Masatoshi Fujita

Importance of collateral circulation for prevention of left ventricular aneurysm formation in acute myocardial infarction.

The effect of preexistent coronary collateral perfusion on the prevention of left ventricular aneurysm formation was examined in 47 patients undergoing an intracoronary thrombolysis within 6 hours after the onset of a first acute anterior myocardial infarction. Left ventricular aneurysm formation and wall motion were analyzed with cineventriculography. A left ventricular aneurysm was determined as well-defined demarcation of the infarcted segment from normally contracting myocardium. In 25 patients with successful thrombolysis (group A), a left ventricular aneurysm was observed in one patient (4%) during the chronic stage of infarction. In 10 patients who had a significant collateral circulation to the infarct-related coronary artery and unsuccessful reperfusion (group B), the left ventricular aneurysm was observed in only one patient (10%). In the remaining 12 patients with unsuccessful recanalization in the absence of a significant collateral perfusion (group C), there was a higher incidence (seven of 12, 58%) of left ventricular aneurysm formation than in groups A and B (p less than 0.05). In group A, both the global ejection fraction and regional wall motion in the infarct areas improved significantly (p less than 0.05) between the acute and chronic stages of infarction. By contrast, in groups B and C, these indexes on the ventricular function did not change significantly during the convalescent period. Thus, although the collateral perfusion existing at the onset of acute myocardial infarction may not improve ventricular function, it exerts a beneficial effect on the prevention of left ventricular aneurysm formation.

Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina.

It has been demonstrated in animal experiments that heparin accelerates the coronary collateral development induced by repeated coronary occlusion. We used this effect of heparin for the treatment of patients with stable effort angina. In 10 patients, treadmill exercise was performed according to standard Bruce protocol twice a day for 10 days. A single intravenous dose of heparin (5000 IU) was given 10 to 20 min before each exercise period. Exercise with heparin pretreatment increased the total exercise duration from 6.3 +/- 1.9 (SD) to 9.1 +/- 2.2 min (p less than .001) and the maximal double product (DP) from 18,900 +/- 5100 to 25,500 +/- 6800 mm Hg.beats/min (p less than .001). The DP at the onset of angina was also increased by 35% (p less than .01) and the DP at which ST depression (0.1 mV) first appeared was 19% (p less than .05) greater after treatment. Repeat coronary cineangiography revealed an increase in the extent of opacification of collaterals to the jeopardized myocardium. In an additional six patients, treadmill exercise was performed with no medication twice a day for 10 days. All of the above-mentioned variables of treadmill capacity remained unchanged, despite 20 exercise periods without heparin pretreatment. Thus, heparin accelerates exercise-induced coronary collateral development by promoting angiogenesis. The development of such a therapeutic modality will open a new field for the treatment of patients with ischemia.

Recent insights into the mechanisms, predisposing factors, and racial differences of coronary vasospasm

Coronary vasospasm is currently considered to be an exaggerated contractile nonspecific response of the vascular smooth muscle in the large coronary artery to various agonists or stimulation, that is established after the process of inflammation and fibrocellular proliferation. Endothelial dysfunction with reduced nitric oxide bioavailability has been reported in angiographically normal coronary arteries in Japanese patients with coronary spastic angina. Recently, several interesting findings concerning the exact mechanism of calcium hypersensitivity of spastic vascular smooth muscle have been reported. In animal models with coro-nary spasm Rho-kinase is upregulated at the spastic site and plays a key role in inducing vascular smooth muscle hypercontraction by inhibiting myosin light chain phosphatase, resulting in enhancement of its phosphorylation. Also, oxidative stress has been given attention as an important mediator of the spastic conversion of vascular smooth muscle cell “phenotype.” The incidence of coronary spastic angina in the Japanese population is reported to be remarkably high compared with that in Caucasians. Clinical and pathophysiological differences between Japanese and Caucasian patients with respect to coronary vasospasm are characterized by a lower prevalence of fixed coronary artery stenoses and diffuse coronary hyperreactivity in the Japanese patients. Recently, several distinct characteristics have been recognized to be associated with coronary vasospasm in studies analyzing data obtained from Japanese patients. In the present review, we will discuss our point of view on the mechanisms and predisposing factors in coronary vasospasm. Predisposing factors include smoking, lipid metabolic disorders, and gene expression, all of which may be interrelated issues.

Significance of collateral circulation in reversible left ventricular asynergy by nitroglycerin in patients with relatively recent myocardial infarction

To evaluate the functional role of coronary collateral circulation in reversible asynergy of the left ventricle, cineventriculography was performed before and after the administration of sublingual nitroglycerin in 19 patients with complete occlusion of the proximal part of the left anterior descending coronary artery. In nine patients who had significant collateral circulation to the infarct-related coronary artery (group A), there was significant improvement in both the left ventricular ejection fraction (53% to 60%, p less than 0.05) and regional wall motion in the infarct zone (8% to 18%, p less than 0.01 in the anterolateral area) with administration of nitroglycerin. In contrast, in the remaining 10 patients without significant collateral perfusion (group B), there were no detectable changes in either global function (49% versus 50%) or regional wall motion (6% versus 8% in the anterolateral area) before and after nitroglycerin. Changes in heart rate and left ventricular peak systolic and end-diastolic pressures with nitroglycerin were comparable in both groups. These results suggest that angiographically demonstrable collaterals preserve viable myocardium, which can improve its contraction when the supply-demand relationship is favorably affected because of increased collateral flow and/or more favorable loading conditions produced by nitroglycerin.

Comparative effect of heparin treatment with and without strenuous exercise on treadmill capacity in patients with stable effort angina

It has recently been demonstrated that treadmill capacity and collateral circulation improve as a result of exercise with heparin pretreatment in patients with effort angina. In the present study, we assessed whether heparin alone is effective in increasing treadmill capacity in 14 patients with effort angina. Patients were randomly assigned to one of two treatment arms: (1) group A--20 treadmill exercise periods with standard Bruce protocol twice a day for 10 days with heparin (5000 IU intravenously) pretreatment (seven patients) or (2) group B--10 injections of heparin calcium (10,000 IU subcutaneously) once a day for 10 days (seven patients). In group A, total exercise time was increased from 6.9 +/- 1.2 (SD) to 9.9 +/- 1.9 minutes (p less than 0.0005), as was the maximal double product, from 21,700 +/- 3,500 to 27,000 +/- 4,800 mm Hg/min (p less than 0.05). The double product at the onset of angina was also increased by 34% (p less than 0.05), and the double product at which ST depression (0.1 mV) first appeared was 22% (p less than 0.05) greater after treatment. In contrast, in group B, all of the above-mentioned parameters of treadmill capacity remained unchanged. These data indicate that heparin does not serve as an angiogenic factor by itself, but that it potentiates the ischemia-derived angiogenic factor.

Improvement of oxygen metabolism in ischemic myocardium as a result of enhanced external counterpulsation with heparin pretreatment for patients with stable angina

Enhanced external counterpulsation (EECP) is noninvasive, safe, and effective for stable angina. We have reported that the development of functional collateral vessels is one of the mechanisms of EECP therapy using ammonia positron emission tomography (PET). The efficacy of heparin treatment on collateral growth is shown in several clinical studies. We evaluated whether EECP combined with intravenous heparin injection is effective for exercise capacity and oxygen metabolism of ischemic myocardium in stable angina. Eleven patients with stable angina were treated with conventional EECP therapy (C group). Seven patients with stable angina were treated with EECP therapy with 5000 IU heparin pretreatment (H group). At baseline and after the completion of treatment H, 7 patients underwent [11C] acetate PET to examine the change in regional myocardial oxygen metabolism. Although the total treadmill exercise time was prolonged after treatment in both groups, the extent of the improvements was significantly greater in the H group compared with the C group. Although k mono, the index of regional myocardial oxygen metabolism, in the nonischemic region remained unchanged, k mono in the ischemic region increased significantly (P ≪ 0.05) from 0.038 ± 0.004 to 0.053 ± 0.007. In conclusion, EECP with heparin pretreatment appears to be a new treatment remedy for patients with stable angina.

Importance of coronary collateral circulation for increased treadmill exercise capacity by nitrates in patients with stable effort angina pectoris

The purpose of this study was to elucidate the mechanism that induces an improvement in exercise capacity by nitrates in patients with stable effort angina pectoris. The study population was composed of 19 patients: group A, 10 patients with chronic stable effort angina who had a well-developed coronary collateral circulation to the potentially ischemic region; group B, 9 patients with chronic stable effort angina who had no collateral circulation to the jeopardized myocardium. Treadmill exercise was performed according to the standard Bruce protocol with and without pretreatment with orally administered 10 mg isosorbide dinitrate. Percent increases (mean +/- SE) in exercise duration were not significantly different between groups A and B (25 +/- 6 vs. 14 +/- 6%). Percent increases in the maximal rate-pressure product tended to be greater in group A than in group B (27 +/- 6 vs. 10 +/- 6%). Percent increases in the rate-pressure product at the onset of angina pectoris were significantly greater in group A than in group B (37 +/- 7 vs. 7 +/- 6%; p less than 0.01). Percent increases in the rate-pressure product at 0.1 mV S-T segment depression were also significantly greater in group A than in group B (26 +/- 6 vs. 1 +/- 5%; p less than 0.01). These results suggest that isosorbide dinitrate dilates epicardial collateral vessels with smooth muscle layers, but fails to dilate the coronary arteries with significant organic stenoses.

Importance of myocardial ischemia for coronary collateral development in conscious dogs

The purpose of this study was to evaluate the effects of myocardial ischemia on the development of collateral circulation. Thirteen conscious dogs were instrumented for serial measurements of subendocardial segment length in the area perfused by the left circumflex coronary artery, left circumflex coronary artery flow and left ventricular pressure. In 6 dogs (group A), 1 min left circumflex coronary artery occlusions were carried out at 30 min intervals. When the 442nd 1 min left circumflex coronary artery occlusion produced a reduction in segment shortening and a significant reactive hyperemia, the occlusion time was increased to 2 min. In the remaining 7 dogs (group B), 2 min left circumflex coronary artery occlusions were conducted hourly. In group A, following 451 +/- 201 (SD) min of total occlusion time with the mixture of 1 and 2 min left circumflex coronary artery occlusions (43 +/- 18 days) a left circumflex coronary artery occlusion produced no reduction in segment shortening and negligible reactive hyperemia. By contrast, in group B, 218 +/- 99 min of total occlusion time (18 +/- 8 days) was required to develop adequate collateral circulation. The relative contribution of the first and second 1 min of left circumflex coronary artery occlusion to the collateral development was mathematically evaluated. This analysis indicated that the second 1 min of left circumflex coronary artery occlusion is 4.43-fold more effective than the first 1 min of occlusion in terms of the collateral induction. We concluded that severe myocardial ischemia plays an important role in the development of collateral circulation.

A case with transient increases in serum S100A8/A9 levels implying acute inflammatory responses after pancreatic islet transplantation.

We investigated a patient with type 1 diabetes mellitus undergoing pancreatic islets transplantation. In this patient, we evaluated the clinical usefulness of serial measurement of serum S100A8/A9 complex levels for detecting acute inflammatory responses associated with rejection of transplanted pancreatic islets. The serum S100A8/A9 complex was a more sensitive marker for acute inflammation associated with islet transplant rejection than the serum C-reactive protein. Thus, the serial measurement of the serum S100A8/A9 complex concentration is useful for monitoring the patients with pancreatic islet transplantation.

Improvement of ST Segment Depression by Gradual Recruitment of Collateral Circulation

The purpose of the present study was to document that the coronary collateral vessels do not open immediately upon the occurrence of myocardial ischemia. A multistage bicycle exercise was performed to determine a maximal tolerable work load until the onset of angina and significant ST segment depression in 10 patients with well-developed collateral circulation. On a different day, exercise with the maximal tolerable work load was repeated for a comparable exercise duration. In 2 of the 10 patients, anginal pain was gradually alleviated despite the continuation of exercise with fixed work load. The extent of ST segment depression at 3 min of exercise with fixed work load was 0.20 +/- 0.10 (SD) mV, significantly (p less than 0.05) greater than 0.16 +/- 0.08 mV at the end of exercise with fixed work load. In contrast, the rate-pressure product was smaller at 3 min than at the end of exercise with fixed work load (20,900 +/- 5,500 vs. 22,700 +/- 5,700 mm Hg.beats/min; p less than 0.05). In 5 patients without well-developed collateral circulation, the extent of ST depression changed in parallel with changes in rate-pressure product during exercise with fixed work load. Thus, it is concluded that the delayed collateral opening plays a critical role in the pathogenesis of myocardial ischemia in patients with a totally occluded coronary artery.