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Basic fibroblast growth factor (bFGF), a growth factor potent in promoting angiogenesis, has been shown to reduce infarct size in experimentally induced acute myocardial infarction. However, the effect of bFGF on regional myocardial blood flow (Qm) in the acutely infarcted myocardium has not been well clarified. In 20 open-chest dogs, the left anterior descending (LAD) coronary artery was occluded and animals were maintained in this condition for 4 weeks. In eight of these dogs, bFGF (300 microg) was injected into the myocardium supplied by the LAD and the artery was ligated (bFGF group), and in the other 12 dogs, saline was injected (control group). Nonradioactive colored microspheres were used to measure Qm. The amount of viable myocardium as percent of visual field in the microscope and the extent of fibrosis scored histologically from 0 to 5 in the infarcted area 4 weeks after occlusion were measured. In the outer layer, the Qm values immediately after and 4 weeks after occlusion were 26 +/- 2% and 70 +/- 6%, respectively, in the control group, and 46 +/- 5% and 121 +/- 13%, respectively, in the bFGF group. The Qm at both times in the bFGF group was significantly higher than the corresponding control group values (p < 0.01). The Qm at 4 weeks in the inner and the middle layers also significantly increased in the bFGF group. There was more viable myocardium (control vs bFGF group; 41 +/- 5 vs 61 +/- 7%, p < 0.05) and less fibrosis (3.1 +/- 0.2 vs 2.0 +/- 0.4, p < 0.01) at the outer layer in the bFGF group. It was found that bFGF caused a marked increase in Qm, an increase of viable myocardium, and a decrease of fibrosis in the infarcted myocardium in dogs.

To clarify the role of coronary spasm or dynamic coronary obstruction in the development of acute myocardial infarction (AMI) with spontaneous recanalization (SR), symptoms in 296 patients with AMI admitted within 24 h after the onset of chest pain were analyzed just before and after onset, and coronary angiograms were analyzed soon after onset. Patients were divided into 3 groups according to the initial angiographic findings in the infarct-related coronary artery (IRCA): group 1 comprised 172 patients with total occlusion (TIMI O); group 2 comprised 57 patients with subtotal occlusion (TIMI 1,2); and group 3 comprised 67 patients with SR (TIMI 3). The incidence of SR was 20.3% at 0-4 h after onset, 22.2% at 4-6 h, 19.7% at 6-12 h, 24.0% at 12-24 h, and 36.0% at 24 h or later. The incidence of SR did not increase significantly as time elapsed. The incidence of angina at rest and variable-threshold angina before the onset of infarction was only 16.2% in group 1, but was significantly higher in groups 2 (64.3%) and 3 (61.9%). The incidence of intermittent chest pain at onset in group 1 (8.4%) was significantly lower than in groups 2 (54.5%) and 3 (38.8%). Vasodilation of the proximal normal segment adjacent to the stenotic site of the IRCA induced by intracoronary nitroglycerin was significantly higher in groups 2 (11.7 +/- 1.2%) and 3 (20.7 +/- 2.6%) than in group 1 (4.0 +/- 0.6%). These results suggest that coronary spasm or dynamic obstruction may be involved in the pathogenesis of thrombus formation or coronary obstruction causing AMI in many Japanese patients.

Background: The administration of calcium antagonists to patients with healed myocardial infarction is a controversial treatment. This study was conducted to elucidate the effect of short-acting nifedipine and diltiazem on cardiac events in patients with healed myocardial infarction., Methods and Results: A controlled clinical open trial of 1115 patients with healed myocardial infarction was carried out between 1986 and 1994. The patients included 595 who received no calcium antagonist, 341 who received short-acting nifedipine 30 mg/d, and 179 who received short-acting diltiazem 90 mg/d. The primary end points were cardiac events, which were defined as fatal or nonfatal recurrent myocardial infarction; death from congestive heart failure; sudden death; and hospitalization because of worsening angina, congestive heart failure, or premature ventricular contractions. Cardiac events occurred in 51 patients (8.6%) in the no-calcium-antagonist group and 54 (10.4%) in the calcium-antagonist group (odds ratio, 1.24; 95% CI, 0.83 to 1.85), demonstrating that the calcium antagonists did not reduce the incidence of cardiac events. Subgroup analysis revealed no beneficial effects of these drugs for reducing cardiac events in patients with such complications as hypertension or angina pectoris., Conclusions: This study showed that use of short-acting nifedipine and diltiazem in this postmyocardial infarction population was associated with a 24% higher cardiac event rate, but this strong adverse trend did not reach statistical significance.

We retrospectively analyzed the effect of beta-blocking agents on the incidence of cardiac events in elderly patients who had had myocardial infarction. A total of 1169 patients who had had a myocardial infarction (age, 60.2 +/- 11.4 years) were followed for a mean of 18.0 +/- 19.7 months and the incidence of cardiac events (fatal or nonfatal myocardial infarction, sudden cardiac death, and death due to congestive heart failure) was computed. There were 21 cardiac events in 653 patients who received beta-blocking agents (3.2%) and 39 events in 516 patients who did not receive beta-blocking agents (7.6%, p < 0.01). Among patients less than 50 years old, the incidences of cardiac events were 4.1% in those who received beta-blocking agents and 7.6% in those who did not; among those 50 to 59 years old the incidences were 3.0% and 7.5%, respectively; among those 60 to 69 years old they were 4.3% and 6.0%, respectively; and among those 70 years old or older they were 0.8% and 11.4%, respectively (p < 0.01). We found that beta-blocking agents prevented cardiac events both in elderly and in younger patients after myocardial infarction.

The present study investigated whether the exercise-induced ST-segment elevation can predict the prognosis for patients with myocardial infarction. Among 529 patients with myocardial infarction, 411 underwent treadmill exercise testing about 5 weeks after the onset. All patients were followed up (mean [+/-SD] 54 +/- 41 months) to compare the incidence of cardiac events. One hundred and eighteen patients (22%) could not perform the exercise test due to cardiac or noncardiac limitation. Ineligibility for exercise test was most useful for risk stratification. Multivariate analysis showed that elimination from the stress test with cardiac limitation was the most significant predictor for cardiac death. Excluding the 16 patients with bundle branch block, the 395 patients were classified into four groups of ST-segment elevation (107 cases, 27%), ST-segment elevation combined with depression (22 cases, 6%), ST-segment depression (106 cases, 27%), ST-segment unchanged (160 cases, 40%). Among the various stress test abnormalities, only low exercise duration was a predictor for cardiac death. ST-depression and ST-elevation combined with depression were independent risk predictors for all cardiac events. Most patients with ST-elevation had single-vessel disease with excellent exercise capacity and low incidence of cardiac events. ST-segment elevation during exercise 5 weeks after myocardial infarction is not associated with a poor prognosis.

The efficacy of combining antiplatelet agents with low doses of aspirin to prevent cardiac events in patients with myocardial infarction was examined. A total of 1,083 patients with prior myocardial infarction were randomly divided into those who were (618) and were not (465) treated with antiplatelet agents, and observed for 12.5 +/- 18.5 months. Those treated with antiplatelet agents included 113 patients treated with aspirin (50 mg) plus dipyridamole (150 mg/day), 253 treated with aspirin (50 mg) plus ticlopidine (200 mg/day), and 252 treated with only 1 of the 3 antiplatelet agents. Cardiac events, including fatal or nonfatal recurrent myocardial infarction, death by congestive heart failure, and sudden death, occurred in 34 patients (7.3%) in the nontreatment group and in 19 patients (3.1%; p < 0.01) in the treatment group; odds ratio 0.40, 95% confidence interval 0.23-0.71. There were only 2 cardiac events (1.8%) in the aspirin + dipyridamole group (p < 0.05 vs nontreatment group: odds ratio 0.28: 0.08-1.03), and 5 such events (2.0%) in the aspirin + ticlopidine group (p < 0.01; odds ratio 0.28: 0.11-0.69). Subgroup analysis to exclude differences in the patients' background confirmed the efficacy of these antiplatelet agents. We conclude that combined treatment with low doses of aspirin plus either dipyridamole or ticlopidine is effective in preventing cardiac events in patients who have had prior myocardial infarction.

The prevention of left ventricular aneurysm formation and left ventricular remodeling by percutaneous transluminal coronary angioplasty (PTCA) performed 24 to 48 hours after onset of acute myocardial infarction was investigated. Left ventriculography and coronary angiography were performed in 25 patients within 24 hours of onset of acute myocardial infarction. The patients were divided into two groups; reperfusion group (n = 17) and successful PTCA group (n = 8). The reperfusion group and the PTCA group included patients whose infarct-related coronary arteries were successfully reperfused to 99%, Thrombolysis in Myocardial Infarction (TIMI) grade II or III, immediately after coronary thrombolysis. However, the reperfusion group did not include the patients with spontaneous reperfusion or reperfusion after PTCA. The PTCA group consisted of patients who underwent successful PTCA performed within 24 to 48 hours after onset of infarction (mean 28.4 +/- 6.0 hours). Non-reperfusion in the acute phase was defined as TIMI grade 0-I. The size of the ventricular aneurysm in the PTCA group was significantly reduced compared with the reperfusion group (PTCA group 4.2 +/- 8.7%, reperfusion group 27.2 +/- 6.6%; p < 0.01). The increase of left ventricular end-diastolic volume (delta LVEDVI) from the acute to chronic phases was calculated to estimate left ventricular remodeling. There was a significant difference between the two groups in delta LVEDVI (PTCA group 4 +/- 19 ml/m2, reperfusion group 19 +/- 17 ml/m2; p < 0.05). PTCA performed within 24 to 48 hours after onset in patients with acute myocardial infarction and infarct-related coronary arteries, resulting in reperfusion to 99% TIMI grade II or III immediately after coronary thrombolysis, prevents left ventricular aneurysm formation and remodeling.

There is controversy with regard to the mechanism of the exercise-induced ST-segment elevation in myocardial infarction. The purpose of the present study was to investigate the mechanism of ST-segment elevation through pharmacologic interventions. Transmural anterior myocardial infarction was produced by gelatin sponge embolization of the left anterior descending artery in seven closed-chest dogs. One and four weeks after myocardial infarction, the dogs underwent the following three interventions: right atrial pacing, norepinephrine infusion (3.75, 7.5, and 15 micrograms/min) with the pacing, and methoxamine injection (2.5 and 5.0 mg) with the pacing. All dogs had transmural infarction with a mean infarct size of 12.0 +/- 4.2% of the left ventricular weight. Right atrial pacing did not induce significant changes in ST-segment. Norepinephrine induced a marked elevation of ST-segment at leads V1 to V4, while methoxamine did not. Norepinephrine induced a significant increase in left ventricular ejection fraction, while methoxamine produced a marked decrease in the ejection fraction and an increase in ventricular volume. The mean percent radial shortening of the non-infarct ventricular wall showed a significant increase with norepinephrine, but a decrease with methoxamine. In conclusion, myocardial ischemia and wall motion abnormality may be excluded as possible mechanisms of ST-segment elevation and an enhanced beta-adrenergic mechanism in the non-infarct myocardium is suggested to be responsible for ST-segment elevation.

The mechanism of exercise-induced ST-segment elevation in previous myocardial infarction was investigated using isoproterenol infusion with atrial pacing to simulate exercise hemodynamics in seven closed chest dogs with myocardial infarction. The myocardial infarction was induced by cellulose embolization of the left anterior descending artery. One week after infarction, 1) isoproterenol 0.3 microgram/min infusion, 2) right atrial pacing alone, and 3) isoproterenol infusion after the injection of propranolol 0.5 mg/kg were performed. The heart rate was kept constant by atrial pacing during the examination. Precordial ST-segment deviation, left ventricular global and regional wall motions, lactate extraction ratio, and regional myocardial blood flow were measured. Isoproterenol induced a significant elevation of the ST-segment, i.e., the sum of ST-segment elevation at chest leads V2, V3 and V4, sigma STV234, increased from 0.32 +/- 0.11 (mean +/- SEM) to 0.82 +/- 0.22 mV (p < 0.01). However, pacing alone and isoproterenol with pretreated propranolol did not. During isoproterenol-induced ST-segment elevation, left ventricular ejection fraction increased (29.2 +/- 3.3 to 39.1 +/- 3.9%, p < 0.01), lactate extraction ratio decreased but within the normal range for lactate metabolism (30.2 +/- 7.0 to 16.7 +/- 4.2%, p < 0.01), and the inner/outer ratio of regional blood flow did not change significantly (0.81 +/- 0.18 to 0.97 +/- 0.13 in the non-infarct border area, NS; 0.37 +/- 0.04 to 0.42 +/- 0.07 in the infarct border area, NS). Isoproterenol enhanced ventricular wall motion in the border and non-infarct areas, but did not induce aggravation in the infarct area.(ABSTRACT TRUNCATED AT 250 WORDS)

Increases in regional myocardial blood flow (Qm) developing soon after myocardial infarction may minimize myocardial necrosis. To test this hypothesis, Qm in the area surrounding an acutely occluded coronary artery was determined successively over 4 weeks in 11 dogs. Non-radioactive colored microspheres were injected into the left atrium 5 s (Qm at this time is referred to as Q1), 3 h (Q2), 12 h (Q3), and 4 weeks (Q4) after occlusion of the coronary artery. After termination of the experiment, the heart was removed, and Qm and three indices of myocardial necrosis i.e., myocardial creatine kinase activity (CK), infarct size determined by triphenyl tetrazolium chloride stain (TTC), and myocardial fibrosis visualized by Azan-Mallory stain, were determined. Each Qm was expressed as a percentage of normal: Qm (% of normal) = [Q/Qc] ischemic area/[Q'/Qc']non-ischemic area x 100, where Qc indicates Qm determined before coronary occlusion. In the ischemic area of the left ventricle, Q1, Q2, Q3, and Q4 were 25 +/- 3%, 30 +/- 3%, 31 +/- 3%, and 42 +/- 3% of normal, respectively, in the inner layer, and 31 +/- 3%, 52 +/- 4%, 52 +/- 4%, and 77 +/- 6% of normal, respectively, in the outer layers. During the 4-week period, the increase of Qm in the outer layer was greater than that in the inner layer. The inner layer showed a small increase of flow from Q3 to Q4 (9 +/- 2%), but in the outer layer there were greater flow increases from Q1 to Q2 (21 +/- 3%) and from Q3 to Q4 (24 +/- 6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in hemodynamics and plasma norepinephrine levels during supine bicycle exercise after myocardial infarction were measured to investigate the mechanism of exercise-induced ST-segment elevation. Seventy-eight patients were divided into groups which showed either ST elevation (STE), ST depression (STD), or no ST changes (STU). Most of the STE group had anterior myocardial infarction (90.6%) and single-vessel disease (76.7%). The STE group achieved a significantly higher workload (119.5 +/- 4.0 watts, mean +/- SEM) than the STD group (82.3 +/- 2.8, p < 0.01). Heart rate and cardiac output at maximal workload were significantly higher in the STE group (136.6 +/- 3.4 beats/min, 7.44 +/- 0.28 l/min/m2) than in the STD group (110.0 +/- 3.9, 4.83 +/- 0.36, p < 0.01). Pulmonary artery pressures were less elevated in STE than STD patients. Plasma norepinephrine levels increased significantly at maximal workload in STE patients, as compared to the other groups. In conclusion, the STE group achieved a higher exercise level associated with augmented sympathetic activity, which may be a possible mechanism of exercise-induced ST elevation after myocardial infarction.

The sum of ST-segment elevation (sigma ST on V2-4) was measured to evaluate ST-segment re-elevation during early convalescence in 57 patients with acute myocardial infarction. Following rapid ST-segment elevation resolution during the first 12 h, sigma ST again increased in many patients without signs of reinfarction or pericarditis, reaching a maximum approximately 5 days after onset. The magnitude of this re-elevation (delta sigma ST) was less than 0.3 mV in 30 patients (group A), and 0.3 mV or more in another 27 (group B). Based upon left ventriculography, the global ejection fraction in group B decreased significantly from 51 +/- 10% at the acute phase to 46 +/- 10% at the chronic phase. No such decreases were seen for group A. Regional ejection fraction in the infarcted portion improved significantly from 28 +/- 13% at the acute phase to 35 +/- 14% at the chronic phase in group A, but did not improve in group B. In addition, the non-infarcted portion in group B showed a significantly reduced regional ejection fraction. These results suggest that myocardial expansion of the infarcted portion may contribute to ST-segment re-elevation, an ominous sign of left ventricular dysfunction soon after acute myocardial infarction.

Assessments of the significance of precordial ST segment depression in acute inferior myocardial infarction (AIMI) have yielded conflicting results. Among 92 AIMI patients admitted within 6 hrs after the onset, 65 showed ST depression, and the remaining 27 showed no ST depression. These depressions were present in all of V1-4 (right type; 17), V2-5 (middle type; 10), V3-6 (left type; 13) and V1-6 (broad type; 25). The clinical severity was Forrester subset I in the majority (89%) of patients without ST change, while complications were prevalent in patients with ST depression, especially in the right type (44% were Forrester subset II-IV). Peak CK was 2,150 +/- 399 U/L in patients without ST depression, but it was elevated to 3,172 +/- 811 in patients with ST depression, especially in the right type (4,506 +/- 499). Wall motion evaluated by echocardiography and QRS scores on ECG also revealed greater abnormality in patients with ST change. The initial right coronary angiogram on admission revealed complete occlusion in 76% of these patients with ST depression of whom all of the right type had completely occluded artery. Abnormal motion of the anterior wall, which suggests remote ischemia associated with AIMI was proved neither by left ventriculography nor echocardiography. Hospital mortality in patients with ST depression (9.2%) was as twice as high as that in those without ST depression (4.6%). We concluded that ST depression in patients with acute inferior infarction may not be indicative of remote ischemia but manifests as a mirror image of a large infarction with a complicated clinical course.

The effectiveness of coronary thrombolysis with urokinase (UK) on short- and long-term outcome after acute myocardial infarction was studied by comparison of 120 patients treated with UK and 124 with conventional therapy followed up for a period of 20 months. UK was administered to patients within 6 hours of the onset of chest pain, by the intracoronary route (20,000 U/min, at a mean dose of 698,000 U) in 46 patients, intravenously (960,000 to 1,920,000 U in 15 or 30 min, at a mean dose of 1,293,000 U) in 56 patients and by the combined route (at a mean dose of 2,333,000 U) in 18 patients. Complete occlusion or 99% stenosis with severe delay of the contrast medium was found in 72.5% and recanalization by UK was achieved in 68.0%. Cumulative mortality rate was significantly reduced in the UK group (9.2% vs. 29.0%). Cardiac death from recurrent MI was also significantly reduced (2.5% vs. 10.5%). The reduction in mortality rate was demonstrated even in older patients as well as in those cases graded as severe according to the Killip and Forrester classifications. Thus, it is concluded that coronary thrombolysis with UK therapy improves the prognosis of acute myocardial infarction.

Left ventriculograms were performed on 65 patients with acute myocardial infarction, once upon admission and again 3 months later. In 29 cases urokinase was injected intravenously and/or intracoronarily. The other 17 were treated without urokinase. In 8 out of 29 patients whose infarct-related coronary arteries remained completely occluded following urokinase therapy, the global ejection fraction was reduced from 54 +/- 3% during the acute stage to 46 +/- 5% during the chronic stage (p less than 0.001). However, for the 21 patients whose coronary arteries were successfully recanalized, the 2 values were the same (52 +/- 2%). The highest global ejection fractions were seen in 19 spontaneously recanalized patients (acute: 54 +/- 2%, chronic: 55 +/- 2%). For the 8 unsuccessful patients, the regional ejection fraction for the infarcted portion was reduced from 20 +/- 5% during the acute stage to 18 +/- 6% during the chronic stage. But for the successful patients there was an improvement from 22 +/- 2% during the acute stage to 27 +/- 2% during the chronic stage. Again, the regional ejection fraction was the highest for the spontaneously recanalized group, being 31 +/- 2% and 36 +/- 3% during the acute and chronic stages, respectively. These results indicate that if the coronary artery remains occluded during the acute stage the reduced left ventricular function continues to deteriorate even more during the chronic stage. Successful coronary thrombolysis, however, might salvage the infarcted myocardium as well as preserve the function of the left ventricle.

The ability of hyperosmolar mannitol to salvage evolving myocardial infarction was studied in 50 open-chest dogs subjected to 3 hours occlusion of the left anterior descending coronary artery. In 28 dogs, 20% hyperosmolar mannitol was infused into the distal half of the infarcted portion after commencement of reperfusion, leaving the proximal half mannitol free. In the other 22 dogs, physiological saline was infused instead of mannitol. The wall thickness at the distal half of the infarcted portion was increased 2 hours after reperfusion in both the saline and the mannitol groups. After 2 hours reperfusion the chest was closed. Thirteen out of 28 dogs in the mannitol group and 12 out of 22 dogs in the saline group died over one week. Seven days later, myocardial samples were measured for myocardial water content and creatine phosphokinase activity (CPK). Myocardial water content was increased in the infarcted portion in both the saline and the mannitol groups. In the saline group, myocardial CPK was reduced markedly in the proximal half (54.8 +/- 7.8% at the inner layer and 53.1 +/- 4.7% at the outer layer). These depletions were even more marked in the distal half (47.9 +/- 5.8 and 48.3 +/- 3.3%). In the mannitol groups, although the CPK was similarly depressed in the proximal half (44.8 +/- 5.8 and 41.1 +/- 5.4%), the CPK depletion in the distal half was less (48.1 +/- 6.1 and 58.1 +/- 6.7%) than the proximal half, suggesting mannitol preserved CPK depletion in the infarcted portion. It was concluded that intracoronary infusion of mannitol after reperfusion may salvage the infarcted myocardium.

In order to investigate relaxation characteristics of the infarcted wall, segment lengths of the left ventricular wall were calculated in 6 patients with anterior myocardial infarction and in 9 angiographically normal subjects. The biplane left coronary cineangiography was performed and coordinates of ramifying points of the left coronary artery on the infarcted or non-infarcted wall were measured and the spatial lengths (segment lengths) on each wall were calculated. If the two points are on the left anterior descending artery (LAD) in infarcted patients, a calculated length is regarded as a segment length in the infarcted portion, while if the length is calculated between the two points located on the coronary artery other than LAD, it is a non-infarcted segment. Each segment length was calculated in frame by frame covering one cardiac cycle. The maximum length (Lmax), minimum length (Lmin) and the length at the beginning of P wave of the electrocardiogram (LECG P) were calculated. The extent of relaxation of the segment caused by atrial kick was calculated as (Lmax--LECG P)/Lmax X 100, (% delta Lla). This value was 2.8 +/- 1.5 and 3.5 +/- 1.4% on anterior and inferior walls, respectively, in 9 normal subjects and 3.6 +/- 1.2 and 4.0 +/- 0.9% in 6 patients with anterior infarction, revealing no significant difference among 4 values. This indicates that the amount of lengthening of the segment by atrial kick remains unchanged even if the wall is infarcted. The extent of diastolic lengthening of the segment by rapid and slow fillings, which excludes atrial filling, was calculated as (LECG P--Lmin)/Lmax X 100, (% delta L1-la).(ABSTRACT TRUNCATED AT 250 WORDS)

To study relaxation characteristics of the infarcted myocardium, cyclic changes in the global left ventricular (LV) volume were measured in 20 patients with old myocardial infarction (OMI) and 17 normals (Normal) and those in the regional segment length were measured in 9 patients with anterior old myocardial infarction (anterior OMI) and 11 normals. The LV volume was calculated by using biplane LV cineangiograms. The regional segment length was calculated by measuring the spatial length between the 2 points of the ramifying branches on the left coronary arteries by using biplane coronary cineangiograms. The LV filling volume before atrial contraction (VR) was significantly less in the OMI compared with that in the normals (Normal 38 +/- 6 (mean +/- SD) ml/m2 vs 30 +/- 7 ml/m2: p less than 0.01), while filling volume by atrial contraction (Va) did not significantly differ (Normal 15 +/- 4 ml/m2 vs OMI 17 +/- 5 ml/m2). The lengthening of the segmental wall during diastole before atrial contraction (%LR) in the infarcted portion was 5.0 +/- 2.9% which was also significantly less than that in the non-infarcted portion (9.6 +/- 4.2%). The extent of lengthening by atrial contraction (%La) did not differ between the 2 portions (non-infarcted portion 3.8 +/- 1.1% vs infarcted portion 3.5 +/- 1.2%). Reduction of %LR was speculated to be caused by the incomplete relaxation in the myocardium adjacent to the infarcted portion and stiff myocardium in the infarcted portion. This study suggests that the infarcted myocardium may lead to a reduction of diastolic expansion before atrial contraction.