Clinical evaluation of urapidil, a new antihypertensive drug: preliminary findings in Japan.

The pharmacokinetics, hypotensive effects, and safety of urapidil were investigated in 22 patients with essential hypertension at four coordinated centers in Japan. The drug was administered in sustained-release capsules given twice daily. The peak plasma concentration of the drug (measured in six patients) was observed four to six hours after administration, and 60% to 70% of the peak concentration was detectable at eight hours. These findings suggest that blood pressure might be controlled by twice-daily administration of urapidil. In 14 outpatients, who received 40 to 80 mg/day of urapidil, systolic and mean blood pressure decreased significantly (P less than 0.05) by week 4, and systolic, diastolic, and mean blood pressure decreased significantly (P less than 0.001) by week 6. In four inpatients, treated with 60 to 120 mg/day of the drug for two weeks, there were significant decreases (P less than 0.05) in systolic, diastolic, and mean blood pressure at day 6 and significant decreases (P less than 0.01) in diastolic and mean blood pressure at day 13. Although side effects were noted in five (23%) of the 22 patients, they were transient and slight in three; in two patients, the side effects disappeared after use of the medication was discontinued. Because the study was carried out in a small number of patients who received different dosages of urapidil over a short period of time, the optimal dosage was not established.

[Characteristics of 201Tl myocardial SPECT and left ventriculography in patients with acute diagonal branch myocardial infarction].

Characteristics of 201Tl myocardial SPECT and ventriculography were studied in 13 patients with acute diagonal branch myocardial infarction. Rest 201Tl myocardial SPECT and left ventriculography were underwent in chronic phase. In 5 patients ECG changes in acute phase were not definite. In 6 patients it was difficult to identify the obstructed coronary artery with coronary angiography in acute phase. Mean value of maximum CPK was 854 (458-1,774) U/l. It seemed to be difficult to diagnose acute diagonal branch myocardial infarction with ECG and/or coronary angiography. In all patients defects were noted on 201Tl SPECT. Defects were small and noted in the central anterior wall and not in the septum. In 2 patients defects were noted at apex. In left ventriculography dyskinetic motion was noted in 10 patients; one patient showed apical aneurysm and 3 patients showed anterior wall aneurysm. In 3 patients anterior wall showed akinesis. It was concluded that 201Tl myocardial SPECT were useful for detecting diagonal branch lesion. In case of diagonal branch myocardial infarction size of defects were small and defects were not noted in the septum, however aneurysmal motion was frequently noted.

[In-111 antimyosin-Fab uptake in contractile myocardium of old myocardial infarction].

As In-111 monoclonal antimyosin antibody (AM) has been thought to bind with human myosin exposed in myocytes irreversibly damaged by an ischemic event. The AM uptake in contractile myocardium after acute myocardial infarction was studied. AM planar images were obtained 48 hours later after injection of 74 MBq of AM in 6 patients 2-10 months later after acute myocardial infarction. Mean ejection fraction was 66% (75-58). Myocardial AM uptake was definite in comparison with mediastinum uptake in all 6 patients and mean heart lung ratio was 2.3 +/- 0.5. AM SPECT images and T1-201 SPECT images were obtained with dual mode. Mean T1-201 uptake at the region of maximal AM uptake was 77% (90-63). Echocardiography showed contractility of the region. Mean maximal AM uptake in the anterior wall region was 83% (100-75) and mean T1-201 uptake at the region was 81% (90-75) and shortening rate of the region was 34% (52-25). The region with AM uptake has been shown to correlate with the region salvaged from necrosis by reperfusion. It has been shown that AM was uptaken in contractile myocardium in chronic phase of acute myocardial infarction. It was suspected that myocardium under severe ischemic event may be salvaged by reperfusion therapy and retain contractility in chronic phase, however irreversible damage, which permit AM uptake, may remain in myocardium.

[Noninvasive estimation of site of lesion of left anterior descending artery with stress 201Tl myocardial SPECT images].

Noninvasive estimation of site of lesion of left anterior descending artery (LAD) is important because of high morbidity of LAD lesion. Utility of stress 201Tl myocardial SPECT images for predicting site of LAD lesion characteristics of ischemic region induced by LAD lesion in the basal coronal image were studied in 53 patients with localized significant LAD lesion. Right margin of ischemic region at basal plane of SPECT images was determined by circumferential maximum count profile analysis of stress 201Tl myocardial images. Right margin of ischemic region induced by the just proximal lesion was 21 +/- 11 degrees, that by proximal lesion was -6 +/- 10 degrees and that by mid portion was -36 +/- 17 degrees. Sensitivity of right margin of ischemic region 0 for just proximal lesion was 100% (20/20) and that of right margin of ischemic region 0 for mid portion lesion was 100% (18/18). These results showed the possibility of detecting site of LAD lesion by stress 201Tl myocardial SPECT images.

[Study of sympathetic nervous function under effort induced ischemia in patients with angina pectoris with I-123 metaiodobenzylguanidine (MIBG) myocardial SPECT images].

I-123 metaiodobenzylguanidine (MIBG) is a norepinephrine analog, which can be used to study the sympathetic nervous function of the heart. With MIBG myocardial SPECT images sympathetic nervous function under effort induced ischemia were studied in 18 patients with significant coronary artery lesions. In 5 patients with effort induced ischemic region in stress T1-201 myocardial images rest MIBG images were collected and then exercise stress test was performed. Patients continued exercising for 3 minutes after onset of symptom. Post-stress MIBG images were collected. Definite ischemic region was noted in stress Tl-201 myocardial images, however no differences were noted between rest and post-stress MIBG images. These results suggested that exercise induced ischemia did not enhance release of uptaken MIBG. In 13 patients with significant coronary artery lesions symptom-limited exercise stress test was performed MIBG and Tl-201 were simultaneously injected at onset of symptom and patients continued exercising for an additional one minute. In 6 cases (46%, 6/13) MIBG defects with Tl-201 uptake were noted. These results showed that exercise induced ischemia depressed net MIBG uptake and that sympathetic nervous function (MIBG images) may be more sensitive to ischemic damage than muscle (Tl-201 images). It is suggested that exercise induced ischemia depressed reuptake of norepinephrine at sympathetic nervous endings. MIBG myocardial SPECT images may be useful for evaluating sympathetic nervous function under ischemia.

[Myocardial viability in QS region after PTCR].

Myocardial viability after PTCR in patients with first anterior myocardial infarction was studied one month after the onset of acute myocardial infarction by profile curve of Tl-201 coronal myocardial SPECT images. Patients were devided into two groups according to left ventricular ejection fraction (EF), i.e. group A (EF more than 50%; 11 cases , EF; 62 +/- 10%) and group B (EF less than 50%; 9 cases, EF; 40 7%). Patients in group A showed an increase in serum GOT at the acute phase of acute myocardial infarction (322 +/- 182IU), decreased %Tl-201 uptake in QS region (65 +/- 7%) significantly less than the normal range, large size of region of infarction (214 +/- 83 degree) and abnormal QS in ECG (V1-3QS; 2 cases, V1-4QS; 8 cases, V1-5QS; 1 case). Improvement of wall motion in region of infarction was noted in 9 cases. Patients in group B showed an increase in serum GOT (651 +/- 382 IU p; ns), %Tl-201 uptake in QS region (48 +/- 7% p greater than 0.001) significantly less than the %Tl-201 uptake in group A, size of defects (243 +/- 45 p; ns) and abnormal QS in ECG (V1-3QS; 1 case, V1-4QS; 7 cases V1-5QS; 1 case). Improvement of wall motion was noted in 2 cases. The study showed that %Tl-201 uptake in region of infarction in patients with well EF was significantly more than that in patients with depressed EF. Mechanism of maintaining well EF after PTCR was suggested as the following, i.e. in the region released from severe ischemic attack part of myocardium resulted in necrosis, accompanying elevation of serum enzyme and appearance of QS, though part of myocardium might be salvaged from necrosis and contribute to EF in chronic phase. It has been generally thought that abnormal QS waves noted in anterior chest leads of ECG in chronic phase indicated transmural myocardial infarction in the anterior region. From this study it was concluded that QS region with %Tl-201 more than 50% did not generally correspond to transmural myocardial necrosis and that for estimation of myocardial viability %Tl-201 uptake might be more useful than ECG.

[Characteristics of stress Tl-201 myocardial SPECT images in patients with coronary artery lesion of just proximal portion of left anterior descending artery or high lateral branch].

Noninvasive detection of coronary artery lesion of just proximal portion of left anterior descending artery (LAD) is important because of its high morbidity. It is angiographically difficult to distinguish LAD and high lateral branch (HL). Utility of stress Tl-201 myocardial SPECT images for this purpose characteristics of ischemic region induced by coronary artery lesion of just proximal portion of LAD or HL were studied in 15 patients with localized stenosis more than 75% at just proximal portion of LAD and 5 patients with localized stenosis more than 75% at HL. Width of ischemic region at basal plane of SPECT images was determined by circumferential maximum count profile analysis of stress Tl-201 myocardial images. Width of ischemic region induced by coronary artery lesion of just proximal portion of LAD was 168 +/- 34 degrees. Right margin of ischemic region was 20 +/- 6 degrees and in 10 of 15 patients right margin lay between 20 degrees and 60 degrees. Left margin was -146 +/- 40 degrees and 7 patients with left margin more than -150 degrees showed left dominant coronary artery. Width of ischemic region induced by coronary lesion of HL was 64 +/- 10 degrees. Right margin of ischemic region was 78 +/- 10 degrees and left margin was 14 +/- 10 degrees. These results showed the possibility of detecting coronary artery lesion of just proximal portion of LAD and lesion of HL by stress Tl-201 myocardial SPECT images.

[Interesting PYP, Tl-201, MIBG and AM myocardial SPECT images in a patient under successful reperfusion therapy].

Various types of radiopharmacons such as Tl-201, Tc-99m pyrophosphate (PYP), I-123 Metaiodobenzylguanidine (MIBG) and In-111 antimyosin Fab (AM), were applied to a patients under successful reperfusion therapy. In the patient QS waves in precordial leads and elevated serum enzyme activity was noted, however well anterior wall movement was maintained in chronic phase. At 4th hospital day PYP uptake was noted at apical region and basal anteroseptal region. Most portion of PYP uptake was overlapped by Tl-201 uptake. Depressed Tl-201 uptake in subacute phase improved. In chronic phase depressed MIBG uptake was noted at the region corresponding to the abnormal region in acute phase. Then months after the ischemic event AM uptake was noted at the region which maintained contractility. From these findings it was concluded as followings. Salvaged jeopardized myocardium remained ischemia in subacute phase. The lesions noted in the MIBG images showed depressed myocardial norepinephrine activity. This suggested that sympathetic nervous function was damaged by severe ischemia and the depressed sympathetic nervous function persisted long after myocardial perfusion had been restored. From abnormal AM uptake ten months after ischemic event it was suspected that myocardial cell membrane damage caused by severe ischemia might be persistent at the region which maintained contractility. Radioisotope image was useful to study pathological myocardium due to ischemic event.

[Tl-201 myocardial images in a patient with dialated cardiomyopathy, who finally received heart transplantation].

The patient responded to treatment at the first onset of heart failure but gradually became irresponsive to treatment, experiencing fatigue and malaise as the chief complaints and suffering from gradually progressive decrease in exercise capacity and body weight. Dose of DOA gradually increased to maintain well clinical state of the patient. Unusual for heart failure, he had bradycardia as the basal rhythm without showing a tendency for tachycardia. Cardiac catheterization revealed pulmonary hypertension and low cardiac output, however, left ventricular ejection fraction was 37%. There were no notable changes in ultrasonic cardiogram or CTR through the clinical course. Tl-201 myocardial images and pulmonary perfusion images showed gradual worsening corresponding to progressive worsening of clinical state. From these findings, the patient was determined as a candidate for heart transplantation.

[Utility of rest Tl-201 myocardial SPECT images for estimating myocardial viability].

Rest Tl-201 myocardial SPECT images were underwent in 19 patients with anterior wall myocardial infarction under PTCR one month after the onset of acute myocardial infarction. The relationship between shortening rate (SR) of the left ventricle estimated by radial method and corresponding %Tl-201 uptake obtained by circumferential profile analysis was studied. For each patients 10 points on the anterior wall were taken into consideration. Seven patients showed depressive flat profile curve and 12 patients showed slant curve, in which %Tl-201 uptake continuously decreased from base to apex. Well correlation was obtained between SR and %Tl-201 uptake (SR = -41.2 +/- 1.03% Tl-201 uptake, r = 0.54, p less than 0.001). Average %Tl-201 uptake corresponding to SR = 0 was 46.3 + 6.8% (36-58). The sensitivity of %Tl-201 uptake greater than or equal to 60% for SR greater than or equal to 20% was 97% (87/90) and specificity was 69% (31/45). Tl-201 myocardial SPECT images were useful for estimating myocardial viability and %Tl-201 uptake was one of excellent parameters for quantitatively estimating myocardial viability.

[Characteristics of Tl-201 myocardial SPECT images of patients with coronary artery lesion of diagonal branch].

Noninvasive detection of coronary artery lesion of diagonal branch is important. Utility of Tl-201 myocardial SPECT images for this purpose was studied in 9 patients with angina pectoris and 4 patients with myocardial infarction, in whom localized stenosis more than 75% was noted at diagonal branch. Position of basal margin of abnormal region in the coronal images lay between -30 degree and 30 degree and basal abnormal region was very narrow. Width of mid portion of abnormal region lay from 5 degree to 70 degree. Abnormal region due to diagonal branch was not noted in septal region. These results showed the utility of Tl-201 myocardial SPECT images for detecting coronary artery lesion of diagonal branch.

[Scintigraphic appearance in stress 201Tl myocardial SPECT of midportion lesion in left anterior descending artery].

Scintigraphic appearance of left anterior descending artery (LAD) lesion in stress 201Tl myocardial SPECT was studied in 43 patients (pts) with midportion lesion in LAD confirmed by coronary angiography. Right margin of ischemic region in the basal short axial image was -36 +/- 17 degrees and left margin was -128 +/- 75 degrees. In 28 pts of 43 pts left margin lied beyond -120 degrees. From the results it was concluded that in most cases basal inferior wall was perfused by septal branches from LAD. In 6 pts with midportion lesion situated proximal to the first diagonal branch and in 12 pts with midportion lesion situated proximal to the second diagonal branch ischemic region in the apical portion was noted at both septum and anterolateral wall. Critical short axial image, in which right margin of ischemic region shifted from plus to minus area, was the 3.2nd short axial image in the former group and the 5.2nd in the latter group (p < 0.01). In 10 pts with midportion lesion situated distal to the large first diagonal branch, ischemic region was noted in septal wall and not in anterolateral wall. It was concluded that right margin of ischemic region in the basal coronal image was the most useful sign for predicting midportion lesion and left margin for dominance between LAD and right coronary artery and that apical anterolateral ischemia was sign for LAD lesion involving diagonal branch. Critical short axial image was useful for determining whether the lesion was situated proximal or distal to the first diagonal branch and whether the lesion was situated proximal to the second diagonal branch.

[Interesting PYP, 201Tl, MIBG, AM and BMIPP myocardial SPECT images in a patient under successful reperfusion therapy].

Various types of radiopharmacons such as 201Tl, 99mTc-pyrophosphate(PYP), 123I-metaiodobenzyl-guanidine(MIBG), 111In-antimyosin Fab (AM) and 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) were applied to a patient under successful reperfusion therapy. In the patient, elevated serum enzyme activity region in the subacute phase. Ten months after the ischemic event, AM uptake was noted at the region which maintained contractility. Two years after the ischemic event, depressed BMIPP uptake and delayed washout were noted at the apical region and the basal anteroseptal region. From these findings, the following conclusions were reached. Depressed 201Tl uptake was noted in the salvaged jeopardized myocardium. The lesions noted in the MIBG images showed depressed myocardial norepenephrine activity. This suggested that depressed sympathetic nervous function caused by severe ischemia persisted long after both myocardial perfusion and myocardial contractility had been restored. From abnormal AM uptake in the contractile myocardium myocardial cell damage, which permitted AM uptake, was persistent ten months after the ischemic event. Depressed BMIPP uptake and delayed washout suggested that abnormal fatty acid metabolism caused by severe ischemia was persistent. Severe ischemia caused various types of pathological states in the myocardium and radioisotope image was useful for studying these states.

Definition of mixing rate of indicator by indicator dilution method: evaluation of relationship between mixing rate of indicator and cardiac output determination.

It is generally agreed that complete mixing of the indicator is one of the most important factors of the indicator dilution method, however, no clear definition of the mixing state has been established. We established a formula for the mixing rate of the indicator by the indicator dilution method, using the concept of entropy in the information theory, and compared the mixing rate of indocyanine green in one mixing chamber (left ventricle) with that in the two mixing chamber system (including the aortic system). The mixing rate of the indicator (M) is shown as M(%) = 100 H/Hcm = -100 (lk sigma ni = 1 Ci + log Ci + log k) (l & k: correction factors in each dye dilution curve, C: mean concentration of the indicator in the region). Left heart and aortic catheterizations by retrograde femoral and carotid artery approach were performed in five anesthetized dogs. Simultaneous dye dilution curves were recorded at the aortic root and at the bifurcation of the abdominal aorta, following the injection of indocyanine green (2.5 mg/1 ml of indocyanine green for each injection) by impulse into the left ventricle at the endsystole, triggered on the R wave of ECG, using the automatic injector devised by the authors. Twenty-five pairs of dye dilution curves were obtained by simultaneous recording in the aortic root and the abdominal aorta under several hemodynamic conditions, and the cardiac output, mean circulation time and the mixing rate of the indicator were determined.(ABSTRACT TRUNCATED AT 250 WORDS)

[Coronary vasospastic activity at sites of percutaneous transluminal coronary angioplasty: evaluation using intracoronary acetylcholine administration].

To investigate coronary vasospastic activity after percutaneous transluminal coronary angioplasty (PTCA), we performed intracoronary injection of acetylcholine in 55 patients, mean 3.3 months after successful PTCA. Coronary spasm was defined as transient total or subtotal occlusion of the PTCA sites. Sixty-nine lesions of the 55 patients were examined to determine whether spasm was provoked by incremental doses of acetylcholine. Restenosis was defined as coronary luminal narrowing of > or = 50% after nitroglycerin or isosorbide dinitrate. Twenty of the 55 patients (36%) and 23 of the 69 lesions (33%) had coronary spasm. There was no correlation between the incidence of coronary spasm and the interval from PTCA to the acetylcholine test. The spasm was provoked in 17 lesions of the 50 non-restenotic lesions (34%) and was also provoked in 6 of the 19 restenotic lesions (32%). On the other hand, restenoses occurred in 6 of the 23 spastic lesions (26%) and in 13 of the 43 non-spastic lesions (28%). There was no correlation between the incidence of coronary spasm and the occurrence of restenoses. Twenty-four patients had undergone acetylcholine provocative test before PTCA. Among these 24 patients, 11 had coronary spasm before PTCA, and 7 had coronary spasticity after PTCA. Four patients who had positive evidence of coronary spasm before PTCA did not show negative spasm after PTCA. On the other hand, 3 patients who did not show evidence of coronary spasm showed positive evidence of coronary spasm after PTCA.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence of acetylcholine-induced spasm of coronary arteries subjected to balloon angioplasty.

To examine the vasospastic activity of coronary arteries which have been subjected to previous balloon angioplasty, we conducted an acetylcholine provocative test at diagnostic catheterization in 147 consecutive patients. All patients underwent successful elective angioplasty and had follow-up angiography 1 to 6 months after the procedure. Sixty-two patients had a history of prior myocardial infarction and 43 patients had multivessel coronary artery disease. Angioplasty was performed on 176 vessels. Incremental doses of acetylcholine (25 micrograms, 50 micrograms, 100 micrograms) were injected into the right and left coronary arteries over a period of 1 min. The incidence of coronary spasm of arteries which had been subjected to angioplasty was 44%. Angiographic restenosis was observed in 59 patients (40%). There was no correlation between the occurrence of coronary spasm and the presence of restenosis. The maximal dose of injected acetylcholine was smaller in patients with positive evidence of spasm than in patients with negative evidence of spasm (55 +/- 27 micrograms vs 82 +/- 28 micrograms, p < 0.01). In patients with single vessel coronary artery disease, the incidence of spasm of the contralateral artery, i.e. the artery without angioplasty, was lower than that of the artery subjected to angioplasty (22% vs 46%, p < 0.01). Thus, the data suggest that coronary arteries which have been previously subjected to angioplasty have enhanced vasospastic activity in response to acetylcholine.

[Denervated myocardium detected by I-123 metaiodobenzylguanidine myocardial imaging following successful percutaneous transluminal coronary thrombolysis].

I-123 metaiodobenzylguanidine (MIBG) is taken up by sympathetic nerve endings. Thirteen patients with acute myocardial infarction, in whom reperfusion was achieved with percutaneous transluminal coronary thrombolysis (PTCR), MIBG and Tl-201 (Tl) images 14 days after PTCR which were simultaneously performed were studied. In the late stage, Tl myocardial stress test was also performed to detect ischemia. The extent of myocardial defect was estimated as percent defect. Wall motion was assessed by echocardiography. Ejection fraction (EF) was assessed in the chronic phase using left ventriculography. In nine of the 13 patients, the denerved myocardial regions having the MIBG defects were noted using a Tl uptake. A percent defect noted in MIBG images was 25 +/- 6% and was greater than those (6 +/- 6%,p less than 0.01) in Tl images. During the convalescent phase, the wall motion of the denerved region was restored (2, normal; 4, mild hypokinesis; 3, moderate hypokinesis) and in the chronic phase, EF was well preserved (61 +/- 14%). Ischemic regions noted in stress images coincided with denerved regions. In four patients without the denerved myocardium, EF was 46 +/- 3% (p less than 0.05) and wall motion of defect areas was akinetic. Both EF and myocardial viability were more preserved in cases with denerved region; i.e., PTCR was successfully performed in these cases. It was suggested that the denerved region was the area of severe ischemia during the acute phase and that it was salvaged by PTCR. The sympathetic nerve was damaged by severe ischemia, and depressed sympathetic function persisted long after the recovery of both myocardial perfusion and the wall motion.(ABSTRACT TRUNCATED AT 250 WORDS)

[Late coronary artery aneurysm formation following directional coronary atherectomy].

The most important factor to reduce late restenosis following directional coronary atherectomy is the technical provision of the largest luminal diameter as possible. However, the safety of deep arterial resection and the resulting arterial perforation or late aneurysm formation is questionable. This study examined the frequency of coronary artery aneurysm formation in patients treated by directional coronary atherectomy. Ninety-eight patients with 123 lesions were analyzed by quantitative angiographic and histologic data. Coronary aneurysms (ratio of dilated vessel segment to the adjacent reference segment > 1.2:1) occurred in seven patients (seven lesions: 5.7%). Specimens were categorized by the deepest layer retrieved. Forty lesions (32.5%) were treated by resection of the intima alone, 65 (52.8%) by resection of the medial tissues and 18 (14.6%) received resections of the adventitial tissues including fatty tissues in three lesions. Late coronary aneurysms occurred often in lesions with resection of adventitial tissue (38.9%) and occurred in all three lesions with resections of fatty tissues. Six coronary aneurysms occurred in the left anterior descending artery (six in segs. 6, 7), and one aneurysm in the left circumflex artery. Among the target lesions in which coronary artery aneurysms were formed, six lesions were primary lesions and one lesion was a restenotic lesion after percutaneous transluminal coronary angioplasty. Statistically, patients with coronary artery aneurysms frequently have associated hypertension (p = 0.02) but rarely diabetes mellitus (p = 0.05). Lesions with late aneurysms had significantly high specimen weight (p = 0.01) and a trend to lower postprocedure % diameter (p = 0.20). There was no significant preprocedural angiographic predictor of aneurysms such as minimal lumen diameter or reference vessel diameter.