Michihito Sekiya

Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis

The present study was conducted to assess the preventive effect of combined treatment with probucol, an antioxidant, and cilostazol, a phosphodiesterase inhibitor, against poststenting restenosis. Study patients were randomized to 4 modality groups 1 week before stenting: control, probucol (500 mg/day), cilostazol (200 mg/day), and probucol plus cilostazol. Treatment on these modalities was conducted from 5 prestent days until the poststenting follow-up evaluation (6 poststenting months). All patients received aspirin (81 mg/day). The efficacy of each modality against restenosis was evaluated in a total 126 patients with 165 coronary arterial lesions, using a quantitative method. The decrease in luminal diameter at the poststenting follow-up was 1.04 +/- 0.57 mm for controls, 0.88 +/- 0.82 mm for those taking probucol, 0.61 +/- 0.59 mm for those taking cilostazol (p <0.05 vs control), and 0.40 +/- 0.52 mm (p <0.01 vs control) for the combined treatment group. Restenosis rate per segment was 31.7% for controls, 16.7% for the probucol group, 12.5% for the cilostazol group (p <0.05 vs control), and 9.5% for the combined treatment group (p <0.05 vs the control). Neither mortality, myocardial infarction, stent thrombosis, or coronary bypass surgery, nor any serious complications were observed in the combined treatment group. Combined treatment with probucol and cilostazol has thus proved safe and effective in preventing acute poststenting complications and suppressing chronic restenosis.

Thallium-201 myocardial tomography with intravenous infusion of adenosine triphosphate in diagnosis of coronary artery disease

OBJECTIVES The purpose of this study was to evaluate the feasibility, safety and diagnostic accuracy of thallium-201 myocardial tomography with intravenous adenosine triphosphate (ATP) infusion in patients with suspected coronary artery disease. BACKGROUND Both ATP and adenosine are potent coronary vasodilators with a very short half-life. Several studies have confirmed that the diagnostic accuracy of adenosine thallium-201 scintigraphy is comparable to that with exercise. However, a high incidence of side effects, including atrioventricular (AV) block, has also been reported. Because the appropriate infusion rate for ATP has not yet been determined, this agent has not been tested in combination with myocardial scintigraphy. METHODS The study group included 253 consecutive patients who underwent thallium-201 myocardial tomography with ATP infusion (0.16 mg/kg body weight per min for 5 min). The occurrence of adverse effects was carefully monitored. Of the 120 patients with coronary angiography, 76 had significant coronary artery disease. Tomographic images were assessed visually and by computer-quantified polar maps, and they were compared with the results of coronary angiography. RESULTS Although 56% of the patients had some adverse effects, they were transient and mild. In all patients, the ATP infusion protocol could be completed, and no patient required aminophylline; AV block occurred in only 2% of the patients. The sensitivity and specificity were 88% and 80%, respectively, by visual analysis and 91% and 86%, respectively, by computer quantification. CONCLUSIONS Thallium tomography with ATP is feasible and has a diagnostic value similar to that with adenosine for detecting coronary artery disease. In addition, it may have fewer side effects than adenosine myocardial tomography.

Preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty

This protocol was performed to elucidate the preventive effects of probucol on restenosis after percutaneous transluminal coronary angioplasty (PTCA). A total of 118 patients with 134 vessels undergoing successful PTCA was randomly and prospectively assigned to the probucol group (group P) or the control group (group C). The subjects consisted of 91 men and 27 women, with a mean age of 63.4 +/- 2.3 years. Sixty-six vessels of 59 patients in group P and 68 vessels of 59 patients in group C were evaluated by coronary angiography at 3 months after PTCA. Probucol (0.5 mg/day) was administered between >7 days before PTCA and 3 months after PTCA. The serum total cholesterol (TC) level and the formula low-density lipoprotein cholesterol (formula LDL-C) in group P decreased from 203.8 +/- 43.1 to 169.6 +/- 39.4 mg/dl and from 131.4 +/- 0.7 to 108.7 +/- 2.5 mg/dl, whereas in group C, the levels decreased only from 202.3 +/- 32.1 to 194.2 +/- 29.8 mg/dl and from 129.2 +/- 38.1 to 124.3 +/- 31.7 mg/dl, respectively. The restenosis rate was significantly lower in group P (19.7%; 13 of 66 vessels) than in group C (39.7%; 27 of 68 vessels; p < 0.05). In group P, the probucol blood concentration was significantly higher in the subjects without restenosis (31 +/- 9 microg/ml) than in those with restenosis (18 +/- 8 microg/ml; p < 0.01), but the serum TC and formula LDL-C levels were not significantly different between these two groups. In summary, long-term administration of probucol significantly reduces the incidence of restenosis after PTCA. it was suggested that the mechanism of this preventive effect was not reducing the serum TC or formula LDL-C levels, but rather an inhibitory action on smooth muscle cell proliferation.

Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis.

This study compared the effects of long-term administration of nicorandil and isosorbide dinitrate (ISDN) on vascular endothelial function and the progression of arteriosclerosis. Forty-two patients with ischemic heart disease were randomly allocated to receive nicorandil (N group; 15 mg/d) or ISDN (I group, 40 mg/d). Twelve normal subjects served as controls. Vascular endothelial function and the progression of arteriosclerosis (intima-media thickness, IMT), as determined by carotid vascular ultrasound, were assessed 1 week before and 3 months after drug administration. Reactive hyperemia was induced in the forearm for 5 minutes, and the percentage change in the diameter of the brachial artery (% change in flow-mediated dilation, %FMD) was calculated. FMD was significantly lower in CAD groups than in controls. The %FMD significantly decreased (7.2 ± 1.9 to 4.2 ± 2.8) in the I group, while rising from 6.8 ± 1.6 to 8.0 ± 2.0 in the N group. IMT increased by 0.036 ± 0.015 mm in the I group but showed no significant change in the N group (−0.01 ± 0.012 mm). Thus, ISDN deteriorates IMT and FMD, whereas a beneficial effect of nicorandil is seen on FMD with no effect on IMT. Long-term treatment with nicorandil may be desirable for prevention of cardiovascular events.

Effect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension

BACKGROUND In hypertensive patients, the relationships between glucose tolerance and left ventricular hypertrophy (LVH) and left ventricular diastolic function (LVDF) have been described in several reports. OBJECTIVE In this study, we examined the relationships between insulin resistance and LVH and LVDF in hypertensive patients from the therapeutic perspective. METHODS AND RESULTS The study participants were essential hypertensive patients with impaired glucose tolerance (IGT-HT, n = 26), hypertensive patients with normal glucose tolerance (NGT-HT, n = 39), and normotensive control individuals (n = 18). Insulin resistance was evaluated by the insulin suppression test by use of the steady-state plasma glucose (SSPG) level. Left ventricular mass index (LVMI) and LVDF, which was determined by the E:A ratio, were estimated by echocardiography. Temocapril, an angiotensin-converting enzyme inhibitor, was administered in an open, non-randomized manner with a mean dose of 2.8+/-0.2 mg/ day, and the mean administration period was 18 weeks. The systolic and diastolic blood pressure, the LVMI, and the SSPG level were significantly higher in the hypertensive patients than in the control individuals. The mean systolic and diastolic blood pressures were significantly decreased by treatment with Temocapril. Before treatment, stepwise regression analysis showed that SSPG is an independent predictor for LVMI and LVDF. After treatment, the changes in LVMI (D-LVMI; %) (-15.1+/-1.5), the changes in LVDF (D-E:A; %) (-38.2+/-4.1), and the changes in insulin resistance (D-SSPG; %) (-13.7+/-1.7) were significantly higher in the IGT-HT group than in the NGT-HT group (-11.4+/-1.1, -18.1+/-1.7, -9.4+/-1.4, respectively), and the D-SSPG was an independent predictor for D-LVMI and D-E :A. CONCLUSIONS The results of this study indicate that insulin resistance is an important factor affecting LVH and LVDF.

Relationship between insulin resistance and cardiac sympathetic nervous function in essential hypertension.

BACKGROUND It has been suggested that hyperinsulinemia and insulin resistance participate in the pathogenesis of hypertension, in part by activating sympathetic activity. OBJECTIVE We aimed to examine the relationship between insulin resistance and cardiac sympathetic nervous function in patients with essential hypertension using 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy. METHODS AND RESULTS Twenty-eight patients (18 men) with essential hypertension and 11 (seven men) control individuals with a mean age of 55.8+/-3.3 years were recruited. Patients with diabetes mellitus, congestive heart failure or coronary artery disease were excluded from this study. To evaluate insulin resistance, we used steady-state plasma glucose (SSPG; mg/dl) levels measured by the SSPG method. To evaluate cardiac sympathetic nervous function, we calculated the heart-to-mediastinum ratio from the delayed MIBG image (H:M-D) and the mean washout rate (WOR, %). There were significant differences (P<0.01) in SSPG, H:M-D and WOR between the essential hypertension and control individual groups (125 versus 103 mg/dl, 2.2 versus 2.4, and 32 versus 23%, respectively). Stepwise regression analysis showed that SSPG and plasma norepinephrine level are independent predictors for the cardiac sympathetic nervous function obtained from MIBG scintigraphy. CONCLUSIONS These findings indicate that insulin resistance is significantly related to activation of the cardiac sympathetic nervous function associated with left ventricular hypertrophy in patients with essential hypertension.

Prognostic Value of Dipyridamole-Thallium Myocardial Scintigraphy in Patients With Kawasaki Disease

BACKGROUND Although coronary artery lesions are critical complications of Kawasaki disease, their long-term outcome is still unclear. It is sometimes difficult to monitor progressive changes from aneurysms to stenotic lesions because coronary angiography (CAG) cannot be repeated very often, especially in infants. Our prospective study was designed to evaluate the prognostic value of dipyridamole-thallium single-photon-emission CT (SPECT) in the long-term follow-up of patients with Kawasaki disease. METHODS AND RESULTS Of 459 consecutive patients with Kawasaki disease, coronary aneurysms were detected in 90 cases by echocardiography during the acute stage. After paired studies of selective CAG and SPECT were conducted, all patients were followed up and monitored for the occurrence of any cardiac events for > or =8 years. During the follow-up interval, there were 15 cardiac events (1 death, 5 infarctions, 2 coronary artery bypass graft operations, and 7 occurrences of unstable angina). Of patients who had some event, thallium redistribution was found on SPECT in 14 (93%, P<0.001). Of the various clinical and scintigraphic image variables, the presence of thallium redistribution was the best multivariate independent predictor of a late cardiac event (chi2=57.8, P<0.0001). The number of aneurysms detected on CAG added minimal statistical improvement to the model (chi2=1.9, P=0.0009). CONCLUSIONS Dipyridamole-thallium SPECT is safely performed and is useful and important for risk stratification in the long-term follow-up of patients with Kawasaki disease.

Effect of cilostazol on vasomotor reactivity in patients with vasospastic angina pectoris

We examined the effects of cilostazol on impaired coronary arterial responses in patients with vasospastic angina (VSA). Thirty patients who were diagnosed with VSA based on an acetylcholine provocation test and 10 subjects with normal coronary arteries were enrolled. The patients were divided into the following 3 groups: no antiplatelet agent treatment group, aspirin treatment, or cilostazol treatment groups. Coronary flow reserve (CFR), coronary flow volume at maximum hyperemia, and epicardial coronary artery diameter after administration of N(G)-monomethyl-L-arginine (L-NMMA) were examined using a Doppler flow wire before and 6 months after the start of this study. CFR, coronary flow volume at maximum hyperemia, and diameter changes by L-NMMA were significantly increased in the cilostazol treatment group compared with the other 2 groups. In conclusion, cilostazol increased CFR and flow-dependent coronary dilation; these changes were attributable to nitric oxide. Cilostazol may improve coronary vascular endothelial dysfunction and coronary hemodynamics in patients with VSA.

Measurement of cardiac chamber volumes by cine magnetic resonance imaging.

Cardiac chamber volumes (both atria and ventricles) in 19 healthy volun teers were measured noninvasively by cine magnetic resonance imaging (MRI). First, cardiac localization was determined from the coronal image by 0.5-T superconducting magnetic imager. Then, transaxial ECG gated multislice spin echo images were obtained from the bottom to the top of the heart. In the last step, cine MRI was performed at each level of all these transaxial spin echo MR images involving the heart. Each cardiac chamber volume at the same phase was calculated by adding chamber areas in each anatomic section multiplied by slice thickness. Left ventricular (LV) end-diastolic volume (EDV) (132.0±26.9 mL) and LV end-systolic volume (ESV) (47.8 ±13.9 mL) were smaller than right ventricular (RV) EDV (141.1 ±24.8 mL) and RVESV (57.0± 12.6 mL), respec tively (p < 0.01). LV stroke volume (84.3±17.9 mL) was equivalent to RV stroke volume (84.2±17.6 mL) (r=0.91, p < 0.01). Left atrial (LA) and right atrial (RA) maximal volumes were 75.8 ±15.4 mL and 84.4±18.7 mL, respectively. LA minimal volume (37.5 ± 10.7 mL) was smaller than RA minimal volume (47.8 ± 12.2 mL). These values measured by cine MRI are satisfactory and cine MRI will be a useful method of determining cardiac chamber volumes, espe cially atrial volumes.

Acetylcholine-Induced Myocardial Ischemia Without Epicardial Coronary Artery Spasm: A Possible Vasospasm of Small Coronary Arteries—A Case Report

Small-vessel vasospasm has been speculated upon as a possible cause of chest pain in patients with normal-appearing coronary angiograms. In this report, a patient who experienced typical chest pain during acetylcholine testing, which caused ST segment elevation without epicardial coronary spasm, is presented. This finding suggests that small-vessel vasospasm may be involved in the induction of myocardial ischemia in patients with normal epicardial coronary arteries.