Background The ability of the coronary vascular bed to dilateand thus increase blood flow to the myocardium may be impairedin coronary artery disease, even in regions of myocardium suppliedby an angiographically normal coronary artery. If this kindof vasomotor dysfunction was present or accentuated after acutemyocardial infarction, it might influence the extent of ischemiaand necrosis in areas not directly injured by the infarction.
Methods We studied 13 patients (mean [±SD] age, 62 ±11years) with single-vessel coronary artery disease after theyhad received thrombolytic therapy for myocardial infarction.Using positron-emission tomography (PET) with oxygen-15-labeledwater, we measured regional myocardial blood flow under basalconditions and after the intravenous administration of dipyridamole(0.5 mg per kg of body weight over a period of four minutes)8 ±3 days after infarction in all 13 patients (1-weekstudy) and 6 ±2 months after infarction in 9 of the 13(6-month study). On both occasions we measured blood flow bothin the infarcted region and in a region of myocardium that wasremote from the infarcted region and supplied by a normal artery.
Results At the one-week PET study, the coronary vasodilatorresponse (the ratio of the myocardial blood flow after the administrationof dipyridamole to basal blood flow) was 1.12 ±0.50 inthe infarct-related artery and 1.53 ±0.36 in the remoteregion (P = 0.015). At the six-month study, the coronary vasodilatorresponse was 1.42 ±0.37 in the infarcted region and 2.19±0.69 in the remote region (P = 0.004 for the comparisonwith the infarcted region; P = 0.011 for the comparison withthe remote region at the one-week study). The value in remotemyocardium remained lower than that in similar regions in 10control patients, who had single-vessel coronary artery diseasebut no evidence of myocardial infarction (3.17 ±0.72;P = 0.009).
Conclusions After acute myocardial infarction, there is a severevasodilator abnormality involving not only resistance vesselsin infarcted myocardium, but also those in myocardium perfusedby normal coronary vessels. This dysfunction may affect theextent of myocardial ischemia and necrosis after coronary occlusion.
Several studies have shown that in patients with chronic stableangina due to single-vessel coronary artery disease, the coronaryvasodilator response (defined as the ratio of maximal to basalcoronary blood flow) is reduced not only in the region of myocardiumperfused by the stenosed artery but also in the regions suppliedby angiographically normal coronary arteries1,2,3. These observationssuggest that in patients with stable coronary disease, thereis a diffuse vasodilator abnormality of the coronary resistancevessels4,5.
After acute myocardial infarction, the coronary vasodilatorresponse in the infarcted myocardial region remains severelyimpaired despite successful recanalization of the infarct-relatedartery by thrombolysis6,7,8; this impairment has been attributedto dysfunction of resistance vessels in the infarcted tissue9.The effect of myocardial infarction on the coronary vasodilatorresponse in the myocardial regions perfused by angiographicallynormal arteries that are remote from the site of tissue necrosisis unknown, however.
Our main purpose was to investigate the effect of acute myocardialinfarction on the coronary vasodilator response in regions ofmyocardium remote from the site of infarction. We used dynamicpositron-emission tomography (PET) to measure regional myocardialblood flow in infarcted myocardium and in remote regions perfusedby angiographically normal coronary arteries under basal conditionsand after maximal vasodilation by dipyridamole approximatelyone week and six months after myocardial infarction. The responsesin the patients with myocardial infarction were compared withthose in controls who had stable single-vessel coronary diseaseand no evidence of myocardial infarction.
Methods
Patients
Thirteen consecutive patients, 11 men and 2 women (mean [±SD]age, 62 ±11 years; range, 40 to 77), with single-vesselcoronary disease and otherwise angiographically normal coronaryarteries were studied after myocardial infarction. Patientswith multi-vessel disease and those who had recurrent myocardialischemia at rest, who had acute heart failure, or who requiredinotropic support were excluded from the study. The infarct-relatedartery was the left anterior descending artery in nine patients,a dominant right coronary artery in three, and a dominant leftcircumflex artery in one. All 13 patients received 1.5 millionunits of intravenous streptokinase and 300 mg of aspirin 4.2±2.4 hours (range, 2.0 to 7.8) after the onset of chestpain (Table 1). All patients had abnormal Q waves on 12-leadelectrocardiography within 24 hours of the onset of chest pain(Table 1).
Table 1. Characteristics of the 13 Patients with Myocardial Infarction.
We also studied a control group made up of 10 men (mean age,52 ±9 years; range, 44 to 72) with chronic stable anginadue to single-vessel coronary disease (in the left anteriordescending artery) and normal left ventricular function.
Study Protocol
The protocol was approved by the Research Ethics Committee ofHammersmith Hospital, and all patients gave written informedconsent.
None of the patients had been given either beta-blockers orcalcium-channel antagonists after myocardial infarction. PETwas performed 8 ±3 days (range, 4 to 13) after infarction(1-week study) and cardiac catheterization was performed 27±35 days (range, 7 to 122) after infarction. Nine ofthe 13 patients underwent repeat positron-emission tomography6 ±2 months after infarction (6-month study); of theremainder, 1 died, 2 declined the procedure, and 1 had scanningperformed outside the designated follow-up period of 12 months.Before the six-month examination, any antianginal medication(except sublingual nitroglycerin) was discontinued for at least72 hours. No patient took nitroglycerin within two hours ofany of the protocol examinations, and all abstained from drinkingtea or coffee on the morning of the PET procedures. Treadmillexercise testing was performed according to the modified Bruceprotocol.
The control group was made up of patients undergoing routinecardiac catheterization. Discontinuation of antianginal medicationand abstinence from compounds containing theophylline were required,as for the study patients.
Cardiac Catheterization and Quantitative Coronary Arteriography
Coronary arteriograms were obtained by the Judkins techniqueand analyzed by a computerized, automated edge-contour detectionsystem (Cardiovascular Angiographic Analysis System, Pie MedicalEquipment, Maastricht, the Netherlands)10. The luminal diametersof the coronary artery in the projection showing maximal severityof stenosis and of the adjacent reference segments were measuredat end diastole. Severity of stenosis was also expressed asthe percent reduction in the estimated luminal diameter, interpolatedfrom the diameter at the proximal and distal boundaries of thestenosis. Patency of the infarct-related artery was definedaccording to the Thrombolysis in Myocardial Infarction (TIMI)trial's system for grading recanalization after myocardial infarction11.
The global left ventricular ejection fraction was measured fromthe left ventricular cineangiogram obtained in the 30 degreesright anterior oblique projection, with an automated, hard-wiredendocardial contour detector linked to a microcomputer12,13.The area affected by infarction was classified as one of fiveregions: anterobasal, anterolateral, apical, inferior, or posterobasal13.In patients with anterior or anterolateral infarction, the posterobasaland inferior regions were considered remote from the infarctedregion; in patients with inferior infarction, the anterobasaland anterolateral regions were considered remote.
Measurement of Regional Myocardial Blood Flow with PET
All PET scans were obtained with an ECAT 931-08/12 camera (CTI,Knoxville, Tenn.). Regional myocardial blood flow (in millilitersper minute per gram) was measured in patients and controls usingoxygen-15-labeled water as a flow tracer, with use of a previouslyvalidated technique for the inhalation of oxygen-15-labeledcarbon dioxide (C15O2)14,15. Measurements were made at rest(basal blood flow) and two minutes after the intravenous administrationof dipyridamole (0.5 mg per kilogram of body weight over a periodof four minutes). The heart rate, systemic blood pressure, anda 12-lead electrocardiogram were recorded every minute duringand after the infusion of dipyridamole.
In our analysis, the images of extravascular volume and washoutof C15O2 were used to delineate four myocardial regions (anterior,lateral, inferoposterior, and septal) over five to seven transaxialplanes, and data were averaged before myocardial perfusion wasmodeled. The regions of interest were superimposed on the kinetictime frames recorded during the inhalation and washout of C15O2to give values for regional myocardial blood flow14. With thismethod of analysis, measurements of flow depend on the amountof perfused tissue but are independent of the size of the regionand ventricular-wall thickness16. The anterior region was drawnfrom the intersection of the right ventricular free wall withthe septum. The demarcation between the lateral and inferoposteriorregions was drawn at the level of the posterior papillary muscle.In patients in whom the left anterior descending artery wasthe infarct-related artery, the anterior region was designatedthe infarcted region, and the inferoposterior region the remoteregion, thus avoiding transition between the two regions. Inpatients in whom the right coronary or left circumflex arterywas the infarct-related artery, the converse procedure was used.
The coronary vasodilator response was defined as the ratio ofpeak myocardial blood flow after the administration of dipyridamoleto the myocardial blood flow under basal conditions. In thecontrols, the inferoposterior region was defined as the remoteregion, since all 10 controls had disease only in the left anteriordescending artery. To exclude the effect of changes in systemichemodynamics on coronary blood flow, the total coronary resistancein the region was calculated from the mean arterial pressuredivided by the myocardial blood flow under basal conditionsand after the administration of dipyridamole. Scores for thechange from basal to peak myocardial blood flow were also derivedby subtracting basal flow from hyperemic flow in each regionof interest.
Statistical Analysis
All data are expressed as means ±SD. Two-tailed pairedand unpaired Student's t-tests were used to compare group means.The simultaneous comparison of more than two mean values wasperformed with one-way analysis of variance, and Fisher's least-significant-differencemethod was subsequently applied to identify the source of thedifference17. Correlations between measurements were examinedwith simple linear regression. A P value of less than 0.05 wasconsidered to indicate statistical significance.
Results
Quantitative Coronary Arteriography and Regional Left Ventriculography
Eleven of the 13 patients underwent successful recanalizationof the infarct-related artery (TIMI grade 3 in 10 of the 11patients), with a residual stenosis of 76.3 ±13.8 percentof the diameter (a minimal luminal diameter of 0.72 ±0.37mm), equivalent to an area stenosis of 92.2 ±6.9 percent(a cross-sectional area of 0.60 ±0.54 mm2). On left ventriculography,the mean left ventricular end-diastolic pressure was 17 ±4mm Hg, which was not significantly different from the pressurein the controls (13 ±3 mm Hg). The mean global left ventricularejection fraction was 56.1 ±9.8 percent. In the fourpatients with inferior infarction, the mean percent contributionof the inferior and posterobasal segments to global wall motionwas 18.3 ±4.2 percent (normal range, 26.3 to 43.6 percent),and the mean percent contribution of the anterobasal and anterolateralsegments was 38.0 ±1.2 percent (normal range, 24.5 to42.7 percent). In the nine patients with anterior or anterolateralinfarction, the mean percent contribution to global wall motionwas 30.2 ±9.2 percent in the inferior and posterobasalsegments and 23.7 ±10.4 percent in the anterobasal andanterolateral segments.
Hemodynamic Measurements on PET Scanning
In the one-week and six-month PET scans, there was a significantincrease in heart rate and systolic blood pressure and thusin the rate-pressure product from basal values to peak valuesafter the receipt of dipyridamole (Table 2). There were no significantdifferences in any hemodynamic measures between the controlgroup and the patients at the one-week and six-month PET studies.However, among the nine patients who underwent repeat studyat six months, although there were no significant differencesin basal values, the systolic blood pressure and mean arterialpressure after the administration of dipyridamole were lowerat the one-week study than at six months.
Table 2. Hemodynamic Values on PET Scanning in Patients and Controls, under Basal Conditions and after the Infusion of Dipyridamole (Peak Values).
Regional Myocardial Blood Flow and Coronary Vascular Resistance
Regional myocardial blood flow in the controls and in the patientswith myocardial infarction at the one-week and six-week PETexaminations is shown in Figure 1, and data on the patientsare shown in Table 3. In the control group, basal flow was 1.00±0.16 ml per minute per gram of perfusable tissue, andpeak flow was 3.08 ±0.53 ml per minute per gram (P<0.001for the comparison with the remote region in the patients atone week and P = 0.027 for the comparison with the remote regionin the patients at six months). The mean coronary vasodilatorresponse in the remote region was lower in the patients thanin the controls, in whom this value was 3.17 ±0.72 (P<0.001for the comparison with the patients at one week and P = 0.009for the comparison with the patients at six months) (Figure 2).In the infarcted regions, there was no improvement betweenthe two PET studies in basal flow, which remained lower thanflow in the remote regions, but there was a small improvementin peak flow. In the remote regions in the patients, peak flowwas higher at six months than at one week, but there was nosignificant change in the basal flow. Despite this improvement,the peak myocardial blood flow, and thus the coronary vasodilatorresponse in the remote regions at the six-month study, remainedlower than in the controls.
Figure 1. Net Change in Regional Myocardial Blood Flow in the Infarcted Region and the Remote Region in Patients and the Remote Region in Controls.
The change was calculated by subtracting the basal flow for each patient from the peak flow after the administration of dipyridamole. The crossed lines show the mean ±SD for each group and region. All 13 patients were studied at one week, and 9 of the 13 at six months. There were 10 controls.
Figure 2. Mean (±SD) Coronary Vasodilator Response in the Infarcted Region and the Remote Region in Patients and the Remote Region in Controls.
The coronary vasodilator response was defined as the ratio of peak myocardial blood flow to basal flow. All 13 patients were studied at one week and 9 of the 13 at six months. There were 10 controls.
Regional coronary resistance in the patients at the one-weekand six-month PET studies is shown in Table 3. As compared withthe value in the remote regions in the patients, total coronaryresistance in the controls was 90.4 ±6.7 mm Hg •min • g per milliliter at base line (P = 0.025 for theone-week study and P<0.001 for the six-month study) and 30.4±6.9 mm Hg • min • g per milliliter after theadministration of dipyridamole (P = 0.001 for the one-week studyand P = 0.026 for the six-month study).
Correlates of the Coronary Vasodilator Response
In the infarcted region, there was no relation between the absoluteseverity of coronary-artery stenosis or its severity expressedas a percentage of the luminal diameter, on the one hand, andbasal myocardial blood flow, peak myocardial blood flow, orthe coronary vasodilator response, on the other. There was alsono relation between peak flow or the coronary vasodilator responsein the infarcted region and peak flow or coronary vasodilatorresponse in the remote region, peak creatine kinase level, orthe length of time from the onset of symptoms to thrombolysis,nor between the peak creatine kinase level and either the coronaryvasodilator response or the reduction in total coronary resistancein the remote region.
Discussion
Our findings show that in patients with acute myocardial infarctionthe coronary vasodilator response is significantly impairedeven in areas of myocardium not directly supplied by the infarct-relatedartery, as compared with similar regions in patients with chronicstable coronary disease. These results may point to a novelmechanism of impaired myocardial perfusion, which could affectthe extension of myocardial ischemia at the periphery of thevascular bed of the infarct-related artery, and may open upnew avenues for research into an additional component of ischemiaafter myocardial infarction.
We confirmed that basal myocardial blood flow per gram of perfusabletissue18 was lower in the infarcted regions than in regionsremote from the infarct, and we found a marked reduction inthe vasodilator response to dipyridamole, not only in the infarctedregions but also in the remote regions perfused by angiographicallynormal arteries. After an average of six months, the basal flowin the infarcted regions remained unchanged, with a small increasein peak flow; in the remote regions, basal flow was also unchanged,and although the coronary vasodilator response increased significantly,it still remained lower than that in the remote regions of myocardiumin the control patients. The mechanisms responsible for thereduced flow in regions of the myocardium remote from infarctedmyocardium, which are supplied by nondiseased arteries, arestill speculative, but these mechanisms may have important clinicalimplications.
In the infarcted region, the lower values for basal flow, withno improvement after six months, may be due to reduced oxygenconsumption in the residual myocardium, caused in turn by reducedmyocardial contractility. The partial improvement in the vasodilatorresponse may occur as a result of the recovery of function ofresistance vessels in some of the areas of viable myocardiumwithin the infarcted region.
In remote myocardium perfused by nondiseased arteries, the reducedflow in response to dipyridamole may be explained by severalpossible mechanisms, some of which can reasonably be ruled out,whereas others should be explored. Our findings cannot be explainedby increased total coronary resistance due to elevated leftventricular diastolic pressure19,20,21. Elevated end-diastolicwall tension, which could increase myocardial oxygen demand22and thus blood flow,23 is unlikely, because end-diastolic pressuresmeasured by ventriculography and basal flow in remote myocardiumwere not increased, in contrast to the changes observed in experimentsin animals24,25. Structural changes in remote myocardium afterinfarction due to fiber slippage26 or to altered systolic regionalgeometry27,28 are also unlikely to have caused the reduced flowresponse in our patients, since remote regions were selectedon the side opposite the site of infarction and there were nosigns of regional hypercontractility.
The most likely explanation for the reduced vasodilator responsein myocardium remote from the site of infarction is an accentuationof the impaired coronary vasodilatation observed in myocardialregions supplied by nondiseased coronary arteries in patientswith chronic coronary disease1,2,3. Impaired endothelium-dependentdilatation in response both to increased blood flow and to acetylcholinemay occur before obstructive coronary artery disease develops4,5,29,30,31,32.The generalized increase in neurohormonal sympathetic activity33,34could lead to an impairment of vasodilator responsiveness inthe remote regions35,36 for several days after infarction. However,the failure of the coronary vasodilator response to return tonormal after six months suggests a persistent resistance-vesselabnormality, because systemic diastolic blood pressure and heartrate were similar at the time of the two PET studies.
If an abnormal vasomotor response were also present during thedevelopment of infarction, inappropriate constriction of resistancevessels distal to the site of coronary thrombosis could influencethe development of myocardial necrosis. Mural thrombi are frequentin unstable angina, and coronary occlusion is often intermittentin myocardial infarction37. Vasoconstrictor substances releasedby coronary thrombi (such as thromboxane A2, serotonin, andthrombin) can constrict the vascular smooth muscle surroundingthe site of a thrombus when the artery is sufficiently compliant,but they can also constrict distal vessels, as suggested bythe effects of the intracoronary infusion of serotonin38. Inthe vascular territory of the infarct-related artery, an enhancedresponse of resistance vessels to substances released by plateletswould cause blood-flow stasis, which, in the presence of muralthrombi, could lead to the formation of an occlusive thrombus.In the vascular bed of the non-infarct-related arteries, anenhanced response of resistance vessels to systemic and localneurohormonal constrictor stimuli could increase the extentof ischemia at the periphery of the infarcted area and reducecollateral flow to the infarct-related arterial bed, thus contributingto the acute impairment of ventricular function and to the extensionof necrosis.
This inappropriate constriction of resistance vessels may notrespond to nitrates or calcium antagonists because the localstimulus and vasoconstrictor response may be too intense tobe prevented by the blood levels achieved with the doses currentlyused, or because the vessels involved have a limited responseto such drugs. The development of a rational strategy to counteractthis abnormal vasomotor response requires a better understandingof the underlying mechanisms.
Drs. Uren and Lefroy are the recipients of Junior Fellowshipsfrom the British Heart Foundation.
Source Information
From the Division of Cardiology (N.G.U., T.C., D.C.L., G.J.D., A.M.) and the Medical Research Council Cyclotron Unit, Hammersmith Hospital, London (R.S.).
Address reprint requests to Dr. Uren at the Department of Cardiology, Glenfield General Hospital, Groby Rd., Leicester LE3 9QF, United Kingdom.
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