Yoshitoshi Urabe

Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms.

BACKGROUND A group of patients has been described who have chest pain resembling angina and positive exercise tests, but normal coronary angiograms and no coronary-artery spasm. This constellation of features has sometimes been called syndrome X or microvascular angina. We attempted to determine whether endothelium-dependent vasodilatation of the coronary vasculature was impaired in patients with this syndrome. METHODS We infused the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilators papaverine and isosorbide dinitrate into the left coronary artery of 9 patients and 10 control subjects. The diameter of the left anterior descending coronary artery was assessed by quantitative angiography, and changes in coronary blood flow were estimated with the use of an intracoronary Doppler catheter. RESULTS Acetylcholine, given in doses of 1, 3, 10, and 30 micrograms per minute, increased coronary blood flow in a dose-dependent manner in both groups. However, the mean (+/- SD) acetylcholine-induced increases in coronary blood flow were significantly less (P < 0.001) in the patient (8 +/- 14, 37 +/- 37, 59 +/- 67, and 103 +/- 77 percent, respectively) than in the controls (62 +/- 52, 186 +/- 93, 341 +/- 128, and 345 +/- 78 percent, respectively). The changes in coronary blood flow in response to 2 mg of isosorbide dinitrate (236 +/- 66 percent vs. 280 +/- 56 percent) and 10 mg of papaverine (366 +/- 168 percent vs. 411 +/- 92 percent) did not differ significantly between the patients and controls. The administration of papaverine resulted in myocardial lactate production in the patients but not in the controls. The three lower doses of acetylcholine caused a similar degree of dilatation of the left anterior descending coronary artery in the two groups, and the highest dose caused a similar degree of constriction in the two groups. Isosorbide dinitrate and papaverine caused a similar degree of dilatation in both groups. CONCLUSIONS These findings suggest that endothelium-dependent dilatation of the resistance coronary arteries is defective in patients with anginal chest pain and normal coronary arteries, which may contribute to the altered regulation of myocardial perfusion in these patients.

Bradykinin-Induced Vasodilation Is Impaired at the Atherosclerotic Site but Is Preserved at the Spastic Site of Human Coronary Arteries In Vivo

BACKGROUND Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. METHODS AND RESULTS The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor responses of the site where acetylcholine caused dilation were compared with the responses of the site where acetylcholine caused constriction. The magnitudes of bradykinin-induced dilation at the site with acetylcholine-induced dilation (mean +/- SD: 6 +/- 6%, 11 +/- 9%, and 15 +/- 9%) were comparable to that (3 +/- 6%, 8 +/- 8%, and 13 +/- 9%) at the site with acetylcholine-induced constriction. In the CAD group, vasomotor responses of the stenotic site (% diameter stenosis, 15% to 50%) and nonstenotic site were examined. The bradykinin-induced dilation at the stenotic site (0 +/- 4%, 3 +/- 8%, and 5 +/- 9%) was significantly less (P < .01) than at the nonstenotic site (3 +/- 4%, 8 +/- 6%, and 16 +/- 11%) and in the control group. Coronary vasodilation with nitrate at the stenotic site (20 +/- 11%) was comparable to that at the nonstenotic site (22 +/- 16%) and in the control group (21 +/- 10%). In the VSA group, vasomotor responses of the site with acetylcholine-induced spasm and the site without spasm were examined. The bradykinin-induced vasodilation at the spastic site (5 +/- 5%, 16 +/- 15%, and 33 +/- 17%) was comparable to that at the nonspastic site (4 +/- 8%, 12 +/- 14%, and 21 +/- 9%). Nitrate-induced dilation was comparable at the spastic site (51 +/- 19%) and the nonspastic site (32 +/- 13%). The ratio of bradykinin-induced vasodilation to nitrate-induced vasodilation at the spastic site was comparable to the control group. CONCLUSIONS These results suggest that bradykinin causes vasodilation of human epicardial coronary arteries in vivo and that bradykinin-induced endothelium-dependent vasodilation is impaired at the stenotic site but is preserved at the angiographically normal site where endothelium-dependent vasodilation by acetylcholine is impaired and at the spastic site.

Apical segmental dysfunction in hypertrophic cardiomyopatfay: Subgroup with unique clinical features

A segmental wall motion abnormality is an unusual finding in patients with hypertrophic cardiomyopathy. To clarify its clinical significance, 48 patients with hypertrophic cardiomyopathy were analyzed. Eight patients (Group A) had apical segmental dysfunction; 40 (Group B) had normal wall motion. No patient in either group had coronary artery stenosis on selective coronary arteriography. In all patients in Group A, apical segmental dysfunction was revealed by left ventriculography; however, it could be detected by echocardiography in only two patients in Group A. Left ventricular hypertrophy by electrocardiogram (ECG) was more common in Group B (p less than 0.05). Abnormal Q waves were more frequently discovered in Group A (p less than 0.005) and were recognized predominantly in the lateral leads. On serial ECGs, a gradual development of abnormal Q waves was noted in six of eight patients in Group A. Malignant arrhythmias were more common in Group A (p less than 0.001). In two patients in Group A, left ventricular dilation and congestive heart failure developed during the follow-up period. Thus, the presence of a Q wave in the lateral leads on an ECG in patients with hypertrophic cardiomyopathy may indicate the presence of apical segmental dysfunction. Left ventriculography should be performed to examine the presence of this abnormality and 24 h ambulatory ECG monitoring should be done to detect malignant arrhythmias in patients who have abnormal Q waves in the lateral leads. Patients with this unique type of hypertrophic cardiomyopathy need careful follow-up evaluation.

Negative Inotropic Effect of Basic Fibroblast Growth Factor on Adult Rat Cardiac Myocyte

BACKGROUND Basic fibroblast growth factor (bFGF) is highly expressed in the myocardium in some cardiac disorders, such as ischemia-reperfusion and cardiac allograft rejection. However, whether bFGF has any effects on myocardial contraction is unknown. METHODS AND RESULTS We examined the effects of bFGF on myocardial contractility using isolated adult rat cardiac myocyte preparations. bFGF exerted a direct negative inotropic effect that was concentration and time dependent. The pretreatment of myocytes with a neutralizing anti-bFGF antibody (100 ng/mL) abolished the negative inotropic effects of bFGF (100 ng/mL). Platelet-derived growth factor (12.5 ng/mL) and transforming growth factor-beta (1 ng/mL) did not exert such effects, which indicated that bFGF-induced negative inotropism was considered to be specific for this growth factor. bFGF decreased the peak intracellular Ca2+ transient by 46% during systole. The enhanced production of nitric oxide was unlikely to be responsible for the bFGF-induced negative inotropic effect. CONCLUSIONS bFGF, primarily a potent growth promoter, produced acute negative inotropic effects in the adult cardiac myocyte that could have resulted from alterations in intracellular Ca2+ homeostasis. The negative inotropic effect of bFGF may contribute to myocardial dysfunction associated with ischemia-reperfusion injury and heart transplant rejection.

Recurrent Myocardial Infarction Provoked by Multiple Giant Coronary Aneurysms A Case Report

A case of multiple coronary aneurysms, complicated with repeated myocardial infarction, is presented. The cine-coronary angiogram and autopsy disclosed marked dilatation of epicardial coronary arteries associated with multiple giant thrombosed aneurysms, which is rare in patients with atherosclerosis.

Effects of intracoronary infusion of atrial natriuretic peptide on pacing-induced myocardial ischemia in patients with effort angina pectoris.

BackgroundAtrial natriuretic peptide (ANP) has been shown to dilate the coronary artery. The aim of this study was to determine whether, in patients with effort angina pectoris, intracoronary infusion of ANP attenuates pacing-induced myocardial ischemia either by dilating the stenotic lesion in a large coronary artery or by dilating collateral vessels. MethodsWe studied six patients who had total or subtotal occlusion in one coronary artery and well-developed, angiographically visible collateral vessels (group A) and five patients who had a significant stenosis in a large coronary artery with no visible collateral vessels (group B). Their heart rate was increased by atrial pacing both before and after intracoronary infusion of ANP (0.03 μg/kg/min for 15min) into the donor artery of collateral vessels in group A or into the stenotic artery in group B. ResultsBefore ANP infusion, all patients of both groups developed an ischemic ST-segment depression (≥ 0.1 mV) and angina-like chest pain from pacing tachycardia. After ANP infusion, significant ST-segment depression was induced by rapid pacing in only one out of six patients of group A, whereas it was noted in all patients of group B (P<0.01). After ANP infusion, chest pain developed in one out of six patients in group A, whereas it appeared in four out of five patients in group B (P< 0.05). ANP significantly dilated the angiographically normal segment of the epicardial coronary artery, but it did not significantly change the severity of the stenotic lesion in either group. ANP did not change the basal arterial pressure or heart rate, nor did it change their response to pacing tachycardia. ConclusionInfusing ANP into the donor artery of collateral vessels, but not into the artery with culprit stenotic lesion, attenuated pacing-induced myocardial ischemia. Therefore, the beneficial effects of ANP in reducing pacing-induced myocardial ischemia may result from the increase in myocardial perfusion to the ischemic area caused by dilating the collateral vessels.

Augmented vasodilator response to L-arginine after coronary angioplasty may attenuate restenosis.

Abstract Nitric oxide (NO) plays an important role in the control of vascular tone as well as structure. This study examined the possibility that the extent of restenosis 3 months after percutaneous transluminal coronary angioplasty (PTCA) might be correlated with the magnitude of NO production at the PTCA sites on the day following PTCA. In 23 consecutive patients who underwent PTCA, we examined the coronary artery diameter response to intracoronary administration of l-arginine (1 μg/kg) and isosorbide dinitrate (ISDN, 40 μg/kg) at the sites of PTCA (n= 25) and at untreated sites distal to the PTCA sites approximately 18 h after PTCA. The coronary artery diameter at the PTCA site was determined 3 months after PTCA in all patients. Normalized vasodilator responses to l-arginine (responses to l-arginine ÷ those to ISDN) were greater at the PTCA sites than at the untreated sites (P= 0.05), whereas vasodilator responses to ISDN did not differ between the PTCA and untreated sites. These results suggest a greater production of NO at the PTCA sites despite presumable loss of the endothelium due to the PTCA. Furthermore, the magnitude of normalized vasodilator responses to l-arginine examined at 18 h after PTCA correlated with the coronary artery diameter 3 months after PTCA (r= 0.592, P= 0.002). These results suggest that augmented NO production after PTCA may protect against the development of coronary restenosis. Treatment that enhances local NO production may be clinically useful in preventing restenosis after PTCA.

Sarcoplasmic reticulum Ca2+ regulatory protein gene expression in human right atrium under hemodynamic overload.

SummarySarcoplasmic reticulum (SR) Ca2+-adenosine triphosphatase (ATPase) mRNA expression is reduced in the failing human myocardium. However, it is not known whether SR Ca2+-regulatory protein gene expression is altered in human myocardial tissue subjected to pressure overload or volume overload. We sought to determine whether SR Ca2+-regulatory protein gene expression is altered in human atrial tissue subjected to mechanical overload. We obtained right atrial myocardial tissue (about 250mg) at open-heart surgery from three groups of patients: no hemodynamic overload to the right atrium (control group; 12 patients), atrial septal defect (ASD group; 8 patients), and tricuspid regurgitation (TR group; 7 patients). We measured the myocyte size, the area of interstitial fibrosis, SR Ca2+-ATPase, and ryanodine receptor mRNA abundance. The isolated cardiocyte area and the percent area of interstitial fibrosis were in the order TR > ASD > control (P < 0.05). The SR Ca2+-ATPase mRNA level in TR was significantly decreased (P = 0.004) compared with the control, whereas in the ASD group it did not differ significantly from control. There were no significant differences in ryanodine receptor mRNA levels among the three groups. SR Ca2+-ATPase gene expression was downregulated in human atrial tissue with TR but not in ASD, which might have resulted from the differences in the degree and/or the type of hemodynamic overload to the myocardium.

A case of biopsy-proven cardiac sarcoidosis without any other extracardiac manifestations

A 49-year-old woman was referred to our hospital for uncontrollable heart failure. She had never been diagnosed as having sarcoidosis. Chest X-ray showed cardiomegaly without bilateral hilar lymphadenopathy. Echocardiography showed diffuse hypokinesis of the left ventricle mimicking idiopathic dilated cardiomyopathy. No specific manifestations implying sarcoidosis were observed. On cardiac catheterization, coronary angiograms were normal, whereas concurrent routine endomyocardial biopsy showed foci of non-caseating granuloma, indicating sarcoidosis. Pathological finding was the only clue to diagnose cardiac sarcoidosis among our standard examinations for heart failure. No other additional investigations found any extracardiac features of sarcoidosis. All serological and immunological examinations were within normal range. This is a challenging case of biopsy-proven cardiac sarcoidosis without any other extracardiac involvement.

Regional Wall Motion in the Ischemic Heart

Determinants of regional wall motion were examined during regional coronary hypoperfusion, changes in regional coronary contractile state, and coronary occlusions. The lowest coronary perfusion pressure for maintaining the regional shortening increased when the level of ventricular pressure was elevated by pulmonary artery constriction, which suggests the importance of afterload as one of determinants of regional shortening. The relationship between regional segment length and ventricular pressure was visualized as a loop, and the end-systolic pressure-length relation was determined during progressive declines of preload following occlusion of the inferior caval vein in homogeneously or heterogeneously contracting heart in open-chest dogs. Although the changes in slope of the end-systolic pressure-length relation theoretically represent the elastance of systolic myocardium, the x-axis intercept, but not the slope of the end-systolic pressure-length relation, altered, correlating with changes in contractile state. The level of the x-axis intercept of the regional myocardium, rendered ischemic, increased following an extension of infarct size, which suggests the stretch of ischemic myocardium from the surrounding intact myocardium. Analysis of regional wall motion on the trajectories of the pressure-length (wall thickness) relation facilitates understanding of regional wall motion unique to muscle properties.