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The Heart in Hypertension
AJH 1996; 9:406-408
EDITORIAL
The Heart in Hypertension Thinking Small Richard O. Cannon III
A
ngina-like chest pain despite normal or near-normal coronary angiograms continues to be a significant clinical problem, and can be encountered in patients with essential hypertension. Some have echocardiographic evidence of left ventricular hypertrophy, a condition shown in animal models and in humans to be associated with abnormal coronary flow dynamics and evidence for myocardial ischemia with noninvasive stress testing. 1 - 6 More controversial is the mechanism of chest pain in normotensive patients and in hypertensive patients without left ventricular hypertrophy? Several groups have reported limited coronary flow responses to pacing stress and to pharmacologic vasodilators, both endothelium-dependent and endothelium-independent, in patients with hypertension but without left ventricular hypertrophy compared with normotensive patients, all undergoing cardiac catheterization because of chest pain syndromes. We reported that 12 hypertensive patients without left ventricular hypertrophy showed a coronary microvascular constrictor response to ergonovine, in contrast to a dilator response to this endothelium-dependent vasodilator (but with smooth muscle constrictor properties) in 13 normotensive patients. 8 We also found that the coronary flow response to pacing stress correlated with the flow response to intracoronary infusion of the endothelium-dependent vasodilator acetylcholine in 20 hypertensive patients with no or minimal left ventricular hypertrophy, suggesting that microvascular endothelial dysfunction may contribute to abnormal flow responses to stress. 9 Received November 16, 1995. Accepted November 21,1995. From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Richard O. Cannon III, MD, National Institutes of Health, Building 10, Room 7815, 10 Center Drive MSC-1650, Bethesda, MD 20892-1650.
© 1996 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
Houghton et al reported a broad spectrum of coronary flow responses to dipyridamole, which blocks myocyte adenosine reuptake, thus relaxing vascular (especially microvascular) smooth muscle, in 48 hypertensive patients who had chest pain syndromes and normal coronary angiograms. Those patients who had perfusion abnormalities by thallium scintigraphy were more likely to have limited flow responses to dipyridamole than those with normal thallium scans. s Although in general the patients with the lowest coronary flow responses to dipyridamole had more severe left ventricular hypertrophy than those with higher flow responses to dipyridamole, some patients without left ventricular hypertrophy also had limited flow responses, suggesting that structural changes in myocardial small arteries might have contributed to limitation in dipyridamole-stimulated flow in these patients. This consideration is support by Schwartzkopff et a!, who reported luminal narrowing in intramural arteries from right ventricular septal biopsies performed in 14 patients with chest pain, hypertension, and normal coronary angiograms. lO There was a significant correlation between the minimum coronary resistance following dipyridamole infusion and the arterial medial wall area, but not the left ventricular mass index by echocardiography. They concluded that the arteriolar wall thickening was causally related to diminished coronary reserve, and partly independent of myocardial hypertrophy. Thus, many groups have provided evidence for both structural and functional abnormalities in the coronary microcirculation of hypertensive patients that appear largely independent of left ventricular mass. Limitation in appropriate coronary flow because of microvascular disease or dysfunction could adversely affect ventricular compliance, thereby elevating filling pressures, and could also contribute to systolic dysfunction because of myocyte necrosis and 0895-7061/96/$1500 PH 50895-7061(96)00038-6
AJH-APRIL 1996-VOL. 9, NO.4, PART 1
scarring. However, the clinical dilemma is how to identify hypertensive patients complaining of anginalike chest pain subsequently found to have normal or near-normal coronary angiograms, who have coronary microvascular dynamics sufficiently abnormal to cause myocardial ischemia, and how can we separate these patients from those who may have abnormal cardiac pain perception,11 or entirely noncardiac pain syndromes. Eugenio Picano and coworkers at the University of Pisa have pioneered dipyridamole echocardiography as a useful noninvasive test for identifying patients with coronary artery disease based on precipitation of wall motion abnormalities during dipyridamole infusion. 12 These abnormalities are likely due to redistribution of coronary flow within the myocardium subserved by the diseased coronary arteries, resulting in the precipitation of regional ischemia. This group also reported that the infusion of dipyridamole commonly provoked ischemic-appearing ST segment depression and chest pain in patients with chest pain despite normal coronary angiograms,13 including hypertensive subjects without left ventricular hypertrophy 14 who were subsequently found to have lesser increases in coronary flow in response to pacing stress compared with hypertensive patient subjects without ST segment depression during dipyridamole infusion. IS The Pisa group has speculated that dipyridamole-stimulated microvascular dilation might cause decreased perfusion pressure distal to anatomically or functionally narrowed intramyocardial arteries. This would, in turn, cause energy losses because of viscosity and turbulence as blood flows through narrowed vessels from epicardium to endocardium resulting in subendocardial hypoperfusion and ischemia. However, in contrast to the abnormal left ventricular wall motion response manifest by patients with coronary artery disease during dipyridamole infusion, patients with chest pain and normal coronary arteries, hypertensive or not, showed generalized increases in contractility, which would seem an unlikely manifestation of myocardial ischemia. In this issue of the Journal, Virdis and coworkers provide an impressive series of observations supporting the clinical and pathophysiological relevance of dipyridamole echocardiography testing (abbreviated DET in the article) in hypertensive patients without left ventricular hypertrophy.16 They report the therapeutic effect of 1 year of angiotensin converting enzyme inhibitor therapy in 16 hypertensive patients who had no evidence of left ventricular hypertrophy by echocardiography and were largely either untreated or minimally treated with antihypertensive therapy prior to this study. Eight of these patients had ischemic-appearing electrocardiographic responses to dipyridamole infusion (DET positive), five of whom
THE HEART IN HYPERTENSION
407
had chest pain syndromes despite normal coronary angiograms, with the remaining 8 patients (all of whom were asymptomatic) showing no ischemic-appearing electrocardiographic changes during dipyridamole infusion (DET negative). The two groups of patients were well matched with regard to age, gender distribution, body mass, left ventricular mass index, and severity of hypertension. However, the authors found that the forearm flow dynamics differed between these groups during baseline testing of all antihypertensive therapy for at least 2 weeks: DET positive patients had less of a flow response both to the endothelium-dependent vasodilator acetylcholine and to the endothelium-independent vasodilator nitroprusside, and a higher minimum forearm vascular resistance following forearm ischemia and exercise compared with DET negative patients. Following 1 year of therapy with captopril 50 mg twice daily (1 patient in each group also received nifedipine), there was an approximately 12% reduction in left ventricular mass in both groups. The forearm flow dynamics in the DET positive group improved such that the differences from the DET negative group in both acetylcholine and nitroprusside-stimulated forearm blood flow noted a baseline were no longer apparent at time of the post-therapy study. Furter, repeat dipyridamole infusion no longer produced ischemic-appearing ST segment changes in the DET positive group, with all measurements performed 2 weeks after discontinuation of drug therapy. The authors concluded that a positive dipyridamole echocardiography test provides evidence of coronary and systemic microvascular disease which can be benefited by 1 year of therapy. The clinical relevance of the DET positive test is suggested by the elimination of chest pain symptoms in three of the five DET positive patients who were symptomatic with chest pain prior to therapy. This study also provided an interesting observation that may be of pathophysiologic relevance regarding essential hypertension: Despite normalization of forearm vascular dynamics with 1 year of treatment in the DET positive group, all patients became hypertensive 2 weeks following cessation of therapy (when the follow-up forearm vascular studies were performed). This observation suggests the abnormal vascular dynamics that has been reported by several groups is likely secondary to prolonged elevation in blood pressure and not a primary process causing hypertension. The findings of this study differ from reports of abnormal endothelium-dependent, but normal endothelium-independent forearm microvascular function in patients with essential hypertension. 17.18 However, the conversion of a DET positive to a DET negative test as indicative of improvement in coronary vascular function due to angiotensin converting enzyme
408
CANNON
AJH-APRIL 1996-VOL. 9, NO.4, PART 1
inhibitor therapy is consistent with the findings of Strauer et al. 19 They reported that approximately 1 year therapy with enalapril resulted in 48% improvement in dipyridamole-stimulated coronary flow despite only an 8% reduction in left ventricular mass compared with pretreatment values in patients with chest pain syndromes, hypertension, and moderate left ventricular hypertrophy. If the findings of Virdis et aI's relatively small series of patients is validated in a larger series of hypertensive patients and with different pharmacotherapies, the dipyridamole echo test could become a useful discriminator for a cardiac origin of pain, likely a consequence of abnormal coronary flow dynamics, in patients with hypertension, chest pain, and normal coronary angiograms, providing the assurances to the patient and physician that a beneficial symptom response to therapy will likely follow.
8.
9.
10.
11. 12.
13.
REFERENCES
1. Mueller TM, Marcus ML, Kerber RE, et al: Effect of renal hypertension and left ventricular hypertrophy on the coronary circulation in dogs. Circ Res 1978;42:543549.
14.
2.
15.
Rembert JC, Kleinman LH, Fedor JM, et al: Myocardial blood flow distribution in concentric left ventricular hypertrophy. J Clin Invest 1978;62:379-386.
3. Strauer BE: Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 1979;44:999-1002. 4.
Opherk D, Mall G, Zebe H, et al: Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984;69:1-7.
5. Houghton JL, Frank MJ, Carr AA, et al: Relations among impaired coronary flow reserve, left ventricular hypertrophy, and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am ColI Cardiol 1990; 15:43-51. 6. Treasure CB, Klein JL, Vita JA, et al: Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation 1993;87:86-93. 7. Cannon RO, Camici PG, Epstein SE: Pathophysiologi-
cal dilemma of syndrome X. Circulation 1992;85:883892. Brush JE, Cannon RO, Schenke WH, et al: Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 1988;319:1302-1307. Quyyumi AA, Cannon RO, Panza JA, et al: Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992; 86:1864-1871. Schwartzkoff B, Motz W, Frenzel H, et al: Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. Circulation 1993;88:993-1003. Cannon RO: The sensitive heart. A syndrome of abnormal cardiac pain perception. JAMA 1995;273:883-887. Picano E, Lattanzi F, Masini M, et al: High dose dipyridamole echocardiography test in effort angina pectoris. J Am ColI Cardiol 1986;8:848-854. Picano E, Lattanzi F, Masini M, et al: Usefulness of a high-dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J CardioI1987;60:508-512. Lucarini AR, Lattanzi F, Picano E, et al: Dipyridamoleechocardiography test in essential hypertensives with chest pain and angiographically normal coronary arteries. Am J Hypertens 1989;2:120-123. Lucarini AR, Picano E, Lattanzi F, et al: Dipyridamole echocardiography stress testing in hypertensive patients. Targets and tools. Circulation 1991;83(suppl III):68-72.
16. Virdis A, Ghiadoni L, Lucarini A, et al: Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term treatment. Am J Hypertens 1996;9:361-369. 17. Panza JA, Quyyumi AA, Brush JE, Epstein SE: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1991;325:1551-1556. 18. Linder L, Kilokowski W, Buhler FR, Luscher TF: Indirect evidence for the release of endothelium-derived relaxing factor in the human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990;81:1762-1767. 19. Strauer BE, Vogt M, Motz W: ACE-inhibitors and coronary microcirculation. Bas Res Cardiol 1993;88 (suppl 1): 97-106.
EDITORIAL
The Heart in Hypertension Thinking Small Richard O. Cannon III
A
ngina-like chest pain despite normal or near-normal coronary angiograms continues to be a significant clinical problem, and can be encountered in patients with essential hypertension. Some have echocardiographic evidence of left ventricular hypertrophy, a condition shown in animal models and in humans to be associated with abnormal coronary flow dynamics and evidence for myocardial ischemia with noninvasive stress testing. 1 - 6 More controversial is the mechanism of chest pain in normotensive patients and in hypertensive patients without left ventricular hypertrophy? Several groups have reported limited coronary flow responses to pacing stress and to pharmacologic vasodilators, both endothelium-dependent and endothelium-independent, in patients with hypertension but without left ventricular hypertrophy compared with normotensive patients, all undergoing cardiac catheterization because of chest pain syndromes. We reported that 12 hypertensive patients without left ventricular hypertrophy showed a coronary microvascular constrictor response to ergonovine, in contrast to a dilator response to this endothelium-dependent vasodilator (but with smooth muscle constrictor properties) in 13 normotensive patients. 8 We also found that the coronary flow response to pacing stress correlated with the flow response to intracoronary infusion of the endothelium-dependent vasodilator acetylcholine in 20 hypertensive patients with no or minimal left ventricular hypertrophy, suggesting that microvascular endothelial dysfunction may contribute to abnormal flow responses to stress. 9 Received November 16, 1995. Accepted November 21,1995. From the Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Richard O. Cannon III, MD, National Institutes of Health, Building 10, Room 7815, 10 Center Drive MSC-1650, Bethesda, MD 20892-1650.
© 1996 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
Houghton et al reported a broad spectrum of coronary flow responses to dipyridamole, which blocks myocyte adenosine reuptake, thus relaxing vascular (especially microvascular) smooth muscle, in 48 hypertensive patients who had chest pain syndromes and normal coronary angiograms. Those patients who had perfusion abnormalities by thallium scintigraphy were more likely to have limited flow responses to dipyridamole than those with normal thallium scans. s Although in general the patients with the lowest coronary flow responses to dipyridamole had more severe left ventricular hypertrophy than those with higher flow responses to dipyridamole, some patients without left ventricular hypertrophy also had limited flow responses, suggesting that structural changes in myocardial small arteries might have contributed to limitation in dipyridamole-stimulated flow in these patients. This consideration is support by Schwartzkopff et a!, who reported luminal narrowing in intramural arteries from right ventricular septal biopsies performed in 14 patients with chest pain, hypertension, and normal coronary angiograms. lO There was a significant correlation between the minimum coronary resistance following dipyridamole infusion and the arterial medial wall area, but not the left ventricular mass index by echocardiography. They concluded that the arteriolar wall thickening was causally related to diminished coronary reserve, and partly independent of myocardial hypertrophy. Thus, many groups have provided evidence for both structural and functional abnormalities in the coronary microcirculation of hypertensive patients that appear largely independent of left ventricular mass. Limitation in appropriate coronary flow because of microvascular disease or dysfunction could adversely affect ventricular compliance, thereby elevating filling pressures, and could also contribute to systolic dysfunction because of myocyte necrosis and 0895-7061/96/$1500 PH 50895-7061(96)00038-6
AJH-APRIL 1996-VOL. 9, NO.4, PART 1
scarring. However, the clinical dilemma is how to identify hypertensive patients complaining of anginalike chest pain subsequently found to have normal or near-normal coronary angiograms, who have coronary microvascular dynamics sufficiently abnormal to cause myocardial ischemia, and how can we separate these patients from those who may have abnormal cardiac pain perception,11 or entirely noncardiac pain syndromes. Eugenio Picano and coworkers at the University of Pisa have pioneered dipyridamole echocardiography as a useful noninvasive test for identifying patients with coronary artery disease based on precipitation of wall motion abnormalities during dipyridamole infusion. 12 These abnormalities are likely due to redistribution of coronary flow within the myocardium subserved by the diseased coronary arteries, resulting in the precipitation of regional ischemia. This group also reported that the infusion of dipyridamole commonly provoked ischemic-appearing ST segment depression and chest pain in patients with chest pain despite normal coronary angiograms,13 including hypertensive subjects without left ventricular hypertrophy 14 who were subsequently found to have lesser increases in coronary flow in response to pacing stress compared with hypertensive patient subjects without ST segment depression during dipyridamole infusion. IS The Pisa group has speculated that dipyridamole-stimulated microvascular dilation might cause decreased perfusion pressure distal to anatomically or functionally narrowed intramyocardial arteries. This would, in turn, cause energy losses because of viscosity and turbulence as blood flows through narrowed vessels from epicardium to endocardium resulting in subendocardial hypoperfusion and ischemia. However, in contrast to the abnormal left ventricular wall motion response manifest by patients with coronary artery disease during dipyridamole infusion, patients with chest pain and normal coronary arteries, hypertensive or not, showed generalized increases in contractility, which would seem an unlikely manifestation of myocardial ischemia. In this issue of the Journal, Virdis and coworkers provide an impressive series of observations supporting the clinical and pathophysiological relevance of dipyridamole echocardiography testing (abbreviated DET in the article) in hypertensive patients without left ventricular hypertrophy.16 They report the therapeutic effect of 1 year of angiotensin converting enzyme inhibitor therapy in 16 hypertensive patients who had no evidence of left ventricular hypertrophy by echocardiography and were largely either untreated or minimally treated with antihypertensive therapy prior to this study. Eight of these patients had ischemic-appearing electrocardiographic responses to dipyridamole infusion (DET positive), five of whom
THE HEART IN HYPERTENSION
407
had chest pain syndromes despite normal coronary angiograms, with the remaining 8 patients (all of whom were asymptomatic) showing no ischemic-appearing electrocardiographic changes during dipyridamole infusion (DET negative). The two groups of patients were well matched with regard to age, gender distribution, body mass, left ventricular mass index, and severity of hypertension. However, the authors found that the forearm flow dynamics differed between these groups during baseline testing of all antihypertensive therapy for at least 2 weeks: DET positive patients had less of a flow response both to the endothelium-dependent vasodilator acetylcholine and to the endothelium-independent vasodilator nitroprusside, and a higher minimum forearm vascular resistance following forearm ischemia and exercise compared with DET negative patients. Following 1 year of therapy with captopril 50 mg twice daily (1 patient in each group also received nifedipine), there was an approximately 12% reduction in left ventricular mass in both groups. The forearm flow dynamics in the DET positive group improved such that the differences from the DET negative group in both acetylcholine and nitroprusside-stimulated forearm blood flow noted a baseline were no longer apparent at time of the post-therapy study. Furter, repeat dipyridamole infusion no longer produced ischemic-appearing ST segment changes in the DET positive group, with all measurements performed 2 weeks after discontinuation of drug therapy. The authors concluded that a positive dipyridamole echocardiography test provides evidence of coronary and systemic microvascular disease which can be benefited by 1 year of therapy. The clinical relevance of the DET positive test is suggested by the elimination of chest pain symptoms in three of the five DET positive patients who were symptomatic with chest pain prior to therapy. This study also provided an interesting observation that may be of pathophysiologic relevance regarding essential hypertension: Despite normalization of forearm vascular dynamics with 1 year of treatment in the DET positive group, all patients became hypertensive 2 weeks following cessation of therapy (when the follow-up forearm vascular studies were performed). This observation suggests the abnormal vascular dynamics that has been reported by several groups is likely secondary to prolonged elevation in blood pressure and not a primary process causing hypertension. The findings of this study differ from reports of abnormal endothelium-dependent, but normal endothelium-independent forearm microvascular function in patients with essential hypertension. 17.18 However, the conversion of a DET positive to a DET negative test as indicative of improvement in coronary vascular function due to angiotensin converting enzyme
408
CANNON
AJH-APRIL 1996-VOL. 9, NO.4, PART 1
inhibitor therapy is consistent with the findings of Strauer et al. 19 They reported that approximately 1 year therapy with enalapril resulted in 48% improvement in dipyridamole-stimulated coronary flow despite only an 8% reduction in left ventricular mass compared with pretreatment values in patients with chest pain syndromes, hypertension, and moderate left ventricular hypertrophy. If the findings of Virdis et aI's relatively small series of patients is validated in a larger series of hypertensive patients and with different pharmacotherapies, the dipyridamole echo test could become a useful discriminator for a cardiac origin of pain, likely a consequence of abnormal coronary flow dynamics, in patients with hypertension, chest pain, and normal coronary angiograms, providing the assurances to the patient and physician that a beneficial symptom response to therapy will likely follow.
8.
9.
10.
11. 12.
13.
REFERENCES
1. Mueller TM, Marcus ML, Kerber RE, et al: Effect of renal hypertension and left ventricular hypertrophy on the coronary circulation in dogs. Circ Res 1978;42:543549.
14.
2.
15.
Rembert JC, Kleinman LH, Fedor JM, et al: Myocardial blood flow distribution in concentric left ventricular hypertrophy. J Clin Invest 1978;62:379-386.
3. Strauer BE: Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 1979;44:999-1002. 4.
Opherk D, Mall G, Zebe H, et al: Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation 1984;69:1-7.
5. Houghton JL, Frank MJ, Carr AA, et al: Relations among impaired coronary flow reserve, left ventricular hypertrophy, and thallium perfusion defects in hypertensive patients without obstructive coronary artery disease. J Am ColI Cardiol 1990; 15:43-51. 6. Treasure CB, Klein JL, Vita JA, et al: Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation 1993;87:86-93. 7. Cannon RO, Camici PG, Epstein SE: Pathophysiologi-
cal dilemma of syndrome X. Circulation 1992;85:883892. Brush JE, Cannon RO, Schenke WH, et al: Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 1988;319:1302-1307. Quyyumi AA, Cannon RO, Panza JA, et al: Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 1992; 86:1864-1871. Schwartzkoff B, Motz W, Frenzel H, et al: Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. Circulation 1993;88:993-1003. Cannon RO: The sensitive heart. A syndrome of abnormal cardiac pain perception. JAMA 1995;273:883-887. Picano E, Lattanzi F, Masini M, et al: High dose dipyridamole echocardiography test in effort angina pectoris. J Am ColI Cardiol 1986;8:848-854. Picano E, Lattanzi F, Masini M, et al: Usefulness of a high-dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J CardioI1987;60:508-512. Lucarini AR, Lattanzi F, Picano E, et al: Dipyridamoleechocardiography test in essential hypertensives with chest pain and angiographically normal coronary arteries. Am J Hypertens 1989;2:120-123. Lucarini AR, Picano E, Lattanzi F, et al: Dipyridamole echocardiography stress testing in hypertensive patients. Targets and tools. Circulation 1991;83(suppl III):68-72.
16. Virdis A, Ghiadoni L, Lucarini A, et al: Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term treatment. Am J Hypertens 1996;9:361-369. 17. Panza JA, Quyyumi AA, Brush JE, Epstein SE: Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1991;325:1551-1556. 18. Linder L, Kilokowski W, Buhler FR, Luscher TF: Indirect evidence for the release of endothelium-derived relaxing factor in the human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990;81:1762-1767. 19. Strauer BE, Vogt M, Motz W: ACE-inhibitors and coronary microcirculation. Bas Res Cardiol 1993;88 (suppl 1): 97-106.