JACC vat . 19 . No . 4 Starch 15, 1992916-7
616
Editorial Comment
Hypertension and ischemia : Evolving Concepts* ALAN N . GRADMAN, MD, FACC Pittsburgh, Perrn.r_lrtnda
The determinants of myocardial ischemia in patients with hypertension are of intense investigative interest . It is well established that hypertension is a major risk factor for coronary atherosclerosis and acute myocardial infarction . The early observation (1,2) that infarction was more likely to be lethal in hypertensive patients pointed en the probability that additional factors are operative in the pathogenesis of myocardial ischemic syndromes in hypertension . It has also been suggested (3,4) that ischemia may he important in the development of chronic left ventricular dysfunction and ventricular arrhythmias characteristic of hypertensive heart disease . In addition, it is now recognized that some hypertensive patients exhibit angina pectoris and demonstrable myocardial ischemia in the absence of significant large vessel coronary obstruction . Relation between myocardial hypertrophy and ischemia . The recognition that left ventricular hypertrophy is an independent risk factor for the development of clinical coronary artery disease (5) focused attention on the relation between myocardial hypertrophy and myocardial ischemia . Clinical and experimental studies document that coronary flow reserve-the maximal increase in blood flow attainable through pharmacologic coronary vasodilation-is markedly reduced in the hypertrophied ventricle (4,6) ; additional data (7) document an increased susceptibility to ischemic damage, In one interesting series of studies (3,8) using a canine model of myocardial infarction, both infarct size and the frequency of arrhythmic death were greater in dogs with hypertension and left ventricular hypertrophy than in control animals . It was postulated that decreased capillary density and extravascalar compressive forces predispose the hypertrophied ventricle to ischemic damage . At the same time, there has been increasing recognition of the rule of the vasculature itself in the pathuphysiotugy of ischemia in hypertension . It is clear that hypertrophy occurs in vascular smooth muscle as well as in the myncardhlm. and that the medial layer of coronary arteries is thickened in
"editorials published in Jadennl of air Atnediiia College ci Cnrsiohrgp noel the vswn of the nmhnr, t,d do nni neces,aruy represent he vie,, or JACC or the American College of Cardiology . From the Divi .dnn of Canboaaacular fOsease,'I'he Western Pennsyvania Hospital . Pittaburgh. Pennsylvania. Address for reotints: Alan H, Gradman. MD . Division of Cardiovascular Disease, The Western Pennsylvania Hnspnal . 4500 Friendship Avenue. Pittsburgh . Pennsylvania 15224 . 01992 by
the American College
of
Cardiology
hypertensive animals and humans (9). For geometric reasons, the direct consequences of medial hypertrophy include a disproportionate reduction in luminal diameter in response to any vasncnnstrictive stimulus . The result is an abnormal increase in coronary vascular resistance under a variety of circumstances . Role of abnormal coronary vasculature in myocardial ischemia . The independent role of the vascttlantre in producing myocardial ischemia was further defined in a report by Brush ct al. (10) in which abnormal coronary blood flow was documented in hypertensive patients without evidence of left ventricular hypertrophy or coronary artery disease . These patients had symptoms suggestive of angina and these symptoms could be reproduced by rapid atrial pacing, Basal coronary blood flow was similar to that of control subjects, but at, attenuated coronary vasodilatory response to trial pacing was noted. In addition. there was evidence of an abnormal vasoconstrictor response to ergonovine, Role of coronary endothelium . An important advance in the general understanding of the regulation of vascular tone has been the recognition of the importance of the endothelium in elaborating vasodilator and vasoconstrictive substances . The importance of endothelium-dependent relaxation factor as a modulator of vascular tone has been established (11), and abnormalities in endothelial function have been described in a variety of disease states including coronary atherosclerosis (12). Studies in animal models of hypertension have also documented abnormalities in endothcliam-depcedent vascular relaxation (13,14) and these observations have recently been extended to humans. Data derived from forearm blood flow studies (15) suggest that abnormalities in endothelium-dependent vascular relaxation are important contributors to the increased systemic vascular resistance seen in hypertensive patients . The present study. The study by Brush et al . (16) reported in this issue of the Journal makes a further contribution to our understanding of coronary blood flow regulation in patients with hypertension . These investigators documented a highly abnormal coronary vascular response to the endothelium-dependent vasodilator acetylcholine in a group of hypertensive patients with normal coronary arteriogratus . Using quantitative angiography and direct coronary flow measurements, the investigators (16) demonstrated an actual reduction in coronary flow during acetylcholine infusion in the hypertensive patients compared with the level in control subjects. In contrast, the vhsadilator response to the endothelium-independent vasodilator nitroglycerin was preserved. These data suggest that in the coronary circulation, as well as in the periphery, hypertensive patients have abnormal endothelial function and this abnormality is capable of impairing coronary perfusion . The study has certain limitations . A relatively small number of patients was studied. The unblinded crossover design raises the possibility of both observer bias and carryover pharmacologic effects from the first (acetylchoa735.1a97192195 .m
JACC Vol. 19 . No. 4 March 15 . 1992:016-7
GRADMAN EDITORIAL COMMENT
line) to the second (nitroglycerin) injection . It is also difficult to exclude the possibility that some degree of coronary atherosclerosis-undetectable by conventional angiography-may have been present and contributed to the observed abnormality in endothelium-dependent vasudilatian . Nevertheless, the data are internally consistent and are in accord with animal studies and with earlier clinical data documenting similar abnormalities in the peripheral circulation . Clinical implications . The sum of current knowledge suggests that myocardial ischemia in patients with hypertension has many causes . Large vessel coronary artery disease is a critical factor and probably accounts for most episodes of clinically recognizable myocardial infarction and angina pectoris . Other factors that can affect myocardial perfusionleft ventricular hypertrophy, vascular hypertrophy and physiologic derangement of coronary blood flow regulation. including abnormalities of endothelium-dependent vasodila • Lion-have now been identified . A series of important clinical questions remain . In what way do these "small vessel" factors affect the size and prognosis of myocardial infarction? In how many hypertensive patients do these factors actually cause angina pectoris . and how frequently do they exacerbate anginal symptoms in patients who also have large vessel coronary obstruction? What contribution, if any, do they make to the development of chronic left ventricular dysfunction and lethal ventricular arrhythmias? How important is it to direct antihypenensive drug therapy toward reversal or attenuation of these newly recognized contributors to decreased coronary flow? We now recognize multiple mechanisms by which coronary flow may be impaired in the hypertensive patient . The contribution of these abnormalities to the clinical manifestations of hypertensive heart disease remains to be determined.
References L Cannel Wit . Role of blood pressure in cardiovascular morbidity and nmrlelily. Pros Cardiovanc on 1974;17:5-24.
817
Labkin SW. Mmheasun FAL. Tate RR. Prognosis afleracule myocardial infarction: section to blood pressure values before infaeliOr in a piospccn'c caNmvascular lady . Am J Cardiol I977:4a:vgo-111. 3 . KoyanapiS.EaahamC.MarcusML .Eaccvorchronichypenensionaed let rortdrular hypertrophy an the incidence of oAJdcn drab r ilo .ins coronary occlusion in conscious dogs. Circulatian 1902 :65 :1192-7. 4 . Slrauer BE . Significance of coronary circulation in hypsatensue heart disease for dt,cbpmcnl and promotion of heart failure Am J Ca,diut AM 65 34G-41F,. 5. Casale AN . D9v;reux R8. Millrer M . et a1 . Value of echucardiographic melt of left ventricular mats in predicting caniiovascnlar mmhid event,In hypenensive men . Ann totem bled 1996 :105:173-8 . 6. Marcus lit . Mueller Tint. Gamho IA, Ke,brr RE, Effects of cardiac hypcrrrnphy secorrdan to hypenennion on the corowry vimalatiun. Am 1 Cordial 1979:44 lOlJ-S. 1 . Gaasch WH . Zile MR . Hashing PK. Unbent EO. Rhodes DR. Apslein GS . Tolerance of the hypenmphic heart to i alxmia . Circulation 1990; In IW-1651 . S . Kuyaragi 5 . Easrham CL. Ham- M .. 6t-u M L . IrxTrared wise of mvoo,ndlal infarction In dogs with chronic hyped,, . and ten venrticular hypertrophy. Circ Res 199230:55-62. 9. Vogt M . Molz W. SchwanzkopaH, Slraner BE . Coronary mlaoangmpalhy and cardiac hypertrophy. Ear Heart 1:1Ilsappl I990 81 :133-8. 10. Brash 1E. Cannon R0. Schenke WH. et al . Angina due to coronary scalar disease in hypenensive patients without left ventricular hypertrophy . N EngIJ kited 1999 :319:1102-7. II . FurchgulIRF.ZawadzkiIV .Theobligatory ruleofendrsheliaicensinthe relaxation of arterial smooth muscle by acetykla line . Nature 1990:'88: 373-6 . 12 Forstermann U . Masse A. Alheid U . Havench A . Frolich JC. Selective attenuation of endotMlium-mediated vasodilation in alherosclerolic human coronary i nertes. Circ ft, 1999 ;62:195-90. 6, LockeueW,OlsukaY .Cmrelero0 .Thelossatnedolbelium-0ependrnt scalar relaxation in hypertension . Hypertension 1986:ttsuppl 111:1161-6. 14, Tesfamenam B. Halpem W Endothelium-dependent and endolheliumindependent -dilation idance gates from hypertemive at, Hypenensinn I98&11-440 in res I5 . Porno JO . Quyyumi AA,Brash JE, Epstein SE . Abnormal endurheliumdependent vascular relaxation in patients with essenttrt hypertension, N End I hind 199JaZ3 :ZL-7 . 16 . Brush JE 1r . Farm DP. Salmon 5. Jacobs AK . Ryan TI . Ahnnrmal cndolbdiam-dependent coronary vasomollon in hypenensive patients . J Am Cull Cardiol 1992;19,809-IS.
616
Editorial Comment
Hypertension and ischemia : Evolving Concepts* ALAN N . GRADMAN, MD, FACC Pittsburgh, Perrn.r_lrtnda
The determinants of myocardial ischemia in patients with hypertension are of intense investigative interest . It is well established that hypertension is a major risk factor for coronary atherosclerosis and acute myocardial infarction . The early observation (1,2) that infarction was more likely to be lethal in hypertensive patients pointed en the probability that additional factors are operative in the pathogenesis of myocardial ischemic syndromes in hypertension . It has also been suggested (3,4) that ischemia may he important in the development of chronic left ventricular dysfunction and ventricular arrhythmias characteristic of hypertensive heart disease . In addition, it is now recognized that some hypertensive patients exhibit angina pectoris and demonstrable myocardial ischemia in the absence of significant large vessel coronary obstruction . Relation between myocardial hypertrophy and ischemia . The recognition that left ventricular hypertrophy is an independent risk factor for the development of clinical coronary artery disease (5) focused attention on the relation between myocardial hypertrophy and myocardial ischemia . Clinical and experimental studies document that coronary flow reserve-the maximal increase in blood flow attainable through pharmacologic coronary vasodilation-is markedly reduced in the hypertrophied ventricle (4,6) ; additional data (7) document an increased susceptibility to ischemic damage, In one interesting series of studies (3,8) using a canine model of myocardial infarction, both infarct size and the frequency of arrhythmic death were greater in dogs with hypertension and left ventricular hypertrophy than in control animals . It was postulated that decreased capillary density and extravascalar compressive forces predispose the hypertrophied ventricle to ischemic damage . At the same time, there has been increasing recognition of the rule of the vasculature itself in the pathuphysiotugy of ischemia in hypertension . It is clear that hypertrophy occurs in vascular smooth muscle as well as in the myncardhlm. and that the medial layer of coronary arteries is thickened in
"editorials published in Jadennl of air Atnediiia College ci Cnrsiohrgp noel the vswn of the nmhnr, t,d do nni neces,aruy represent he vie,, or JACC or the American College of Cardiology . From the Divi .dnn of Canboaaacular fOsease,'I'he Western Pennsyvania Hospital . Pittaburgh. Pennsylvania. Address for reotints: Alan H, Gradman. MD . Division of Cardiovascular Disease, The Western Pennsylvania Hnspnal . 4500 Friendship Avenue. Pittsburgh . Pennsylvania 15224 . 01992 by
the American College
of
Cardiology
hypertensive animals and humans (9). For geometric reasons, the direct consequences of medial hypertrophy include a disproportionate reduction in luminal diameter in response to any vasncnnstrictive stimulus . The result is an abnormal increase in coronary vascular resistance under a variety of circumstances . Role of abnormal coronary vasculature in myocardial ischemia . The independent role of the vascttlantre in producing myocardial ischemia was further defined in a report by Brush ct al. (10) in which abnormal coronary blood flow was documented in hypertensive patients without evidence of left ventricular hypertrophy or coronary artery disease . These patients had symptoms suggestive of angina and these symptoms could be reproduced by rapid atrial pacing, Basal coronary blood flow was similar to that of control subjects, but at, attenuated coronary vasodilatory response to trial pacing was noted. In addition. there was evidence of an abnormal vasoconstrictor response to ergonovine, Role of coronary endothelium . An important advance in the general understanding of the regulation of vascular tone has been the recognition of the importance of the endothelium in elaborating vasodilator and vasoconstrictive substances . The importance of endothelium-dependent relaxation factor as a modulator of vascular tone has been established (11), and abnormalities in endothelial function have been described in a variety of disease states including coronary atherosclerosis (12). Studies in animal models of hypertension have also documented abnormalities in endothcliam-depcedent vascular relaxation (13,14) and these observations have recently been extended to humans. Data derived from forearm blood flow studies (15) suggest that abnormalities in endothelium-dependent vascular relaxation are important contributors to the increased systemic vascular resistance seen in hypertensive patients . The present study. The study by Brush et al . (16) reported in this issue of the Journal makes a further contribution to our understanding of coronary blood flow regulation in patients with hypertension . These investigators documented a highly abnormal coronary vascular response to the endothelium-dependent vasodilator acetylcholine in a group of hypertensive patients with normal coronary arteriogratus . Using quantitative angiography and direct coronary flow measurements, the investigators (16) demonstrated an actual reduction in coronary flow during acetylcholine infusion in the hypertensive patients compared with the level in control subjects. In contrast, the vhsadilator response to the endothelium-independent vasodilator nitroglycerin was preserved. These data suggest that in the coronary circulation, as well as in the periphery, hypertensive patients have abnormal endothelial function and this abnormality is capable of impairing coronary perfusion . The study has certain limitations . A relatively small number of patients was studied. The unblinded crossover design raises the possibility of both observer bias and carryover pharmacologic effects from the first (acetylchoa735.1a97192195 .m
JACC Vol. 19 . No. 4 March 15 . 1992:016-7
GRADMAN EDITORIAL COMMENT
line) to the second (nitroglycerin) injection . It is also difficult to exclude the possibility that some degree of coronary atherosclerosis-undetectable by conventional angiography-may have been present and contributed to the observed abnormality in endothelium-dependent vasudilatian . Nevertheless, the data are internally consistent and are in accord with animal studies and with earlier clinical data documenting similar abnormalities in the peripheral circulation . Clinical implications . The sum of current knowledge suggests that myocardial ischemia in patients with hypertension has many causes . Large vessel coronary artery disease is a critical factor and probably accounts for most episodes of clinically recognizable myocardial infarction and angina pectoris . Other factors that can affect myocardial perfusionleft ventricular hypertrophy, vascular hypertrophy and physiologic derangement of coronary blood flow regulation. including abnormalities of endothelium-dependent vasodila • Lion-have now been identified . A series of important clinical questions remain . In what way do these "small vessel" factors affect the size and prognosis of myocardial infarction? In how many hypertensive patients do these factors actually cause angina pectoris . and how frequently do they exacerbate anginal symptoms in patients who also have large vessel coronary obstruction? What contribution, if any, do they make to the development of chronic left ventricular dysfunction and lethal ventricular arrhythmias? How important is it to direct antihypenensive drug therapy toward reversal or attenuation of these newly recognized contributors to decreased coronary flow? We now recognize multiple mechanisms by which coronary flow may be impaired in the hypertensive patient . The contribution of these abnormalities to the clinical manifestations of hypertensive heart disease remains to be determined.
References L Cannel Wit . Role of blood pressure in cardiovascular morbidity and nmrlelily. Pros Cardiovanc on 1974;17:5-24.
817
Labkin SW. Mmheasun FAL. Tate RR. Prognosis afleracule myocardial infarction: section to blood pressure values before infaeliOr in a piospccn'c caNmvascular lady . Am J Cardiol I977:4a:vgo-111. 3 . KoyanapiS.EaahamC.MarcusML .Eaccvorchronichypenensionaed let rortdrular hypertrophy an the incidence of oAJdcn drab r ilo .ins coronary occlusion in conscious dogs. Circulatian 1902 :65 :1192-7. 4 . Slrauer BE . Significance of coronary circulation in hypsatensue heart disease for dt,cbpmcnl and promotion of heart failure Am J Ca,diut AM 65 34G-41F,. 5. Casale AN . D9v;reux R8. Millrer M . et a1 . Value of echucardiographic melt of left ventricular mats in predicting caniiovascnlar mmhid event,In hypenensive men . Ann totem bled 1996 :105:173-8 . 6. Marcus lit . Mueller Tint. Gamho IA, Ke,brr RE, Effects of cardiac hypcrrrnphy secorrdan to hypenennion on the corowry vimalatiun. Am 1 Cordial 1979:44 lOlJ-S. 1 . Gaasch WH . Zile MR . Hashing PK. Unbent EO. Rhodes DR. Apslein GS . Tolerance of the hypenmphic heart to i alxmia . Circulation 1990; In IW-1651 . S . Kuyaragi 5 . Easrham CL. Ham- M .. 6t-u M L . IrxTrared wise of mvoo,ndlal infarction In dogs with chronic hyped,, . and ten venrticular hypertrophy. Circ Res 199230:55-62. 9. Vogt M . Molz W. SchwanzkopaH, Slraner BE . Coronary mlaoangmpalhy and cardiac hypertrophy. Ear Heart 1:1Ilsappl I990 81 :133-8. 10. Brash 1E. Cannon R0. Schenke WH. et al . Angina due to coronary scalar disease in hypenensive patients without left ventricular hypertrophy . N EngIJ kited 1999 :319:1102-7. II . FurchgulIRF.ZawadzkiIV .Theobligatory ruleofendrsheliaicensinthe relaxation of arterial smooth muscle by acetykla line . Nature 1990:'88: 373-6 . 12 Forstermann U . Masse A. Alheid U . Havench A . Frolich JC. Selective attenuation of endotMlium-mediated vasodilation in alherosclerolic human coronary i nertes. Circ ft, 1999 ;62:195-90. 6, LockeueW,OlsukaY .Cmrelero0 .Thelossatnedolbelium-0ependrnt scalar relaxation in hypertension . Hypertension 1986:ttsuppl 111:1161-6. 14, Tesfamenam B. Halpem W Endothelium-dependent and endolheliumindependent -dilation idance gates from hypertemive at, Hypenensinn I98&11-440 in res I5 . Porno JO . Quyyumi AA,Brash JE, Epstein SE . Abnormal endurheliumdependent vascular relaxation in patients with essenttrt hypertension, N End I hind 199JaZ3 :ZL-7 . 16 . Brush JE 1r . Farm DP. Salmon 5. Jacobs AK . Ryan TI . Ahnnrmal cndolbdiam-dependent coronary vasomollon in hypenensive patients . J Am Cull Cardiol 1992;19,809-IS.
