Yuji Nakazato

Clinical and Electrophysiological Characteristics of Atrial Standstill

NAKAZATO, Y., et al.: Clinical and Electrophysiological Characteristics of Atrial Standstill. To clarify the clinical and electrophysiological characteristics of atrial standstill (AS) we studied 11 patients (7 males and 4 females), whose average age was 62 years and who were followed over a period of 4–179 months. Underlying heart disease was present in nine patients and two cases were idiopathic. Major clinical symptoms in the 11 cases included Adams‐Stokes attacks, and dyspnea on exertion. In the standard 12‐lead ECGs obtained on admission, the P wave was absent in six cases. Atrial flutter (AF) was noted in 3, atrial fibrillation (Af) in 1, and multifocal atrial tachycardia in 1. In some cases, the ECG initially showed AF or Af, and was transformed after several years into ectopic atrial tachycardia or an ectopic atrial rhythm with a markedly decreased amplitude of the P wave. Finally, the P wave disappeared over a prolonged period. When intracardiac mapping was performed, the atrial electrograms tended to diminish at the site of high, mid‐lateral right atrium (RA). Electrograms were remained present in the vicinity of the tricuspid valve (TV) annulus. A repeated mapping and pacing study conducted in two patients revealed that the “silent” area spread toward the lower site of RA. During the average follow‐up period of 64 months, four patients died. The interval until death in one patient with myocarditis was 6 months, and in another with dilated cardiomyopathy (DCM) it was 8 months. It appears that the atrial muscular lesion starts in the high lateral RA and progresses toward the lower RA, then to the vicinity of the TV annulus. A diffuse and progressive disturbance may occur not only in the atrial muscle, but also in the atrioventricular conduction system in patients with AS who had progressive myocarditis or DCM.

Response to head-up tilt testing in patients with situational syncope.

The results of head-up tilt testing were compared between 24 patients with situational syncope and 44 age-matched patients with typical vasovagal syncope. Patients with situational syncope showed poor positive responses, especially in the passive tilt results (8.3% vs. 39%, p = 0.0078).

Clinical Significance of QRS Duration During Ventricular Pacing

To clarify the clinical significance of an abnormally prolonged paced QRS duration, we studied 114 patients who had undergone pacing for atrioventricular block (AVB). Patients were divided into two groups: group I consisted of 29 patients with at least one paced QRS duration ≥ 180 msec during the follow‐up period; group II consisted of 85 patients with paced QRS durations < 180 msec. The clinical background, QRS complexes before pacing, and the echocardiographic findings were assessed. Males (P < 0.05), those with H‐V block (P< 0.05) and a wider QRS complex of conducted and escape beats (both P < 0.01) were dominant in group I. The incidence of underlying heart disease was greater in group I than in group II (83% vs 32%, P < 0.01). Reduced left ventricular ejection fraction (LVEF) and increased left ventricular end‐diastolic dimension (LVDd) were more prominent in group I than in group II (LVEF 0.49 ± 0.17 vs 0.68 ± 0.10, P < 0.01, LVDd 57.1 ± 7.9 mm vs 48.5 ± 5.6 mm, P < 0.01). The paced QRS duration correlated with LVEF (r = ‐0.61) and LVDd (r = 0.81). A paced QRS duration ≥ 180 msec was sensitive and specific for a LVEF < 0.5 (83.3% and 85.2%) and LVDd ≥ 60 mm (100% and 81.4%). We conclude that patients with a prolonged paced QRS duration have more serious heart disease, and the paced QRS duration can be a useful indicator of impaired LV function.

Does an Early Increase in Heart Rate During Tilting Predict the Results of Passive Tilt Testing

Head‐up tilt testing is a useful but time‐consuming procedure. If we could accurately predict the tilt testing results; we would be able to substantially shorten the duration of tilt protocol. To clarify the hypothesis that an early increase in heart rate (HR) during tilting can predict the passive tilt results in our protocol (80‐degree angle for 30 minutes), we studied 115 consecutive patients (72 men, 43 women, mean age 46 ± 19 years) who were clinically diagnosed with neurally mediated syncope. Twentynine (25%) patients had a positive tilt test (P group), whereas 86 (75%) patients had a negative test (N group). The early HR increase was defined as the maximum HR during the first 5 minutes of tilting minus the resting HR before tilting. The early HR increase was significantly higher in the P group (23.8 ± 9.5 beats/min) than in the N group (17.5 ± 8.2 beats/min, P = 0.0008), but it was negatively correlated with the tilt duration to positive response (r =−0.52, P = 0.0032) and the patient age in the entire study population (r = 0.62, P < 0.0001). Results of multiple regression analysis indicated that age, tilt result, and tilt duration were independently associated with the early HR increase. As a result, an early HR increase ± 18 beats/min, the best apparent cut‐off point obtained in our study, was a sensitive (100%) marker for prediction of a positive response at ± 15 minutes of tilting, but it showed a low specificity (61 %). In conclusion, an early HR increase during 80‐degree tilting may be only predictive for a positive result ± 15 minutes because it depends on the tilt duration to a positive response and patient age.

Effectiveness of amiodarone versus bepridil in achieving conversion to sinus rhythm in patients with persistent atrial fibrillation: a randomised trial

Aims Pharmacological conversion to sinus rhythm is generally difficult to achieve, particularly in long-lasting persistent atrial fibrillation (AF). The purpose of this study is to compare the effectiveness of two agents, amiodarone and bepridil, in achieving conversion to sinus rhythm in patients with persistent AF. Methods and results Amiodarone (A) or bepridil (B) was administered to 40 consecutive patients (36 male subjects, age 61 years) with persistent AF in a prospective, randomised, open label fashion. The pharmacological effects in bringing about conversion to sinus rhythm and subsequently maintaining sinus rhythm were evaluated. If sinus rhythm was not restored within 3 months, direct current (DC) cardioversion was performed. The incidence of adverse effects was also evaluated. Sinus rhythm was restored in seven (35%) of 20 patients in group A (average follow-up of 3.2 months) and in 17 (85%) of 20 in group B (average follow-up of 2.3 months) (p<0.05). After pharmacological or DC cardioversion, sinus rhythm could be maintained in 10 (50%) of 20 patients in group A (average follow-up of 14.7 months) and 15 (75%) of 20 patients in group B (average follow-up of 15.6 months). QT interval and QTc were significantly prolonged compare with the baseline values in group B, but no torsade de pointes was recognised in any of the patients. One patient in the group B developed interstitial pneumonia, but steroid therapy cured the condition. Conclusions Bepridil was superior to amiodarone in achieving sinus conversion and in maintaining sinus rhythm after cardioversion in patients with persistent AF. Even so, we must be watchful for potentially serious adverse complications when administering bepridil.

Aberrant cell-to-cell coupling in Ca2+-overloaded guinea pig ventricular muscles

To investigate how intercellular coupling can be changed during Ca2+ overloading of ventricular muscle, we studied Ca2+ signals in individual cells and the histochemistry of the major gap junction channel, connexin43 (Cx43), using multicellular preparations. Papillary muscles were obtained from guinea pig ventricles and loaded with rhod-2. Sequential Ca2+ images of surface cells were obtained with a confocal microscope. In intact muscles, all cells showed simultaneous Ca2+ transients in response to field stimulation over a field of view of 0.3 x 0.3 mm2. In severely Ca2+-overloaded muscles, obtained by high-frequency stimulation in nonflowing Krebs solution, cells became less responsive to stimulation. Furthermore, nonsimultaneous but serial onsets of Ca2+ transients were often detected, suggesting a propagation delay of action potentials. The time lag of the onset between two aligned cells was sometimes as long as 100 ms. Similar lags were also observed in muscles with gap junction channels inhibited by heptanol. To investigate whether the phosphorylation state of Cx43 is affected in Ca2+-overloaded muscles, the distributions of phosphorylated and nonphosphorylated Cx43 were determined using specific antibodies. Most of the Cx43 was phosphorylated in the nonoverloaded muscles, whereas nonphosphorylated Cx43 was significantly elevated in severely Ca2+-overloaded muscles. Our results suggest that the propagation delay of action potential within a small area, a few square millimeters, can be a cause of abnormal conduction and a microreentry in Ca2+-overloaded heart. Inactivation of Na+ channels and inhibition of gap junctional communication may underlie the cell-to-cell propagation delay.

Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Background Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation ΔK210 in cardiac troponinT. Methodology/Principal Findings By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K+ (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K+ channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed. Conclusions/Significance Our results suggest that at least three steps of electrical remodeling occur in the hearts of DCM model mice, and that the combined down-regulation of Kv4.2, Kv1.5 and KChIP2 prior to the onset of HF may play an important role in the premature sudden death in this DCM model. DCM mice at 1 month or before, on the contrary, are associated with low risk of death in spite of inborn disorder and enlarged heart.

ST segment elevation in the right precordial leads following administration of class Ic antiarrhythmic drugs.

Electrocardiographic changes were evaluated retrospectively in five patients without previous episodes of syncope or ventricular fibrillation who developed abnormal ST segment elevation mimicking the Brugada syndrome in leads V1–V3 after the administration of class Ic antiarrhythmic drugs. Pilsicainide (four patients) or flecainide (one patient) were administered orally for the treatment of symptomatic paroxysmal atrial fibrillation or premature atrial contractions. The QRS duration, QTc, and JT intervals on 12 lead surface ECG before administration of these drugs were all within normal range. After administration of the drugs, coved-type ST segment elevation in the right precordial leads was observed with mild QRS prolongation, but there were no apparent changes in JT intervals. No serious arrhythmias were observed during the follow up periods. Since ST segment elevation with mild QRS prolongation was observed with both pilsicainide and flecainide, strong sodium channel blocking effects in the depolarisation may have been the main factors responsible for the ECG changes. As the relation between ST segment elevation and the incidence of serious arrhythmias has not yet been sufficiently clarified, electrocardiographic changes should be closely monitored whenever class Ic drugs are given.

Increased extracellular and intracellular Ca²⁺ lead to adipocyte accumulation in bone marrow stromal cells by different mechanisms.

Mesenchymal stem cells found in bone marrow stromal cells (BMSCs) are the common progenitors for both adipocyte and osteoblast. An increase in marrow adipogenesis is associated with age-related osteopenia and anemia. Both extracellular and intracellular Ca(2+) ([Ca(2+)]o and [Ca(2+)]i) are versatile signaling molecules that are involved in the regulation of cell functions, including proliferation and differentiation. We have recently reported that upon treatment of BMSCs with insulin and dexamethasone, both high [Ca(2+)]o and high [Ca(2+)]i enhanced adipocyte accumulation, which suggested that increases in [Ca(2+)]o caused by bone resorption may accelerate adipocyte accumulation in aging and diabetic patients. In this study, we used primary mouse BMSCs to investigate the mechanisms by which high [Ca(2+)]o and high [Ca(2+)]i may enhance adipocyte accumulation. In the process of adipocyte accumulation, two important keys are adipocyte differentiation and the proliferation of BMSCs, which have the potential to differentiate into adipocytes. Use of MTT assay and real-time RT-PCR revealed that high [Ca(2+)]i (ionomycin)-dependent adipocyte accumulation is caused by enhanced proliferation of BMSCs but not enhanced differentiation into adipocytes. Using fura-2 fluorescence-based approaches, we showed that high [Ca(2+)]o (addition of CaCl2) leads to increases in [Ca(2+)]i. Flow cytometric methods revealed that high [Ca(2+)]o suppressed the phosphorylation of ERK independently of intracellular Ca(2+). The inhibition of ERK by U0126 and PD0325901 enhanced the differentiation of BMSCs into adipocytes. These data suggest that increased extracellular Ca(2+) provides the differentiation of BMSCs into adipocytes by the suppression of ERK activity independently of increased intracellular Ca(2+), which results in BMSC proliferation.

Enhanced accumulation of adipocytes in bone marrow stromal cells in the presence of increased extracellular and intracellular [Ca2+]

The bone marrow stroma contains osteoblasts and adipocytes that have a common precursor: the pluripotent mesenchymal stem cell found in bone marrow stromal cells (BMSCs). Local bone marrow Ca(2+) levels can reach high concentrations due to bone resorption, which is one of the notable features of the bone marrow stroma. Here, we describe the effects of high [Ca(2+)](o) on the accumulation of adipocytes in the bone marrow stroma. Using primary mouse BMSCs, we evaluated the level of adipocyte accumulation by measuring Oil Red O staining and glycerol-3-phosphate dehydrogenase (GPDH) activity. High [Ca(2+)](o) enhanced the accumulation of adipocytes following treatment with both insulin and dexamethasone together but not in the absence of this treatment. This enhanced accumulation was the result of both the accelerated proliferation of BMSCs and their differentiation into adipocytes. Using the fura-2 method, we also showed that high [Ca(2+)](o) induces an increase in [Ca(2+)](i). An intracellular Ca(2+) chelator suppressed the enhancement in adipocyte accumulation due to increased [Ca(2+)](o) in BMSCs. These data suggest a new role for extracellular Ca(2+) in the bone marrow stroma: increased [Ca(2+)](o) induces an increase in [Ca(2+)](i) levels, which in turn enhances the accumulation of adipocytes under certain conditions.