Kouichi Sagara

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.

What are Arrhythmogenic Substrates in Diabetic Rat Atria

Introduction: Diabetes mellitus is one of the significant independent risk factors for the development of atrial fibrillation (AF). However, the pathophysiological mechanisms of the relationship have not been fully elucidated.

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.

Angiotensin II type 1 receptor blocker attenuates diabetes-induced atrial structural remodeling

BACKGROUND Diabetes mellitus promotes atrial structural remodeling, thereby producing atrial arrhythmogenicity, where advanced glycation endproducts (AGEs) and their receptor (RAGE) are implicated to play a role in the pathogenesis. PURPOSE We investigated the effects of candesartan, an angiotensin type II receptor blocker, on the diabetes-induced atrial structural change. METHODS AND RESULTS Diabetes was induced in 8-week-old female Sprague-Dawley rats by intraperitoneal injection of streptozotocin at 70 mg/kg. Osmotic pumps were simultaneously set to infuse candesartan at a subdepressor dose of 0.05 mg/kg/day. Twelve weeks after the induction of diabetes, the blood glucose and glycated hemoglobin A1c were significantly higher in streptozotocin-injected rats than those in control rats, and were not affected by candesartan treatment. The atria of diabetic rats showed remarkable diffuse interstitial fibrosis with more enhanced protein expressions of RAGE and connective tissue growth factor (CTGF) compared with control ones. The treatment with candesartan significantly reduced CTGF expression and effectively suppressed the development of fibrotic deposition in diabetic animals. CONCLUSIONS Candesartan reduced CTGF expression and attenuated the fibrosis in diabetic rat atria. These results implied the protective effects of candesartan on diabetes-related atrial arrhythmias.

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.

A Case of a Pseudomalfunction of a DDD Pacemaker

DDD pacemaker pseudomalfunction occurred in a 65‐year‐old man. This was due to premature ventricular contraction (PVC) response option and cross‐talk detection window, which are designed to protect against pacemaker related tachycardia or cross‐talk. Pseudomalfunction disappeared by eliminating PVC response option.

Relation between frequency of activated partial prothrombin time measurements and clinical outcomes in patients after initiation of dabigatran: A two-center cooperative study

Although activated partial prothrombin time (aPTT) has often been used as a biomarker for evaluating the safety of dabigatran use in patients with non‐valvular atrial fibrillation (NVAF), the optimal frequency of aPTT measurements is unclear. This study aimed to identify the frequency distribution of aPTT measurements in clinical practice and its clinical significance.

Detection of regional low myocardial perfusion helps predict a response to cardiac resynchronization therapy in patients with non-ischemic cardiomyopathy: Results of the Find Index by Nuclear Imaging for Dyssynchrony (FIND) study

The aim of this study was to investigate the use of imaging techniques to predict the response to cardiac resynchronization therapy (CRT) in patients with non‐ischemic cardiomyopathy (NICM) by simultaneous assessment of left ventricular (LV) dyssynchrony and myocardial perfusion in a single nuclear scan of the heart.

PROGRESSIVE NATURE OF PAROXYSMAL ATRIAL FIBRILLATION - OBSERVATIONS FROM A 14-YEAR FOLLOW-UP STUDY -

BACKGROUND Atrial fibrillation (AF) is believed to occur first as paroxysmal, then be gradually perpetuated, and finally become chronic as the end result. However, this presumed clinical course has not been well confirmed. METHODS AND RESULTS The clinical course of recurrent paroxysmal AF (PAF) from its onset was examined in 171 patients (mean follow-up period: 14.1+/-8.1 years). This study population consisted of patients with no structural heart disease (n=88), ischemic heart disease (n=28), dilated or hypertrophic cardiomyopathy (n=17), valvular heart disease (n=35) or other cardiac diseases. The mean age at the onset of AF was 58.3 +/-11.8 years old. During the mean follow-up period of 14.1 years, PAF eventually developed into its chronic form in 132 patients under conventional antiarrhythmic therapy (77.2%, 5.5% of patients per year). The independent factors for early development into chronic AF were aging (hazard ratio (HR) 1.27 per 10 years, 95% confidence interval (CI) 1.06-1.47)), dilated left atrium (HR 1.39 per 10 mm, 95% CI 1.11-1.69), myocardial infarction (HR 2.33, 95% CI 1.13-4.81), and valvular diseases (HR 2.29, 95% CI 1.22-4.30). CONCLUSIONS The present long-term observations definitely and quantitatively revealed the progressive nature of PAF.