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Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease
Coronary Artery Dilation and Hemodynamic Responses After lsosorbide Dinitrate Therapy in Patients with Coronary Artery Disease RODNEY S. BADGER, MD, B. GREG BROWN, MD, PhD, CHRISTIAN A. GALLERY, BS, EDWARD L. BOLSON, MS, and HAROLD T. DODGE, MD
The response to sublingual isosorbide dinitrate (ISDN) was studied in IO men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53 % reduction (p
normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to iuminai area (1 to 4,4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at IO minutes of 55% (p
Isosorbide dinitrate (ISDN) is an organic nitrate that has effects on the cardiovascular system that are qualitatively similar to those of nitroglycerin (NTG). Goldberg1 reported in 1948 that ISDN ranked consistently among the most active of the long-acting nitrates in speed of action and magnitude and duration of effect. Organic nitrates are known for their effectiveness in
relieving angina pectoris, although their mechanisms are complex and often debated. The classic description of nitrate action is reduction of myocardial oxygen demand through reduced afterload (systemic pressure) and preload (left ventricular end-diastolic volume and pressure).2-5 The effectiveness of NTG as a coronary vasodilator has been well studied. Early angiographic observations by Winbury, Sones, Gensini, and Likoff and co-worker@ described coronary arterial dilation after NTG administration. Further observations established NTG as a dilator of coronary collaterals and large undiseased epicardial arteries.l&i2 However, there were no apparent changes in the caliber of diseased coronary segments. In clinically effective doses, NTG does not dilate the coronary arteriolar resistance bed.1°J2-14 Gensini et a1,i5 in 1971, demonstrated significant dilation of apparently normal segments of human coronary arteries after sublingual ISDN treat-
From the Department of Medicine, Cardiology Division, and Cardiovascular Research and Training Center, University of Washington School of Medicine, Seattle, Washington. This study was supported in part by Grants HL 13517 and HL 19451, U.S. Public Health Service, Washington, DC., a grant from the Washington State Heart Association, Seattle, Washington, and in part by a grant from the R.J. Reynolds Foundation, Winston-Salem, North Carolina. Dr. Brown is an Established Investigator of the American Heart Association. Manuscript received October 12, 1984; revised manuscript received April 8, 1985, accepted April 12, 1985. Address for reprints: Rodney S. Badger, MD, Pinole Cardiology Group, 1580 Mann Drive, Pinole, California 94564. ir 390
September
ment. Rafflenbeul et ali6 found that ISDN dilates diseased segments. The hypothesis that NTG caused a hemodynamically significant dilation of the actual atherosclerotic coronary lesion has been reexamined.lg Using a method for computer-assisted analysis of angiograms,18 the physiologic importance of seemingly small amounts of NTG-induced stenosis dilation was demonstrated. In this study, we examine the hypothesis that ISDN, as a potent and long-acting organic nitrate, causes a similar dilation of the atherosclerotic coronary lesion. Our approach includes computer-assisted measurements of the response of normal and diseased epicardial coronary artery segments to ISDN over 30 minutes. We believe that in most cases, an important component of the beneficial effect of ISDN derives from direct stenosis dilation, and that ISDN is at least as potent and is more prolonged in its effect on epicardial coronary arteries than NTG.
Methods Patient study-sublingual isosorbide dinitrate: Ten men with symptomatic coronary artery disease underwent cardiac catheterization. Five patients had exertional angina plus episodes of rest pain with associated ST-segment depression; none had variant angina.lg All cardiac medications were held for 12 hours before catheterization. Patients were excluded from the study if they used sublingual NTG within
_
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THE AMERICAN
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~~~~R~ 1. Averaged responses to sublingual isosorbide din&&e (ISDN) in 10 patients. Paired t and l-way analysis of variance statistical comparison of measured values at given point with those at time 0 control: t p <0.05; * p
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4 hours of catheterization. Patients were also excluded if they had a myocardial infarction within the preceding 2 weeks, severe hypertension (blood pressure greater than 180/120 mm Hg), systolic blood pressure of less than 90 mm Hg, severe coexistent cardiac or systemic disease state, or a history of nitrate intolerance. Patients underwent left- and right-sided cardiac catheterization using Seldinger technique via the femoral artery and vein, with placement of selected aortic catheters and a Swan-Ganz thermodilution catheter in the pulmonary artery. Hemodynamic measurements included right atrial, pulmonary artery, and pulmonary capillary wedge pressures, thermodilution cardiac output averaged over 3 injections of iced saline solution, and systolic, diastolic and mean arterial pressures. Left ventricular angiography and coronary angiography were performed, the videotape was reviewed to select a projection that best demonstrated 1 or several diseased epicardial coronary artery segments. Hemodynamic measurements before ISDN and the selected angiographic view were repeated a mean of 20 minutes after the initial measurements. ISDN was given sublingually as 5 mg in 6 patients and 10 mg in 4. Then, at intervals of 1, 3, 6, 10, 15 and 30 minutes after ISDN administration, angiographic and hemodynamic determinations were repeated. Systemic and pulmonary vascular resistances were calculated from the direct hemodynamic measurements.20 Angiograms performed before and after administration were reviewed and 43 diseased and 57 normal epicardial coronary segments were selected for image clarity and to include a wide spectrum of epicardial vessel sizes. Quantitative angiography: A computer-assisted method was used to analyze the selected coronary segments. The application of this method for study of epicardial coronary vasodilation has been described in detail.17Js Using a digital representation of the angiogram, the computer analysis determines vessel diameter and cross-sectional area in the “normal” proximal and distal segments, and at the point of maximal narrowing in the diseased segment. Further calculations determine percent diameter and area stenoses, lesion length, atheroma mass, and estimated stenosis resistance at an assumed coronary blood flow of 1 ml/s using published formulas.1sv21A detailed analysis of the effects of ISDN was made only for normal luminal area, minimum area, percent diameter stenosis and stenosis flow resistance. The accuracy of this method is within 0.08 mm for measurements of known dimensions; its variability averages f3% (& standard deviation) for percent stenosis estimates and 0.10 mm for minimum diameter estimates.18*21,22Using a single angiographic view to assesscross-sectional area of a lumen within an eccentrically located atheroma may, in some cases,underestimate the response to a vasodilating agent. Statistical analysis: The significance of the group average responses was determined using a l-way analysis of variance comparing summed observations before and after treatment with ISDN. Statistical analysis was accomplished using an established computer application.23 Further statistical analysis was made using a paired t comparison of each individual value at a given time point with the appropriate set of 0 time control values. Significance was defined as less than 5% probability of the null hypothesis.
30
I SDN
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Results Effects
of ~soso~bid~
measurements:
d~ni~~a~e
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ISDN administration significantly lowered the mean arterial blood pressure at both 5-mg or IO-mg dosages (Fig. l), with an average reduction of 20% (p
ISOSORSIDE
392
DINITRATE
AND
CORONARY
ARTERY
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wedge pressure decreased an average of 53% (p
segments were identified and analyzed sequentially over time (Fig. 3). The epicardial coronary segments were then categorized by size into 3 groups: group I (luminal area 1 to 4 mm2, diameter 1.1 to 2.3 mm), group II (luminal area 4 to 8 mm2, diameter 2.3 to 3.2 mm), and group III (luminal area more than 8 mm2, diameter more than 3.2 mm). Patients in group I were the most responsive; luminal area increased a mean of 55% (p
0-4 e--o H
8r
5mg ISDN IOmg ISDN All Patients
significant vessel dilation occurred as early as 1 minute after ISDN administration. Peak drug effect occurred at 10 minutes and persisted for the remaining 20 minutes of the study. Patients in Group II were next most responsive; luminal area increased a mean of 29% (p
ments were identified and analyzed (average 4.3 per patient). Lesions varied in severity from 20% to 75% stenosis. Thirteen lesions were identified as significant (50% or more diameter stenosis). These significantly diseased segments were then separated into 2 groups based on the size of the adjacent normal segment, small and medium-sized epicardial vessels (luminal area 1 to 8 mm2, n = 7), and larger vessels (luminal area more than 8 mm2, n = 6). The effect of ISDN on minimum luminal area was then analyzed for each group separately and for all significantly diseased segments combined, and is summarized in Figure 4. Vessels with a luminal area of 1 to 8 mm2 showed the greatest response of the diseased segment to ISDN, with a mean 77% increase (p
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FIGURE 2. Averaged responses to sublingual isosorbide dinitrate (ISDN) in 10 patients. Paired t and l-way analysis of variance-statistical comparison. p
0
30
3
6
,
,
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15 Time
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<0.05.
3. Percent increase in luminal cross-sectional area of normal segments after administration of sublingual isosorbide din&ate Vessels are grouped according to lumen size. p CO.01; t p l
September
minutes (76%, p
Effect of isosorbide dinitrate on stenosis flow resistance: The effect of ISDN on predicted stenosis flow resistance is summarized in Figure 5. Lesions were subclassified by severity, with 13 significantly diseased segments (50% or more stenosis) and 30 less severely diseased segments (less than 50% stenosis). Physiologically and statistically significant reductions in predicted flow resistance occurred at both levels of disease severity. Assuming an estimated coronary blood flow of 1 ml/s in the control state, predicted group average stenosis flow resistance in less severely diseased segments was 1.9 mm Hg/ml/s, and 18.7 mm Hg/ml/s in significant lesions. After sublingual ISDN administration, predicted stenosis flow resistance fell an average of 43% and 39% (p
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nificant lesions demonstrated a resistance reduction by at least 35%. Undoubtedly, coronary blood flow changes as ISDN affects both myocardial preload and afterload. Using an assumed coronary flow of 1 ml/s as the control value, instead of 2 or 3 mijs, the predicted change in stenosis flow resistance is underestimated. Calculated percent diameter stenosis measurement changed very little, and was never statistically significant for any size vessel regardless of severity of disease. Group average change in percent stenosis for small, medium and large vessels was -15%, -17% and -6% respectively (difference not significant for all). This lack of significant change probably reflects the relatively equal proportion to which ISDN dilates both normal and diseased segments.
Discussion This study shows that ISDN is a potent coronary vasodilator with hemodynamic effects similar to those of NTG. The observation that normal segments of coronary arteries dilate in response to NTG is well established. This effect has recently been quantified to reflect an average increase of 18% in luminal cross-sectional area.17 Using the same quantitative technique, it has also been shown that NTG dilates segments narrowed by atherosclerosis, thus confirming stenosis dilation as a mechanism of the benefit from NTG. ISDN is a potent organic nitrate, longer lasting than NTG, with similar clinical efficacy in relieving angina. Using the same quantitative technique, this study has evaluated the coronary arterial response and hemodynamic effects of sublingual ISDN over 30 minutes. The effect of sublingual ISDN was rapid in onset, significant at 3 minutes after administration, with peak
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I SDN of minimum luminal area in 13 significant diseased coronary segments (50% or more stenosis before drug) by sublingual isosorhide dinitrate (ISDN). Lesions in small and medium vessels (luminal cross-sectional area of normal portion 6 mm* or less) (n = 7) are substantially more vasoactive than those in large vessels (luminal crosssectional area more than 6 mm*, n = 6). ’ p
FIGURE
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FiGWE 5. Estimated change in stenosis flow resistance post isosorbide &nitrate (ISDN) at an assumed coronary blood flow of 1 ml/s. Diseased segments are grouped by severity of stenosis: (50% or more n = 13; less than 50%, n = 30) Numbers in parenthesis are f 1 standard deviation. p
394
iSOSORBlDE
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effect occurring at 10 minutes and persisting unchanged for at least 20 minutes more. Data regarding the time course of arterial dilation after NTG in humans was demonstrated by Mason and Braunwald,24 peak arterial NTG effect occurred at 5 minutes, and returned to normal over the subsequent 20 minutes. Gensini et al15 showed in dogs that the response of NTG disappears after 25 minutes. The time course of coronary dilation and hemodynamic response after ISDN administration corresponds to previous pharmacologic studies by Assinder et al.25 Six healthy men were given ISDN, 5 mg sublingually, and had a peak of 8.9 rig/ml at 15-minutes with a calculated half-life of 30 minutes. The prolonged effect of ISDN may be the result of a longer plasma half-life or to its potent mononitrate metabolites.26 Measurement of severely diseased coronary artery segments (stenosis 50% or greater) revealed a direct effect of ISDN on the atherosclerotic lesion. The original diseased luminal area dilated an average 51%. Dilation of the diseased segment after ISDN was most prominent in midsized epicardial vessels, where many clinically significant atherosclerotic lesions occur. This study shows the marked vasomobility of a typical diseased coronary segment. Atheromas are not usually fixed and calcified circumferential cholesterol lesions, but are more often eccentrically located, with a portion of the vessel lumen surrounded by an arc of normal arterial ~all.~‘*~~ We believe that this reactive arc of smooth muscle allows for the change in the minimum luminal area and for the reduction in stenosis flow resistance observed after ISDN administration.29930 More important than absolute luminal area or percent stenosis, the predicted physiologic resistance to blood flow was significantly reduced by ISDN. A formula that has been validated experimentallysl was used to estimate stenosis flow resistance at an assumed coronary flow of 1 ml/s. Both significant (50% or more) and mild to moderate (less than 50%) atherosclerotic lesions averged 39% and 43% reductions in resistance. Thus, the apparently small increase in luminal diameter from 1.1 mm to 1.25 mm in significant lesions translated to a physiologically significant resistance reduction through the l/d4 factor in the resistance calculation. The hemodynamic effects of ISDN are also similar to those of NTG. Significant decreases in preload (pulmonary capillary wedge pressure) and afterload (mean arterial pressure) were seen, with a slight decrease in cardiac output and increased heart rate. Trends toward decreases in systemic and pulmonary vascular resistance were seen, but were not significant; these data support the position that ISDN, like NTG, is more potent as a venodilator than an arteriolar dilator. Although the slight increase in heart rate may be detrimental to myocardial oxygen consumption during cardiac ischemic events, the prominent decrease in afterload reduces myocardial oxygen consumption in parallel with systolic wall tension,3 whereas the decrease in preload improves the transmural distribution of myocardial blood flow.32 We conclude that ISDN is a potent dilator of coronary arteries and systemic veins with effects that are similar to those of NTG. These effects are rapid in onset and sustained over 30 minutes after sublingual drug
administration. ISDN directly dilates both atherosclerotic lesions and normal coronary segments. In therapy of cardiac ischemia, the principal mechanisms by which ISDN relieves transient myocardial ischemia are: (1) dilation of coronary stenoses with resultant reduction in flow resistance; (2) decrease in ventricular filling pressure by venous pooling, thus reducing subendocardial microvascular compression and ventricular size; and (3) reduction in coronary flow requirement in response to a peripherally mediated decrease in myocardial oxygen consumption (decreased afterload). Acknowledgment: The aid of Clarence Denton, MD, of Ives Laboratories, Inc., New York, in providing the drug supply is greatly appreciated.
References 1. Goldberg L. Pharmacologic properties of sorbide dinitrate. Acta Physiol Stand 1948;15:173-187. 2. Burggraf GW, Parker JO. Left ventricular volume changes after amyl nitrate and nitroglycerin in man, as measured by ultrasound. Circulation 1974; 49:136-143. 3. Greenberg H, Dwyer EM, Jameson AG, Pinkerneil BH. Effects of nitroglycerin on the major determinants of myocardial oxygen consumption. An angiographic and hemcdynamic assessment. Am J Cardioi 1975;36: d3GLdRO 4. Williams JF Jr, Glick 0, Braunwaid E. Studies on cardiac dimensions in intact unanesthetized man. V. Effects of nitroglycerin. Circulation 1965; 32787-771. 5. DeMaris ANI Vismara LA, Audltore K, Amsterdam EA, Zells R, Mason DT. Effects of nttroglycerin on left ventricular cavity size and cardiac performance in man, determined by ultrasound. Am J Med 1974;57:754-780. 8. Winbury MM. Redistribution of teft ventricular blood flow produced by nitroglycerin. An example of integration of the macro- and niicrocirculaiion. Circ Res 1971:28:suppl l:l-l-140. 7. Sones FM Jr, ‘Shlrey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis 1962:31:735-738. 8. Genslnl GO, DiGiorgi S, Murad-Netto S, Black A. Atteriographic demonstration of coronary artery spasm and its release after the use of a vasodilater in a case of angina pectoris and in the experimental animal. Angiolcgy 1962;13:550-553. 9. Llkoff W, Kasparlan H, Lehman JS, Segal BL. Evaluation of “coronary vasodiiators” by coronary arteriography. Am J Cardioi 1964;13:7-9. 10. Cohn PF, Maddox D, Holman BL, Markis JE, Adams DF, See JR. Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease. Am J Cardiol 1977;39:872R7R 11. Goldstein RE, Stlnson EB, Scherer JL, Senlngen RP, Grehl TM, Epsteln SE. lntraoperative coronary collateral function in patients with coronary occlusive disease. Nitroglycerin responsiveness and angiographic correlations. Circulation 1974;49:298-308. 12. Feldman RL, Peplne Gf, Curry RC, Contl CR. Coronary arterial responses to graded doses of nitroglycerin. Am J Cardioi 1979;43:91-97. 13. Mehta J, Peplne CJ. Effects of sublingual nitroglycerin on regional flow in fM$tts with and without coronary disease. Circulation 1978;58:803-e”
“,
““.
T”_.
-.
.
14. Miller RR, Awan NA, DeMaris AN, Amsterdam EA, Mason DT. Importance of maintaining systemic blood pressure during nitroglycerin admlnistration for reducing ischemic injury in patients with coronary disease. Effect of coronary blood flow, myocardiai energetlcs. and left ventricular function. Am J Cardioi 1977;40:504-508. 15. Genslni GO, Kelley AE, DaCosta BCB, Huntington PP. Quantitative angiography: the measurement of coronary vasomobillty in the intact animal and man. Chest 1971;60:522-530. 16. Rafflenbeul W, Urthaler F, Russell RO, Llchtlen P, James TN. Dilation of coronary artery stenoses after isosorbide dinitrate in man. Br Heart J 1980;43:546-549. 17. Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT. Ths mechanisms of nitroglycerin action: stenosis vasodilation as a major component of the drug response. Circulation 1981;64:1089-1097. 18. Brown BG, Bolson E, Frlmer M, Dodge HT. Quantitative coronary arteriography: Estimation of dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation. Circulation 1977;55:329-337. 19. Prinzmetal M, Kennamer R, Merllss R, Wada T, Bar N. A variant form of angina pectoris: preliminary report. Am J Med 1959;27:375-388. Grossman W: Cardiac Catheterization and Angiography. Philadelphia: Lea & Febiger, 1980:117. 21. McMahon MM, Brown BG, Cuklngnan R, Rolett EL, Bolson E, Frlmer M, Dodge HT. Quantitative coronary angiography: measurement of the “critical” stenosis in oatients with unstable anaina and sinale-vessel disease ” without collaterals.. Circulation 1979;80:1~6-113. 22. Koh D, Mitten S, Stewart D, Bolson E, Dodge HT. Comparison between computerized quantitative coronary angicgraphy and clinical interpretation (abstr). Circulation 1979;6O:suppl il:ll-160. 23. Kim JO, Kohout FJ. Analysis of variance and covarlance: subprograms ANOVA and ONEWAY. In: Nie NH, ed. Statistical Package for the Social Sciences. 2nd ed. New York: McGraw-Hill, 1975:398-433. 24. Mason DT, Braunwald E. The effects of nitroglycerin and amyi nitrite on
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25. 26. 27. 28.
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arterioiar and venous tone in the human forearm. Crrcuiation 1965;32: 755-766. Assinder DF, Chasseaud LF, Taylor T. Plasma isosorbide dinitrate concentrations in human subjects after administration of standard and sustained-release formulations. J Pharm Sci 1977;66:775-778. Wendt RL. Systemic and coronary vascular effects of the 2- and 5-mononitrate esters of isosorbfde. J Pharm Exp The; 1972;180:732 742. Vlodaver 2, Edwards JE. Pathology of coronary arteriosclerosis. Prog cardiovasc Dis 1971;14:256-274. Freudenberg H, Llchtlen PR. The normal wall segment in coronary stenosis-A postmortem study. Z Cardioi 1981;70:863-869.
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. Brown BG, Bolson E, Frtmer WI, Dodge l#T. Angiographic distinction between variant angina and non-vasospastic chest pain. Circulation 1978; 58:suppl lll:lll-122. 30. Brown BG. Coronary vasospasm: observations linking the clinical spectrum of ischemic heart diseasse to the dynamic pathology of coronary athero. sclerosis. Arch intern Med 1981;141:716-722. 31. Gould XL, Xe::ey X0, B&on EL. ExpeGmenta! vaffdation’of quantitttivc coronary arteriography for determining pressure-flow characteristics of coronary stenosis. Circulation 1982;66:930-937. 32. Becker LC, Fortuln NJ, Pitt B. Effect of ischemia and antianginai drugs on distribution of radioactive microspheres in the canine left ventricle. Circ Res 1971;28:263-269.
Life Adaptation After Percutaneous Transluminal Coronary Angioplasty and Coronary Artery Bypass Grafting DAVID RAFT, MD, DAPHNE C. MCKEE, PhD, KENNETH A. POPIO, MD, and JOHN J. HAGGERTY, Jr., MD
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Life adaptation of 32 patients who had undergone percutaneous transluminal coronary angioplasty (PTCA) for coronary stenosis was compared with that of 15 patients who had coronary artery bypass grafting (CABG). Patients were matched for psychosocial, anatomic and cardiac functions. Life adaptation was measured at 6 and 15 months after PTCA or CABG by the Psychosocial Adjustment to Illness Scale (PAIS), a multidimensional instrument that evaluates change in 7 primary life domains. The overall PAIS scores for patients who had undergone
PTCA were significantly better (p
In a previous study of patients who had undergone coronary artery bypass grafting (CABG), we found that despite correction of anatomic defects many subjects experienced considerable disabi1ity.l We suggested that such maladaptation was partially a result of the surgical procedure itself. When percutaneous transluminal coronary angioplasty (PTCA) became available, we compared rehabilitation of subjects who underwent procedure with those who underwent CABG. In 1983, Jang et al2 reported that after PTCA, patients returned to work in 2.9 weeks compared with 11.1 weeks after CABG, and the cost of PTCA is,less than half of that of CABG. An independent multicenter report3 documents the success of PTCA both in relief of coronary symptoms and improvement of patients’ global function in 83% of cases. In the present study we used a multidimensional psychosocial adjustment scale to compare patients who underwent PTCA with those who under-
went CABG for coronary stenosis. Psychological symp toms and social adaptation of successfully treated pa. tients are compared over lr/s years. Medical complications of PTCA have been well reviewed by Dorros et al4 in a recent multicenter study of 1,500 patients and are not addressed in this report.
From the Departments of Psychiatry and Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Manuscript received February 15, 1985; revised manuscript received May 3, 1985, accepted May 6, 1985. Address for reprints: David Raft, MD, University of North Carolina School of Medicine, Department of Psychiatry, Chapel Hill, North Carolina 27514.
Methods From May 1982 to June 1983,36 patients with 1 or 2 proximal coronary stenotic lesions (over 70%) were chosen for PTCA after angiography by the Judkins technique using the femoral artery approach. Dilation was performed using the Gruentzig method with a balloon 1.2 or 2 cm long and 2.5 to 3.7 mm in diameter. Inflation was carried out multiple times with a pressure inflation device. All vessels were dilated more than 50%, using the following agents: heparin, low-molecu k-weight dextran, intravenous nitroglycerin and nifedipine. After the procedure, coronary angiography was repeated; the patients received aspirin, propranolol, calcium channel blockers and/or nitrates, depending on their condition. They were monitored for 24 hours. Complications developed in 4 patients; 1 patient died and 2 underwent successful emergency CABG. All 32 patients (23 men, 9 women) who underwent successful PTCA were evaluated by a variety of psychological measures and were followed every 6 months after the proce-’
The response to sublingual isosorbide dinitrate (ISDN) was studied in IO men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53 % reduction (p
normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to iuminai area (1 to 4,4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at IO minutes of 55% (p
Isosorbide dinitrate (ISDN) is an organic nitrate that has effects on the cardiovascular system that are qualitatively similar to those of nitroglycerin (NTG). Goldberg1 reported in 1948 that ISDN ranked consistently among the most active of the long-acting nitrates in speed of action and magnitude and duration of effect. Organic nitrates are known for their effectiveness in
relieving angina pectoris, although their mechanisms are complex and often debated. The classic description of nitrate action is reduction of myocardial oxygen demand through reduced afterload (systemic pressure) and preload (left ventricular end-diastolic volume and pressure).2-5 The effectiveness of NTG as a coronary vasodilator has been well studied. Early angiographic observations by Winbury, Sones, Gensini, and Likoff and co-worker@ described coronary arterial dilation after NTG administration. Further observations established NTG as a dilator of coronary collaterals and large undiseased epicardial arteries.l&i2 However, there were no apparent changes in the caliber of diseased coronary segments. In clinically effective doses, NTG does not dilate the coronary arteriolar resistance bed.1°J2-14 Gensini et a1,i5 in 1971, demonstrated significant dilation of apparently normal segments of human coronary arteries after sublingual ISDN treat-
From the Department of Medicine, Cardiology Division, and Cardiovascular Research and Training Center, University of Washington School of Medicine, Seattle, Washington. This study was supported in part by Grants HL 13517 and HL 19451, U.S. Public Health Service, Washington, DC., a grant from the Washington State Heart Association, Seattle, Washington, and in part by a grant from the R.J. Reynolds Foundation, Winston-Salem, North Carolina. Dr. Brown is an Established Investigator of the American Heart Association. Manuscript received October 12, 1984; revised manuscript received April 8, 1985, accepted April 12, 1985. Address for reprints: Rodney S. Badger, MD, Pinole Cardiology Group, 1580 Mann Drive, Pinole, California 94564. ir 390
September
ment. Rafflenbeul et ali6 found that ISDN dilates diseased segments. The hypothesis that NTG caused a hemodynamically significant dilation of the actual atherosclerotic coronary lesion has been reexamined.lg Using a method for computer-assisted analysis of angiograms,18 the physiologic importance of seemingly small amounts of NTG-induced stenosis dilation was demonstrated. In this study, we examine the hypothesis that ISDN, as a potent and long-acting organic nitrate, causes a similar dilation of the atherosclerotic coronary lesion. Our approach includes computer-assisted measurements of the response of normal and diseased epicardial coronary artery segments to ISDN over 30 minutes. We believe that in most cases, an important component of the beneficial effect of ISDN derives from direct stenosis dilation, and that ISDN is at least as potent and is more prolonged in its effect on epicardial coronary arteries than NTG.
Methods Patient study-sublingual isosorbide dinitrate: Ten men with symptomatic coronary artery disease underwent cardiac catheterization. Five patients had exertional angina plus episodes of rest pain with associated ST-segment depression; none had variant angina.lg All cardiac medications were held for 12 hours before catheterization. Patients were excluded from the study if they used sublingual NTG within
_
120
I” z
100
,g
80
+-a e-4 -
5mg ISDN IOmg ISDN All Patients
60
$ E Y la”
12 * 8 4
t
L
100 c t-,
”
’
’
,
I
* *
I
4
-g 80 2;;: I
60 40 c -20
J
.036-----t
IO 15 Time (mm)
1, 1965
THE AMERICAN
JOURNAL
~~~~R~ 1. Averaged responses to sublingual isosorbide din&&e (ISDN) in 10 patients. Paired t and l-way analysis of variance statistical comparison of measured values at given point with those at time 0 control: t p <0.05; * p
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4 hours of catheterization. Patients were also excluded if they had a myocardial infarction within the preceding 2 weeks, severe hypertension (blood pressure greater than 180/120 mm Hg), systolic blood pressure of less than 90 mm Hg, severe coexistent cardiac or systemic disease state, or a history of nitrate intolerance. Patients underwent left- and right-sided cardiac catheterization using Seldinger technique via the femoral artery and vein, with placement of selected aortic catheters and a Swan-Ganz thermodilution catheter in the pulmonary artery. Hemodynamic measurements included right atrial, pulmonary artery, and pulmonary capillary wedge pressures, thermodilution cardiac output averaged over 3 injections of iced saline solution, and systolic, diastolic and mean arterial pressures. Left ventricular angiography and coronary angiography were performed, the videotape was reviewed to select a projection that best demonstrated 1 or several diseased epicardial coronary artery segments. Hemodynamic measurements before ISDN and the selected angiographic view were repeated a mean of 20 minutes after the initial measurements. ISDN was given sublingually as 5 mg in 6 patients and 10 mg in 4. Then, at intervals of 1, 3, 6, 10, 15 and 30 minutes after ISDN administration, angiographic and hemodynamic determinations were repeated. Systemic and pulmonary vascular resistances were calculated from the direct hemodynamic measurements.20 Angiograms performed before and after administration were reviewed and 43 diseased and 57 normal epicardial coronary segments were selected for image clarity and to include a wide spectrum of epicardial vessel sizes. Quantitative angiography: A computer-assisted method was used to analyze the selected coronary segments. The application of this method for study of epicardial coronary vasodilation has been described in detail.17Js Using a digital representation of the angiogram, the computer analysis determines vessel diameter and cross-sectional area in the “normal” proximal and distal segments, and at the point of maximal narrowing in the diseased segment. Further calculations determine percent diameter and area stenoses, lesion length, atheroma mass, and estimated stenosis resistance at an assumed coronary blood flow of 1 ml/s using published formulas.1sv21A detailed analysis of the effects of ISDN was made only for normal luminal area, minimum area, percent diameter stenosis and stenosis flow resistance. The accuracy of this method is within 0.08 mm for measurements of known dimensions; its variability averages f3% (& standard deviation) for percent stenosis estimates and 0.10 mm for minimum diameter estimates.18*21,22Using a single angiographic view to assesscross-sectional area of a lumen within an eccentrically located atheroma may, in some cases,underestimate the response to a vasodilating agent. Statistical analysis: The significance of the group average responses was determined using a l-way analysis of variance comparing summed observations before and after treatment with ISDN. Statistical analysis was accomplished using an established computer application.23 Further statistical analysis was made using a paired t comparison of each individual value at a given time point with the appropriate set of 0 time control values. Significance was defined as less than 5% probability of the null hypothesis.
30
I SDN
OF CARDIOLOGY
Results Effects
of ~soso~bid~
measurements:
d~ni~~a~e
on
mie
ISDN administration significantly lowered the mean arterial blood pressure at both 5-mg or IO-mg dosages (Fig. l), with an average reduction of 20% (p
ISOSORSIDE
392
DINITRATE
AND
CORONARY
ARTERY
DISEASE
wedge pressure decreased an average of 53% (p
segments were identified and analyzed sequentially over time (Fig. 3). The epicardial coronary segments were then categorized by size into 3 groups: group I (luminal area 1 to 4 mm2, diameter 1.1 to 2.3 mm), group II (luminal area 4 to 8 mm2, diameter 2.3 to 3.2 mm), and group III (luminal area more than 8 mm2, diameter more than 3.2 mm). Patients in group I were the most responsive; luminal area increased a mean of 55% (p
0-4 e--o H
8r
5mg ISDN IOmg ISDN All Patients
significant vessel dilation occurred as early as 1 minute after ISDN administration. Peak drug effect occurred at 10 minutes and persisted for the remaining 20 minutes of the study. Patients in Group II were next most responsive; luminal area increased a mean of 29% (p
ments were identified and analyzed (average 4.3 per patient). Lesions varied in severity from 20% to 75% stenosis. Thirteen lesions were identified as significant (50% or more diameter stenosis). These significantly diseased segments were then separated into 2 groups based on the size of the adjacent normal segment, small and medium-sized epicardial vessels (luminal area 1 to 8 mm2, n = 7), and larger vessels (luminal area more than 8 mm2, n = 6). The effect of ISDN on minimum luminal area was then analyzed for each group separately and for all significantly diseased segments combined, and is summarized in Figure 4. Vessels with a luminal area of 1 to 8 mm2 showed the greatest response of the diseased segment to ISDN, with a mean 77% increase (p
36
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4
r
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(f83)
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120
.’
0 t ISDN
3
6
IO 15 Time (min)
FIGURE 2. Averaged responses to sublingual isosorbide dinitrate (ISDN) in 10 patients. Paired t and l-way analysis of variance-statistical comparison. p
0
30
3
6
,
,
IO
15 Time
, 30 (min)
ISDN FIGURE coronary (ISDN).
<0.05.
3. Percent increase in luminal cross-sectional area of normal segments after administration of sublingual isosorbide din&ate Vessels are grouped according to lumen size. p CO.01; t p l
September
minutes (76%, p
Effect of isosorbide dinitrate on stenosis flow resistance: The effect of ISDN on predicted stenosis flow resistance is summarized in Figure 5. Lesions were subclassified by severity, with 13 significantly diseased segments (50% or more stenosis) and 30 less severely diseased segments (less than 50% stenosis). Physiologically and statistically significant reductions in predicted flow resistance occurred at both levels of disease severity. Assuming an estimated coronary blood flow of 1 ml/s in the control state, predicted group average stenosis flow resistance in less severely diseased segments was 1.9 mm Hg/ml/s, and 18.7 mm Hg/ml/s in significant lesions. After sublingual ISDN administration, predicted stenosis flow resistance fell an average of 43% and 39% (p
1, 1985
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
nificant lesions demonstrated a resistance reduction by at least 35%. Undoubtedly, coronary blood flow changes as ISDN affects both myocardial preload and afterload. Using an assumed coronary flow of 1 ml/s as the control value, instead of 2 or 3 mijs, the predicted change in stenosis flow resistance is underestimated. Calculated percent diameter stenosis measurement changed very little, and was never statistically significant for any size vessel regardless of severity of disease. Group average change in percent stenosis for small, medium and large vessels was -15%, -17% and -6% respectively (difference not significant for all). This lack of significant change probably reflects the relatively equal proportion to which ISDN dilates both normal and diseased segments.
Discussion This study shows that ISDN is a potent coronary vasodilator with hemodynamic effects similar to those of NTG. The observation that normal segments of coronary arteries dilate in response to NTG is well established. This effect has recently been quantified to reflect an average increase of 18% in luminal cross-sectional area.17 Using the same quantitative technique, it has also been shown that NTG dilates segments narrowed by atherosclerosis, thus confirming stenosis dilation as a mechanism of the benefit from NTG. ISDN is a potent organic nitrate, longer lasting than NTG, with similar clinical efficacy in relieving angina. Using the same quantitative technique, this study has evaluated the coronary arterial response and hemodynamic effects of sublingual ISDN over 30 minutes. The effect of sublingual ISDN was rapid in onset, significant at 3 minutes after administration, with peak
O--O
0
3
t
6
IO
15 Time
v (mlnf
L -10
I SDN of minimum luminal area in 13 significant diseased coronary segments (50% or more stenosis before drug) by sublingual isosorhide dinitrate (ISDN). Lesions in small and medium vessels (luminal cross-sectional area of normal portion 6 mm* or less) (n = 7) are substantially more vasoactive than those in large vessels (luminal crosssectional area more than 6 mm*, n = 6). ’ p
FIGURE
893
56
il
I-.
t 50% <50%
..L-L~-.&-.-~
036 t
Stenosis Stenosis
IO Time
(min
15
30
)
ISDN
4. Dilation
FiGWE 5. Estimated change in stenosis flow resistance post isosorbide &nitrate (ISDN) at an assumed coronary blood flow of 1 ml/s. Diseased segments are grouped by severity of stenosis: (50% or more n = 13; less than 50%, n = 30) Numbers in parenthesis are f 1 standard deviation. p
394
iSOSORBlDE
DINITRATE
AND
CORONARY
ARTERY
DISEASE
effect occurring at 10 minutes and persisting unchanged for at least 20 minutes more. Data regarding the time course of arterial dilation after NTG in humans was demonstrated by Mason and Braunwald,24 peak arterial NTG effect occurred at 5 minutes, and returned to normal over the subsequent 20 minutes. Gensini et al15 showed in dogs that the response of NTG disappears after 25 minutes. The time course of coronary dilation and hemodynamic response after ISDN administration corresponds to previous pharmacologic studies by Assinder et al.25 Six healthy men were given ISDN, 5 mg sublingually, and had a peak of 8.9 rig/ml at 15-minutes with a calculated half-life of 30 minutes. The prolonged effect of ISDN may be the result of a longer plasma half-life or to its potent mononitrate metabolites.26 Measurement of severely diseased coronary artery segments (stenosis 50% or greater) revealed a direct effect of ISDN on the atherosclerotic lesion. The original diseased luminal area dilated an average 51%. Dilation of the diseased segment after ISDN was most prominent in midsized epicardial vessels, where many clinically significant atherosclerotic lesions occur. This study shows the marked vasomobility of a typical diseased coronary segment. Atheromas are not usually fixed and calcified circumferential cholesterol lesions, but are more often eccentrically located, with a portion of the vessel lumen surrounded by an arc of normal arterial ~all.~‘*~~ We believe that this reactive arc of smooth muscle allows for the change in the minimum luminal area and for the reduction in stenosis flow resistance observed after ISDN administration.29930 More important than absolute luminal area or percent stenosis, the predicted physiologic resistance to blood flow was significantly reduced by ISDN. A formula that has been validated experimentallysl was used to estimate stenosis flow resistance at an assumed coronary flow of 1 ml/s. Both significant (50% or more) and mild to moderate (less than 50%) atherosclerotic lesions averged 39% and 43% reductions in resistance. Thus, the apparently small increase in luminal diameter from 1.1 mm to 1.25 mm in significant lesions translated to a physiologically significant resistance reduction through the l/d4 factor in the resistance calculation. The hemodynamic effects of ISDN are also similar to those of NTG. Significant decreases in preload (pulmonary capillary wedge pressure) and afterload (mean arterial pressure) were seen, with a slight decrease in cardiac output and increased heart rate. Trends toward decreases in systemic and pulmonary vascular resistance were seen, but were not significant; these data support the position that ISDN, like NTG, is more potent as a venodilator than an arteriolar dilator. Although the slight increase in heart rate may be detrimental to myocardial oxygen consumption during cardiac ischemic events, the prominent decrease in afterload reduces myocardial oxygen consumption in parallel with systolic wall tension,3 whereas the decrease in preload improves the transmural distribution of myocardial blood flow.32 We conclude that ISDN is a potent dilator of coronary arteries and systemic veins with effects that are similar to those of NTG. These effects are rapid in onset and sustained over 30 minutes after sublingual drug
administration. ISDN directly dilates both atherosclerotic lesions and normal coronary segments. In therapy of cardiac ischemia, the principal mechanisms by which ISDN relieves transient myocardial ischemia are: (1) dilation of coronary stenoses with resultant reduction in flow resistance; (2) decrease in ventricular filling pressure by venous pooling, thus reducing subendocardial microvascular compression and ventricular size; and (3) reduction in coronary flow requirement in response to a peripherally mediated decrease in myocardial oxygen consumption (decreased afterload). Acknowledgment: The aid of Clarence Denton, MD, of Ives Laboratories, Inc., New York, in providing the drug supply is greatly appreciated.
References 1. Goldberg L. Pharmacologic properties of sorbide dinitrate. Acta Physiol Stand 1948;15:173-187. 2. Burggraf GW, Parker JO. Left ventricular volume changes after amyl nitrate and nitroglycerin in man, as measured by ultrasound. Circulation 1974; 49:136-143. 3. Greenberg H, Dwyer EM, Jameson AG, Pinkerneil BH. Effects of nitroglycerin on the major determinants of myocardial oxygen consumption. An angiographic and hemcdynamic assessment. Am J Cardioi 1975;36: d3GLdRO 4. Williams JF Jr, Glick 0, Braunwaid E. Studies on cardiac dimensions in intact unanesthetized man. V. Effects of nitroglycerin. Circulation 1965; 32787-771. 5. DeMaris ANI Vismara LA, Audltore K, Amsterdam EA, Zells R, Mason DT. Effects of nttroglycerin on left ventricular cavity size and cardiac performance in man, determined by ultrasound. Am J Med 1974;57:754-780. 8. Winbury MM. Redistribution of teft ventricular blood flow produced by nitroglycerin. An example of integration of the macro- and niicrocirculaiion. Circ Res 1971:28:suppl l:l-l-140. 7. Sones FM Jr, ‘Shlrey EK. Cine coronary arteriography. Mod Concepts Cardiovasc Dis 1962:31:735-738. 8. Genslnl GO, DiGiorgi S, Murad-Netto S, Black A. Atteriographic demonstration of coronary artery spasm and its release after the use of a vasodilater in a case of angina pectoris and in the experimental animal. Angiolcgy 1962;13:550-553. 9. Llkoff W, Kasparlan H, Lehman JS, Segal BL. Evaluation of “coronary vasodiiators” by coronary arteriography. Am J Cardioi 1964;13:7-9. 10. Cohn PF, Maddox D, Holman BL, Markis JE, Adams DF, See JR. Effect of sublingually administered nitroglycerin on regional myocardial blood flow in patients with coronary artery disease. Am J Cardiol 1977;39:872R7R 11. Goldstein RE, Stlnson EB, Scherer JL, Senlngen RP, Grehl TM, Epsteln SE. lntraoperative coronary collateral function in patients with coronary occlusive disease. Nitroglycerin responsiveness and angiographic correlations. Circulation 1974;49:298-308. 12. Feldman RL, Peplne Gf, Curry RC, Contl CR. Coronary arterial responses to graded doses of nitroglycerin. Am J Cardioi 1979;43:91-97. 13. Mehta J, Peplne CJ. Effects of sublingual nitroglycerin on regional flow in fM$tts with and without coronary disease. Circulation 1978;58:803-e”
“,
““.
T”_.
-.
.
14. Miller RR, Awan NA, DeMaris AN, Amsterdam EA, Mason DT. Importance of maintaining systemic blood pressure during nitroglycerin admlnistration for reducing ischemic injury in patients with coronary disease. Effect of coronary blood flow, myocardiai energetlcs. and left ventricular function. Am J Cardioi 1977;40:504-508. 15. Genslni GO, Kelley AE, DaCosta BCB, Huntington PP. Quantitative angiography: the measurement of coronary vasomobillty in the intact animal and man. Chest 1971;60:522-530. 16. Rafflenbeul W, Urthaler F, Russell RO, Llchtlen P, James TN. Dilation of coronary artery stenoses after isosorbide dinitrate in man. Br Heart J 1980;43:546-549. 17. Brown BG, Bolson E, Petersen RB, Pierce CD, Dodge HT. Ths mechanisms of nitroglycerin action: stenosis vasodilation as a major component of the drug response. Circulation 1981;64:1089-1097. 18. Brown BG, Bolson E, Frlmer M, Dodge HT. Quantitative coronary arteriography: Estimation of dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation. Circulation 1977;55:329-337. 19. Prinzmetal M, Kennamer R, Merllss R, Wada T, Bar N. A variant form of angina pectoris: preliminary report. Am J Med 1959;27:375-388. Grossman W: Cardiac Catheterization and Angiography. Philadelphia: Lea & Febiger, 1980:117. 21. McMahon MM, Brown BG, Cuklngnan R, Rolett EL, Bolson E, Frlmer M, Dodge HT. Quantitative coronary angiography: measurement of the “critical” stenosis in oatients with unstable anaina and sinale-vessel disease ” without collaterals.. Circulation 1979;80:1~6-113. 22. Koh D, Mitten S, Stewart D, Bolson E, Dodge HT. Comparison between computerized quantitative coronary angicgraphy and clinical interpretation (abstr). Circulation 1979;6O:suppl il:ll-160. 23. Kim JO, Kohout FJ. Analysis of variance and covarlance: subprograms ANOVA and ONEWAY. In: Nie NH, ed. Statistical Package for the Social Sciences. 2nd ed. New York: McGraw-Hill, 1975:398-433. 24. Mason DT, Braunwald E. The effects of nitroglycerin and amyi nitrite on
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25. 26. 27. 28.
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arterioiar and venous tone in the human forearm. Crrcuiation 1965;32: 755-766. Assinder DF, Chasseaud LF, Taylor T. Plasma isosorbide dinitrate concentrations in human subjects after administration of standard and sustained-release formulations. J Pharm Sci 1977;66:775-778. Wendt RL. Systemic and coronary vascular effects of the 2- and 5-mononitrate esters of isosorbfde. J Pharm Exp The; 1972;180:732 742. Vlodaver 2, Edwards JE. Pathology of coronary arteriosclerosis. Prog cardiovasc Dis 1971;14:256-274. Freudenberg H, Llchtlen PR. The normal wall segment in coronary stenosis-A postmortem study. Z Cardioi 1981;70:863-869.
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. Brown BG, Bolson E, Frtmer WI, Dodge l#T. Angiographic distinction between variant angina and non-vasospastic chest pain. Circulation 1978; 58:suppl lll:lll-122. 30. Brown BG. Coronary vasospasm: observations linking the clinical spectrum of ischemic heart diseasse to the dynamic pathology of coronary athero. sclerosis. Arch intern Med 1981;141:716-722. 31. Gould XL, Xe::ey X0, B&on EL. ExpeGmenta! vaffdation’of quantitttivc coronary arteriography for determining pressure-flow characteristics of coronary stenosis. Circulation 1982;66:930-937. 32. Becker LC, Fortuln NJ, Pitt B. Effect of ischemia and antianginai drugs on distribution of radioactive microspheres in the canine left ventricle. Circ Res 1971;28:263-269.
Life Adaptation After Percutaneous Transluminal Coronary Angioplasty and Coronary Artery Bypass Grafting DAVID RAFT, MD, DAPHNE C. MCKEE, PhD, KENNETH A. POPIO, MD, and JOHN J. HAGGERTY, Jr., MD
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Life adaptation of 32 patients who had undergone percutaneous transluminal coronary angioplasty (PTCA) for coronary stenosis was compared with that of 15 patients who had coronary artery bypass grafting (CABG). Patients were matched for psychosocial, anatomic and cardiac functions. Life adaptation was measured at 6 and 15 months after PTCA or CABG by the Psychosocial Adjustment to Illness Scale (PAIS), a multidimensional instrument that evaluates change in 7 primary life domains. The overall PAIS scores for patients who had undergone
PTCA were significantly better (p
In a previous study of patients who had undergone coronary artery bypass grafting (CABG), we found that despite correction of anatomic defects many subjects experienced considerable disabi1ity.l We suggested that such maladaptation was partially a result of the surgical procedure itself. When percutaneous transluminal coronary angioplasty (PTCA) became available, we compared rehabilitation of subjects who underwent procedure with those who underwent CABG. In 1983, Jang et al2 reported that after PTCA, patients returned to work in 2.9 weeks compared with 11.1 weeks after CABG, and the cost of PTCA is,less than half of that of CABG. An independent multicenter report3 documents the success of PTCA both in relief of coronary symptoms and improvement of patients’ global function in 83% of cases. In the present study we used a multidimensional psychosocial adjustment scale to compare patients who underwent PTCA with those who under-
went CABG for coronary stenosis. Psychological symp toms and social adaptation of successfully treated pa. tients are compared over lr/s years. Medical complications of PTCA have been well reviewed by Dorros et al4 in a recent multicenter study of 1,500 patients and are not addressed in this report.
From the Departments of Psychiatry and Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Manuscript received February 15, 1985; revised manuscript received May 3, 1985, accepted May 6, 1985. Address for reprints: David Raft, MD, University of North Carolina School of Medicine, Department of Psychiatry, Chapel Hill, North Carolina 27514.
Methods From May 1982 to June 1983,36 patients with 1 or 2 proximal coronary stenotic lesions (over 70%) were chosen for PTCA after angiography by the Judkins technique using the femoral artery approach. Dilation was performed using the Gruentzig method with a balloon 1.2 or 2 cm long and 2.5 to 3.7 mm in diameter. Inflation was carried out multiple times with a pressure inflation device. All vessels were dilated more than 50%, using the following agents: heparin, low-molecu k-weight dextran, intravenous nitroglycerin and nifedipine. After the procedure, coronary angiography was repeated; the patients received aspirin, propranolol, calcium channel blockers and/or nitrates, depending on their condition. They were monitored for 24 hours. Complications developed in 4 patients; 1 patient died and 2 underwent successful emergency CABG. All 32 patients (23 men, 9 women) who underwent successful PTCA were evaluated by a variety of psychological measures and were followed every 6 months after the proce-’