Left ventricular dyskinesia reversed by intravenous nitroglycerin: A manifestation of silent myocardial ischemia

left VentricularDyskinesiaReversedby Intravenous Nitroglycerin:A Manifestationof Silent Myocardial lschemia CARL J. PEPINE, MD, PATRICK HOLLAND, MD,

ROBERT L. FELDMAN, MD, PHILLIP LUDBROOK, MB, CHARLES R. LAMBERT, MD, C. RICHARD CONTI, MD, and PATRICK D. McGRATH, RPh

Patients with coronary artery disease (CAD) frequently have left ventricular (LV) wall motion abnormalities in the absence of symptoms. Thirtyone patients with such LV wall motion abnormalities in the absence of symptoms parllcipated in a study of the response of these abnormalities to ascending doses of intravenous nitroglycerin (NTG). In a subgroup of 20 patients the relation between the location of LV wall motion abnormalities and the presence or absence of significant CAD (250 % diameter reduction), in the vessel supplying the LV region, was assessed. Wall motion improved after intravenous NTG; the ejection fraction increased by 3.7% (mean p <0.05) and by 9.4% in the 19 patients who responded. There was no significant

increase in heart rate; both LV systolic and enddiastolic pressures decreased minimally (12.5 and 3.5 mm Hg, respectively, p <0.05). The ejection fraction response was observed with NTG doses 5200 w and no dose-response relation was apparent. In the subgroup subjected to regional wall motion analysis, the presence of dyskinesia was significantly (p = 0.007) associated with the presence of important CAD in a vessel supplying that region. Further, the fact that wall motion improvement after NTG was significantly (p = 0.002) associated supports the concept that silent ischemia results in LV regional wall motion abnormalities, which can be reversed with low dose intravenous NTG. (Am J Cardiol 1986;58:38B-428)

T

here is growing concern that silent myocardial ischemia is a major clinical problem and that its detection and treatment require more attention1 Episodes of transient ST-segment changes characteristic of myocardial ischemia occur frequently in the absence of symptoms in patients who have angina at other times.2-7 However, the functional and clinical importance of silent myocardial ischemia requires further study. Contractile left ventricular (LV) function is closely coupled to the adequacy of myocardial perfusion. In clinical studies this principle underlies LV wall mo-

tion abnormalities observed during stress-induced8 or spontaneously occurring angina.g Reversal of clinical manifestations of myocardial ischemia by sublingual nitroglycerin (NTG) is generally associated with improved wall motion.g Dyskinetic LV segments that respond to NTG contain histologically normal myocardiurn but areas not responding to NTG contain mostly fibrotic scar.lO Although LV wall motion abnormalities are common in patients with coronary artery disease (CAD), in general, previous studies have not focused on these abnormalities as manifestations of silent ischemia. If this notion is true, reversible LV wall motion abnormalities in patients with CAD detected during asymptomatic intervals should be localized to regions supplied by arteries with severe stenosis. Further, such LV wall motion abnormalities should be improved by nitrates, which prevent or reduce silent ischemic episodes.3J1J2 Accordingly, we investigated LV dyskinesia occurring without symptoms by assessing (1) the relation

From the Division of Cardiovascular Medicine, University of Florida, and Veterans Administration Medical Center, Gainesville, Florida, and the Washington University School of Medicine, St. Louis, Missouri. Address for reprints: Carl J. Pepine, MD, Department of Medicine, Box J-277, Division of Cardiology, Gainesville, Florida 32610. 388

August

between location of dyskinesia and location and (2) wall motion responses to ascending intravenous NTG.

15,

of CAD, doses of

Methods Study population: Patients undergoing cardiac catheterization to define further the basis of signs or symptoms thought to be due to myocardial ischemia were candidates for this study. Patients whose symptoms historically did not respond to NTG, who could not tolerate NTG or who had taken NTG within 4 hours of the study were excluded. Patients who had chest pain consistent with ischemia or spontaneous ST-segment changes during the procedure before LV angiography were also excluded. Following a thorough history and physical examination, informed consent was obtained. The procedure, specifically the intravenous NTG administration and repeated ventriculography, was approved by appropriate institutional review committees. Left-sided heart catheterization: This was performed from either the brachial or femoral artery by conventional techniques. Recordings of LV pressure and electrocardiographic signals were made. LV angiography was done using Renographin 76TM and recorded on both 35-mm cinefilm at 30 to 60 frames/s and videotape. Videotape recordings were then reviewed and 31 patients with obvious LV dyskinesia were selected for study. During the control period these patients were observed as LV pressure and heart rate were monitored until effects of contrast material dissipated (10 to 15 minutes). Intravenous NTG (Marion Laboratories] was then given in 50 to 200 pg bolus injections directly into a peripheral vein using a glass syringe. Pressure and electrocardiographic signals were monitored continuously and recorded each minute. When these values stabilized between 3 and 5 minutes after injection, NTG period recordings were made. A second LV angiogram was recorded using exactly the same projection, injection rate and angiographic technique used in the control period. Selective coronary angiography was performed in every patient using conventional diagnostic techniques.

Data Analysis Assessment of global left ventricular function: Cinefilms were viewed on a projector (Vanguard XR35) coupled to a cinefilm ventriculography system [Honeywell]. Tracings of the LV cavity were made in end-diastole and systole; care was taken to avoid extrasystolic and post extrasystolic beats. The major LV axis was defined by a line drawn from the apex to the midpoint of the aortic valve. All reference points were applied independently to end-systolic and end-diastolic silhouettes. Ejection fraction was calculated and LV systolic and end-diastolic pressures were measured for at least 10 consecutive beats and averaged. Heart rate was calculated from the electrocardiogram. Assessment of regional left ventricular wall motion: Control and NTG period LV angiograms from 20 patients were subjected to more detailed regional analysis. In these patients, the LV cavity was divided

1986

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into 3 anterior and 2 posterior-inferior segments using the rectilinear chord system.13 Perpendicular lines were drawn from points that divided the major axis into thirds to points of intersection of the LV cavity outline. The area method was used to quantify LV regional wall motion since it has been shown to provide the best results.13 Relation of regional wall motion and coronary anatomy: Area changes were related to the potential perfusion to these LV regions. The 3 anterior segments (the anterior region) were considered supplied by the left anterior descending coronary artery and its branches. The 2 posterior-inferior segments (the inferior region) were considered supplied by the left circumflex and anatomically dominant right coronary arteries, The remaining inferior apical segment was not included because its blood supply is highly variable. Regions of the LV wall supplied by arteries with important CAD were considered potentially abnormal in their perfusion. Important CAD was taken as 250% diameter reduction in any of the 3 major coronary arteries or their epicardial branches. Statistical analysis: Mean and standard deviation values were calculated for hemodynamic data. The Wilcox signed rank test for paired observations was used to establish the significance of any difference between hemodynamic, ejection fraction and regional area data during control and NTG periods. Simple linear regression analysis was used,to test the association between changes in hemodynamic variables, LV ejection fractions and regional areas occurring between control and NTG periods. The association between the location of dyskinesia and location of CAD and response to NTG was tested using the Fisher exact test. A p value of SO.05 was considered significant.

Results Data of all patients relative to the hemodynamic effects of intravenous NTG are summarized in Table I. The mean age of the patients was 57 years (range 29 to 751; 90% were men. In 27 patients, symptoms were considered typical for angina pectoris. In 2 others symptoms were not typical for angina. The remaining two patients were asymptomatic after myocardial infarction. Fifteen (48%) patients had a previous myocardial infarction and 4 had a history of hypertension. There were no serious adverse effects related to the study. No patient developed hypotension with a systolic pressure 590 mm Hg. Two patients developed chest pain at 14 and 23 minutes, respectively, after the NTG period LV angiogram. In each, chest pain was promptly relieved with the addition of more NTG. Hemodynamic responses to intravenous nitroglycerin: The mean change in heart rate after intravenous NTG was only 1.7 beats/min. This change was not of statistical significance. LV systolic pressure declined 12.5 mm Hg and LV end-diastolic pressure declined 3.5 mm Hg after NTG (both p
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NTGDOSECII~) FIGURE 1. Relation between ejection fraction change (AEF%) and intravenous nitroglycerin (NTG) dose. No apparent relation exists between NTG dose and Improvement In ejection fraction. Most of the responders were in the lOO- to 200~pg dose range.

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NTG dose. In the patients receiving 5200 pg NTG, changes in heart rate, LV systolic pressure and enddiastolic pressure were either minimal or not significant (Table I).

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Global left ventricular function responses to intravenous nitroglycerin: In an asymptomatic interval before administration of NTG, global LV ejection fraction was 51.7 f 15% (mean f standard deviation]. After the bolus of intravenous NTG, global LV ejection fraction increased to 55.4 f 14% (p <0.05). The ejection fraction increased in 19 of the 31 patients and the mean change in responders was 9.4%. The average dose of NTG administered was 289 pg. There was no significant association between NTG dose and change in ejection fraction (Table II, Fig. 1). The change in ejection fraction did not correlate with changes in either heart rate or LV end-diastolic pressure but was associated with the change in LV systolic pressure in an unexpected manner. The greater decrease in systolic pressure was associated with lesser improvement or even a decrease in ejection fraction (Fig. 2). The ejection fraction increase, however, appeared particularly sensitive to low doses of intravenous NTG (Table I]. Six patients received only 100 pg and ejection fraction increased in 4 of these (range 2% to 13%). A total of 18 patients received 5200 pg and the ejection fraction increased in 12 of these with a range of 2% to 20%. Abnormal regional left ventricular wall motion location and response to intravenous nitroglycerin: LV wall motion was abnormal in 24 of 28 (p = 0.007)

TABLE II Relation Dose, Hemodynamics

Between Intravenous Nitroglycerin and Ejection Fraction

(NTG)

TABLE Ill Location of Dyskinesis and Coronary Artery Disease and Response to Intravenous Nitroglycerin (NTG) (n = 20)

r

F Ratio

p Value

-0.16 0.02 -0.04 -0.18 0.40 0.19

0.781 0.017 0.051 0.930 5.390 1.150

NS NS NS NS
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NTG dose vs ejection fraction NTG dose vs heart rate NTG dose vs LV systolic pressure Ejection fraction vs heart rate Ejection fraction vs LV systolic pressure Ejection fraction vs LV end-diastolic pressure LV = left ventricular;

NS = difference

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Anterior Pt. No.

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regions supplied by vessels with important CAD in the 20 patients whose angiograms were subjected to this analysis (Table III). Fourteen of these dyskinetic regions supplied by vessels with important CAD were anterior and 10 were inferior. The presence of anterior regional wall motion abnormality was associated with CAD in vessels supplying the anterior region (p = 0.03). All of the 14 dyskinetic anterior regions supplied by vessels with CAD showed improved motion after intravenous NTG (p = 0.001). The anterior wall motion response was very sensitive to low dose intravenous NTG (Fig. 3). Wall motion improved in only 7 of 10 inferior dyskinetic regions supplied by vessels with important CAD (p
Discussion In patients with CAD, abnormalities in LV regional function are frequently observed. However, there is controversy concerning the basis for these abnormalities and the response of these abnormalities to NTG. McAnulty et all4 found that sublingual NTG improved LV wall motion abnormalities in CAD patients. Helfant,15 Chesebro*” and their co-workers observed that regional LV responses to sublingual NTG were a reliable predictor for improvement in regional dynamics

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after successful bypass surgery. Dumesnil et all7 reported that sublingual NTG improved regional LV function but that the response differed within regions of the same ventricle. Recently Sasayama et all8 suggested considerable variation in regional LV responses after sublingual NTG. Another study suggested deterioration in wall motion or no change after NTG in the majority of LV regions showing asynergy.lg Studies f11 dogs using intravenous NTG suggest no improvement in regional LV wall motion in an acutely ischemic preparation.20 Although improvement in wall motian after sublingual NTG is well documented using LV angiography, 1 study suggested that such improvement does not correlate with the magnitude of the hemodynamic change induced .21 Sublingual NTG has also

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FIGURE 2. Relation between change in left ventricular systolic pressure (ALVSP) and ejection fraction change (AEF). Although there is considerable scatter, there Is an association between the magnitude of the blood pressure decrease and the deterioration in EF or failure to increase, despite the fact that no patient became hypotensive.

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been shown to increase regional myocardial perfusion in LV regions supplied by coronary vessels with important stenosis.22 Coronary flow could increase by favorable redistribution either transmurally or regionally through improved collateral circulation, through increases in a port& of subendocardial flow or simply in relative terms through reduction in determinants of myocardial oxygen demand. Intravenous nitroglycerin and left ventricular regional and global function: In the present study of patients undergoing evaluation for ischemic heart disease we selected those who had LV dyskinetic regions in the absence of symptoms or electrocardiographic evidence of transient myocardial ischemia. None had taken NTG before the study. The location of these motion abnormalities was significantly associated with potentially abnormal perfusion via coronary arteries containing important stenoses. After intravenous NTG, there was overall improvement in global LV performance, manifest by an increase in ejection fraction and a decrease in LV end-diastolic pressure. In the subgroup undergoing regional wall motion analysis, improvement was generally seen in regions with potentially abnormal perfusion. The association between anterior CAD and anterior regional dyskinesis was highly significant. In potentially abnormally perfused inferior regions, however, improvement was seen in only 7 of 10 patients; this may be related to prior inferior infarction in some. The improvement in LV wall motion observed after intravenous NTG occurred in the absence of a significant change in heart rate. In fact, even the LV pressure changes overall were only minimal in magnitude. Further, the correlation between changes in LV systolic pressure and ejection fraction was the opposite of that expected. This result suggests that the decrease in systolic pressure may adversely affect LV wall motion in patients with dyskinesia, perhaps by a decrease in coronary perfusion pressure resulting in a reduction of coronary flow. An unexpected finding in this study was the relatively low doses of intravenous NTG associated with improved LV wall motion. These doses (100 to 200 pg) are known to cause very little, if any, important systemic and LV pressure changes as confirmed by this study. Although the evidence is indirect, these data support the concept of silent ischemia as the basis for reversible asynergy in patients with CAD. Left ventricular segmental wall motion abnormality as a marker of silent myocardial ischemia: Recently, Deanfield et a14-6 found that myocardial perfusion defects on positron emission tomography occurred coincident with ST-segment changes in the absence of angina. They also observed periods when perfusion defects occurred with neither angina nor ST-segment changes; these defects were similar in location to defects observed during angina associated with ST-segment changes. Alterations in LV end-diastolic pressure and LV dP/dt, not accompanied by symptoms, in angina patients indicate that transient ischemia without pain also causes LV dysfunction.7

MYOCARDIAL

ISCHEMIA

IN CORONARY

ARTERY

DISEASE

It seems reasonable to conclude that transient myocardial ischemia occurs frequently in the absence of pain and even without ST-segment changes in patients with CAD. Results of this study suggest that dyskinetic LV wall motion may, at times, be a manifestation of silent myocardial ischemia. Low dose intravenous NTG may unmask this silent ischemia. Further studies relative to the direct and indirect cardiac effects of low dose intravenous NTG are indicated.

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3. Schang SJ, Pepine CJ. Transient, asymptomatic ST segment depression during dailv activitv. Am T Cordial 1977:39:396-402. 4. Deinfieid JE, Selwyn ‘AP, Chierchia S, Maseri A, Ribeiro P, Krikler S, Morgan M. Myocardi$ ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;12:753758.

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11. Pepine CJ. Asymptomatic myocardial ischemia during daily activities: observations in persons with and without coronary heart disease. In: Stern S, ed. Ambulatory EGG Monitoring. 1st ed. Chicago: Year Book Medical, 1978:107-119. 12. Distante

A, Maseri A, Severi S, Biagini A, Chierchia S. Management vasospostic angina at rest by continuous infusion of isosorbinde dinitrate. double-blind crossover study in coronary care unit. Am J CardioI1979;44:533539. 13. Gelberg

of A

HJ, Bnmdage BH, Glantz S, Parmely WW. Quantitative Ieft ventricular wall motion analysis: a comparison of area, chord, radial methods. Circulation 1979:59:991-1000. 14. McAnulty JH, Hattenhauer MT, Rosch J, Kloster FE, Rahimtoola SH. Improvement in left ventricular wall motion following nitroglycerin. Circulation 1975;51:140-145. 15. Helfant RH, Pine R, Meister SG, Feldman MS, Trout RG, Banka VS. Nitroglycerin to unmask reversible asynergy. Correlation with post coronary bypass ventricuiography. Circulation 1974;50:108-113. 16. Chesebro JH, Ritman EL, Frye RL, Smith HC, Rutherford BD, Fnlton RE, Plnth JR, Barnhorst DA. Regionai myocardial wall thickening response to nitroglycerin-a predictor of myocardial response to aortocoronary bypass surgery. Circulation 1978;57:952-957. 17. Dumesnil JG, Ritman EL, Davis GD, Gau ST, Rutherford BD, Frye RL. Regional left ventricular wall dynamics before and after sublingual administration of nitroglycerin. Am J CardioI1975;36:419-425. 18. Sasayama g;Nonogi H, Pujita M, Sakurai T, Wakabayashi A, Kawai C, Eiho S, Kuwahara M. Three-dimensional analysis of regional myocardial function in response to nitroglycerin in patients with coronary artery disease. JACC 1984;3:1187-1196. 19. Tei C, Chin K, Vijayaraghavan G, Boltwood CM, Shah PM. Paradoxical deterioration of left ventricular osynergy after administration of nitroglycerin. Am J Cardioll985;55:677-679. 20. Komer RR, Edalji A, Hood WB. Effects of nitroglycerin on echocardiographic measurements of left ventricular wolf thickness and regional myocardial performance during acute coronary &hernia. Circulation 1979;59:926-937. 21. Dove JT, Shah PM, Schreiner BF. Effects of nitroglycerin on left ventricular wall motion in coronary artery disease. Circulation 1976;49:682-687. 22. Mehta J, Pepine CJ. Effect of sublingual nitroglycerin on regional ffow in patients with and without coronary disease. Circulation 1978:58:803-807.