Effects of ischemia, bypass surgery and past infarction on myocardial contraction, relaxation and compliance during exercise

Effects of Ischemia, Bypass Surgery and Past nfarction on Myocardial Contraction, Relaxation nd Compliance During Exercise John D. Carroll, MD, Otto M. Hess, MD, Heinz 0. Hirzei, MD, Marko Turina, MD, and Hans Peter Krayenbuehl, MD

Abnormalities of left ventricular function during ischemia have been described in animal models and in humans. Exercise, while a physiologic means of inducing ischemia, has a complex effect on lefl ventricular function by itself. In addition, patients with coronary artery disease have a diversity of chronic changes in myocardial structure and function. Therefore, with use of micromanometer left ventricular pressure measurements and ventricular volumes, calculated from biplane cineangiograms, left ventricular function at rest and during exercise was studied in 57 patients. Exercise-induced ischemia produced a decrease in ejection fraction, an increase in end-systolic volume, dramatic increases in diastolic pressures and an upward shift in the diastolic pressure-volume relation. Central to these changes was abnormal myocardial contraction and relaxation, with reduced regional shortening and impaired left ventricular pressure decay. However, nonischemic areas were capable of augmented shortening, and global pressure decay did accelerate slightly. These findings demonstrate that exercise-induced adjustments in contraction and relaxation are intertwined with ischemia-related abnormalities. Exercise studies in patients after bypass surgery and in patients with scars from distant myocardial infarction were useful in clarifying confounding factors. For example, asynchrony of contraction and relaxation, and chronic changes in passive chamber properties, also compromise systolic and diastolic function during exercise. In patients with coronary artery disease without ischemia during exercise, left ventricular end-diastolic pressure, but not early diastolic pressure, increased during exercise. The increase in pressure was appropriate for a slight increase in end-diastoiic volume in a ventricle with a steep pressure-voiume relation. Furthermore, end-systolic volume, ile maintained during exercise, was not reduce occurs normally. lntraoperative myocardial biopsy specimens showed myocardial hypertrophy and increased interstitial fibrosis in many patients. Thus, the acute abnormalities of exercise-inted ischemia are superimposed on the hemodymics of exercise and occur in the setting of onic structural and functional abnormalities uently seen in coron rtery disease. ardiol ~969~6~:

any episodes of ischemia, with or without angina, occur during exercise, particularly in the patient with stable, chronic coronary artery disease. Therefore, dynamic exercise was used to induce ischemia in a series of studies over a 5-year period.le7 The use of micromanometer pressures and biplane cineangiographic volumes allowed the acquisition of high-quality data for subsequent analysis. These studies were undertaken to both quantify the abnormalities in left ventricular function during exercise and understand the mechanisms important in producing these functional abnormalities. Certain patient groups were of particular interest and useful in achieving these goals. The first group consisted of patients who were found to have no significant cardiovascular abnormalities. They represented our control group and are believed to show normal or near normal left ventricular function during exercise. The second group comprised patients with severe coronary artery disease and inducible ischemia. Their exercise hemodynamics allowed a characterization of ischemia to be contrasted with controls. A third group consisted of patients who had undergone successful bypass surgery. They provided an opportunity to assess the efficacy of surgery in reversing systolic, diastolic and relaxation abnormalities. Furthermore, with the aid of intraoperative biopsy specimens, the role of chronic structural changes and abnormalities in passive muscle compliance could be assessed during exercise. Finally, a fourth group comprised patients with past myocardial infarction but no inducible ischemia. During exercise, this group like the group with ischemia, had an inhomogeneous contraction pattern that, by itself, may have affected left ventricular systolic performance, pressure decay and diastolic properties. ETHODS Patient

group: The characteristics of the patients studied have previously been reported in detail.le7 The control group consisted of 5 patients who had no or minimal cardiovascular disease. All were n~dergoing cardiac catheterization because of atypical chest pain. The ischemia group, consisting of 23 patients, had significant coronary artery disease (greater than 50% di-From the Department of Medicine, University of Chicago and th, Medical Policlinic, Cardiology and Surgery Clinic A, University Hospital, Zurich, Switzerland. Address for reprints: John D. Carroll, MD, University of Chicago Nospitals, Hans Hecht Hemodynamics Laboratory, Box 124, 5841 South Maryland Avenue, Chicago, Illinois 60637. THE AMERICAN

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ameter narrowing). Fifteen patients had 3-vessel, 5 had 2vessel and 3 had l-vessel disease. All had exercise-induced regional wall motion abnormalities with a decrease in ejection fraction. Fourteen had accompanying angina. The bypass group, consisting of 24 patients, had stable angina refractory to medical therapy before surgery. Six had 2-vessel and the remaining 18 had 3-vessel disease. All had exercise-induced ischemia at the time of preoperative catheterization. All patients subsequently underwent bypass surgery with a total of 83 distal anastomoses placed. After an average of 7.7 months after operation, cardiac catheterization was completed with a repeat exercise study. These patients were selected for repeat study on the basis of improved symptoms after operation (only 5 having any angina) and having 81 of 83 patent grafts. The scar group (n = 5) had a prior infarction with a large akinetic/dyskinetic area with reduced ejection fraction on an angiogram at rest. None showed a new wall motion abnormality with exercise. None had angina, 2 had normal coronary arteries, and 3 had l-vessel disease of the coronary artery appropriate to the site of prior infarction.

Cardiac catheterization: All patients gave informed consent. Premeditation consisted of 10 mg of chlordiazepoxide. Cardiovascular medications were withheld for 12 to 24 hours before cardiac catheterization. Patients were evaluated by right- and left-sided cardiac catheterization and biplane cineangiography at rest and during supine bicycle exercise. Left ventricular pressure was measured with a Millar pigtail angiographic catheter introduced from the femoral artery. Pressures were recorded at a paper speed of 250 mm/s. Mean right atria1 pressure was recorded in some patients with a fluidfilled catheter. Biplane left ventricular cineangiograms were obtained at a filming rate of 50 frames/s. Volumes were calculated by the area-length method. Each angiographic frame had a digital time corresponding to time marks on the pressure recordings. Exercise protocol: All patients underwent bicycle exercise testing before catheterization to determine achieved work load and exercise limitations. At catheterization, pressures were recorded before and after each patient’s feet were strapped to the bicycle device. After

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FIGURE 1. Pressure-volume loops were determined during pre- and postcoronary artery bypass operation (CABG). Solid ci~ c/es, data at rest, open circles, data during exercise. The typical changes of exercise-induced ischemia are replaced at the postoperative study by exercise hemodynamics typical of the stiff, but nonischemic, left ventricle of chronic coronary artery disease. LV = left ventricular. 66E

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angiography at rest and a subsequent 12- to 15-minute pause, patients began to exercise at a low level. Work loads were progressively increased until either angina or other limiting symptoms occurred or until they achieved a predicted submaximal heart rate. Scar group and control group patients generally achieved target heart rate. Bypass group patients followed the same exercise protocol they had followed before surgery to match external work loads. Exercise duration and maximal work load were, therefore, identical for both studies. At the point of peak exercise, pressures were again recorded and simultaneous cineangiography was completed. Coronary arteriograms by the Judkins technique were recorded after exercise. Data analysis: Methods of analysis have previously been described in detail.‘-’ In summary, resting and exercise data were derived from well-opacified beats that were not immediately postextrasystolic. Pressure tracings were digitized. The characteristics of isovolumic pressure decay were derived from the linear regression of pressure and dP/dt coordinates. Thus, 2 variables, T, representing the negative reciprocal of the slope, and the pressure axis intercept (Pn), were derived for each patient at rest and during exercise. Ventricular volumes were calculated by frame-byframe analysis of biplane angiograms. Three-point smoothing of volume calculations was performed, and the peak rate of filling was identified. End-diastolic and endsystolic volumes and ejection fraction were calculated. Intraventricular pressure and volume were matched to construct pressure-volume loops (Fig. 1). Regional wall motion analysis was completed for both right and left anterior oblique projections using a longaxis (mitral-aortic junction to apex) with 3 perpendicular, equidistant chords measuring the dimension at the base, middle and apex of the left ventricle. Regional function was quantitated by fractional shortening (expressed as a percent of end-diastolic chord dimension) and shortening velocity.8 Four patients from the ischemia group with isolated anteroapical hypokinesia during exercise and 4 patients from the scar group with anteroapical infarction were compared with the control patients. Rest and exercise regional fractional shortening and shortening velocity were compared for the right anterior oblique long axis and chords. In this manner, the base chord represented a normal or at least not clearly abnormal region of the left ventricle in all patients. In addition, the apical abnormality improves the utility of our reference system by limiting long-axis movements. Pressure-volume relations were constructed for each patient, but to permit comparisons, we derived mean diastolic pressure-volume relations for each group at rest and during exercise. Four diastolic pressure-volume coordinates were used, including the first frame after mitral valve opening, the early diastolic pressure nadir, enddiastole, and the time halfway through the filling period. Three systolic pressure-volume coordinates were also used, including the first frame after aortic valve opening, peak systolic pressure, and the frame immediately before aortic valve closure (end-systole). Rest and exercise data within groups and between pre- and postoperative studies were tested for significant

differences by use of the paired t test. Differences between groups were tested with an unpaired t test. Data on figures are mean f standard error of the mean while those in the text are mean f standard deviation. RESULTS Control group: During exercise, the control group had no significant changes in end-diastolic volume (96 f 6 to 102 f 11 ml/m2), while end-systolic volume decreased from 35 f 5 to 28 f 6 ml/m* (p <0.05) and ejection fraction increased from 64 f 3 to 73 f 4% (p . Heart rate increased from 70 f 18 to 120 f 21 beats/min (p KO.01). Volumetric cardiac index increased from 4.2 to 8.8 liters/min/m* (p
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chord fractional shortening (30.3 f 5.2 to 20.3 f 2.1%, p
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FIGURE 2. Average pressure-volume loops were derived from the data of 13 patients before and after surgery. systolic and diastolic function is brought out by the exercise study. See text for details. CABG = coronary artery ing; LV = left ventricular.

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cise. However, patients in the scar group often had the slight increase in end-diastolic pressure which appeared appropriate for the increase in end-diastolic volume. Peak filling rate increased from 590 f 209 to 1,185 f 161 ml/s (p
augmentation of regional function in the base of the left ventricle. Thus, regional variations in function, both depressed and augmented, are present in patients with coronary artery disease both at rest and during exercise. Global indexes of performance reveal the net outcome of these interactions. In the subgroup of patients studied before and after operation, all patients had exercise-induced asynergy at the preoperative study, and none had it after revascularization. There was a postoperative improvement in both the shortening characteristics and pressure generation capability of the left ventricle. There was also a small increase in ejection fraction during postoperative exercise. The mechanism of this augmentation of ejection fraction was the significant increase in end-diastolic volume and preload, not a reduction in end-systolic volume as occurs in normal subjects. Thus, an increase in stroke volume during exercise does occur and combines with the tachycardia to allow a clear increase in exercise cardiac output, which is blunted before operation. The increase in ejection fraction and maximal positive dP/dt appeared due to the ability of the ischemic segments on preoperative study to now shorten and contribute to systolic pressure generation. DISCUSSION Diastolic pressure during ischemia: Patients in the Normal adjustments in ventricular function during ischemia group had increases in pressure throughout exercise: Augmented pump function is required during diastole. In early diastole, the nadir was elevated far exercise to produce the increase in cardiac output to beyond the limit of a normal pressure at end-diastole. match the increased metabolic needs. In systole, an aug- This was unique in the group with ischemia; patients in mentation of preload and contractile state increase pres- the scar and bypass groups often had increased end-diasure generation and combine with peripheral vascular stolic pressure, but never minimal diastolic pressure duradjustments to increase chamber emptying. In diastole, ing exercise. The resultant effects on left atria1 and puladjustments in pressure decay and filling dynamics occur monary venous pressure would clearly be of the magniwhich shorten the isovolumic relaxation period, increase tude to produce pulmonary edema, if sustained with total transmitral flow in an abbreviated filling period and prolonged ischemia. By study design, patients with signifmaintain low diastolic pressures. Alterations in autonomicant mitral regurgitation during exercise were excluded. ic tone undoubtedly play a vital role in these adjustments Therefore, the acute increase in diastolic pressures was in function. It is well established that myocardial contrac- related to alterations in left ventricular chamber complition and relaxation are directly potentiated and acceler- ance. Several mechanisms for this acute increase in diaated by fi-adrenergic receptor activation.gm12 Alterations stolic pressures are suggested by the data. in heart rate and loading conditions may also facilitate Effect of ischemia on relaxation: The alterations in adjustments in systole and diastole during exercise.g,13J4 left ventricular relaxation during exercise-induced ischeGlobal augmentation of left ventricular performance mia are probably related to changes in multiple determiwas noted during exercise in all groups of patients. Cardinants of relaxation.‘J5 The abnormal systolic dynamics ac output, maximal positive dP/dt and mean normalized of ischemia, including asynchrony and increased endsystolic ejection rate increased despite the acute dysfunc- systolic volume, are factors that combine with direct distion of an ischemic region or the chronic dysfunction of an ruption of muscle relaxation to produce the reduced rate, infarcted region; however, the augmentation of pump and perhaps extent, of pressure decay. The myocardium performance was clearly suboptimal when compared may never completely relax between systoles, especially with that of control patients. Patients in whom ischemia since diastole is so brief during exercise. In addition, with developed and those with prior infarction had an increase the high incidence of 3-vessel disease in this study, it is in cardiac output only by tachycardia. In general, those reasonable to suggest global ischemia occurred in many with coronary artery disease were unable to achieve the subjects. reduction in end-systolic volume seen in all control subDelayed and incomplete relaxation translates, at the jects. One factor accounting for the variability in global ventricular or chamber level, into slow pressure decay performance during exercise-induced ischemia was the that fails to achieve an intracavitary pressure expected for extensiveness of the regional dysfunction.3 Many patients a totally relaxed chamber.’ During exercise, the effects of with exercise-induced ischemia also had areas of aug- ischemia are superimposed on the hemodynamics of exermented fractional shortening and shortening velocity. Pa- cise with changes in heart rate, contractile state and loadtients with a distant anteroapical infarction had a rest ing conditions.i3,14 Pressure decay was actually accelerTHE AMERICAN

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ated in many patients with exercise-induced ischemia. However, when compared with a control group, the true extent of abnormal pressure decay during exercise-induced ischemia was apparent. A problem arises when only comparing the ischemia group with the control group. Those with exercise-induced ischemia may also have chronic abnormalities of both passive and active chamber compliance. Therefore, 2 groups with coronary artery disease, but no ischemia during exercise, were also studied. Effect of an akinetic scar on contraction, relaxation and compliance: The presence of a large akinetic area or

ischemic region may impair systolic emptying and the rate of pressure decay simply because of the inhomogenous contraction/relaxation pattern. A temporal disruption in the contraction/relaxation pattern is associated with a prolongation of pressure decay.9 In this study, the scar group demonstrated a different form of regional abnormality that was associated with a prolonged resting T. During exercise the ejection fraction did not increase, and the large end-systolic chamber size did not decrease. Pressure decay acceleration occurred, as shown by a decrease in T and no change in Pa; however, the reduction in T was not that normally expected for heart rate.’ Nevertheless, the adjustment in pressure decay was adequate in the scar group to maintain low early diastolic pressures and the augmentation in end-diastolic volume allowed an increase in stroke volume. Therefore, the unique effects of ischemia become most apparent when examining diastolic compliance and comparing it with patients in the scar group. No pressure-volume shifts occurred during exercise in the scar group. The acutely ischemic myocardium, itself, appears to be a key determinant in the increase in diastolic pressures, not the presence of a regional abnormality of contraction by itself.

in chamber stiffness. Viscous factors are important to consider, especially in exercise-induced ischemia when filling rates are increased and diastole is quite brief.23 Second, the normal pericardium resists stretch if there is a significant and acute increase in total intrapericardial volume.24 The atria and right ventricle may acutely dilate from the elevation of left ventricular filling pressures during ischemia. If total intrapericardial volume increases so that intrapericardial pressure increases above its normal low values, an acute pericardial effect on left ventricular chamber properties may become manifest.25-30 Tyberg et aP” pointed out the close correlation of right atria1 and pericardial pressures in a group of patients after thoracotomy. However, we noted a lack of consistency in the presence of elevated right atria1 pressure during exercise-induced ischemia, a lack of correlation between the degree of increase in right atria1 pressure and pressure-volume shift, and a clear inconsistency in patients studied postoperatively.4,5 Chronic changes in passive chamber compliance in coronary artery disease: Patients in the bypass and scar

groups did not have a shift in the diastolic pressurevolume relation during exercise. The rest and exercise data are basically on the same line, indicating stable chamber properties. There was an increase in end-diastolic pressure in many of these patients which, according to the pressure-volume relation, appeared due to a simple increase in end-diastolic chamber size, i.e., a preloaddependent change in chamber stiffness. The absolute increase in end-diastolic pressure was often great with a small increase in volume, indicating the steepness of the pressure-volume relation. is Fibrosis, either localized as a postinfarction scar, or patchy in areas served by severely diseased vessels, is a common feature of these 2 groups. Intraoperative biopsy specimens, reported by Hess et al,6 Effect of revascularization on contraction, relaxation also show myocardial hypertrophy, even in the absence of and compliance: Exercise ejection fraction and abnormal systemic hypertension. Chronic changes in chamber compliance need to be pressure decay in the left ventricle, along with other hemodynamic abnormalities, can be greatly improved by considered in interpreting exercise hemodynamics. The revascularization. The change can be easily seen in the acute changes in.chamber compliance, produced by isleft ventricular pressure-volume loop (Fig. 1). During chemia, are superimposed on any chronic changes. The postoperative exercise, systolic pressure increases, the resultant elevation of diastolic pressures should be draventricle empties more completely and the diastolic pres- matic, and often was. Sasayama et aP1 showed that the sure-volume is not shifted. Persistent abnormalities in ischemic region of the left ventricle has an upward shift in contraction, relaxation and compliance may be related to its pressure-segment length relation; the nonischemic rethe residual inhomogeneities of contraction and relaxa- gion had no shift, but simply moved to a higher pressure tion, myocardial hypertrophy and interstitial fibrosis, and on the same pressure-segment length relation. Thus, subclinical ischemia. within the same ventricle, acute and chronic changes in Diastolic pressure-volume relation: The increase in compliance may be observed. Types of ischemia: Exercise-induced ischemia has diastolic pressures during ischemia is not simply due to an increase in end-diastolic volume (i.e., it is not merely a unique features, as previously discussed, and further studpreload-dependent change in left ventricular chamber ied in animal models.13J4 The resultant left ventricular stiffness).16-‘9 Chamber dilatation did occur in many dysfunction is often profound. The imbalance in myocarof our subjects during exercise-induced ischemia, yet dial oxygen supply and demand primarily involves an the diastolic pressure-volume relations showed an up- increase in the determinants of myocardial oxygen conward shift, indicating an acute shift in chamber stiffness. sumption. However, a reduction in coronary flow may This has previously been reported in pacing-induced an- also accompany exercise, as demonstrated by the study of gina.20-22 Whereas abnormal pressure decay has been Gage et a1.7 These considerations of the way ischemia is demonstrated in both pacing and exercise-induced ische- produced are important. As demonstrated by Paulus et mia, other factors could contribute to this acute alteration a1,32the regional dysfunction, both systolic and diastolic, 70E

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is different for coronary occlusion vs pacing-induced ischemia with a coronary stenosis. Ischemia in humans is further modified by the anatomic and physiologic diversity of coronary artery disease. Thus, the acute abnormalities of myocardial contraction, relaxation and chamber compliance due to ischemia are (1) influenced by the mechanism of ischemia induction, (2) intertwined with the hemodynamics of exercise, (3) described by global changes with gross spatial heterogeneity in regional function, and (4) superimposed on the chronic chamber/structural abnormalities frequently seen in coronary artery disease. Acknowledgment: We thank Amy Nirtaut and Petrit Alibali for their assistance in the preparation of the manuscript.

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