Takaaki Ochi

Class Ia Antiarrhythmic Drug Cibenzoline A New Approach to the Medical Treatment of Hypertrophic Obstructive Cardiomyopathy

BACKGROUND The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM. METHODS AND RESULTS Ten patients with HOCM (mean age, 59+/-12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123+/-60 to 39+/-33 mm Hg (P=.0026). The E/A ratio in transmitral Doppler flow increased from 1.20+/-0.84 to 2.00+/-1.72 (P=.029). Isovolumic relaxation time increased from 73+/-16 to 101+/-23 ms (P=.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6+/-2.4 to 26.2+/-3.3 mm (P=.0004). Fractional shortening decreased from 47.6+/-6.1% to 34.6+/-8.8% (P=.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline. Conclusions These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.

Major complications during spasm provocation tests with an intracoronary injection of acetylcholine

This study sought to clarify major complications associated with acetylcholine testing. Serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade were determined in 4 of 715 patients (0.56%), but no cases of death or irreversible complications occurred. The spasm provocation test using acetylcholine should be performed carefully, although it is considered a safe and reliable method.

Effect of prazosin on serum lipids.

On the premise that serum lipids may be correlated with the increased mortality from coronary heart disease seen in Japan despite successful antihypertensive therapy, we undertook an open, noncomparative study to determine the effect of prazosin on serum lipids. All patients were adults (mean age of 59. with a range of 45 to 72), and all had a sitting blood pressure greater than 160 mm Hg systolic or 90 mm Hg diastolic. After a stabilization period of 2 to 4 weeks, prazosin was started at 0.5 mg t.i.d. This dose was maintained for I week and was then titrated upwards to achieve optimal antihypertensive effect. Maximum dose permitted was 12 mg/day. All patients were treated for at least 12 weeks. Concomitant therapy was allowed in patients who had been stabilized on other drugs prior to entry into the study. At the end of 12 weeks of therapy, prazosin (at an average dose of 4.5 mg) had lowered blood pressure by an average of 10/9 mm Hg in the sitting position, 11/7 mm Hg in the supine position, and 19/13 mm Hg in the standing position. Pulse rate did not change. Total cholesterol and triglycerides were essentially unchanged, and LDL and VLDL decreased by 4.5%. However. high density lipoprotein (HDL) cholesterol increased by 12.5%. These changes were statistically significant and yielded an increase of 20.3% in the cholesterol ratio. No side effects were noted in any patient, and none of the patients discontinued therapy during the study. This is an ongoing study, in which 14 patients have so far completed the 12 weeks of therapy. On the basis of these preliminary results, prazosin would seem to be an effective and safe antihypertensive agent with considerable favorable effects on serum lipids

Clinical and angiographical characteristics of acetylcholine- induced spasm: relationship to dose of intracoronary injection of acetylcholine.

ObjectivesThe purpose of this study was to clarify clinical and angiographical characteristics of acetylcholine (ACh)-induced spasm in the right and left coronary artery. Methods and resultsWe performed 557 consecutive procedures of spasm provocation tests of ACh from January 1991 to December 2000 in patients without significant stenosis. ACh was injected in incremental doses of 20, 50 and 80 μg into the right coronary artery and in incremental doses of 20, 50 and 100 μg into the left coronary artery if spasm had not been provoked. Coronary spasm was defined as positive with more than 99% transient luminal narrowing. Proximal spasm was defined as that of segments 1, 2, 5, 6, 7 and 11 and distal spasm as that of segments 3, 4, 8, 9, 12, 13 and 14. Low-ACh-dose-induced spasms showed the clinical findings and angiographical characteristics of higher incidence of variant angina, proximal spasms, focal spasms, more ST elevation and ischemic heart disease. In contrast, angiographical characteristics of high-Ach-dose-induced spasms were distal spasms and diffuse spasms and there was less variant angina and less ST elevation. ConclusionsLower ACh doses induced spasms more proximally and focally in the coronary artery, while higher doses of ACh provoked spasms more distally and diffusely.

Clinical Characteristics of Female Patients With Coronary Spastic Angina

There are many patients with vasospastic angina who have minor atherosclerosis, and in Japan the majority of them are male. No data exist concerning sex differences in patients with coronary spastic angina, so the present study sought to clarify the clinical characteristics between male and female patients with vasospastic angina. Between April 1991 and June 1998, 204 consecutive patients were diagnosed with vasospastic angina and of these, 26 (12.7%) were female. An acetylcholine test was performed with incremental doses of 20, 50, and 80 microg injected into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Ergonovine was injected in a total dose of 40 microg into the right coronary artery and 64 microg into the left coronary artery. Coronary spasm was defined as 99% or more luminal narrowing accompanied by ischemic changes on ECG. Compared with male patients, female patients had less organic stenosis (12 vs 33%, p<0.05), less history of smoking (15 vs 85%, p<0.01), and fewer focal spasms (31 vs 64%, p<0.01). There were no other differences between the 2 groups. In conclusion, Japanese female patients with vasospastic angina had the characteristics of diffuse provoked spasm, less organic stenosis, and less history of smoking, but only 1 in 10 of all patients with vasospastic angina are female.

Coronary abnormal response has increased in Japanese patients: Analysis of 17 years’ spasm provocation tests in 2093 cases

BACKGROUND Abnormal coronary response on acetylcholine test is observed in patients with early coronary atherosclerosis. OBJECTIVES We analyzed retrospectively the abnormal response rate during 17 years of spasm provocation tests in 2093 consecutive patients. METHODS We performed 2093 spasm provocation tests, consisting of 1198 acetylcholine tests and 895 ergonovine tests, between January 1991 and December 2007. Spasm provocation test was mainly performed in patients with ischemic heart disease. Abnormal response was defined as transient >90% luminal narrowing during spasm provocation tests. We classified these 17 years into two periods: former period from January 1991 to December 2000, and the latter period from January 2001 to December 2007. In the former period, 1300 spasm provocation tests were performed and 793 spasm provocation tests were done in the latter period. RESULTS The incidences of hypertension, dyslipidemia, and diabetes mellitus were significantly increased in the latter period. The values of total cholesterol, triglycerides, and fasting blood sugar were also significantly increased in the latter period. The frequency of abnormal response in the latter period was significantly higher than that in the former period (46.0% vs. 33.2%, p<0.05). The frequency of abnormal coronary response to acetylcholine in the latter period was significantly higher than that in the former period (60.0% vs. 34.0%, p<0.01), whereas there was no difference concerning abnormal response of ergonovine between the two periods (31.9% vs. 30.7%, ns). CONCLUSIONS In Japanese patients, abnormal coronary response to acetylcholine has increased and coronary endothelial dysfunction is suggested to have progressed.

Overview of the Acetylcholine Spasm Provocation Test

The acetylcholine (ACh) spasm provocation test proposed by Yasue, Okumura et al more than a quarter‐century ago has become a popular method for induction of coronary spasm. This test is safe and has a low rate of complications. However, it may be limited in its ability to document attacks in daily life because previously it was the gold‐standard method for diagnosing active variant angina. There may be some clinical issues to modify for the next generation of cardiologists. A maximal ACh dose of 50/100 µg in the right coronary artery/left coronary artery is recommended in the Japanese Circulation Society guidelines. We often experienced the usefulness of a maximal ACh dose of 80/200 µg for the induction of coronary spasm in some cases with low or moderate disease activity. It may be necessary to reconsider the maximal ACh dose as a modified method for todays real‐world clinical practice. In young patients with rest angina, intracoronary injection of ACh is less sensitive for diagnosis; in these cases, we recommend performing sequential spasm provocation tests. Especially in female patients, to document coronary artery spasm we recommend performing ACh tests first, instead of ergonovine tests, due to the supersensitivity of ACh. We also recommend supplementary use of ACh and ergonovine. This review summarizes our experiences with the ACh spasm provocation test over a period of 24 years. We have found it to be a reliable and useful method for contributing a variety of clinical information and recommend it to the next generation of cardiologists.

Left ventricular mass and atrial volume determined by cine magnetic resonance imaging in essential hypertension

To evaluate the relationship between left atrial volume determined by cine magnetic resonance imaging and progression of left ventricular hypertrophy (LVH), left atrial volume and echocardiographic left ventricular mass (LVM) were measured in 30 hypertensive patients (15 without LVH and 15 with LVH) and 10 normotensive control subjects. We also evaluated the effects of antihypertensive therapy on the cardiac chamber volumes and LVM in hypertensive patients. The cardiac chamber volumes and LVM were indexed by body surface area. Although there were no significant differences in left ventricular chamber volumes among the three groups, both maximum and minimum left atrial volume indexes, and the LVM index were greater in hypertensive patients with LVH than in the other two groups. The LVM index was correlated with maximum left atrial volume index (r = 0.74, P < .0001), and minimum left atrial volume index (r = 0.76, P < .0001), respectively. Furthermore, in multivariate models, the LVM index was significantly correlated with maximum left atrial volume index. In hypertensive patients with LVH, both maximum and minimum left atrial volume indexes, and the LVM index significantly reduced after treatment. The percent of changes in maximum left atrial volume index after treatment was significantly correlated with the percent of changes in LVM index after treatment. In conclusion, our data indicate that LVH is an independent determinant of left atrial enlargement, and both LVH and left atrial enlargement may be reversed by some effective therapeutic interventions.

Both a Calcium Antagonist and ACE Inhibitor Reverse Hypertrophy in Hypertension But a Calcium Antagonist also Depresses Contractility

The aim of this study was to compare the effects of a calcium antagonist, nicardipine SR, with an angiotensin-converting enzyme (ACE) inhibitor, alacepril, on the regression of left ventricular hypertrophy (LVH) and function. Twenty patients with LVH, aged 42–73 years, were treated with nicardipine SR or alacepril. Ten patients were treated with nicardipine SR (40–80 mg) for 21 months, and the other 10 patients were treated with alacepril (25–100 mg) for 18 months. All patients underwent echocardiography to assess left ventricular structure and function before and after the treatment. After nicardipine SR or alacepril treatment, blood pressure was decreased significantly from 176.0 ± 13.9/97.0 ± 5.3 mmHg to 140.0 ± 14.0/77.4 ± 7.2 mmHg and from 168.2 ± 22.3/99.0 ± 5.5 mmHg to 138.4 ± 12.5/85.2 ± 9.7 mmHg, respectively (both p < 0.01), whereas heart rate did not change (73.8 ± 14.6 beats/min vs. 69.9 ± 13.5 beats/min and 71.6 ± 9.7 vs. 65.8 ± 8.1 beats/min, respectively). The left ventricular mass index decreased significantly from 133.2 ± 11.7 g/m2 to 114.4 ± 15.7 g/m2 with nicardipine SR and from 137.1 ± 14.8 g/m2 to 99.3 ± 23.0 g/m2 with alacepril (both p < 0.01). The fractional shortening, peak shortening rate, and peak lengthening rate all improved significantly after each treatment. The end-systolic wall stress/left ventricular end-systolic volume index, as an index of left ventricular contractility, was decreased significantly after treatment with nicardipine SR but was not changed after treatment with alacepril. In conclusion, both nicardipine SR and alacepril similarly reduced LVH and improved left ventricular systolic and diastolic function. However, alacepril did not alter left ventricular contractility, whereas nicardi-pine SR decreased left ventricular contractility.

A long-acting calcium antagonist over one year did not improve BMIPP myocardial scintigraphic imagings in patients with pure coronary spastic angina.

Background: Calcium antagonists (Ca) have been effective in reducing angina attacks in patients with variant angina. However, there are no reports regarding the effectiveness of Ca on myocardial fatty acid metabolic images in patients with pure coronary spastic angina (CSA).Objectives: This study sought to examine the correlation between myocardial fatty acid metabolic images and the medical treatment of Ca in patients with pure CSA.Methods and Results: This study included 35 consecutive patients (28 men, mean age of 66±10 years) with angiographically confirmed coronary spasm and no fixed stenosis. Long-acting Ca was administered to all 35 patients. Isosorbide dinitrate /nicorandil/another Ca/beta-bloker were administered when chest pain was not controlled. Using an iodinated fatty acid analogue, 15-(p-[iodine-123]iodophenyl)-3-(R,S)methylpentadecanoic acid (BMIPP), myocardial scintigraphies with intravenous adenosine triphosphate infusion were performed before cardiac catheterization and 12 mo after medical therapy. According to the medical control states, these 35 patients were classified into 3 groups; response (disappearance of angina attacks, 12 pts, 60±11 years), partial response (angina attacks <4/mo, 12 pts, 67±10 years), and no response to therapy (angina attacks ≥4/mo, 11 pts, 71±6 years). Reduced BMIPP uptake was observed in 24 (69%) of 35 patients before the treatment. Reduced BMIPP uptake was also found in 18 patients (51%) after 12 mo. Normal BMIPP uptake after 12 mo therapy was observed in about half (response: 42%, partial response: 58%, no response: 45%) of patients among the 3 groups. There was no difference regarding the value of washout rate (WOR) (response; 10±7 (before), 14 ±8% (12 mo)), partial response; 11±7, 10±5%, no response; 13±9, 14±8%) among the 3 groups. The defect scores of BMIPP in the three groups were not different during at least one year medical therapy. No difference regarding the distribution of other medical therapies (angiotensin converting enzyme inhibitors/angiotensin receptor blockers/beta-blockers/statins) was found. The administration of Ca and isosorbide dinitrate/nicorandil and 2 Ca was significantly higher in the poor than in the good control patients.Conclusions: Long-acting Ca over one year did not improve myocardial fatty acid metabolic images in patients with pure CSA. This may be related to silent ischemia.