Wataru Mitsuoka

Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause

OBJECTIVES This study was undertaken to assess myocardial adrenergic activity using iodine-123 metaiodobenzylguanidine (MIBG) imaging in patients with heart failure. BACKGROUND In patients with congestive heart failure, adrenergic nerve activity is accelerated. However, whether myocardial adrenergic nerve activity reflects the severity of heart failure and its relation to the underlying cause have not yet been elucidated. METHODS Planar MIBG images were obtained from 96 patients with heart failure and compared with images from 9 age-matched healthy subjects. Groups 1 and 2 included 65 patients with heart failure related to impaired myocardial function and whose left ventricular ejection fraction was < 40% (group 1 = 40 patients with dilated cardiomyopathy; group 2 = 25 patients with ischemic cardiomyopathy). Group 3 included 31 patients with heart failure related to a mechanical abnormality and whose left ventricular ejection fraction was > 40% (mitral regurgitation in 16, aortic regurgitation in 9, aortic and mitral regurgitation in 4, ruptured aneurysm of Valsalva in 2). Myocardial uptake of MIBG was calculated as the heart/mediastinal activity ratio. Storage and release of MIBG were calculated as percent myocardial MIBG washout from 15 min to 4 h after isotope injection. RESULTS The heart/mediastinal activity ratio in the immediate images (15 min) showed a significant decrease only in patients with severe heart failure (groups 1 and 2). The myocardial washout was accelerated in all three heart failure groups. The level of myocardial washout was related to severity of heart failure and correlated well with New York Heart Association functional classification. CONCLUSIONS In severe heart failure associated with cardiomyopathy, norepinephrine uptake is reduced. In addition, myocardial adrenergic nerve activity is accelerated in proportion to severity of heart failure, independent of the underlying cause.

Role of coronary artery spasm in progression of organic coronary stenosis and acute myocardial infarction in a swine model. Importance of mode of onset and duration of coronary artery spasm.

BackgroundCoronary spasm may play an important role in progression of organic coronary stenosis and myocardial infarction, but the mechanisms responsible for these complications are not known. This study aimed to examine whether the mode of onset and the duration of coronary spasm influenced progression of organic coronary stenosis and acute myocardial infarction in a swine model of coronary spasm. Methods and ResultsGottingen miniature pigs were subjected to cholesterol feeding, balloon-induced coronary arterial denudation, and x-ray irradiation. Five months later, coronary spasm was induced by intracoronary injection of serotonin. In 10 pigs, coronary spasm was provoked abruptly and maintained for 25 minutes by five repeated intracoronary injections of serotonin (10 μg/kg) every 5 minutes (group A, abrupt onset and short duration). In group B, coronary spasm was provoked gradually by intracoronary injections of serotonin at graded doses of 0.1, 0.3, and 0.6 μg/kg every 5 minutes and was then maintained for 25 minutes in four pigs (group BR, gradual onset and short duration) and for 120 minutes in six pigs (group B2, gradual onset and long duration) by repeated intracoronary injections of serotonin (10 μg/kg) every 5 minutes. Intramural hemorrhage was noted histologically at the spastic site more frequently in group A with abrupt onset (nine of 10 pigs) than in group B with gradual onset (two of 10 pigs) (p<0.01). Progression of organic coronary stenosis due to intramural hemorrhage was noted in seven pigs (six pigs in group A and one pig in group B), including three cases of total coronary occlusion. Evidence for the evolution of acute myocardial infarction (serial ECG findings, left ventriculograms, and histological findings) was noted in one pig (7%) of group A or B1 with short duration and in five of six pigs (83%) in group B2 with long duration (p<0.01 versus group A and Bi). ConclusionThese results indicate that 1) intramural hemorrhage was frequently induced by coronary spasm of abrupt but not of gradual onset, 2) intramural hemorrhage resulted in acute progression of coronary stenosis and sometimes resulted in persistent total coronary occlusion leading to acute myocardial infarction, and 3) prolonged coronary spasm resulted in acute myocardial infarction without progression of organic coronary stenosis.

Augmentation of coronary responsiveness to serotonin at the site of X-ray-induced intimal thickening in miniature pigs

OBJECTIVE X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs. METHODS In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber. RESULTS The percent reduction in coronary diameter evoked with 10 micrograms.kg-1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M[ [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 micrograms.kg-1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2[52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) microns] than at the denuded sites without X-irradiation [group 2, 58(5) microns] (P < 0.05). CONCLUSIONS These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle.

Mechanisms of ergonovine-induced hyperconstriction of coronary artery after x-ray irradiation in pigs

Mechanisms of ergonovine-induced coronary hyperconstriction were examined in vivo and in vitro in miniature pigs. To provoke coronary hyperconstriction, the endothelium of a segment of a major branch of the left coronary artery was denuded in 19 Göttingen miniature pigs (4 to 6 months of age). In Group I (n=12), the denuded site of the coronary artery was selectively irradiated with 15 Gy of x-ray twice, 3 and 4 months after endothelial denudation. The remaining 7 pigs were not irradiated (Group II). The vasoconstrictive effect of intracoronary administration of ergonivine (1 to 1000 μg) was examined angiographically 3 months (just before irradiation in group I) and 5 months after denudation in the two groups. After the angiographical study, the vessels were isolated and isometric tensions were measured in an organ chamber. In the in vivo studies, ergonovineinduced vasoconstriction at the denuded and x-ray irradiated site in Group I was significantly greater than that at the control site or that at the denuded site in Group II. Pretreatments with serotonin receptor blockers (ketanserin or methysergide) significantly attenuated ergonovine-induced hyperconstriction, while an alpha-adrenergic receptor blocker (prazosin) did not (% inhibition; ketanserin 74±9%, p<0.01, methysergide 60±10%, p<0.01, prazosin 9±5%, NS). In the in vitro studies, ergonivine produced significantly greater tension at the denuded and x-ray irradiated site (Group I) than at the control site or at the denuded site (Group II). Ergonovine-induced endotheliumdependent relaxation was impaired at the denuded site in both groups to a similar extent. These results suggest that ergonovine-induced hyperconstriction at the denuded and x-ray irradiated coronary artery resulted mainly from the hyperreactivity of medial smooth muscle mediated by serotonin2 receptors.

Angiographically documented coronary vasospasm as a cause of myocardial infarction during the acute phase of aortic dissection

SummaryWe angiographically documented coronary vasospasm which resulted in myocardial infarction during the acute phase of aortic dissection (Stanford A). Coronary and aortic angiography performed at admission of the patient revealed complete occlusion of the right coronary artery and dissection of the aorta. Intracoronary injection of isosorbide dinitrate and intravenous administration of verapamil opened the occluded right coronary artery and blood flow was fully restored. We conclude that, in this case of aortic dissection, the severe stimulation by the aortic dissection brought about vasospasm of the right coronary artery which was the major cause of myocardial infarction. This is the first case report showing clear evidence that myocardial infarction is brought about by vasospasm associated with aortic dissection.

Cascade of Pathophysiological Events Leading to Spasm of Coronary Arteries

Coronary spasm plays an important role in variant angina, effort angina, acute myocardial infarction, and/or sudden death [1–4]. Augmented responses of the coronary artery to vasotonic agents have been documented angiographically in patients with variant angina; however, the mechanisms of enhanced luminal narrowing remain unclarified, both clinically and experimentally. In order to elucidate factors involved in the enhanced responses of the coronary artery, we developed an animal model with the following features [5,6]: (1) transient changes in coronary diameter can be assessed angiographically, (2) coronary spasm can be repeatedly provoked, and (3) myocardial ischemia at the area distal to the site of the stenosed coronary artery can be documented. We chose Gottingen miniature swine as an animal model of coronary spasm [5], because (1) repeated examinations of coronary angiography and endothelial balloon-denudation were feasible using a catheterization technique and (2) pigs seem to be the most appropriate animal model for inducing atherosclerosis by changes which occur that closely resemble those seen in humans. We used mainly coronary arteriography for documentation of spastic events, because this technique is the only available tool for determining regional differences in vascular responsiveness to vasoactive substances in situ [6]. Regional intimai thickening along the left coronary artery was produced to mimic the diseased state of humans, this being the area in which the endothelial denudation had been one of procedures for inducing atherosclerotic lesions in experimental animals [7,8].