Hiroyuki Iinuma

Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina : a multicenter study

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.

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.

Mechanisms of acute gain and late lumen loss after atherectomy in different preintervention arterial remodeling patterns.

The main mechanism of restenosis after directional coronary atherectomy (DCA) remains obscure. We investigated mechanisms of restenosis after DCA in different coronary artery remodeling patterns. DCA was performed in 51 de novo lesions. The lesions were evaluated by intravascular ultrasound (IVUS) before, immediately after, and 6 months after the procedure. According to the IVUS findings before DCA, we classified the lesions into the following 3 groups: (1) positive (n = 10), (2) intermediate (n = 25), and (3) negative (n = 16) remodeling. We measured lumen area, vessel area, and plaque area using IVUS before DCA, immediately after DCA, and at follow-up. Lumen area increase after DCA was mainly due to plaque area reduction in the positive and intermediate remodeling groups (90 plus minus 15% and 80 plus minus 25% increase in lumen area, respectively), whereas that in the negative remodeling group was due to both plaque area reduction (57 plus minus 22% increase in lumen area) and vessel area enlargement (43 plus minus 33% increase in lumen area). The plaque area increase correlated strongly with late lumen area loss in the positive and intermediate remodeling groups (r = 0.884, p <0.001; r = 0.626, p <0.001, respectively), but the decrease in vessel area was not correlated with lumen area loss. In contrast, both an increase in plaque area and a decrease in vessel area were correlated with late lumen area loss (r = 0.632, p = 0.009; r = 0.515, p = 0.041) in the negative remodeling group. Coronary artery restenosis after atherectomy was primarily due to an increase in plaque in the positive and/or intermediate remodeling groups. However, in the negative remodeling group, late lumen loss might have been caused by both an increase in plaque and vessel shrinkage.

Comparison between Japan and North America in the post-hospital course after recovery from an acute coronary event

We compared the post-hospital prognosis after an acute coronary event (acute myocardial infarction and unstable angina) in 106 patients in Japan vs. 789 patients in North America who were prospectively enrolled in the Multicenter Study of Myocardial Ischemia and were followed-up for an average of 26 months per patients. Risk factors more frequent in Japan were older age, males and smoking at enrollment, but the rest of many risk factors were similar. After adjusting for differences in clinical and medication variables, Cox analyses indicated patients in North America had a significantly greater risk of experiencing a primary end-point (cardiac death, non-fatal myocardial infarction or unstable angina) than patients in Japan (hazard ratio [North America:Japan] = 3.1, P = 0.003). There was a non-significant trend in the restricted end-points (cardiac death or non-fatal myocardial infarction) with North America having more frequent events than Japan (hazard ratio = 2.2, P = 0.12). The long-term outcome after recovery from an acute coronary event is more favorable in Japan than in North America, mostly due to a reduction in subsequent hospitalization for unstable angina. The reason for these findings cannot be explained by differences in the measured risk factors or medications.

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.

The response of digitalized canine ventricle to programmed stimulation: a study on triggered activity arrhythmias in the whole heart.

Triggered activity (TA) has recently received increased attention as a mechanism responsible for cardiac arrhythmias. However, few studies have shown TA in the intact heart. In an ouabain‐treated dogs heart we have shown: (a) overdrive acceleration, (b) a concordant relationship between the postpacing interval (PI) and pacing cycle length (CL), and (c) a discordant relationship between the PI and number of paced beats necessary to induce TA. These findings appeor to agree with the distinctive characteristics of TA arrhythmias elucidated in previous in vitro studies and suggest TA rather than a reentrant tachycardia. In addition, it is possible that this heart preparation could be considered as a suitable model for the study of TA arrhythmias. These results were obtained using a programmed stimulation protocol in this dog model: (1) Following single programmed ventricular stimulation during sinus rhythm, a repetitive ventricular response (RVR) of more than 3 beats occurred in only 20% of hearts. The relationship between PI and the coupling interval (CI) of the extrastimulus was concordant in 80% (12/15) and discordant in 13% (2/15) of all experiments. The Pl‐CI relationship was influenced by the mutual relationship between the stimulating, recording, and originating sites of TA. (2) RVR of more than 3 beats was induced by consecutive overdrive ventricular stimulation during sinus rhythm (78%). In addition, the PI‐pacing CL relationship was concordant (100%). (3) The transient termination of sustoined VT that occurred spontaneously after administration of a large dose of ouabain was seen in only 15% of the cases after a single programmed premature ventricular stimulation. The return cycle‐CI relationship was biphasic in 75% (15/20) experiments and discordant in 25% (5/20) of the experiments. (4) The termination of spontaneous sustained VT by overdrive ventricular stimulation occurred in only 8% of the cases. Transient overdrive acceleration of VT occurred after overdrive pacing (53%). In contrast, overdrive suppression occurred in only 13%. Thus, the characteristics of TA arrhythmias observed in the whole heart preparations differed, in some respects, from those obtained by in vitro studies. These quantitative observations could suggest a differentiation, based on probability, between TA and the reentrant mechanism that would respond to programmed stimulation in a similar manner. The differentiation between reentrant and triggered ventricular tachycardia can be made with reasonable assurance using these programmed stimulation techniques.

The effect of hypoxia on the refractoriness of the canine ventricular muscle.

The effect of hypoxia on the relationship between refractoriness and transmembrane action potential was studied in isolated canine papillary muscle preparations. Test stimuli were applied at variable intervals after every 10 to 15 driving stimuli, and action potentials were recorded through an intracellular microelectrode located near the stimulus site. During hypoxia of 30 to 90 min duration, induced by nitrogenization of the perfusate, action potential duration (APD) was tremendously decreased in association with decline in the amplitude and rising velocity. The resting potential was also reduced. Concurrently the effective refractory period (ERP) was decreased, but its decrement was smaller than that of the APD. The total refractory period (TRP) was, on the other hand, prolonged. In consequence, not only the TRP but the ERP as well fairly outlasted full repolarization as a result of the hypoxia. The duration of the relative refractory period (RRP) was increased during hypoxia as the result of the changes in ERP and TRP, and graded local responses were registered frequently in the early phase of RRP. These facts were thought to be related to the genesis of arrhythmias in the ischemic 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.