circadian variations in their transcripts: ≈2-fold increase of Kv1.5 mRNA from trough at Zeitgeber time (ZT) 6 to peak at ZT18 and a completely reverse pattern in Kv4.2 mRNA (≈2-fold increase from trough at ZT18 to peak at ZT6). Actually, along with the variations in the immunoreactive proteins, the density of the transient outward and steady-state currents in isolated myocytes and the responses of atrial and ventricular refractoriness to 4-aminopyridine in isolated-perfused hearts showed differences between ZT6 and ZT18, a circadian pattern comparable to that of Kv1.5 and Kv4.2 gene expression. Reversal of light stimulation almost inverted these circadian rhythms, although pharmacological autonomic blockade only partially attenuated the rhythm of Kv1.5 but not of Kv4.2 transcripts. Conclusions—Among all the cardiac K+ channels, Kv1.5 and 4.2 channels are unique in showing characteristic circadian patterns in their gene expression, with Kv1.5 increase during the dark period partially dependent on &bgr;-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

Recovery of atrioventricular block following steroid therapy in patients with cardiac sarcoidosis

BACKGROUND Atrioventricular (AV) block is one of the main clinical manifestations in patients with cardiac sarcoidosis (CS). Although steroid therapy is considered to be effective for AV block, the efficacy has not been demonstrated in detail. METHODS AND RESULTS Fifteen CS patients presenting with advanced or complete AV block were retrospectively investigated. All patients were treated with 30mg/day of prednisone after device implantation, which was tapered to a maintenance dosage of 5-10mg/day. During a mean follow-up of 7.1 years, AV block resolved to normal conduction or first-degree AV block in 7 patients (recovery group). The improvement was driven within the first week of steroid therapy in 4 patients, while 3 patients showed late recovery of AV conduction. The remaining 8 patients were classified as the non-recovery group. The recovery group showed a higher left ventricular ejection fraction (69.4±8.9% versus 44.1±19.3%, p=0.029) and higher prevalence of advanced AV block (87.5% versus 28.6%, p=0.040) compared with those of the non-recovery group. In patients with the recovery group, there was no late recurrence of AV block during the follow-up period. CONCLUSIONS Early initiation of steroid therapy may be effective for AV block, and steroid therapy before device implantation is a possible therapeutic strategy for some selected patients.

Antiarrhythmic effect of cardiac resynchronization therapy with triple-site biventricular stimulation

AIMS The antiarrhythmic effect of triple-site biventricular stimulation (Tri-V) is poorly understood. This study aims to evaluate the effect of cardiac resynchronization therapy (CRT) on ventricular arrhythmia (VA) with Tri-V using a single right ventricular (RV) and double left ventricular (LV) lead. METHODS AND RESULTS Over a period of 3.5 years, 58 consecutive patients with New York Heart Association class II-IV heart failure, an LV ejection fraction of ≤ 0.35, and a QRS interval of ≥ 120 ms were enrolled. Acute haemodynamic responses to dual-site biventricular stimulation (Bi-V) and Tri-V were evaluated by assigning patients to a Bi-V or Tri-V group. Electrocardiogram parameters [QT interval, JT interval, and transmural dispersion of repolarization (TDR)] were measured over time after CRT. Spontaneous VA detected by telemetry was reviewed and confirmed. During a mean follow-up of 481 days after implantation, VA occurred in 2 of 22 patients in the Tri-V group and 14 of 36 patients in Bi-V group. Triple-site biventricular stimulation was thus associated with a decreased VA risk (P = 0.044). Multivariate Cox analysis showed that Tri-V pacing prevented arrhythmic events as compared with Bi-V pacing (hazard ratio, 0.13; 95% confidence interval, 0.029-0.610; P = 0.009). Ventricular repolarization indices at 6 months were significantly shortened in Tri-V compared with Bi-V (QTc, -23.6 vs. -14.1%, P = 0.008; JTc, -21.4 vs. -7.7%, P = 0.005; TDRc, -39.9 vs. -17.0%, P < 0.001). CONCLUSION Compared with Bi-V, Tri-V reduced VA during long-term follow-up. Improvements in repolarization parameters may result in antiarrhythmic effects.

Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing.

The purpose of the present study was to assess the influence of autonomic blockade on shortening of effective refractory period (ERP) induced by short‐term rapid atrial pacing (RAP) and its recovery process. Fifteen patients (8 men, 7 women, age 52 ± 16 years) without structural heart disease and without a history of atrial fibrillation were included in this study. All patients underwent RAP at a cycle length of 300 ms for 5 minutes, after which the ERP was measured in all patients at 1, 3, 5, 7.5, and 10 minutes following cessation of RAP. In ten patients, these RAP and measurements of ERPs were repeated after administration of propranolol (P) and subsequent administration of atropine (P + A), respectively. In the remaining five patients atropine (A) was given first and then the administration of propranolol followed (P + A). Relative to the baseline value, the ERP immediately after RAP did not differ significantly from the Control(C), P, A, or P + A (C, 79%± 8%; P, 82%± 9%; A, 80%± 6%; P + A, 82%± 13%). However, the ERP 3 minutes after cessation of RAP was significantly (P < 0.05) longer in A (93%± 4%) and P + A (97%± 5%) than that in C (86%± 5%) and P (86%± 5%). The recovery time for ERP to return to pre‐RAP value was significantly shorter during A and P + A than during either C or P (C, 536 ± 161 s; P, 503 ± 172 s; A, 282 ± 111 s; P + A, 291 ± 147 s; P < 0.05). Parasympathetic blockade may promote recovery from ERP shortening induced by short‐term RAP. (PACE 2004; 27:33–37)

Cardiac resynchronization therapy restored ventricular septal myocardial perfusion and enhanced ventricular remodeling in patients with nonischemic cardiomyopathy presenting with left bundle branch block

BACKGROUND Left bundle branch block (LBBB) causes intraventricular conductional delay, which results in left ventricle (LV) mechanical dyssynchrony. In the absence of coronary artery disease, patients with LBBB often have diminished accumulation of technetium-99m compounds at the myocardial septal area in electrocardiogram-gated single-photon emission computed tomography. OBJECTIVE To investigate whether cardiac resynchronization therapy (CRT) could improve septal myocardial perfusion, leading to favorable reverse remodeling. METHODS The study included all 26 patients with nonischemic cardiomyopathy eligible for CRT, who presented with LBBB, New York Heart Association class II-IV heart failure, and LV ejection fraction ≤35%. Single-photon emission computed tomography was performed at baseline and 6 months after CRT. Perfusion counts were measured at the ventricular septum and LV lateral free wall. Left ventricular end-systolic volume (LVESV) was measured by echocardiography to evaluate LV reverse remodeling by CRT. RESULTS At baseline, a perfusion defect at the LV septal myocardial area was confirmed in 19 of 26 (73%) patients. In these patients, septal perfusion significantly increased 6 months after CRT (56.1% ± 22.8% vs 82.9% ± 21.2%; P < .001). LVESV reduction and improved septal perfusion index were positively correlated (r = .561; P = .012), whereas no correlation was found between LVESV reduction and the difference of QRS duration before and 6 months after CRT (r = .218; P = .371). The improvement in LV septal perfusion was associated with LV reverse remodeling. CONCLUSIONS CRT could restore LV septal myocardial perfusion and ameliorate ventricular reverse remodeling in most patients with nonischemic cardiomyopathy and LBBB.

Successful radiofrequency catheter ablation of an anteroseptal (superoparaseptal) atrioventricular accessory pathway from the left ventricular outflow tract.

This case report describes a patient with Wolff‐Parkinson‐White syndrome in whom the ECG exhibited a typical pattern of an anteroseptal (superoparaseptal) accessory pathway. Successful radiofrequency catheter ablation was achieved from the septal side of the left ventricular outflow tract. It might be worthwhile to map the left side of the anterior septum if an accessory pathway potential is not appreciable along the tricuspid annulus to avoid the potential complication of AV block in patients with a typical anteroseptal accessory pathway ECG pattern. (PACE 2004; 27:668–670)

Angiotensin type 1 receptor blockade prevents endocardial dysfunction of rapidly paced atria in rats

Introduction. Atrial fibrillation (AF) per se causes atrial endocardial dysfunction leading to local coagulation imbalance on the internal surface of the atrium, which contributes to thrombus formation in the fibrillating left atrium. Materials and methods. To test a hypothesis that blockade of angiotensin II type 1 receptor (AT1-receptor) prevents the endocardial dysfunction by AF, we examined the effects of olmesartan on the expression of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), endothelial nitric oxide synthase (eNOS) and plasminogen activator inhibitor-1 (PAI-1) in the endocardium of the rapidly paced rat atria. Results. Rapid pacing induced a significant decrease in TFPI,TM and eNOS and an increase in PAI-1 protein in the left atrium. Pre-administration of low-dose olmesartan significantly prevented the down-regulation of TFPI,TM and eNOS and also attenuated the up-regulation of PAI-1. Immunohistochemistry identified these changes predominantly in the atrial endocardium. While the drug was without any effect on mRNA levels of TFPI,TM and eNOS, there was a significant decrease in its PAI-1 mRNA expression. Conclusions. AT1-receptor blocker could partially prevent the atrial endocardial dysfunction by rapid atrial pacing, which would provide one theoretical basis for beneficial effects for stroke prevention in AF.

Urgent catheter ablation for sustained ventricular tachyarrhythmias in patients with acute heart failure decompensation

AIMS Ventricular tachycardia (VT) and ventricular fibrillation (VF) are not uncommon in patients hospitalized with acute heart failure (AHF). We sought to evaluate the efficacy of urgent radiofrequency catheter ablation (RFCA) for recurrent VT/VF during AHF decompensations. METHODS AND RESULTS The present study retrospectively analysed the data of 15 consecutive patients (69 ± 9 years, ischaemic heart disease in 10), who underwent urgent RFCA for frequent drug-refractory VT/VF episodes during an AHF decompensation with pulmonary congestion. The target arrhythmias were clinically documented monomorphic VTs in 10 patients, frequent premature ventricular contractions (PVCs) triggering VF in 4, and both in 1. The mean left ventricular ejection fraction was 26 ± 8%. The maximum number of arrhythmia episodes over 24 h was 9.1 ± 11.7. All RFCA sessions were completed without any major complications except for a temporary deterioration of pulmonary congestion in three patients (20%). Elimination and non-inducibility of the target arrhythmias were achieved in 13 patients (87%). Successful ablation site electrograms showed Purkinje potentials for all 5 PVCs triggering VF and 4 of 14 clinically documented monomorphic VTs (29%). Five patients (33%) underwent second sessions 10 ± 4 days after the first session for acute recurrences. Sustained VT/VF was completely suppressed during admission in 12 patients (80%), and the AHF ameliorated in 13 patients (93%). Twelve patients (80%) were discharged alive. CONCLUSION Urgent RFCA for drug-resistant sustained ventricular tachyarrhythmias during AHF decompensations would be an appropriate therapeutic option. Purkinje fibres can be ablation targets not only in those with PVCs triggering VF, but also in those with monomorphic VT.