Noninvasively induced postextrasystolic potentiation of ischemic and infarcted myocardium in patients with coronary artery disease

Experimental

and laboratory

reports

Noninvasively induced postextrasystolic potentiation of ischemic and infarcted myocardium in patients with coronary artery disease

Peter F. Cohn, M.D. Gerald H. Angoff, M.D. Laurence J. Sloss, M.D.

With the technical

assistance of Priscilla

Peters

Boston, Mass.

Echocardiography has proven useful in demonstrating abnormal left ventricular wall motion (asynergy) in patients with coronary artery disease(CAD).’ Recent angiographic-echocardiographic studies have shown a correlation between lesions of the left anterior descending artery (LAD) and reduced interventricular septal wall excursion,2-5 and between lesions of the right coronary artery (RCA) and/or left circumflex artery (LCF) and reduced excursion of the posterior wa11.3These wall motion abnormalities are most frequent when the ECG also shows evidence of a transmural myocardial infarction in the region subserved by the stenosed vessel.2 One of the clinical questions that remains unanswered is wether such wall motion abnormalities-with or without corresponding Q waves-are due primarily to myocardial ischemia without extensive scar formation and thus potentially reversible, or are largely the result of scar formation and probably irreversible. Techniques are currently available to determine the reversibility of regional myocardial asynergy during left ventriculography. These techniques include the use of a ventricular premature beat (VPB) to induce postextrasystolic From the Cardiovascular Bent Brigham Hospital Supported 7049.

by United

and

Division, Harvard

States

Public

Department Medical

Received

for publication

Feb.

12, 1978.

Accepted

for publication

May

2, 1978.

Reprint requests: Peter Bent Brigham Hospital,

0002~8703/79/020187

F. Cohn, M.D., 721 Huntington

+ 08$00.80/O

Health

of Medicine, School, Boston, Service

Cardiovascular Ave., Boston,

0 1979

The

Grant

Peter Mass. No.

HL-

Division, Peter Mass. 02115.

C. V. Mosby

Co.

potentiation (PESP),6 a potent inotropic stimulus in mammalian heart muscle,’ but until recently there has been no reliable method of inducing VPB’s noninvasively, and hence no comparable way of detecting contractile reserve during noninvasive evaluation of wall motion. With the development of an external mechanical cardiac stimulator by Zoll and associates,showever, such studies are now possible. We have previously used this device to introduce VPB’s noninvasively during echocardiography and evaluate over-all ventricular,reserve in a variety of cardiac disease states.g In the present study, we use it to evaluate the effect of PESP on the reversibility of localized abnormalities of wall motion in patients with CAD. Materials

and methods

Patient selection. Criteria for selection of CAD patients for this study included (1) angiographic evidence of significant coronary artery obstruction, i.e., greater than 75 per cent reduction in lumen diameter, without concomitant valvular or congenital heart disease, (2) regular sinus rhythm without evidence of left bundle branch block, (3) technically adequate echocardiographic tracings of at least the basal septum and left ventricular posterior wall (and, whenever possible, the apex) with the patient lying supine or rotated slightly to the left. The 29 CAD patients who were studied ranged in age from 40 to 62 years. All patients gave informed consent for these studies. Four additional patients with chest pain syndromes

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Cohn,

Angoff,

and

Sloss

Fig. 1. External mechanical graphic transducer.

cardiac

stimulator

positioned

on patient’s

precordium

just

lateral

to the echocardio-

Fig. 2. Echocardiogram demonstrating augmentation of septal (S) and posterior wall (PW) motion following a noninvasively-induced ventricular premature beat (VPBJ. Although this patient had a prior inferior myocardial infarction, posterior wall excursion was normal in the control beat (9 mm.) and increased to 11 mm. following the VPB. Septal wall motion excursion was abnormal in the control beat (2 mm.), but increased to normal levels (4 mm.) following the VPB. There was no electrocardiographic evidence of anterior wall infarction. At coronary arteriography, the patient demonstrated significant stenosis of the left anterior descending and right coronary arteries. mu = mitral valve apparatus; EKG = Lead II of the electrocardiogram.

and totally normal cardiac catheterization studies served as a control group. Electrocardiography. Standard New York Heart Association electrocardiographic and vectorcardiographic criteria’” were used for defining transmural anteroseptal, inferior, and posterior myocardial infarctions. Induction

of

premature

ventricular

beats.

These procedures have been described in detail previously and have proven safe and reliable.” Briefly, the VPB’s were induced with the external

188

mechanical stimulator positioned on the precordium, either at or near the point of maximum impulse but not over the nipple (Fig. 1). The stimulator was a modified stapling gun which was discharged manually after the T wave was observed on an oscilloscope. Stimuli were calibrated from 0.7 to 1.5 joules. EchocardioEchocardiographic procedures. grams were recorded using M-mode scans with the patients either supine or rotated slightly to the left (Fig. 2). A Smith Kline Instruments

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Postextrasystolic

P

C NL

P

c

LAD

ABNL (NO

LAD ML

potentiation

C

of ischemic myocardium

P ABNL LAD :Mll

Fig. 3. Effect of postextrasystolic potentiation on septal wall excursion. Septal wall excursion is plotted in the control(C) and potentiated (P) beats in regions with normal (NL) left anterior descending (LAD) arteries (panelA), stenosed (ABNL) LAD but no evidence of anterior wall myocardial infarction (MI) on ECG bane1 B), and stenosed LAD with ECG evidence of anterior wall MI (panel C). The increase in septal wall excursion following postextrasystolic potentiation is significant in all three subgroups. Normal septal excursion is 2 4 mm.

Ekoline 20 System employing a 2.25 MHz transducer coupled to an Irex Continutrace 101 Multichannel Recorder was utilized for all studies. The transducer was placed in the standard position in the left fourth intercostal space lateral to the left sternal margin and an M-mode sweep was performed from the aortic root to the apex of the left ventricle. The site with the most pronounced asynergy was selected as the area of interest for evaluating the effect of PESP. A standard Lead II electrocardiogram was simultaneously recorded on the echocardiogram. Excursion of the left interventricular septum and posterior wall endocardium was measured from end-diastole (onset of QRS complex) to maximum posterior and anterior excursion, respectively, in beats preceding and following the VPB. Measurements were to the nearest millimeter. The lower limit of normal values in our laboratory for endocardial excursion for the interventricular septum and posterior wall are 4 mm. and 9 mm., respectively. A ratio of posterior wall to septal wall excursion was obtained by dividing the posterior wall excursion by the septal excursion, with a value of 2.5 or greater considered abnorma1.j Echocardiographic measurements were made within 24 hours of the cardiac catheterization and without knowledge of the results of coronary arteriography or left ventriculography (and vice versa). Cardiac catheterization procedures. Selective coronary arteriograms were obtained in multiple views using either the Judkins or Sones tech-

American Heart Journal

niques and recorded on 35 mm. film. The coronary arteriograms were analyzed without knowledge of the echocardiograms. Obstructive lesions were classified as significant if there was greater than 75 per cent narrowing of the lumen of the LAD, LCF, or RCA, or any of their major branches. Technically adequate biplane tine left ventriculograms demonstrating the septal and posterolateral walls (in the left anterior oblique projection) were obtained in 15 patients (all with CAD) and seven of these included single ventricular premature beats of approximately the same RVPB interval as that obtained during echocardiography. The VPB’s were induced by methods described in detail previously.” The septal and posterolateral radii of the major transverse diameter in this projection were measured in the beat preceding and the beat following the VPB. Normal shortening from end-diastole to endsystole is 1 20 per cent in our laboratory.” Results

In none of the patients in this series did serious complications (such as repetitive ventricular tachyarrhythmias or angina) occur following external mechanical stimulation, nor was there more than minimal chest wall discomfort. No premeditation was necessary, nor were analgesics required in any patient. No patient experienced more than five attempts at inducing VPB’s. The interval between the R wave of the sinus beat and

189

Cohn,

Angoff,

and

Slose

I c

P IWXMAL RCA & LCf

P

C RCA

ABhtWMAL AND/OR ilm MI1

LCF

c RCA

I

P ABNORMAL AND/OR (Ml

LCF

Fig. 4. Effect of postextrasystolic potentiation on posterior wall excursion. Same format as Fig. 3, except that MI refers to inferior and/or posterior myocardial infarction, RCA to right coronary artery, and LCF to left circumflex artery. All three subgroups had significant increases in posterior wall excursion. Normal posterior wall excursion 29mm.

the onset of the VP3 induced by the mechanical stimulator averaged 486 msec. + 20 (mean k S.E.M.) and the range was 370 to 610 msec. Previous studies” from our hospital demonstrated no significant changes in PESP in the same patient when coupling intervals within this range were compared. 1. Septal

wall

motion

(Fig.

3).

A. Relation between reduced septa2 wall excursion, LAD disease, and anteroseptal myoeardial infarction. Twenty-five patients had > 75 per cent obstruction of the LAD. Abnormal septal wall excursion could be demonstrated in 13 of the 25 patients (52 per cent), including six of the 12 patients without evidence of infarction and seven of the 13 patients with such findings. An abnormal posterior wall/septal wall excursion ratio was present in nine of the 13 patients with reduced septal wall excursion, but in no patients with LAD lesions and normal septal wall excursion. B. Effect of PESP. In all eight patients without significant LAD disease (four control subjects and four CAD patients, panel A of Fig. 3), there was increased excursion during PESP: 6.2 mm. +- 0.6 (mean _t S.E.M.) to 7.9 mm. t 0.7, p < .OOl.* In the 12 patients with LAD disease but no anteroseptal infarction (panel B), only two *Statistical

190

comparison

by paired t test, unless otherwise

noted.

patients failed to increase their excursion and the group as a whole also demonstrated significantly increased excursion: 4.2 mm. + 0.7 to 5.7 mm. + 0.8, p < 901. Five patients in this subgroup did not have normal wall excursion at rest and two reached the normal range during PESP (an example is depicted in Fig. 2). In the 13 patients with prior infarctions (pane2 C of Fig 3), five .patient.s showed no change, but the group again showed a significant increase in excursion: 3.3 mm. + 0.8 to 4.0 mm. f 0.8, p < -05. Seven patients in this subgroup had abnormal wall excursion at rest and only one achieved normal excursion with PESP. In none of the patients did an abnormal posterior wall to septal wall excursion ratio revert to normal. 2. Posterior

wall

motion

(Fig. 4).

A. Relation between reduced posterior wall excursion, RCA and/or LC disease, and inferior or posterior myocardial infarction. Twenty-one patients had either > 75 per cent stenosis of the RCA or LCF, and 16 had disease of both vessels. Reduced posterior wall excursion was demonstrated in 12 of the 21 (60 per cent), including four of 10 without evidence of infarction and eight of 11 with evidence of infarction. B. Effect of PESP. In all 12 patients without either RCA or LCF disease (four control subjects and eight CAD patients, panel A of Fig. 4), there was increased excursion during PESP: 10.4

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Postextrasystolic

potentiation

of ischemic myocardium

”

NO CAD

CAD WITH MI

CAD

Fig. 5. Increase in wall excursion with postextrasystolic potentiation in relation to presence or absence of ECG evidence of myocardial infarction (MI). Twenty regions without cornary artery disease (CAD) are compared to 22 regions with CAD but no myocardial infarction and 24 CAD regions with evidence of prior MI (see text). Increase in echocardiographic (ECHO) wall excursion with PESP was significantly less in the MI regions (1.1 + 0.2) compared to either of the other two subgroups (1.8 -C 0.2 and 1.7 f 0.3).

k 0.8 to 12.8 mm. f 0.7, p < .OOl (panel A). with RCA and/or LCF disease In the 10 patients but no infarction (panel B of Fig. 4), only one did not show an increased excursion during PESP and the group as a whole also had significantly increased excursion: 9.9 mm. f 0.9 to 11.6 mm. + 0.8, p < .OOl. Four in this subgroup did not have normal wall excursion at rest, but three reached the normal range with PESP. In the 11 patients with prior infarction (panel C), three showed no increase in excursion with PESP, but in the group as a whole, the change with PESP was again significant: 6.7 mm. + 0.8 to 7.3 mm. k 0.9, p < .05. Three patients had normal wall motion at rest. Eight patients in this subgroup did not have normal wall excursion at rest and six of the eight did not achieve normal excursion with PESP. 3. Effect of PESP in relation to presence or absence of myocardial infarction. Although PESP caused a significant increase in echocardiographic wall motion in all three subgroups plotted in panels A, B, and C in Figs. 3 and 4, the increase in CAD regions* with corresponding infarctions (i.e., panel 3C combined with 4C) was significantly less (by unpaired t test) than either the increase observed in regions without CAD banels 3A plus 4A) or CAD regions without infarctions banels 3B plus 4B). These differences are graphically depicted in Fig. 5. The effect of PESP in relation to prior infarction was also evaluated in the 24 regions plotted mm.

*“Region”

indicates

either

septal

American Heart Journal

wall

or posterior

wall.

38%

ABNL ECHO WALL EXCURSION

No CHANGE

FTO-=NL RANGE

*m

NL RANGE

Fig. 6. Effect of postextrasystolic potentiation (PESP) in regions of abnormal (ABNL) echocardiographic (ECHO) wall excursion in relation to ECG evidence of myocardial infarction (MI). Twenty-four regions had ABNL ECHO wall excursion. Fifteen of these regions had ECG evidence of MI. With PESP, seven regions showed no change, and six of seven had MI; 9 regions improved, but to less than the normal (NL) range and six out of nine had MI. Eight regions improved to the normal range and only three out of eight had MI.

in Figs. 3 and 4 that showed abnormal wall excursion in the control state (Fig. 6). In 15 of these 24 regions, there was evidence of an infarction on ECG. During PESP, seven regions showed no change and six of these had prior infarctions, and nine regions showed less than normal response with six of the nine demonstrating prior infarction. By contrast, of the eight regions that improved to the normal range with PESP, only three had ECG evidence of a prior infarction. 4. Relation Between Echocardiographic and Ventriculographic Findings. In the 15 patients with biplane studies, a total of 30 regions of interest were evaluated; there were 12 regions of < 20 per cent systolic shortening (five septal and seven posterolateral wall). Eleven of these 12 regions also showed < 4 mm. (septal) or < 9 mm. (posterolateral) excursion on the echocardiogram-the exception being a patient with normal echocardiographic posterior wall excursion, Of the remaining 18 regions of normal systolic motion on the ventriculogram, there were two patients who demonstrated abnormal septal wall excursion on the echocardiogram. In the seven patients with biplane tine studies that included VPB’s, there were six regions of either reduced septal systolic shortening and/or reduced posterolateral systolic shortening. During PESP, two of these six abnormally moving

191

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regions on the ventriculogram reached the normal range (i.e., > 20 per cent), and the same two of six similarly affected areas on the echocardiograms also reached normal excursion. Discussion

Several aspects of this study merit particular attention: (1) frequency of echocardiographic wall motion abnormalities in CAD, (2) experience with noninvasive interventions during echocardiography in ischemic heart disease, and (3) implications of the effect-or lack of effect-of PESP in patients with CAD. Abnormal

wall

motion

on the echocardiogram.

Despite recognized limitations of M-mode scanning in CAD,’ prior studies by several groups?-s have demonstrated that lesions of the LAD are often associated with abnormal septal wall motion. The most commonly employed measurement to describe this abnormality is septal wall excursion, and the lower limit of normal has ranged from 3 mm. 2-4to 5 mm.j in these studies. The frequency of reduced septal wall excursion in patients with LAD disease has varied with two groups reporting a frequency of 46 per cent4, j and two other groups a frequency of 80 per cent.?, 3 In the present study-using 4 mm. excursion as the lower limit of normal-we found reduced septal wall excursion in 52 per cent of our patients with LAD disease. The reasons for the variations between studies done at different institutions are severalfold and include ability in individual patients to successfully scan and record from the apex where abnormalities are presumably more marked, as well as inhomogeneity in the patient population so that varying numbers of patients from different serieshave prior myocardial infarctions, LAD lesions proximal to the first septal branch, well functioning collaterals to the LAD, etc. It was not the purpose of the present study to attempt to further clarify such differences, but rather to establish a resting baseline in our patients so that we could then evaluate the effects of PESP. (Since Joffe and colleagues” have suggested the value of using the ratio of posterior wall to septal wall excursion rather than absolute measurements alone in identifying patients with LAD lesions-particularly proximal to the first septal branch-we also calculated this ratio but, like others,4 found it to have no significant advantage over absolute measurements.) Our frequency of reduced posterior wall excursion (60 per cent)

192

in patients with RCA and/or LCF diseaseis in the range reported by others-37 per cent” and 52 per cent%but again blood supply to this area is varied and our data serve primarily to establish a baseline for evaluating the effects of PESP. The relation between echocardiographic and ventriculographic evidence of asynergy has generally been good even when the right anterior oblique projection is utilized, We also found good correlations in a limited number of patients with left anterior oblique ventriculograms. Even though this view is better suited to visualize the same wall regions that are detected on the echocardiogram, the echocardiogram appears to be more sensitive to a reduction in septal wall motion in certain patients. Noninvasive interventions during echocardiography. Although it is often difficult to obtain

technically good echocardiograms in patients who are performing dynamic exercise, static (handgrip) stress has been successfully attempted and transient abnormalities of septal motion in patients with coronary artery disease have been demonstrated during this stress.‘” That the echocardiogram can be used to investigate the effects of various pharmacologic interventions in ischemic regions of the heart has been demonstrated by Kerber and colleagues*” in an experimental canine preparation, but there had been no prior clinical studies using inotropic agents. Several group&+, I3 have studied the effect of nitrates on abnormal wall motion, however, and reported a beneficial response in patients with asynergy. The mechanism of action of the nitrates is different from that of PESP, and although of obvious clinical importance does not directly determine the response of ischemic or infarcted zones of myocardium to inotropic stimulation. Both methods of intervention echocardiography appear to be safe and reliable in humans, although an additional piece of equipment (the external cardiac stimulator) is necessary for consistently inducing VPB’s noninvasively. Effect of PESP in CAD. Animal studies have demonstrated that of the commonly used inotropic stimuli, PESP appears to be the most powerful stimulus of contractile reserve in ischemic myocardium.‘j The results of these experimental studies have been applied to clinical studies employing tine left ventriculography,” and the response to PESP has been useful in demonstrating contractile reserve in local regions

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Postextrasystolic

of abnormal wall motion as well as in over-all ventricular performance. Thus, a significant response to PESP suggests that (1) local regions of asynergic myocardium are not irreversibly damaged and will show enhanced motion after revascularization,“. I8 and (2) short-term prognosis with either medical or surgical therapy approaches that of patients with normal wall motion.‘“, 2oAdapting this technique to noninvasive cardiac evaluation (especially echocardiography) is now possible with the external mechanical stimulator developed by Zoll and colleagues8 This device (Fig. 1) can safely and reproducibly introduce VPB’s into the cardiac cycle.g In the present study, the effect of PESP on ischemic as well as presumably infarcted myocardium has been investigated noninvasively (Fig. ‘2). PESP caused a significant increase in wall excursion in all three groups of patients (Figs. 3 and 4), but the degree of improvement was significantly less in patients with ECG evidence of a transmural myocardial infarction in the affected region (Fig. 5). Because the response to PESP is variable in individual patients, the results can also be analyzed in a different manner. Using the same criteria (normalization of reduced motion) employed in our ventriculographic study of the effect of PESP on hemiaxial shortening,6 we found that eight regions of reduced septal or posterior wall excursion increased to the normal range with PESP while 16 did not (Fig. 6). Of the seven regions that showed no change at all, six were in areas of prior infarction. By contrast, only three of the eight regions that improved to the normal range had ECG evidence of prior infarction. Prior ventriculographic-pathologic correlations have shown that areas unresponsive or minimally responsive to inotropic stimulation are usually totally scarred while more responsive regions contain mostly viable muscle with or without some fibrous tissue.21(Similar pathologic findings have been reported in patients studied with nitroglycerin.“) Responsive areas have usually returned to normal function following myocardial revascularization.“. lR In conclusion, the present study suggests that (1) the combination of abnormal echocardiographic wall excursion and ECG evidence of a transmural myocardial infarction usually-but not always-indicates a poor response to PESP, hence probable limited myocardial viability and potential for improvement with revasculariza-

American

Heart

Journal

potentiation

of ischemic

myocardium

tion; (2) the finding of abnormal echocardiographic wall excursion zuithout definite ECG evidence of a prior infarction usually-but not always-indicates a good response to PESP. It should be emphasized that part of the unpredictability of the response to PESP in individual patients may be due to the unreliability of the ECG in reflecting areas of infarction (especially nontransmural infarction) that are subsequently demonstrated pathologically. Thus, an apparently normal region of myocardium on the ECG may not respond fully to PESP. In addition to “falsenegative” ECG’s, the opposite situation may also occur: the presence of a transmural infarction on the ECG may still be associated with enough islands of viable myocardium to produce a dramatic response to PESP. Because of the limitations of the resting echocardiogram, noninvasively induced PESP or other forms of intervention echocardiography (such as with nitrates) may be useful adjuncts to the noninvasive evaluation of patients with coronary artery disease. By demonstrating the presence or absence of contractile reserve in patients with echocardiographic evidence of either ischemic or apparently infarcted myocardium, these techniques can help to evaluate (within the limits described above) the viability of the region in question. Whether these areas will return to normal function following revascularization can only be determined from ongoing surgical followup studies, but the prior experience cited with contrast ventriculography suggests that this indeed may be the case. Summary To evaluate noninvasively-induced postextrasystolic potentiation (PESP) of ischemic or apparently infarcted regions of myocardium, an external mechanical cardiac stimulator (develoepd by Zoll) was used to induce ventricular extrasystoles during M-mode echocardiography in 29 patients with coronary artery diseaseand in four control subjects. Twenty-five patients had > 75 per cent stenosis of the left anterior descending artery including 13 with ECG evidence of anteroseptal myocardial infarction; 21 patients had > 75 per cent stenosis of the right coronary and/or left circumflex arteries, including 11 with ECG evidence of inferior and/or posterior myocardial infarction. Twenty-four regions with reduced wall excursion showed vary-

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ing effects of PESP: eight regions improved to the normal range, while 16 did not. Twelve of the latter had ECG evidence of prior infarction. Similarly, regions of asynergy that did not respond at all to PESP were usually, but not always, seen in patients with infarctions. Based on prior ventriculographic-histopathologic correlates, non-responding regions are probably totally scarred with irreversible contraction abnormalities, whereas regions with evidence of contractile reserve are potentially viable. Because the ECG and resting echocardiogram are not totally accurate predictors of contractile reserve, noninvasively induced PESP may be a useful adjunct technique in delineating local contractile reserve in patients with echocardiographic evidence of hypocontractile myocardium of uncertain viability. The authors wish to thank cooperation in these studies.

Paul

M.

Zoll,

M.D.,

for

9.

10.

11.

12. 13.

14.

15.

his 16.

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1979, Vol. 97, No. 2