Moriharu Ishida

Ischemic preconditioning preserves creatine phosphate and intracellular pH.

BackgroundIschemic preconditioning slows ATP depletion and ultrastructural damage during the final episode of ischemia. To define the influence of creatine phosphate (CP) and intracellular pH (pHi) on this effect, CP and pHi were serially measured in porcine hearts without collateral circulation by using 31P-NMR spectroscopy and ultrastructural examination. Methods and ResultsFarm pigs weighing 12–15 kg were anesthetized with Fluothane. The control group underwent a single occlusion (20 minutes or 60 minutes); the preconditioned group underwent four episodes of 5-minute occlusion and 5-minute reperfusion followed by a sustained occlusion (20 minutes or 60 minutes). After ischemic preconditioning, CP increased to 115 ± 11% (p < 0.05) of preischemic value and ATP decreased to 84 ± 8% (p < 0.05) of preischemic value, but pH; returned to preischemic value. At 5 and 10 minutes of sustained ischemia, CP was significantly preserved in the preconditioned group (control group, 19 ± 3% versus preconditioned group, 29 ± 4% at 5 minutes; control group, 5 ± 3% versus preconditioned group, 11 ± 3% at 10 minutes; p < 0.05). At 15 and 20 minutes of sustained ischemia, ATP was significantly preserved in the preconditioned group (control group, 64 ± 3% versus preconditioned group, 73 ± 3% at 15 minutes; control group, 51 ± 7% versus preconditioned group, 62 2% at 20 minutes; p < 0.05). At 10, 15, 20, and 25 minutes of sustained ischemia, pH; was significantly higher in the preconditioned group (control group, 6.5 0.05 versus preconditioned group, 6.7 ± 0.1 at 10 minutes; control group, 6.3 0.05 versus preconditioned group, 6.6 0.06 at 15 minutes; control group, 6.1 ± 0.1 versus preconditioned group, 6.4 % 0.1 at 20 minutes; control group, 6.0 0.2 versus preconditioned group, 6.3 ± 0.1 at 25 minutes; p < 0.05). Ultrastructural changes were milder in the preconditioned group at 20 minutes of sustained ischemia. ConclusionsIn addition to ATP and ultrastructure, preconditioning preserved CP and pHi during sustained ischemia. These protective effects might be due to overshoot phenomenon of CP and/or reduced ATP consumption. The relatively longer period of preservation of pH;, which probably is the result of reduced ATP consumption, indicates its greater contribution to reducing infarct size than that of CP and ATP.

Importance of coronary collaterals for restoration of left ventricular function after intracoronary thrombolysis

In an evaluation of the role of coronary collaterals in the early period of acute myocardial infarction (AMI), 30 patients with acute total coronary occlusion treated with intracoronary thrombolysis 2 to 8 hours after the onset of symptoms were studied. Only 13 patients with well-developed collaterals in the early period of AMI and successful thrombolysis showed improvement of global and regional ejection fraction (EF) from the acute phase to the chronic phase (global EF from 50% to 71%, p less than 0.001; regional EF from 25.4% to 49.2%, p less than 0.001). In patients with no or less well-developed collaterals and successful thrombolysis, global and regional EF were similar to those in patients in whom thrombolysis was unsuccessful. Among the 19 patients with successful thrombolysis, there was no significant correlation between the duration of ischemia and the improvement of regional EF (r = -0.03, difference not significant). These data suggest that the extent of coronary collateral vessels in the early period of AMI is an important determinant of restoration of left ventricular function after intracoronary thrombolysis.

Expression and distribution of atrial natriuretic peptide in human hypertrophic ventricle of hypertensive hearts and hearts with hypertrophic cardiomyopathy.

To investigate the ventricular expression of atrial natriuretic peptide (ANP) in human hypertrophic hearts, we conducted an immunohistochemical study of 130 endomyocardial biopsy specimens obtained from the right side of the ventricular septum (RVB), left ventricular free wall (LVB), or both from a total of 80 patients: 44 patients with hypertrophic cardiomyopathy (HCM), 14 with apical hypertrophic cardiomyopathy (APH), 13 with hypertensive hearts (HHD), and nine without hypertrophy (controls). No patients had apparent congestive heart failure. ANP was not seen in ventricular myocytes in controls but was identified in biopsy specimens of hypertrophic hearts, and its distribution was characteristic in each hypertrophic group: 15 RVB (37%) and two LVB (7%) of the HCM group, one RVB (7%) and two LVB (18%) of the APH group, and zero RVB (0%/) and five LVB (46%) of the HHD group. Clinical data (including echocardiographic, hemodynamic, and angiographic data) were not directly related to ventricular ANP expression in HCM, APH, or HHD with one exception. In HHD patients, LVB specimens with ANP showed greater ventricular wall thickness than LVB specimens without ANP. According to histological data, however, the ANP-present RVB specimens of HCM or ANP-present LVB specimens of HHD had greater myocyte size than did the ANP-absent specimens. In addition, in HCM patients, the ANP-present RVB specimens showed more severe fibrosis and myofiber disarray than did the ANP-absent specimens. We conclude that a failing state and hemodynamic overload are not likely to be indispensable for ANP expression in human hypertrophic ventricles and that ventricular ANP expression occurs as a response to disease-specific changes: hemodynamic overload in HHD and histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis in HCM, which may reflect the characteristic distribution of intraventricular ANP.

Effects of percutaneous transluminal coronary angioplasty: Intracoronary thrombolysis with urokinase in acute myocardial infarction

Coronary angiography and percutaneous transluminal coronary angioplasty (PTCA) were performed in 32 patients with evolving acute myocardial infarction. Of the 25 patients with complete occlusion of an infarct-related coronary artery, in 18 (72%) the occluded vessel was successfully opened by an intracoronary infusion of urokinase. With a small dose of urokinase the successful recanalization was achieved in only 25%; with a larger dose it was achieved in 94%. After PTCA, all patients received glucose-insulin-potassium solution for 76 hours. Repeat angiography 42 days later showed a patent coronary artery in 12 (group A) of 18 patients with successful PTCA. In group A, left ventricular ejection fraction increased from 51 +/- 13% to 72 +/- 10% (p less than 0.01) and regional wall shortening from 4.5 +/- 9.5% to 29 +/- 19% (p less than 0.01). In contrast, these variables did not change significantly in patients with unsuccessful PTCA or late reocclusion of an infarct-related vessel (group B). These data suggest that successful PTCA with sustained patency of an infarct-related coronary artery has a beneficial effect on the salvage of the jeopardized myocardium, and glucose-insulin-potassium therapy may enhance the beneficial effect of PTCA.

Ventricular expression of atrial natriuretic polypeptide and its relations with hemodynamics and histology in dilated human hearts. Immunohistochemical study of the endomyocardial biopsy specimens.

To investigate the mechanism of expression of atrial natriuretic polypeptide (ANP) in human ventricles, we conducted an immunohistochemical study of ANP in biventricular endomyocardial biopsy specimens obtained from a total of 49 patients with cardiac dilatation due to dilated cardiomyopathy (21 patients), postmyocarditis (18 patients), or volume overload (five patients) and subjects with no dilatation as controls (five patients). Four-micron thick sections were stained by an indirect immunoperoxidase method using monoclonal antibody to alpha-human ANP as the primary antibody. The frequency of ANP-present myocytes was calculated in each specimen and compared with clinical, echocardiographic, hemodynamic, angiographic, and histologic parameters. ANP-present myocytes were noted in all of the 21 patients with dilated cardiomyopathy, in 11 of the 18 patients with postmyocarditis, in four of the five patients with volume overload, and in zero of the five controls. The mean percentage of ANP-present myocytes was significantly greater in the left-side specimens (35 +/- 37%) than in the right-side ones (2 +/- 4%). The percentage of ANP-present myocytes in the left-side specimens significantly correlated with peak systolic or end-diastolic wall stress (r = 0.67 and 0.58), left ventricular end-systolic or end-diastolic volume index (r = 0.75 and 0.69), or left ventricular end-diastolic pressure (r = 0.42) and inversely correlated with ejection fraction (r = -0.73), systolic left ventricular wall thickness (r = -0.58), or cardiac index (r = -0.30). Expression of ANP was rarely seen in the cases with normal wall stresses, normal ejection fraction, normal volume, or normal myocyte size. However, it was seen frequently even in hearts with normal levels of left ventricular end-diastolic pressure and cardiac index (compensated hearts). The percent of ANP-present myocytes in both sides significantly correlated with size of myocytes (r = 0.48 at right and r = 0.57 at left side) or degree of fibrosis (r = 0.45 at right and r = 0.48 at left side). These results suggest that ANP expression is augmented in the dilated ventricles regardless of the causes of dilatation and that the augmentation is a compensatory mechanism as prevention against decompensation responding to reduced contractility, excess of wall stresses, or both, concomitantly occurring with cardiac dilatation and myocardial hypertrophy.

Acceleration of cell necrosis following reperfusion after ischemia in the pig heart without collateral circulation

A study of whether reperfusion accelerates cell death was performed in 35 pig hearts without collateral circulation. In 15 animals, the distal one-third of the left anterior descending coronary artery was occluded for 1 hour followed by 1-, 3-, or 7-hour reperfusion in 5 animals each. As controls, 5 hearts each were examined after 1, 2, 4 and 8 hours of occlusion of the artery without reperfusion. Heart rate and aortic pressure before and during occlusion and reperfusion did not change in any group. The subepicardial and subendocardial regional blood flow decreased to almost zero in all hearts after occlusion (85 +/- 1 to 2 +/- 2) but recovered during reperfusion (65 +/- 15 ml/100 g/min). Specimens were histologically examined by an enzyme method using nitrotetrazolium blue, an immunohistochemical method using myoglobin antibody, by staining with hematoxylin-eosin and Massons trichrome. In the control hearts, clear demarcation of the infarct area was observed 4 hours after occlusion. However, in the reperfusion group, clear demarcation of the infarct was seen after 1-hour reperfusion, namely, 2 hours after the onset of infarct. Demarcation was seen not only in the tissue with contraction band necrosis, but also in the tissue with coagulation necrosis. Therefore, it is concluded that reperfusion accelerates cell death due to both contraction band necrosis and coagulation necrosis.

Angiographic and Pathologic Evidence of Hemorrhage Into the Myocardium After Coronary Reperfusion

Severe myocardial hemorrhage can occur as a potential adverse effect of reperfusion therapy in evolving myocardial infarction. This report describes a 83-year-old man, who showed angiographic evidence of extravasation of con trast medium from the reperfused right coronary artery into the inferoposterior left ventricular wall. At autopsy, severe hemorrhage was transmurally observed in the inferoposterior wall of the left ventricle. The finding of extravasation is a useful angiographic sign of the production of hemorrhage during coronary re perfusion therapy, and great attention should be focused to the existence of this sign to prevent further hemorrhage.

Cineangiographic and pathological features of the infarct related vessel in successful and unsuccessful thrombolysis.

The postmortem histology and the results of cineangiography after selective intracoronary thrombolysis in vessels that were recanalized and in those that were not were compared in 21 patients who died within seven days (mean 2 days) of selective intracoronary thrombolysis. There was a persistent intraluminal thrombus in the infarct related coronary artery in five of six segments in which recanalisation was unsuccessful and in one of 15 segments in which recanalisation was successful. Rupture and haemorrhage of the atheromatous plaque were seen in most of the infarct related segments, both in those in which recanalisation was achieved and in those in which it was not. Irregular narrowing and filling defects on the coronary cineangiograms were associated with rupture and haemorrhage of the atheromatous plaque. These results suggest that failure of coronary thrombolysis to recanalize the infarct related artery does not indicate that the occlusion was not caused by thrombus.

Response of large and small coronary arteries of pigs to intracoronary injection of acetylcholine: angiographic and histologic analysis

With coronary arteriography we examined the effect of acetylcholine (ACh) on large and small coronary arteries. ACh (12.5 to 200 micrograms) was injected into the right coronary arteries of 10 pigs during left ventricular pacing. The percentage of narrowing of the epicardial major coronary artery was used as an indicator of the constriction of the large coronary arteries, and the time required for the contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery (blood-flow delay) was used as an indicator of the constriction of the same coronary arteries. A small dose of ACh (12.5 to 100 micrograms) induced mild narrowing (14 to 41%) of the epicardial major coronary artery and a marked blood-flow delay of over 7.0 sec (control: less than or equal to 1.8 sec) in all 10 pigs. A large dose of ACh (100 to 200 micrograms) caused over 75% narrowing of the epicardial major coronary artery and a marked blood-flow delay in 4 of the 10 pigs. When the marked blood-flow delay appeared, the perfused right ventricular myocardium became macroscopically anemic (ischemic). The constriction of large and small coronary arteries was not prevented by diphenhydramine (H1 blocker: 100 mg i.v.), but was prevented by pretreatment with atropine (1.0 mg i.v.). The intracoronary injection of histamine (1.5 mg) in 5 pigs constricted the epicardial major coronary artery over 75% in 2 pigs, 50 to 75% in 1 pig, and 25 to 50% in 2 pigs, but there was no evidence of blood-flow delay. Neither methoxamine nor norepinephrine caused any significant coronary artery narrowing. The histology of the large and small coronary arteries was examined quantitatively with an image analyzer. The coronary artery showed no intimal thickening, and the endothelium was intact on light microscopic examination. The % area of the smooth muscle layer (media) to the calculated total vascular area, and the ratio of the calculated medial thickness to the calculated inner radius (h/Ri) were 64 +/- 7% (mean +/- SD) and 0.69 +/- 0.16, respectively, in the small coronary arteries less than 100 microns in external diameter, 47 +/- 9% and 0.39 +/- 0.12 in the small coronary arteries 100 to 2000 microns in external diameter, and 34 +/- 4% and 0.24 +/- 0.03 in the large right coronary arteries over 2000 microns in external diameter; the % area of the media and the h/Ri showed a negative correlation with the size of the coronary arteries.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinicopathological study of myocardial infarction with normal or nearly normal extracardiac coronary arteries. Quantitative analysis of contraction band necrosis, coagulation necrosis, hemorrhage, and infarct size

SummaryIn order to clarify the pathogenesis of acute myocardial infarction (MI) in hearts with normal coronary arteries, infarct size, and the extent of contraction band necrosis (CBN), coagulation necrosis, and hemorrhage were quantitatively examined using an image analyzer in 5 autopsy cases of MI with normal or nearly normal extracardiac coronary arteries. One patient died 40 h after acute MI. A second patient with acute MI due to severe spasm of segment 6, confirmed by cineangiography, died three days later. The third patient had already suffered a subarachnoid hemorrhage, and died 10 h after the onset of acute MI. The fourth patient had aortic stenosis and regurgitation. She developed acute MI due to total occlusion of segment 6, confirmed by cineangiography 4 h after the onset, and died 61 days later. Autopsy revealed old anteroseptal MI with normal coronary arteries and valvular thrombi. The fifth patient had a malignancy, and died one day after the onset of acute MI. Autopsy revealed multiple occlusive thrombi in the small intramural coronary arteries of the left ventricular wall supplied by segment 14, without any stenosis in the feeding vessel. Most infarcts were localized in the territory supplied by 1 or 2 of the 3 epicardial coronary arteries, and coincided with the clinically diagnosed infarct site. The infarct size ranged from 3%–26% of the left ventricular wall, and infarcts were generally localized to the inner third of the wall (67±20%). Histological examination of the four patients with acute MI revealed diffuse CBN (86±14% of the infarcted area) and/or hemorrhage. The findings suggested that MI associated with normal coronary arteries was caused by transient coronary arterial occlusion due to spasm and/or thromboembolism, with the CBN seen in these hearts representing reperfusion injury.