Effect of nitroprusside on local contractile performance after coronary ligation and reperfusion.

To study the effects of nitroprusside infusion on the regional contractile performance of the left ventricle after coronary occlusion, local tension and segment length of the ischemic, border and nonischemic zones were studied using Walton-Brodie strain gauge arches and mercury-in-Silastic tubing segment length gauges in open chest dogs. The effect of this intervention on the time period for functional reversibility of the affected areas after revascularization was also examined. Fifteen minutes after occlusion of the left anterior descending coronary artery, nitroprusside (4 to 11 mug/kg per min) was infused to keep systolic pressure 20 to 25% below control levels for 2 hours after occlusion and then 1 hour after reperfusion. The ischemic zone showed no change in either tension or length although there was a gradual continuing decrease in tension. However, in the border zone total tension which had decreased to 81.4 +/- 9.6 (standard error of the mean) percent of control level 15 minutes after coronary occlusion, increased to 87.5 +/- 11.3% immediately after nitroprusside infusion and continued at that level for 2 hours. Preejection tension rate of tension rise and ejection tension demonstrated parallel increases. Segment length, which had increased to 144.1 +/- 4.5% of control level after coronary occlusion, declined to 115 +/- 10.7% (P less than 0.02) immediately after the onset of infusion. The nonischemic zone showed a sustained increase in all tension variables (P less than 0.01) and a decrease in segment length during the period of nitroprusside infusion with a return to control value after discontinuation of the infusion. The immediate deterioration in tension in the ischemic zone caused by reperfusion after 2 hours of occlusion was prevented by nitroprusside. The border zone continued to maintain improved tension after reperfusion but exhibited an immediate decrease from 84.1 +/- 7.8% to 69.1 +/- 11.7% (P less than 0.05) after discontinuation of nitroprusside. In summary, nitroprusside infusion provides a sustained increase in tension and decrease in length of the border and the nonischemic zones after acute coronary occlusion whereas the ischemic zone remains unaffected. Although administration of nitroprusside fails to prolong the time period for functional reversibility of the affected zones with reperfusion, it appears to prevent further deterioration.     

Temporal sequence of dynamic contractile characteristics in ischemic and nonischemic myocardium after acute coronary ligation

The contractile characteristics of ischemic, border and nonischemic myocardium were studied In vivo for 4 hours with coronary ligation in 15 dogs utilizing Walton-Brodle strain gauge arches and “mercury in Silastic tubing” segment length gauges. In the ischemic zone, preejection tension fell precipitously by 17.3 ± 3.0 percent (mean ±1 standard error of the mean) (P < 0.02) within 15 seconds and 30.4 ± 5.1 percent (P < 0.001) within 1 minute. A gradual further decrease by 66.0 ± 6.3 percent of control values was seen after 4 hours. The rate of rise of tension ($\text{dT}\text{dt}$) showed similar changes. Tension during ejection also decreased abruptly and dramatically within the first 3 to 12 seconds after occlusion and exhibited a characteristic negative slope indicating aneurysmal bulging. A decrease from +10 ± 1.3 to ?4.3 ± 0.8 occurred In 15 seconds, although subsequently the negative slope diminished.Segment length similarly exhibited a continuous Increase in preejection lengthening over 10 to 30 minutes and segment shortening during ejection was replaced by segment lengthening during aneurysmal bulging. Phasic segment length showed increases of 22 percent in the first 15 seconds, 44 percent in 1 minute and 138 percent in 15 minutes, then a gradual decline for 4 hours. The border and nonischemic zones showed minimal and inconsistent changes.Therefore, the Ischemic myocardium is still able to generate tension, although at a progressively reduced level after coronary occlusion. Aneurysmal bulging takes place only during ejection. It becomes apparent 3 to 12 seconds after occlusion, Is maximal at 15 minutes and then decreases, probably as a result of reduced compliance. The data sugggest that the Ischemic zone is operating on a depressed lengthtension curve, but no significant changes are evident in the nonischemic and border zones of the left ventricle.     

Progressive transmural electrographic,myocardial potassium ion/sodium ion ratio and ultrastructural changes as a function of time after acute coronary occlusion

The progressive transmural electrographic, biochemical and ultrastructural changes as a function of time after acute coronary occlusion were systematically assessed in eight dogs. Transmural plunge electrodes with poles 1 mm apart were placed in the ischemic and nonischemic zones, and coronary occlusion was maintained for 4 hours. Transmural full thickness biopsy specimens were obtained from each zone for electron microscopy before, and 1 and 4 hours after occlusion. Endocardial and epicardial layers were also obtained for assessment of myocardial potassium ion (K⁺) and sodium ion (Na⁺) concentrations. Before coronary occlusion, local Q waves were recorded an average depth of 1.0 ± 0.34 mm from the endocardial surface. After 1 hour of occlusion, Q waves appeared at an average depth of 3.8 ± 0.67 mm and progressed to a depth of 5.2 ± 0.7 mm at 2 hours, 6.2 ± 0.5 mm at 3 hours and 7.0 ± 0.5 mm at 4 hours. After 1 hour, ultrastructural changes of early ischemia, including a decrease in glycogen and mild mitochondrial swelling, were seen in the endocardial layer; the epicardial layer showed normal morphologic features. After 4 hours, the endocardial layer showed well developed ischemic changes marked by the loss of mitochondrial cristae, vacuolization, the appearance of amorphous mitochondrial densities, an increase in interfibrillary space and the appearance of I bands. In contrast, the epicardial layer at this time showed only early ischemic changes. At the end of 4 hours, the endocardial layer showed a marked decrease in myocardial K⁺ concentration and an increase in Na⁺ concentration leading to complete reversal of the $\text{K}{}^{\mathrm{+}}\text{Na}{}^{\mathrm{+}}$ ratio (0.7 ± 1.0; P < 0.001). In the epicardial layer, a smaller decrease in K⁺ concentration and an increase in Na⁺ concentration occurred, resulting in a diminution but not a reversal of the $\text{K}{}^{\mathrm{+}}\text{Na}{}^{\mathrm{+}}$ ratio (1.4 ± 0.2; P < 0.005).Thus, the dynamic evolution of an acute myocardal infarction involves a sequential progression from endocardium to epicardium as a function of time, resulting in an epicardial “border zone” in the early stages after acute coronary occlusion.     

Beneficial effects of propranolol and digitalis on contraction and S-T segment elevation after acute coronary occlusion

Propranolol and digitalis each have limltations in acute myocardial infarction, the former because of negative inotropic effects and the latter because of increased ischemia. To evaluate their combined effects, ouabain (in a priming dose of 7.5 μg/kg body weight followed by 2 to 3 μg/kg per min intravenous infusion) and propranolol (1 mg/kg intravenously) were administered randomly in 22 open chest dogs after acute coronary occlusion, and changes were observed in epicardial S-T segment (10 to 14 sites) and local tension (strain gauge measurements). Heart rate was controlled by atrial pacing. After acute coronary occlusion, tension in the nonischemic zone decreased to 92.8 ± 3.4 percent of control level. Propranolol reduced It further to 67.3 ± 4.9 percent (P < 0.005), but ouabain increased it to 92.9 ± 4.9 percent (P < 0.005). Tension in the border zone decreased to 84.9 ± 4.11 percent (P < 0.005) after acute occlusion and to 54.5 ± 5.5 percent (P < 0.001) with propranolol but increased to 73.6 ± 5.1 percent (P < 0.005) with ouabain. Tension in the ischemic zone decreased from 59.3 ± 5.5 percent to 45.8 ± 5.0 percent (P < 0.001) with propranolol but was unaffected by ouabain. The sum of S-T elevation, which increased from 27.8 ± 5.3 to 72.1 ± 10.8 mv after occlusion, decreased to 62.8 ± 11.8 mv (P < 0.05) with propranolol and further to 53.0 ± 10.4 mv (P < 0.005) with ouabain. The pattern of changes in average S-T elevation was similar. When propranolol administration followed ouabain infusion, essentially similar effects on tension and the sum of S-T and average S-T elevation were observed. In summary, the combination of propranolol and digitalls favorably affects both tension and S-T segment abnormalities after acute coronary occlusion.     

Digitalis in experimental acute myocardial infarction: Differential effects on contractile performance of ischemic, border and nonischemic ventricular zones in the dog

The effects of digoxin (priming dose of 0.04 mg/kg body weight followed by infusion of 0.02 mg/kg per min) on local tension and length characteristics of the nonischemic, border and ischemic left ventricular zones were studied in 30 dogs using Walton-Brodie strain gauge arches and mercury-in-Silastic segment length gauges. Total tension in the nonischemic zone increased to 130.9 ± 5.3 percent (P < 0.001) of the control level in association with parallel changes in preejection and ejection tension and rate of rise of tension when infusion of digoxin was instituted 15 to 30 minutes after ligation. Consistent increases in tension variables were noticed when infusion of digitalis was initiated 45 to 60 minutes or 2 to 3 hours after ligation. Segment length remained unchanged. In the border zone, total tension decreased to 68.9 ± 5.9 percent (P < 0.01) 15 to 30 minutes after coronary occlusion and increased to 106.8 ± 9.7 percent (P < 0.01) after infusion of digitalis. When infusion of digitalis was instituted 45 to 60 minutes or 2 to 3 hours after occlusion, similar increases in total tension and other tension variables were seen. Segment length again showed no significant changes. There was an increase in total tension in 5 of the 12 ischemic zones studied when digitalis was infused 15 to 30 minutes after coronary arterial ligation, whereas a consistent (3 to 5 percent) decrease in tension was observed when infusion of digitalis was instituted 45 to 60 minutes and 2 to 3 hours after coronary occlusion. There was no increase in segment length. In summary, digitalis uniformly increased contraction of the nonischemic and border zones after coronary arterial ligation, but the effects on contraction and aneurysmal bulging in the ischemic zone were minimal.     

Limitations of myocardial revascularization in restoration of regional contraction abnormalities produced by coronary occlusion

The effect of reperfusion instituted from 30 minutes to 3 hours after coronary occlusion on the contractile characteristics of the ischemic zone, border zone and nonischemic myocardium was studied in 29 dogs using Walton-Brodle strain gauge arches and mercury-in-Silastic^® tubing segment length gauges. After 30 and 45 minutes of coronary occlusion, reperfusion resulted in an immediate reversal of abnormalities in segment length and tension of the ischemic zone to near normal. Preejection tension Increased from 32.3 ± 5.1 to 95.2 ± 4.7 percent of control level, ejection tension from zero to 71.7 ± 7.0 percent, total tension from 27.5 ± 2.5 to 87.1 ± 6.2 percent and $\text{dT}\text{dt}$ from 42.1 ± 4.1 to 100.0 ± 4.5 percent. Phasic segment length decreased from 150.2 ± 5.1 percent to 100.0 ± 5.0 percent of control value. Aneurysmal bulging disappeared completely. However, after 1 hour of coronary occlusion, reperfusion resulted In a significant (P < 0.01) further decrease in all contraction variables In the ischemic zone. Preejection tension decreased from 58.7 ± 7.9 to 31.2 ± 5.5 percent, ejection tension decreased initially but recovered to prereperfusion levels, total tension decreased from 48.5 ± 5.9 to 24.0 ± 4.0 percent and $\text{dT}\text{dt}$ declined from 60.7 ± 7.2 to 30.9 ± 5.7 percent of control levels. Phasic segment length gradually decreased from 162.5 ± 6.0 to 137.5 ± 12.5 percent of control value. The border zone exhibited similar decreases in function In four studies, and improved in two. After 2 and 3 hours of coronary occlusion, reperfusion was uniformly followed by further decreases In function of both ischemic and border zones.In conclusion, contraction abnormalities produced by 45 minutes of coronary occlusion are reversible with reperfusion. However, when reperfusion is instituted after 1 hour of occlusion, the abnormalities are often accentuated and this becomes invariable after 2 hours of occlusion. Thus, the myocardial impairment appears to be functionally irreversible after this time period.     

Pathophysiologic significance of S-T and T wave abnormalities in patients with the intermediate coronary syndrome.

The frequent association of new ST-T wave changes without Q waves in the surface electrocardiogram of patients with the intermediate coronary syndrome necessitates a better understanding of the pathophysiologic significance of this finding. A previous study in patients with stable coronary artery disease indicated that the surface electrocardiogram is insensitive in detecting epicardial Q waves. This relation was evaluated in 21 patients with the intermediate syndrome, characterized by recurrent chest pain at rest associated with significant new S-T or T wave abnormalities, or both, and no new Q waves in the surface electrocardiogram at the time of open heart coronary bypass surgery. Unipolar electrograms were recorded from the epicardial surface of the left ventricle before the bypass procedure. In 19 patients, epicardial electrograms revealed initial R waves over areas of the left ventricle in which the acute S-T and T wave abnormalities were evident in the surface electrocardiogram. Two patients had epicardial Q waves (one laterally and one inferiorly). In seven patients, a transmural biopsy specimen was also obtained from the ischemic area. All showed histologically normal myocardium without evidence of early inflammatory or necrotic tissue. Of the 19 patients discharged, only one demonstrated new postoperative Q waves that had been detected by epicardial recordings before bypass. In summary, patients with the intermediate syndrome exhibiting S-T or T wave abnormalities, or both without new Q waves in the surface electrocardiogram generally do not have Q waves either in the intraoperative epicardial or postoperative surface electrocardiogram. In addition, no histopathologic abnormalities are apparent in biopsy specimens taken from the ischemic area.     

Differential effects of Renografin-76 on the ischemic and nonischemic myocardium

The effects of intracoronary diatrizoate meglumine and diatrizoate sodium (Renografin-76) on regional contraction were examined in the normal coronary circulation and during partial (50 percent) coronary occlusion in 11 dogs using strain and length gauges. Intracoronary injections of Renografin-76 (1.5 cc) (1,690 mosM/liter; 0.19 mEq Na/ml), equiosmolar dextrose solution and 0.19 mEq Na⁺/ml saline solution were made randomly. Renografin-76 caused a decrease in preejection tension to 87.4 ± 4.3 percent (p < 0.025), total tension to 74.6 ± 3.3 percent (p < 0.01) and ejection tension to 11.9 ± 12.6 percent (p < 0.001) of control value. Segment length increased to 106.7 ± 7.3 percent of control value. These changes lasted only 12 ± 2 (range 5 to 20) seconds (mean ± standard error of the mean). During partial coronary occlusion and after injection of Renografin-76, preejection tension decreased from 91.7 ± 6.3 to 53.8 ± 3.9 percent (p < 0.01), total tension from 89.9 ± 5.0 to 59.7 ± 3.5 percent (p < 0.01) and ejection tension from 22.8 ± 8.1 to 17.8 ± 10.9 percent, whereas segment length increased from 112.7 ± 3.7 to 130.7 ± 4.6 percent (p < 0.01) of control value. In contrast to findings in the normal coronary circulation, tension and length changes lasted 54 ± 16 (range 15 to 180) seconds (p < 0.05). The hyperemic response during normal coronary circulation was completely abolished during partial coronary occlusion. Prior administration of nitroglycerin did not shorten the duration of the myocardial depressant effects of Renografin. Injections of equiosmolar dextrose or saline solution produced qualitatively similar but quantitatively less marked changes. Thus, intracoronary Renografin-76 has an accentuated and prolonged depressant effect on the ischemic as compared with the normally perfused myocardium; this effect is not solely due to its hyperosmolarity or sodium concentration.     

Quantitative radionuclide angiography in the right anterior oblique view: Comparison with contrast ventriculography

Because the right anterior oblique view is widely accepted as the best “single” projection for assessing wall motion, the utility of this view during first pass radionuclide angiography was studied in 44 patients who also underwent contrast ventriculography and coronary arteriography. Of the 44 patients, 8 had a normal heart and 14 had coronary artery disease with normal wall motion on contrast ventriculography. All also had normal contraction on radionuclide angiography. On contrast ventriculography, 22 patients had coronary artery disease and asynergy involving 34 left ventricular segments. Of 17 segments localized to the anterior and apical asynergic areas on contrast ventriculography, 16 were accurately localized with radionuclide angiography. Similarly, of 17 inferior asynergic areas, 13 were also shown to be inferior on radionuclide angiography. In addition, quantitative assessment of the severity of asynergy using the hemiaxis method demonstrated a good correlation between asynergic severity as defined with radionuclide angiography and contrast ventriculography. Of 11 anterior areas, 7 defined as hypokinetic with contrast ventriculography demonstrated chordal shortening of 20.1 ± 5.2 percent (mean ± standard error of the mean) (P < 0.005 compared with normal) on radionuclide angiography. Similarly, four akinetic or dyskinetic segments on contrast ventriculography demonstrated a greater reduction (4.0 ± 4.0 percent) in chordal shortening on radionuclide angiography (P < 0.05 compared with hypokinetic segments). Akinetic apical and inferior segments as defined with contrast ventriculography also showed a marked reduction in wall motion to 10.4 ± 7.3 percent and 7.5 ± 4.1 percent, respectively.After appropriate background subtraction, determination of ejection fraction using radionuclide angiography showed a correlation of 0.839 between the left anterior oblique and right anterior oblique projections independent of the sequence of injection. In addition, ejection fraction determined with radionuclide angiography in the left (r = 0.824) and right (r = 0.801) anterior oblique views correlated well with ejection fraction assessed from contrast ventriculography. Thus, first pass radionuclide angiography performed in the right anterior oblique view is a sensitive noninvasive means of assessing the location and severity of asynergy as well as global left ventricular performance in patients with coronary artery disease.     

Q waves and ventricular asynergy: Predictive value and hemodynamic significance of anatomic localization

Two hundred sixteen consecutive patients were evaluated to determine the value of pathologic Q waves in predicting the presence and severity of ventricular asynergy. Of 64 patients with pathologic Q waves, 95 percent demonstrated asynergy. Q waves in the anterior leads denoted asynergy in 30 of 30 patients, anterior asynergy in 29 of 30 and an anterior aneurysm in 25. Q waves in the inferior leads indicated asynergy in 30 of 33 patients, inferior asynergy in 25 of 30 and an associated aneurysm in 19. Conversely, of 52 patients with an aneurysm, 44 also had pathologic Q waves. If Q waves were present, 72 percent of asynergic zones exhibited akinesis or dyskinesis; however, in the absence of Q waves an aneurysm was present in only 22 percent (P < 0.001). Hemodynamically, anterior asynergy, whether defined by Q waves or by ventriculography, was associated with more left ventricular dysfunction than was inferior asynergy (P < 0.01). Of 21 patients with a cardiomyopathy, none had pathologic Q waves.The data indicate that pathologic Q waves can aid significantly in predicting the presence and location of a severely asynergic zone. Although their absence does not exclude the possibility of asynergy, the latter is much less likely and, if present, may be of milder form.     

Local characteristics of the normal and asynergic left ventricle in man

The significance of ventricular asynergy in determining medical prognosis and surgical risk in patients with coronary artery disease and its delineation by ventriculography have been of increasing interest. To determine the underlying histopathologic and electrographic features of left ventricular asynergy, 39 patients undergoing open heart surgery were studied. Thirty-six histopathologic specimens were obtained in 31 patients (26 as transmural needle biopsies and 10 as aneurysm resections). In four normally contracting areas and 12 hypokinetic areas, neither fibrosis nor early changes of myocardial damage was evident. In contrast, of eight akinetic areas there was more than 50 per cent muscle loss in four and from 30 to 35 per cent muscle loss in three, in only one area was there less than 10 per cent muscle loss. Of 12 dyskinetic zones there was more than 75 per cent muscle loss in 10 zones, 35 per cent in one and no pathologic abnormalities in one.Epicardial electrograms were obtained from 35 areas in 29 patients. Of 10 normally contracting ventricles, in one, pathologic Q waves were demonstrated only over the inferior area. Progressive increases in the severity of asynergy were associated with a progressive increase in frequency of initial abnormal Q waves. In only one of nine hypokinetic areas were epicardial Q waves exhibited, but they were present in six of 10 akinetic and five of six dyskinetic areas.Both histopathologic and electrographic data were available from 20 asynergic areas in 16 patients. Initial epicardial R waves were associated with normal biopsy specimens in seven of eight hypokinetic areas. Of seven akinetic areas, initial R waves were associated with 30 to 35 per cent muscle loss in three; of four areas with initial Q waves, there was a 35 per cent muscle loss in one and more than 50 per cent muscle loss in three. Similarly, of five dyskinetic segments, a QS pattern was associated with more than 75 per cent fibrosis in four. In one dyskinetic area there was an initial R wave in association with a normal appearing biopsy specimen.In summary, a good correlation exists between the severity of asynergy by ventriculography, the degree of muscle loss and the presence of epicardial Q waves. However, a significant amount of histologically and electrographically normal myocardium may be present even in severely asynergic areas.