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

BACKGROUND: 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. METHODS: This was a retrospective cooperative study conducted in 2 sites. All NVAF patients who underwent aPTT measurements before and after dabigatran treatment were included (n=380). The patients were divided into 2 groups according to the frequency of aPTT measurements during the first 3 months after drug prescription: Group A: infrequent group with only 1 measurement; and Group B: frequent group with ≥2 measurements. The clinical characteristics and outcomes were compared between the groups. RESULTS: The frequency of aPTT measurements in the 3 months after dabigatran initiation varied: 240 patients underwent 1 measurement (Group A), and the remaining 140 patients underwent repeated measurements (Group B). There were significant differences in age and creatinine clearance (Ccr) between the groups (Group A vs. Group B: age 64.0±11.7 vs. 67.0±11.1 years, p=0.01; Ccr 83.8±30.3 vs.76.7±31.1 mL/min, p=0.03). During the mean follow-up period of 310 days, there were no significant differences in the discontinuation rate and incidence of bleeding (17% vs. 15% and 5% vs. 3%, respectively; both not significant). In Group B, the aPTT rarely increased beyond twice the upper normal limit within the 3 months (2.1%), although the correlation between the initial and subsequent aPTT measurements was low (r=0.366). CONCLUSIONS: In this retrospective study, the frequency of aPTT measurements after dabigatran initiation might have been dependent on patient characteristics. However, frequent aPTT measurements did not lead to a reduction in adverse clinical events.

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.

Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model.

BACKGROUND: Since the prevalence of atrial fibrillation (AF) increases progressively with aging, especially in men, we hypothesized that testosterone might affect the occurrence of AF. METHODS AND RESULTS: We examined the electrophysiological properties of the atria in isolated-perfused hearts of sham-operated male (SM), female (SF), orchiectomized male with and without administration of testosterone (ORCH-T and ORCH), and ovariectomized female (OVX) Sprague-Dawley rats. An electrophysiological study revealed that repetitive atrial responses induced by electrical stimuli significantly increased in ORCH rats without changes in other electrophysiological properties and were abolished by administration of testosterone. To investigate the underlying mechanisms, we evaluated the expression level of calcium-handling proteins. In ORCH rats, the immunoreactive protein level of ryanodine receptor type 2 (RyR2) and sodium-calcium exchanger significantly increased as compared with SM and ORCH-T rats without alterations in the level of FK506-binding protein (FKBP12.6), sarcoendoplasmic reticulum Ca-ATPase, and phospholamban. Immunoprecipitation analysis demonstrated decreased binding of FKBP12.6 to RyR2 in ORCH rats, which was prevented by testosterone. In contrast, the expression levels of these proteins showed no significant differences between SF and OVX rats. CONCLUSION: Deficiency of testosterone was arrhythmogenic in rat atria possibly through less binding of FKBP12.6 to RyR2, which could induce feasible calcium leakage from the sarcoendoplasmic reticulum. These results would explain, at least in part, the increase in the prevalence of AF in accordance with the decline of testosterone particularly in elderly men.

AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat.

BACKGROUND: Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling. METHODS AND RESULTS: Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8-week-old female Sprague-Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA(1c) value of induced-DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes-induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB-9195, along with reduction of CTGF expression. CONCLUSIONS: DM promoted atrial structural remodeling via the activation of the AGEs-RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes-related atrial fibrosis.

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.

Development of congestive heart failure in Japanese patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) and congestive heart failure (CHF) are frequently coexistent, but their temporal relationship in Japanese patients is unclear. METHODS AND RESULTS: 248 AF patients (63.6+/-10.0 years old) without a history of CHF were enrolled for analysis of the development of CHF during the follow-up period of 49.7+/-29.8 months. Of them, 195 did not have structural heart disease, 22 had dilated or hypertrophic cardiomyopathy, 18 had an old myocardial infarction, and 15 had valvular heart disease. During the follow-up period, 16 patients (6.5%) developed CHF requiring hospitalization (2.0% per patient-year). Although age, gender, fractional shortening, left atrial diameter, hypertension and diabetes mellitus were not associated with CHF development, existence of structural heart disease and left ventricular hypertrophy by Cornell voltage criteria on ECG were significantly associated with CHF development. Cox-Hazard regression analysis revealed that the existence of structural heart disease was the only independent risk factor (hazard ratio 3.50, 95% confidence interval 1.21-10.1). CONCLUSIONS: In the present group of Japanese AF patients, CHF requiring hospitalization occurred at a rate of 2% per year. The existence of structural heart disease was the only independent risk factor in this population.

A method for the simultaneous analysis of mRNA levels of multiple cardiac ion channels with a multi-probe RNase protection assay.

AIMS: Various pathological conditions can alter cardiac electrophysiological properties not only by physiological responses but also by modifying the gene expression of ion channels (electrical remodelling). To investigate the underlying mechanisms of the latter, electrophysiological alterations would require a simultaneous and comprehensive analysis of the mRNA level of the ion channel genes. METHODS AND RESULTS: We designed 19 cardiac ion channel cDNA templates to analyse the corresponding mRNAs and classified them into three template sets. Those sets were a voltage-dependent K(+) channel series (rat erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2), an inwardly rectifying K(+) channel series (rat Kir6.2, SUR2A/B, Kir3.4, Kir3.1, Kir2.2, Kir2.1), and an inward cationic ion channel series (rat SCN5A, alpha1C, beta2, alpha2delta2 of cardiac L-type Ca(2+) channel and alpha1G). These cDNA templates were used to synthesize antisense digoxigenin-labelled RNA probes. An amount of the total RNA of 25 microg was adequate to analyse simultaneously the mRNA levels of the ion channel genes with the use of multi-probe RPA, and these three multi-probe template sets enabled us to evaluate the profile of the spatial and temporal transcripts of the cardiac ion channels. CONCLUSION: The newly developed ion channel multi-probe RPA templates provide an aid in the comprehensive analysis of the electrical remodelling of the heart.

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. METHODS AND RESULTS: The genetic type II diabetes (GK) rats and their original (Wistar) ones were subjected to electrophysiological (n = 8 per group) and histological (n = 7 per group) studies. At 40 weeks old, when GK rats had significantly (P < 0.01) more increased plasma glucose and HbA(1c) values than Wistar rats, atrial electrical stimuli in the isolated-perfused hearts induced significantly greater number of repetitive atrial responses in GK rats than in Wistar rats (47.9 +/- 17.5 vs 3.1 +/- 1.3 beats, respectively, P < 0.01). GK rats showed significantly longer intra-atrial activation time than Wistar rats (18.3 +/- 0.4 ms vs 15.9 +/- 0.5 ms, P < 0.01) without any significant difference in the atrial refractoriness. The histological examination revealed significantly increased diffuse fibrotic deposition in GK rats atria compared with Wistar ones (P < 0.01). CONCLUSION: The present diabetic GK rat showed increased atrial arrhythmogenicity with intra-atrial conduction disturbance, and thus indicated that the structural remodeling of atrium characterized by diffuse interstitial fibrosis would be a major substrate for diabetes-related AF.

Premature atrial complex with P'R prolongation indicates multiple atrioventricular nodal pathways.

BACKGROUND: The goal of the present study was to test if ambulatory Holter recordings can predict the electrophysiologic study (EPS) findings in patients with supraventricular tachycardia (SVT). METHODS AND RESULTS: The study involved 110 patients with SVT who underwent Holter recording, and then EPS. The hypotheses were that (1) a P'R interval of premature atrial complexes (PACs) between 280 and 400 ms in the Holter recordings predicted dual atrioventricular nodal (AVN) pathways, (2) P'R interval >400 ms predicted triple or more AVN pathways, and (3) SVT initiated by a single PAC suggested easy SVT induction during the EPS. The EPS revealed dual AVN pathways in 14 (93%) of 15 patients with P'R intervals between 280 and 400 ms on the Holter recordings, and triple or more AVN pathways in 18 (90%) of 20 patients with P'R intervals >400 ms. In addition, a single extrastimulus easily induced SVT during the EPS in 11 (85%) of 13 patients in whom SVT was initiated by a single PAC during Holter recording. CONCLUSION: The ambulatory Holter recording criteria specifically predicted the EPS findings, thereby providing useful advance information.

Pilsicainide-induced coronary vasospasm in a patient with Brugada-type electrocardiogram.

A 65-year-old man with Brugada-type electrocardiogram (ECG) was admitted to our hospital for chest pain, palpitation and faintness. In the cardiac electrophysiological study, no ventricular tachyarrthymia was induced either at baseline or after pilsicainide (50 mg) infusion. Intravenous administration of pilsicainide exaggerated ST-segment elevation in V(1-4) and converted it to the coved type in V(1), accompanied by severe chest pain. Coronary angiography revealed the vasospasm of the right coronary artery was induced by pilsicainide, not by ergonovine. This is the first case report of coronary vasospasm induced by a pure sodium channel blocker in a patient with Brugada-type ECG.

Cibenzoline attenuates upregulation of Kv1.5 channel gene expression by experimental paroxysmal atrial fibrillation.

Antiarrhythmic drugs exert their effects by inhibiting the ion channels of cardiomyocytes. However, these effects could also modify the ionic environment around them, and thereby affect the expression of ion channels, leading to biochemical enhancement or attenuation of the antiarrhythmic effects. To test this hypothesis, the physiological and biochemical effects of cibenzoline were evaluated in a rapid atrial pacing model in rats. In rats with rapid atrial pacing, pretreatment with cibenzoline significantly inhibited the increases in Kv1.5 mRNA at 2 hours and immunoreactive protein at 4 hours by 35 +/- 15% and 30 +/- 10%, respectively. These effects were observed only in the rapid atrial pacing group, not in the sham-operated group. With cibenzoline pretreatment, 4-hour rapid atrial pacing resulted in significant prolongation of the atrial refractory period compared to the untreated group even after removal of cibenzoline. In contrast, the sham and rapid atrial pacing model with and without cibenzoline pretreatment showed similar acute physiological responses to cibenzoline. In conclusion, in addition to the acute physiological effects, pretreatment with cibenzoline exerted pleiotropic effects of inhibition of Kv1.5 channel upregulation by rapid pacing, implying differences in the cibenzoline effects when administered before and after onset of paroxysmal atrial fibrillation.

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.

Relation between variability of ventricular response intervals and exercise capacity in patients with non-valvular atrial fibrillation.

BACKGROUND: Reduced variability of the ventricular response interval (VRI) has been reported to predict adverse prognosis in patients with atrial fibrillation (AF). To examine whether it could be related also to the quality of the daily life of patients with AF, the relationships between VRI variability and exercise tolerance, one of the markers for quality of life, were determined in patients with persistent AF. METHODS AND RESULTS: Thirty-one patients with idiopathic AF were included in the present study. Holter monitoring results and symptom-limited treadmill exercise testing were correlated in these patients without medications for the rate control of AF. The VRI variability, both the SD of the mean R-R interval (SDNN) and the SD of the 5-min mean R-R interval (SDANN), showed significant positive correlation with the exercise capacity (r=0.583, p=0.0004, and r=0.543, p=0.0013, respectively), whereas age, left ventricular ejection fraction and body mass index did not have any significant relationships. Multiple regression analysis revealed that increased SDNN was the only independent predictor of good exercise capacity during the treadmill exercise testing. CONCLUSIONS: Increased VRI variability, independently of other clinical variables, can predict good exercise capacity in patients with idiopathic AF, thus being a new sensitive maker for quality of life in AF.

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.

Nifekalant hydrochloride, a novel class III antiarrhythmic agent, suppressed postoperative recurrent ventricular tachycardia in a patient undergoing coronary artery bypass grafting and the Dor approach.

A patient with 3-vessel coronary artery disease and left ventricular aneurysm underwent coronary artery bypass grafting combined with the Dor approach. Five days later, ventricular tachycardia following short-coupled ventricular premature contractions suddenly occurred and was not responsive to class IB drugs (lidocaine and mexiletine), requiring frequent electrical cardioversion. After the administration of a novel class III drug, nifekalant hydrochloride, this electrical storm of ventricular tachycardia was completely suppressed together with the disappearance of ventricular premature contractions. Nifekalant hydrochloride (MS-551), a pure K(+) channel blocker, might be effective for postoperative recurrent ventricular tachyarrhythmias that are refractory to other antiarrhythmic agents.

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: approximately 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 ( approximately 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 beta-adrenergic activities and Kv4.2 increase during the light period independent of the autonomic nervous function.

J wave and ST segment elevation in the inferior leads: a latent type of variant Brugada syndrome?

In a patient referred for the evaluation of non-sustained monomorphic ventricular tachycardia on Holter recordings, ventricular fibrillation was electrically induced during electrophysiologic study. Despite the absence of structural heart diseases, his ECG revealed J wave and ST segment elevation in the inferior leads, which showed circadian variation and were augmented by the sodium channel blocker, pilsicainide. This case might lead us to notice a new concept, a 'latent' type of variant Brugada syndrome, and these ECG findings and changes might serve as its diagnostic sign.