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Factors affecting exercise left ventricular performance in patients free of obstructive coronary artery disease
FactorsAffecting Exerciseleft Ventricular Performancein Patients Free of Obstructive CoronaryArtery Disease ABDULMASSIH
S. ISKANDRIAN, MD, JAEKYEONG HEO, MD, ALAN ASKENASE, RICHARD H. HELFANT, MD, and BERNARD L. SEGAL, MD
R
MD,
high normal subjects, while patients with normal coronary arteriograms represent the low normal subjects. The LV performance during exercise is affected by factors other than stenosis of the epicardial coronary arteries. These factors will be discussed next. The subjective method of interpreting the coronary arteriogram is often less than ideal. The concept of percent diameter stenosis as an indicator of the hemodynamic severity of coronary stenosis has been seriously challenged by recent studies that show the lack of correlation between percent diameter stenosis and reactive hyperemic flow, and suggest that multiple factors can influence hemodynamic severity of the coronary lesion. These include exit angle, entrance angle, length, absolute cross-sectional area, eccentricity, multiple lesions and size of the vascular territory. Other factors include the presence of diffuse disease, changes in the vasomotor tone, variation in the systolic blood pressure and associated factors such as LV hypertrophy, anemia and medications.8-ll Coronary artery ectasia, a localized or a diffuse dilatation of a coronary artery, should not be overlooked.*z In the elderly patients, atherosclerosis is probably the most common cause of ectasia, although the etiology in the younger patient is less clear and may be related to a congenital defect in the muscular component of the vessel wall. Patients with ectasia may have angina1 symptoms. A striking finding on arteriography is the slow washout of the contrast medium. The disturbances in the vessel wall and the flow may predispose to thrombus formation and acute myocardial infarction. Therefore, patients with ectasia cannot be accepted as normal subjects even though there is no obstructive disease in the epicardial vessels. The concept of exercise-induced spasm is now well documented.13 The residual muscular tissue at the site of focal atherosclerotic lesion is the mechanism by which such stenosis reacts to stimuli that produce spasm. Although chest pain and associated electrocardiographic changes may accompany exercise-induced
adionuclide ventriculographic evaluation of left ventricular (LV] performance during exercise has shown that normal subjects manifest a slight increase in end-diastolic volume (Frank-Starling mechanism], a decrease in the end-systolic volume (increase in contractility] and an increase in the stroke volume [due to both mechanisms]. The increase in cardiac output is due to increases,in stroke volume and heart rate. There is improvement in the ejection fraction (EF]; the EF increases by 5% or more from rest to exercise depending on the EF at rest.1-4 An abnormality in LV response to exercise has been defined in terms of failure to augment the EF, appearance of wall motion abnormality or failure to decrease the end-systolic volume. Other less often used indexes include changes in pulmonary blood volume, pressure-volume relation and LV diastolic filling characteristics.5 The “normal” subjects who have been used to define the “normal” physiologic responses can be categorized into 3 types+ healthy volunteers, usually young and usually men; patients with a low pretest probability of coronary artery disease (CAD] based on clinical presentation and coronary risk factors; and patients with normal coronary arteriograms. Such patients are generally older and have troublesome or severe enough symptoms to warrant coronary arteriography. Coronary risk factors are more common in this group of patients.7 If normality can be viewed as a continuum rather than discrete, the healthy volunteers represent the From the Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, Pennsylvania. Manuscript received May 19,1987; revised manuscript received and accepted July 14,1987. Address for reprints: AS. Iskandrian, MD, Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, 39th and Market Streets, Philadelphia, Pennsylvania 19104. 1173
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spasm, it is possible that some episodes may only be manifested by abnormalities in LV function during exercise. Some patients with anomalous origin of the coronary arteries may have symptoms due to myocardial ischemia despite the presence of normal epicardial vessels. This has been well described in patients with anomalous origin of the left main coronary artery from the right coronary sinus (with the course of the left main between the great vessels). More recently, however, it has also been described in patients with anomalous origin of the right coronary artery from the left coronary sinus (with a course of the right coronary artery between the great vessels).14J5 Systolic bridging of the coronary arteries is another possible cause. This entity, which is also known as “milking” of the coronary arteries, is characterized by narrowing of the diameter of the coronary artery during systole only. l6 The severity of the narrowing may be mild but occasionally total obliteration of the lumen may be observed. The site and the length of the narrowing are variable and although more common in the left anterior descending artery, it has been described in the other coronary arteries. The narrowing may spill over to early diastole. In general, the more severe the bridging, the more likely it is that it involves the early part of diastole as well. In some patients, the bridging can be provoked by sublingual administration of nitroglycerin.16 Other noncoronary diseases may modify the LV response to exercise. Regional or global abnormalities have been described on the left ventriculograms in patients with mitral valve prolapse syndrome. The etiology of chest pain is not clear; abnormalities in LV performance have been reported to be age- and gender-related; that is, abnormalities are more common in the elderly patients and in women.17 Abnormal LV function during exercise has been observed even in asymptomatic diabetic patients with normal epicardial coronary arteries. It is not clear whether the dysfunction is due to primary myocardial cellular dysfunction (due to metabolic derangement) or to microvascular disease. Thickening of the capillary basal membrane has been documented in diabetic retinopathy and nephropathy as well as in the skeletal muscle and in the skin. More recently, increased basal membrane thickness has been observed in biopsy specimens from myocardium in such patients.lsJg Abnormality in the reserve coronary blood flow has been observed in patients with LV hypertrophy due to aortic stenosis, hypertrophic cardiomyopathy and hypertension. This finding may be due to abnormal reactivity of the coronary microvascular circulation, elevated basal and stress coronary flow requirements that could prematurely exhaust coronary flow reserve, deleterious effects of abnormal diastolic function and altered capillary density on flow reserve and, possibly, also to small vessel disease.20-z7This vascular and flow abnormality may also explain the angina1 symptoms and the abnormality in the exercise LV function observed in some of these patients.
Other diseases can modify the LV function during exercise, such as primary cardiomyopathy, valvular heart diseases, congenital heart diseases, chronic obstructive pulmonary disease, endocrine disorders, severe anemia, connective tissue disorders and extreme obesity.16J8 Some patients with myocarditis may recover and have normal or near normal LV function at rest; the reserve function remains abnormal.2g It is possible that some patients with new onset conduction defects may have a latent form of cardiomyopathy, which could explain the LV dysfunction during exercise. The abnormal LV response to exercise in such patients may also be the result of abnormal sequence of depolarization. Over 20 years ago, syndrome X was described as chest pains and electrocardiographic changes in patients with normal coronary angiograms.30Various hypotheses were suggested to explain the chest pains but none was documented. Although initially described in women, subsequent studies have shown that such a syndrome may also be seen in men. Recent hemody namic, metabolic, exercise and coronary blood flow studies have suggested the presence of inappropriate tone in the small coronary artery vessels in such patients.25,31B2Improvement in symptoms and exercise LV performance have been reported after treatment with calcium channel blocking agents, suggesting that the abnormality is at least partially reversible.33 The mode of inheritance and the natural history are unknown. Endomyocardial biopsy studies in small numbers of patients suggest the presence of histologic changes both on light microscopy and electron microscopy.34However, it is not clear whether these patients are representative of other patients with small vessel disease. Aging may modify the LV performance during exercise.35-37Since there is an increased prevalence of CAD and hypertension in elderly patients who may be totally asymptomatic, age-related changes are often difficult to differentiate from disease-related changes. There is a decrease in exercise capacity, peak exercise heart rate and maximum oxygen consumption and there is a decrease in diastolic LV performance with aging consistent with increased stiffness.38 It has also been suggested that women are more likely to have abnormal LV performance during exercise than men.3g,4oThe exact reasons are not clear but may partly be related to lower exercise capacity and the exercise protocol. It has been found, for example, that sudden strenuous exercise without the warm-up period may induce abnormalities in exercise LV function even in normal men. 41The type of exercise may have an important effect on exercise LV performance.42-45For example, at submaximal level of exercise, the main contribution to the increased stroke volume is a decrease in end-systolic volume while at peak exercise the Frank-Starling mechanism becomes important. This issue, however, is controversial because other studies suggest that the Frank-Starling mechanism is used early in the exercise while the increase in contractility is used at peak exercise.46,47Serial mea-
November
15,1987
surements of the EF during the exercise show stepwise increments as the level of exercise in&eases. It is possible therefore that inadequate stress may be the cause of why some normal subjects fail to show an increase in EF with exercise. The utilization of the Frank-Starling mechanism is greater during upright exercise than supine exercise. Medications, especially p blockers and calcium blockers, also may modify the LV rer sponse during exercise.48 The m&hod of measuring LV volumes and its technical limitations should also be considered.16 It is important to note that spontaneous variability in the resting EF in normal subjects is quite common and in some subjects a variation of 110% has been observed in sequential studies .16Further, cardiac adaptation during regular training and rehabiIitation programs may also modify the cardioGascular responses.49 High-quality studies are necessary to interpret the changes in LV performance.50 The exercise data should reflect the changes observed at or near peak exercise and should be void of data originating in the recovery peripd. Contamination of peak exercise data with data in the recovery period may falsely lower the exekcise EF in normal subjects (and may elevate the EF in patients with CAD). In summary, because a concise definition of normality is difficult and controversial, it may be appropriate to adopt 2 definitions: anatomic normality and physiolpgic normality. Anatomic normality, defined as the absence of “significant” CAD, is important because it identifies patients with good prognosis. Physiologic normaIity can be altered by a number of factors that are unrelated to the presence of CAD. These factors may at times indicate cellular dysfunction or myo: cardial ischemia despite the presence of normal epicardial coronary arteries. For this reason the ‘term “false-positive” may be a misnomer and scientifically incorrect. Acknowledgment: The authors thank Phyllis Hartsfield for secretarial assistance.
References 1. Rerych SK, Scholz PM, Newman GE, Sebiston DE Jr, Jones RH. Cardiac function at rest and during exercise in normals and in patients with coronary hkarf disease: evaluation by radionuclide angiography. Ann Surg 1978;187: 449-463. 2. Borer JS, Kent KM, Bacharach SL, Green MV, Rosing DR. Seides ST, Epstein SE, Johnston GS’. Sensitivity, specificity and predictive accuracy of radionuclide cineangiography during exercise in patients with coronary artery disease: comparison with exercise electrocardiography. Circulation 1979;60:572-580. 3. Iskandrian AS, Hakki AH, DePace NL, Manno B, Segal BL. Evaluation of Ieft veritricufar function during exercise in normal subjects and in patients with chronic coronary heart disease. JACC 1983;1:518-529. 4. Iskandrian AS, Hakki AH, Kane SA, Segal BL. Quantitative radionuclide angiography in the assessmentof hemodynamic changes during upright exercise: observations in normal subjects, patients with coronary arter? disease, and patients with aortic regurgitation. Am J Cardjol 1981;48:239-246. 5. Iskandrian AS, Hakki AH. Radionuclide evaluation of exercise left ventricular performance in patients with coronary artery disease. Am Heart J 1985; 11~851-860. 6. Rozanski 4, Diamond GA, Forrester JS, Berman DS, Morris D, Swan HJS. Alternative referknce standards for cardiac normality: implications for diagnostic testing. Ann Intern Med 1984;101:164-171. 7. Iskandrian AS, Heo J. Left ventricular pressure-volume relationship in coronary artery disease. Am Heart J 1986:112:375-381. 8. Legrand V, Mancini J, Bates ER, Hodgson JM, Gross MD, Vogel RA. A
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comparative study of coronary flow reserve, coronary anatomy and the res&s of radionucIide exercise tests in patients with coronary artery disease. JACC 1986;8:1022-1032. 9. White CW, Wright CB, Doty DB, Hiratzka LF, Eastham CL, Harrison DG, Marcus ML. Does the visual interpretation of the coronary arteriogram predict the physiological significcince of a coronary ‘stellosis? N Engl J Med 1984;310:819-824. 10. Harrison DG, White CW, Hiratzka LF, Doty DB, Barnes DH, Eastham CL, Mar& ML, The value of lesion cross-sectional aria determined by quantitative coronary angiography in assessingthe physiologic significance of proximal left anterior descending coronary arterial stenoses. Circulation 1984; 69:1111-1119. 11. Legrand V, Hodgson J MCB, Bates ER, Aueron PM, Maneini GBJ, Smith JS, Gross MD, Vogel RA. Abnormal coronary flow reserve and abnormal radionuclide exercise test results in patiknts with normal coronary angiograms. JACC 1985;6:1245-1253: 12. Befeler B, Aranda JM, Embi SA, Mullin FL, El-Sherif N, Lazzara R. Coronary artery aneurysms: study of their etiology, clinical course and effect on left ventficular function and prognosis. Am J Caidiol 1977;62:597-607. 13. Fuller CM, Raizner AE, Chahine PA, Nahormek P, Ishimori T, Verani M, Nitishin A, Mokotoff D, Luchi R. Exercise-iliduced coronary arterial spasm: angiographic demonstration, documentation of ischemia by myocardial scintigraphy and results of pharmacologic intervention. Am ‘J Cardiol 1980;46: 500-506. 14. Kucefa RF, Bowden WD, Thomas HM, Blue PW. Anomalous origin of the right coronary artery from the left sinus of vafsalva: a case.report. Cathet Cardiovosc Diagn 1986;12:334-336. 15. Iskandrian AS, Hakki AH, Bemis CE. Myocardial ischemia in a patient with anomalous origin of the left main coronary artery. Cathet Cardiovasc Diagn 1986;12:48-50. 16. Iskandrian AS. Thallium-201 myocardial imaging and radionuclide ventriculography: theory, technical considerations and interpretation. In: Iskandrian AS, ed. Nuclear Cardiac Imaging: Principles and Applications. Philadelphia: FA Davis Company, 1986:96 17. Iskandrian AS, Heo J, Hakki AH, Mandler JM. Age-gender reIated changes in exercise left ventricular function in mitral valve prolapse. Am J Cardiol 1986;58:117-220. 18. Vered Z, Battler A, Segal P, Liberman D, Yerushalmi Y, Berezin M, Neufeld HN. Exercise-induced left ventricular dysfunction in young men with asymptomatic diabetes mellitus. (Diabetic cardiomyopathy]. +m r Cardial 1984;54:633-637. 19. Felsher J, Meissner MD, Hakki AH, Heo J, Kane-Marsh SA, Iskandrian AS. Prognostic implications of exercise thbllium imag&g in patients wjth diabetes mellitus. Arch Intern Med 1985;145:253-256. 20. Wgsserman AG, Katz RJ, Varghees PJ, Leiboff-RH, Bren GG, Schlesselman S, Varma VM, Reba RC. Ross AM. Exercise radionuclide ventriculographic responses in. hypertensive patients with chest pain. N EngI J Med 1984:Q11:1276-1280. 21. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve: a mechanism for hngina pectoris in patients with oortic stenosis and normal coronary arteries. N EngI J Med 1982;307:13621366. 22. Pichard AD, Gorlin R, Smith H, Ambrose J. Meller J. Coronary flow studies in patients with left ventricular hypertrophy of the hypertensive type: evidence for an impaired coronary vascular reserve. Am J Cardiol 1981; 47547-554. 23. Opherk D, Mall G, Zebe H, Schwartz F, Weihe E, Manthey J, Kubjer W. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984; 692-7. 24. Cannon RD III, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, Epstein SC. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated Ieft ventricular filling pressure. Circulation 1985;71:234-243. 25. Opherk D, Zebe H, Weihe E, Mall G, Durr C, Garvert B, Mehmel HC, Schwartz F. Kubler W. Reduced coronary dilatory capacity and ultrastructura1 changes of the myochrdium in patients with angina pectoris but normal coronary arteriograms. Circulation 1981;63:817-825. 26. Iskandrian AS, Heo J. Exciggerated systoIic blood pressure response to exercise. Int J Cardiol [in press). 27. James TN. Small arteri& of the heart. Circulation 1977;56:2-14. 28. Iskandrian AS. Radionuclide evaluation of cardiac function in obesity, Am Heart J 1986;111:1003-1004. 29. Hadjimiltiades S, Panidis IP, Segal BL, Iskandrian AS. Recovery of left ventricular function in periparfum cardiomyopathy. Am Heart J 1986;112: 1097-1099. 30. Likoff W, Segal BL, Kasparian H. Paradox of normai selective coronary angiograms in patients considered to have unmistakable’ coronary heart disease. N EngI J Med 1967;276:1063-1067, 31. Cannon RO III, Bonow RO, Bacharach SL, Green MV, Rosing DR, Leon MB, Watson RM, Epstein SE. Left’ventricular dysfunction in patients with angina pectoris, normal epicardia1 coronary arteries, and abnormal vasodiiatar reserve. CircuIation 1985;71:218-236. 32. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Angina caused by
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reduced vasodilator reserve of the small coronary arteries, IACC 1983;1:13591373. 33. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve. Am j Cardiol 1985; 56:242-246. 34. Mosseri M, Yarom R, Gotsman MS, Hasin Y. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries. Circulation 1986;74:964-972. 35. Port S, Cobb FR, Coleman RE, Jones RH. Effect of age on the response of the left ventricular ejection fraction to exercise. N EngJ J Med 1989;303:11331137. 36. Rodeheffer RJ, Gerstenblith G, Becker LC, Fleg JL, Weisfeldt ML, Lakatta EG. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for diminished heart rate. Circulation 1984;69:203-213. 37. Iskandrian AS, Hakki AH. The effects of aging on the regulation of cardiac output during exercise after coronary arterial bypass grafting. Int J CardioJ 1985:7:347-360. 38. Iskandrian AS, Hakki AH. Age-related changes in diastolic Jefi ventricuJar performance. Am Heart j 1986;112:15-18. 39. Higginbotham MB, Morris KG, Coleman RE, Cobb FC. Sex related differences in the normal cardiac response to upright exercise. Circulation 1984;70:357-366. 40. Hakki AH, Iskandrian AS. Effect of gender on left ventricular function during exercise in patients with coronary artery disease. Am Heart j 1986;111:543-546. 41. Foster C, Anholm JD, Hellman CK, Carpenter J, Pollock ML, Schmidt DH. Left ventricular function during sudden strenuous exercise. Circulation 198i;63:592-596.
42. Poliner LR, Dehmer GJ, Lewis SE, Parkey RW, Blomqvist DR, Willerson JT. Left ventricular performance in normal subjects: a comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528-534. 43. Manyari DE, Kostuk Wj. Left and right ventricular function at rest and during bicycle exercise in the supine and sitting positions in normal subjects and patients with coronary artery disease. Am j Cardiol 1983;51:36-42. 44. Crawford MH, Petru MA, Rabinowitz C. Effect of isotonic exercise training on left ventricular volume during upright exercise. Circulation 1985; 72:1237-1243. 45. Steingart RM, Wexler J, Slagle S, Scheuer J. Radionuciide ventriculographic responses to graded supine and upright exercise: critical role of the Frank-Starling mechanism at submaximal exercise. Am J CardioJ 1984;53: X71-1677. 46. Higginbotham MB, Morris KG, Williams RS, Meltale PA, Coleman RE, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281-291. 47. Iskandrian AS, Heo J, Hakki AH. Changes in left ventricular end-diastolic volume during upright exercise in normal subjects. j Cardiopulm Rehab 1987;7:29-36. 48. Iskandrian AS, Nestico PF, Hakki AH, Heo J, Fernandes M, Fiorentini R, Schenk C. Effects of beta blockade on systolic and diastolic left ventricular functions at rest and during exercise in patients with stable angina pectoris. Am Heart j 1987;113:791-798. 49. Rerych SK, Scholz PM, Sabiston DC Jr, Jones RH. Effects of exercise training on left ventricular function in normal subjects: a longitudinal study by radionuclide angiography. Am j CardioJ 1980;45:244-252. 50. Iskandrian AS, Hakki AH, Segal BL. The dilemma of advances in cardiac scintigraphy vis-a-vis persuasive communication (editorial). Arch Intern Med 1986;146:249-250.
S. ISKANDRIAN, MD, JAEKYEONG HEO, MD, ALAN ASKENASE, RICHARD H. HELFANT, MD, and BERNARD L. SEGAL, MD
R
MD,
high normal subjects, while patients with normal coronary arteriograms represent the low normal subjects. The LV performance during exercise is affected by factors other than stenosis of the epicardial coronary arteries. These factors will be discussed next. The subjective method of interpreting the coronary arteriogram is often less than ideal. The concept of percent diameter stenosis as an indicator of the hemodynamic severity of coronary stenosis has been seriously challenged by recent studies that show the lack of correlation between percent diameter stenosis and reactive hyperemic flow, and suggest that multiple factors can influence hemodynamic severity of the coronary lesion. These include exit angle, entrance angle, length, absolute cross-sectional area, eccentricity, multiple lesions and size of the vascular territory. Other factors include the presence of diffuse disease, changes in the vasomotor tone, variation in the systolic blood pressure and associated factors such as LV hypertrophy, anemia and medications.8-ll Coronary artery ectasia, a localized or a diffuse dilatation of a coronary artery, should not be overlooked.*z In the elderly patients, atherosclerosis is probably the most common cause of ectasia, although the etiology in the younger patient is less clear and may be related to a congenital defect in the muscular component of the vessel wall. Patients with ectasia may have angina1 symptoms. A striking finding on arteriography is the slow washout of the contrast medium. The disturbances in the vessel wall and the flow may predispose to thrombus formation and acute myocardial infarction. Therefore, patients with ectasia cannot be accepted as normal subjects even though there is no obstructive disease in the epicardial vessels. The concept of exercise-induced spasm is now well documented.13 The residual muscular tissue at the site of focal atherosclerotic lesion is the mechanism by which such stenosis reacts to stimuli that produce spasm. Although chest pain and associated electrocardiographic changes may accompany exercise-induced
adionuclide ventriculographic evaluation of left ventricular (LV] performance during exercise has shown that normal subjects manifest a slight increase in end-diastolic volume (Frank-Starling mechanism], a decrease in the end-systolic volume (increase in contractility] and an increase in the stroke volume [due to both mechanisms]. The increase in cardiac output is due to increases,in stroke volume and heart rate. There is improvement in the ejection fraction (EF]; the EF increases by 5% or more from rest to exercise depending on the EF at rest.1-4 An abnormality in LV response to exercise has been defined in terms of failure to augment the EF, appearance of wall motion abnormality or failure to decrease the end-systolic volume. Other less often used indexes include changes in pulmonary blood volume, pressure-volume relation and LV diastolic filling characteristics.5 The “normal” subjects who have been used to define the “normal” physiologic responses can be categorized into 3 types+ healthy volunteers, usually young and usually men; patients with a low pretest probability of coronary artery disease (CAD] based on clinical presentation and coronary risk factors; and patients with normal coronary arteriograms. Such patients are generally older and have troublesome or severe enough symptoms to warrant coronary arteriography. Coronary risk factors are more common in this group of patients.7 If normality can be viewed as a continuum rather than discrete, the healthy volunteers represent the From the Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, Philadelphia, Pennsylvania. Manuscript received May 19,1987; revised manuscript received and accepted July 14,1987. Address for reprints: AS. Iskandrian, MD, Philadelphia Heart Institute, Presbyterian-University of Pennsylvania Medical Center, 39th and Market Streets, Philadelphia, Pennsylvania 19104. 1173
1174
EDITORIALS
spasm, it is possible that some episodes may only be manifested by abnormalities in LV function during exercise. Some patients with anomalous origin of the coronary arteries may have symptoms due to myocardial ischemia despite the presence of normal epicardial vessels. This has been well described in patients with anomalous origin of the left main coronary artery from the right coronary sinus (with the course of the left main between the great vessels). More recently, however, it has also been described in patients with anomalous origin of the right coronary artery from the left coronary sinus (with a course of the right coronary artery between the great vessels).14J5 Systolic bridging of the coronary arteries is another possible cause. This entity, which is also known as “milking” of the coronary arteries, is characterized by narrowing of the diameter of the coronary artery during systole only. l6 The severity of the narrowing may be mild but occasionally total obliteration of the lumen may be observed. The site and the length of the narrowing are variable and although more common in the left anterior descending artery, it has been described in the other coronary arteries. The narrowing may spill over to early diastole. In general, the more severe the bridging, the more likely it is that it involves the early part of diastole as well. In some patients, the bridging can be provoked by sublingual administration of nitroglycerin.16 Other noncoronary diseases may modify the LV response to exercise. Regional or global abnormalities have been described on the left ventriculograms in patients with mitral valve prolapse syndrome. The etiology of chest pain is not clear; abnormalities in LV performance have been reported to be age- and gender-related; that is, abnormalities are more common in the elderly patients and in women.17 Abnormal LV function during exercise has been observed even in asymptomatic diabetic patients with normal epicardial coronary arteries. It is not clear whether the dysfunction is due to primary myocardial cellular dysfunction (due to metabolic derangement) or to microvascular disease. Thickening of the capillary basal membrane has been documented in diabetic retinopathy and nephropathy as well as in the skeletal muscle and in the skin. More recently, increased basal membrane thickness has been observed in biopsy specimens from myocardium in such patients.lsJg Abnormality in the reserve coronary blood flow has been observed in patients with LV hypertrophy due to aortic stenosis, hypertrophic cardiomyopathy and hypertension. This finding may be due to abnormal reactivity of the coronary microvascular circulation, elevated basal and stress coronary flow requirements that could prematurely exhaust coronary flow reserve, deleterious effects of abnormal diastolic function and altered capillary density on flow reserve and, possibly, also to small vessel disease.20-z7This vascular and flow abnormality may also explain the angina1 symptoms and the abnormality in the exercise LV function observed in some of these patients.
Other diseases can modify the LV function during exercise, such as primary cardiomyopathy, valvular heart diseases, congenital heart diseases, chronic obstructive pulmonary disease, endocrine disorders, severe anemia, connective tissue disorders and extreme obesity.16J8 Some patients with myocarditis may recover and have normal or near normal LV function at rest; the reserve function remains abnormal.2g It is possible that some patients with new onset conduction defects may have a latent form of cardiomyopathy, which could explain the LV dysfunction during exercise. The abnormal LV response to exercise in such patients may also be the result of abnormal sequence of depolarization. Over 20 years ago, syndrome X was described as chest pains and electrocardiographic changes in patients with normal coronary angiograms.30Various hypotheses were suggested to explain the chest pains but none was documented. Although initially described in women, subsequent studies have shown that such a syndrome may also be seen in men. Recent hemody namic, metabolic, exercise and coronary blood flow studies have suggested the presence of inappropriate tone in the small coronary artery vessels in such patients.25,31B2Improvement in symptoms and exercise LV performance have been reported after treatment with calcium channel blocking agents, suggesting that the abnormality is at least partially reversible.33 The mode of inheritance and the natural history are unknown. Endomyocardial biopsy studies in small numbers of patients suggest the presence of histologic changes both on light microscopy and electron microscopy.34However, it is not clear whether these patients are representative of other patients with small vessel disease. Aging may modify the LV performance during exercise.35-37Since there is an increased prevalence of CAD and hypertension in elderly patients who may be totally asymptomatic, age-related changes are often difficult to differentiate from disease-related changes. There is a decrease in exercise capacity, peak exercise heart rate and maximum oxygen consumption and there is a decrease in diastolic LV performance with aging consistent with increased stiffness.38 It has also been suggested that women are more likely to have abnormal LV performance during exercise than men.3g,4oThe exact reasons are not clear but may partly be related to lower exercise capacity and the exercise protocol. It has been found, for example, that sudden strenuous exercise without the warm-up period may induce abnormalities in exercise LV function even in normal men. 41The type of exercise may have an important effect on exercise LV performance.42-45For example, at submaximal level of exercise, the main contribution to the increased stroke volume is a decrease in end-systolic volume while at peak exercise the Frank-Starling mechanism becomes important. This issue, however, is controversial because other studies suggest that the Frank-Starling mechanism is used early in the exercise while the increase in contractility is used at peak exercise.46,47Serial mea-
November
15,1987
surements of the EF during the exercise show stepwise increments as the level of exercise in&eases. It is possible therefore that inadequate stress may be the cause of why some normal subjects fail to show an increase in EF with exercise. The utilization of the Frank-Starling mechanism is greater during upright exercise than supine exercise. Medications, especially p blockers and calcium blockers, also may modify the LV rer sponse during exercise.48 The m&hod of measuring LV volumes and its technical limitations should also be considered.16 It is important to note that spontaneous variability in the resting EF in normal subjects is quite common and in some subjects a variation of 110% has been observed in sequential studies .16Further, cardiac adaptation during regular training and rehabiIitation programs may also modify the cardioGascular responses.49 High-quality studies are necessary to interpret the changes in LV performance.50 The exercise data should reflect the changes observed at or near peak exercise and should be void of data originating in the recovery peripd. Contamination of peak exercise data with data in the recovery period may falsely lower the exekcise EF in normal subjects (and may elevate the EF in patients with CAD). In summary, because a concise definition of normality is difficult and controversial, it may be appropriate to adopt 2 definitions: anatomic normality and physiolpgic normality. Anatomic normality, defined as the absence of “significant” CAD, is important because it identifies patients with good prognosis. Physiologic normaIity can be altered by a number of factors that are unrelated to the presence of CAD. These factors may at times indicate cellular dysfunction or myo: cardial ischemia despite the presence of normal epicardial coronary arteries. For this reason the ‘term “false-positive” may be a misnomer and scientifically incorrect. Acknowledgment: The authors thank Phyllis Hartsfield for secretarial assistance.
References 1. Rerych SK, Scholz PM, Newman GE, Sebiston DE Jr, Jones RH. Cardiac function at rest and during exercise in normals and in patients with coronary hkarf disease: evaluation by radionuclide angiography. Ann Surg 1978;187: 449-463. 2. Borer JS, Kent KM, Bacharach SL, Green MV, Rosing DR. Seides ST, Epstein SE, Johnston GS’. Sensitivity, specificity and predictive accuracy of radionuclide cineangiography during exercise in patients with coronary artery disease: comparison with exercise electrocardiography. Circulation 1979;60:572-580. 3. Iskandrian AS, Hakki AH, DePace NL, Manno B, Segal BL. Evaluation of Ieft veritricufar function during exercise in normal subjects and in patients with chronic coronary heart disease. JACC 1983;1:518-529. 4. Iskandrian AS, Hakki AH, Kane SA, Segal BL. Quantitative radionuclide angiography in the assessmentof hemodynamic changes during upright exercise: observations in normal subjects, patients with coronary arter? disease, and patients with aortic regurgitation. Am J Cardjol 1981;48:239-246. 5. Iskandrian AS, Hakki AH. Radionuclide evaluation of exercise left ventricular performance in patients with coronary artery disease. Am Heart J 1985; 11~851-860. 6. Rozanski 4, Diamond GA, Forrester JS, Berman DS, Morris D, Swan HJS. Alternative referknce standards for cardiac normality: implications for diagnostic testing. Ann Intern Med 1984;101:164-171. 7. Iskandrian AS, Heo J. Left ventricular pressure-volume relationship in coronary artery disease. Am Heart J 1986:112:375-381. 8. Legrand V, Mancini J, Bates ER, Hodgson JM, Gross MD, Vogel RA. A
THE AMERICAN
JOURNAL
OF CARDIOLOGY
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comparative study of coronary flow reserve, coronary anatomy and the res&s of radionucIide exercise tests in patients with coronary artery disease. JACC 1986;8:1022-1032. 9. White CW, Wright CB, Doty DB, Hiratzka LF, Eastham CL, Harrison DG, Marcus ML. Does the visual interpretation of the coronary arteriogram predict the physiological significcince of a coronary ‘stellosis? N Engl J Med 1984;310:819-824. 10. Harrison DG, White CW, Hiratzka LF, Doty DB, Barnes DH, Eastham CL, Mar& ML, The value of lesion cross-sectional aria determined by quantitative coronary angiography in assessingthe physiologic significance of proximal left anterior descending coronary arterial stenoses. Circulation 1984; 69:1111-1119. 11. Legrand V, Hodgson J MCB, Bates ER, Aueron PM, Maneini GBJ, Smith JS, Gross MD, Vogel RA. Abnormal coronary flow reserve and abnormal radionuclide exercise test results in patiknts with normal coronary angiograms. JACC 1985;6:1245-1253: 12. Befeler B, Aranda JM, Embi SA, Mullin FL, El-Sherif N, Lazzara R. Coronary artery aneurysms: study of their etiology, clinical course and effect on left ventficular function and prognosis. Am J Caidiol 1977;62:597-607. 13. Fuller CM, Raizner AE, Chahine PA, Nahormek P, Ishimori T, Verani M, Nitishin A, Mokotoff D, Luchi R. Exercise-iliduced coronary arterial spasm: angiographic demonstration, documentation of ischemia by myocardial scintigraphy and results of pharmacologic intervention. Am ‘J Cardiol 1980;46: 500-506. 14. Kucefa RF, Bowden WD, Thomas HM, Blue PW. Anomalous origin of the right coronary artery from the left sinus of vafsalva: a case.report. Cathet Cardiovosc Diagn 1986;12:334-336. 15. Iskandrian AS, Hakki AH, Bemis CE. Myocardial ischemia in a patient with anomalous origin of the left main coronary artery. Cathet Cardiovasc Diagn 1986;12:48-50. 16. Iskandrian AS. Thallium-201 myocardial imaging and radionuclide ventriculography: theory, technical considerations and interpretation. In: Iskandrian AS, ed. Nuclear Cardiac Imaging: Principles and Applications. Philadelphia: FA Davis Company, 1986:96 17. Iskandrian AS, Heo J, Hakki AH, Mandler JM. Age-gender reIated changes in exercise left ventricular function in mitral valve prolapse. Am J Cardiol 1986;58:117-220. 18. Vered Z, Battler A, Segal P, Liberman D, Yerushalmi Y, Berezin M, Neufeld HN. Exercise-induced left ventricular dysfunction in young men with asymptomatic diabetes mellitus. (Diabetic cardiomyopathy]. +m r Cardial 1984;54:633-637. 19. Felsher J, Meissner MD, Hakki AH, Heo J, Kane-Marsh SA, Iskandrian AS. Prognostic implications of exercise thbllium imag&g in patients wjth diabetes mellitus. Arch Intern Med 1985;145:253-256. 20. Wgsserman AG, Katz RJ, Varghees PJ, Leiboff-RH, Bren GG, Schlesselman S, Varma VM, Reba RC. Ross AM. Exercise radionuclide ventriculographic responses in. hypertensive patients with chest pain. N EngI J Med 1984:Q11:1276-1280. 21. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve: a mechanism for hngina pectoris in patients with oortic stenosis and normal coronary arteries. N EngI J Med 1982;307:13621366. 22. Pichard AD, Gorlin R, Smith H, Ambrose J. Meller J. Coronary flow studies in patients with left ventricular hypertrophy of the hypertensive type: evidence for an impaired coronary vascular reserve. Am J Cardiol 1981; 47547-554. 23. Opherk D, Mall G, Zebe H, Schwartz F, Weihe E, Manthey J, Kubjer W. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984; 692-7. 24. Cannon RD III, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, Epstein SC. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated Ieft ventricular filling pressure. Circulation 1985;71:234-243. 25. Opherk D, Zebe H, Weihe E, Mall G, Durr C, Garvert B, Mehmel HC, Schwartz F. Kubler W. Reduced coronary dilatory capacity and ultrastructura1 changes of the myochrdium in patients with angina pectoris but normal coronary arteriograms. Circulation 1981;63:817-825. 26. Iskandrian AS, Heo J. Exciggerated systoIic blood pressure response to exercise. Int J Cardiol [in press). 27. James TN. Small arteri& of the heart. Circulation 1977;56:2-14. 28. Iskandrian AS. Radionuclide evaluation of cardiac function in obesity, Am Heart J 1986;111:1003-1004. 29. Hadjimiltiades S, Panidis IP, Segal BL, Iskandrian AS. Recovery of left ventricular function in periparfum cardiomyopathy. Am Heart J 1986;112: 1097-1099. 30. Likoff W, Segal BL, Kasparian H. Paradox of normai selective coronary angiograms in patients considered to have unmistakable’ coronary heart disease. N EngI J Med 1967;276:1063-1067, 31. Cannon RO III, Bonow RO, Bacharach SL, Green MV, Rosing DR, Leon MB, Watson RM, Epstein SE. Left’ventricular dysfunction in patients with angina pectoris, normal epicardia1 coronary arteries, and abnormal vasodiiatar reserve. CircuIation 1985;71:218-236. 32. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Angina caused by
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reduced vasodilator reserve of the small coronary arteries, IACC 1983;1:13591373. 33. Cannon RO III, Watson RM, Rosing DR, Epstein SE. Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve. Am j Cardiol 1985; 56:242-246. 34. Mosseri M, Yarom R, Gotsman MS, Hasin Y. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries. Circulation 1986;74:964-972. 35. Port S, Cobb FR, Coleman RE, Jones RH. Effect of age on the response of the left ventricular ejection fraction to exercise. N EngJ J Med 1989;303:11331137. 36. Rodeheffer RJ, Gerstenblith G, Becker LC, Fleg JL, Weisfeldt ML, Lakatta EG. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for diminished heart rate. Circulation 1984;69:203-213. 37. Iskandrian AS, Hakki AH. The effects of aging on the regulation of cardiac output during exercise after coronary arterial bypass grafting. Int J CardioJ 1985:7:347-360. 38. Iskandrian AS, Hakki AH. Age-related changes in diastolic Jefi ventricuJar performance. Am Heart j 1986;112:15-18. 39. Higginbotham MB, Morris KG, Coleman RE, Cobb FC. Sex related differences in the normal cardiac response to upright exercise. Circulation 1984;70:357-366. 40. Hakki AH, Iskandrian AS. Effect of gender on left ventricular function during exercise in patients with coronary artery disease. Am Heart j 1986;111:543-546. 41. Foster C, Anholm JD, Hellman CK, Carpenter J, Pollock ML, Schmidt DH. Left ventricular function during sudden strenuous exercise. Circulation 198i;63:592-596.
42. Poliner LR, Dehmer GJ, Lewis SE, Parkey RW, Blomqvist DR, Willerson JT. Left ventricular performance in normal subjects: a comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528-534. 43. Manyari DE, Kostuk Wj. Left and right ventricular function at rest and during bicycle exercise in the supine and sitting positions in normal subjects and patients with coronary artery disease. Am j Cardiol 1983;51:36-42. 44. Crawford MH, Petru MA, Rabinowitz C. Effect of isotonic exercise training on left ventricular volume during upright exercise. Circulation 1985; 72:1237-1243. 45. Steingart RM, Wexler J, Slagle S, Scheuer J. Radionuciide ventriculographic responses to graded supine and upright exercise: critical role of the Frank-Starling mechanism at submaximal exercise. Am J CardioJ 1984;53: X71-1677. 46. Higginbotham MB, Morris KG, Williams RS, Meltale PA, Coleman RE, Cobb FR. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res 1986;58:281-291. 47. Iskandrian AS, Heo J, Hakki AH. Changes in left ventricular end-diastolic volume during upright exercise in normal subjects. j Cardiopulm Rehab 1987;7:29-36. 48. Iskandrian AS, Nestico PF, Hakki AH, Heo J, Fernandes M, Fiorentini R, Schenk C. Effects of beta blockade on systolic and diastolic left ventricular functions at rest and during exercise in patients with stable angina pectoris. Am Heart j 1987;113:791-798. 49. Rerych SK, Scholz PM, Sabiston DC Jr, Jones RH. Effects of exercise training on left ventricular function in normal subjects: a longitudinal study by radionuclide angiography. Am j CardioJ 1980;45:244-252. 50. Iskandrian AS, Hakki AH, Segal BL. The dilemma of advances in cardiac scintigraphy vis-a-vis persuasive communication (editorial). Arch Intern Med 1986;146:249-250.