- Email: [email protected]
Cardiac function in experimental hypertension
Cardiac
function
Carlos M. Taquini,
in experimental
MD Buenos Aires, Argentina
Cardiac growth is controlled by two sets of factors. The first set includes factors that are time dependent and not related to functional demands, which occur mainly in the embryogenic period. The second set is related to the contractile activity of the heart, which depends on the hemodynamic load.’ Despite the different underlying pathophysiologies, pressure or volume overload of the ventricles increases left ventricular systolic or diastolic circumferential wall stress. As defined by the Laplace equation, this is a function of the product of intracavitary pressure (P) times the chamber radius (R) divided by myocardial wall thickness (h): Stress = P . R/2h. In response to the increased stress caused by pressure overload, a rapid biochemical response of the myocardium with increased protein synthesis is induced.2 The intimate mechanism of the induced activation of protein synthesis is presently unresolved. Many factors responsible for the development and maintenance of hypertension may play a role in the stimulation of left ventricular hypertropb. It is known that in hypertensive patients, as well as in different models of experimental hypertension, the extent of cardiac enlargement is not always proportionate to the level of arterial pressure. Moreover, it has been established that at the same level of mean blood pressure, the observed target organ damage is also related to the variability of arterial pressure.3t * PATiOGENESiS HYPERTROPHY
OF LEFT VENTRICULAR IN HYPERTENSION
Because of the previously mentioned poor correlation between cardiac hypertrophy and blood pressure, other factors have been implicated in the pathogenesis of myocardial hypertrophy in hypertension. Among them, the sympathetic nervous sysFrom
Institute
de Investigaciones
hypertension
Cardiologicae.
Reprint requests: Carloe M. Taquini, MD, Instituto de Investigsciones Cardiologicas, Marcel0 T. de Alvear 2270 (1122). Buenos Aires, Argentina.
tern and catecholamines have important roles since it is known that suppressor doses of norepinephrine or synthetic catecholamines will similarly produce ventricular hypertrophy,5-7 each independent of hemodynamic alteration. Moreover, Yamori et al.S have demonstrated that norepinephrine infusion induces cardiac hypertrophy in rate, but an increase in blood pressure is prevented with cw-blockers. On the other hand, Tomanek et al.9 have shown that regardless of blood pressure control, the use of a-methyldopa, a drug that has a sympatholitic effect on the heart, reverses hypertrophy in spontaneously hypertensive rate (SHR). There is also evidence that the renin-angiotensin system could be involved in the development of cardiac hypertrophy. In fact, angiotensin II can exert a direct or indirect growth action on myocardial tissue. Sen et a1.‘osl1 demonstrated that in rats treated with an angiotensin II antagonist, cardiac hypertrophy developed that was associated with an increase in catecholamine concentration. When bilateral adrenalectomy was performed, cardiac hypertrophy was prevented.lOT” Moreover, it was reported that angiotensin II increases the myocardial protein synthesis.12 Genetic factors have been implicated in cardiac hypertrophy in some models of hypertension. Prevention of hypertension in SHR with neonatal administration of nerve-growth factor antiserum does not alter the development of cardiac hypertrophy.13, l4 Sodium may also modulate cardiac hypertrophy. In experimental two kidney, one clip hypertension, a low-sodium diet led to a reduced cardiac mass when compared with rats fed a normal diet.15 Still other factors such as aging, race, and sexual hormones must be taken into consideration as modulating factors in the cardiac hypertrophy process.14 CARDIAC FUNCTION IN HYPERTENSIVE VENTRICULARHYPERTROPHY
LEFT
Structurally, cardiac hypertrophy involves (1) an increase in the size and sometimes in the number of cardiac muscle cells, (2) an increase in the number of 6D7
606
Taquini
connective tissue cells, and (3) the deposition of connective tissue proteins in the interstitial space.16 From a functional point of view, Meerson and Breger17 described the following three different stages in the evolution of left ventricular hypertrophy: (1) phase I, development of hypertrophy, which was characterized by increased protein synthesis and energy production; (2) phase II, stable hyperfunction or compensated hypertrophy, and (3) phase III, contractility depression caused by failure of a mitochondrial renovation with myofibrillar damage and cellular atrophy. l7 According to this, the analysis of data related to the performance of the heart during cardiac hypertrophy must consider in which of these periods the studies were performed. Early in hypertension, diastolic heart function is impaired in humans. Signs of reduced ventricular distensibility have been registered during the passive filling phase in the form of a reduced left ventricular filling rate, as measured by radioisotopic techniques16 and echocardiography.lg In experimental hypertension in SHR, it has also been found that cardiac distensibility is alteredzO and that the pressure-volume curve is shifted to the pressure axis. However, in renal hypertensive rats with 3 weeks of hypertension, Gomez et a1.21 found no difference in the pressure-volume curve of hypertensive rats with already developed hypertrophy when compared with control animals. This could be attributed to the short period of hypertension. However, similar results were obtained by Saragoca et al.22 after 6 weeks of hypertension in the same model. Thus changes in distensibility are not always present in cardiac hypertrophy in hypertension, and they cannot be solely attributed to the increase in the thickness of the ventricle. Other mechanisms for diastolic abnormalities are probably involved in different models of hypertension. Accordingly, because essential hypertension is a multifactorial disease, the changes in ventricular compliance are not necessarily present in all hypertensive patients. In agreement with previous observations, Gomez et a1.21found an increase in the end-diastolic pressure in renal hypertension. Since distensibility is not altered, this indicates, as has been postulated, that this model demonstrates an increase in the enddiastolic volume and that the heart is more dependent on Starling’s mechanism to generate the adequate force to cope with the increased pressure.22 Despite the normal cardiac output observed in the two kidney, one clip model during early periods of inotropic response to hypertension,23 an impaired &adrenergic stimulation was described in renovas-
cular hypertensive rate as well as in the SHR model.2*s22*24 In fact, our observations after 3 weeks of hypertension, as well as those of other investigators at different periods of hypertension, indicate that hypertensive rate have a blunted response of cardiac contractility to isoproterenol infusion, which is measured by dP/dt. Since coronary reserve is decreased during cardiac hypertrophy, it was suggested that this impaired response could be caused by an insufficient coronary flow.25926To test this possibility, we measured the maximal rate of tension development (+T) by papillary muscles of hypertrophied ventricles from animals with the same period of hypertension to different doses of isoproterenol. Once more, the +T response was decreased in papillary muscles of hypertensive rats when compared with those from control rate, thereby discarding the participation of the coronary flo~.~~ Because the concentration in &receptors from these hearts are similar to that of the control rats, mechanisms related to alteration at the postreceptor adenyl cyclase level could be related to the diminished response.27 In summary, the contractile response of the ventricle to ,&stimulation is limited during cardiac hypertrophy. This alteration occurs in the early stages of hypertension and is probably related to postreceptor alteration. Whether this blunted response is responsible for the dependence of the heart on the Frank-Starling mechanism remains speculation. REGRESSION
OF HYPERTROPHY
Normalization of blood pressure by surgery or medical treatment of hypertension with some drugs is accompanied by regression of cardiac hypertropk. 9.2840 It has been shown that regression of cardiac mass with different maneuvers is followed by normalization of the contractile response to isoproterenol.28 These results suggest that regression of cardiac mass toward normal is followed by normalization of the contractile response to isoproterenol. However, we have shown that 24 hours after unclipping, normalization of blood pressure is followed by a regression of cardiac mass and a decrease in cardiac protein content without changes in the water concentration of the ventricles.31 This regression of cardiac mass is not followed by normalization of the contractile resnonse to &stimulation. since the maxima! rate of tension development of the papillary muscles from these hearts is not different from that of hypertrophic ventricles.32 This indicates that the impaired cardiac response to isoproterenol is not exclusively
vohlma Number
116 2, Part 2
Cardiac function
CARDIAC
Blood
Fig.
diagram
Other
of cardiac
609
HYPERTROPHY
Pressure
1. Schematic
in hypertension
hypertrophy
related to the muscle hypertrophy and that its recovery lags behind the normalization of the cardiac mass. Some drugs, such as a-methyldopa, can produce regression of cardiac hypertrophy even without complete normalization of arterial blood pressure.* In either SHR or renovascular hypertensive rats, the reversal of hypertrophy with this drug led to higher cardiac output for the same end-diastolic pressure. Although the ventricles were reduced in mass, this did not impair their ability to sustain increased volume 1oads.23,33This improvement in cardiac ability was probably related to the lower afterload. On the other hand, the increase in blood pressure by an infusion of phenylephrine led to a greater reduction of peak output in hearts with reversed hypertrophy than in either untreated hypertensive rats or untreated control rats.33 Other drugs, such as captopril, in either SHR or renovascular hypertension, normalize the ventricular weight and the left ventricular function.28~34 In the two kidney, one clip model we also found that enalapril lowers the arterial blood pressure and regress cardiac hypertrophy.36 However, the contractile response to isoproterenol stimulation of papiliary muscles from treated hypertensive rats remained diminished after normalization of cardiac mass, Moreover, the maximal tension development of the papillary muscles (+T) from treated normotensive control animals is blunted when compared with those of untreated control rats.% Regression of hypertrophy with captopril is followed by normalization of the number of &receptors,28 whereas with enalapril p-receptors remain elevated.36 This suggests that this drug could interfere with the sympathetic drive to the heart or may produce postrecep-
and regression
tor alterations, to &stimulation.
Factors
in hypertension.
which alter the contractile
response
CONCLUSION
Although other mentioned mechanisms may also be involved, cardiac hypertrophy caused by arterial hypertension is a result of increased blood pressure, which modulates the response of the cardiac cells to the increased afterload. On the one hand, to obtain regression of cardiac hypertrophy, these other mechanisms must be suppressed, since simple normalization of blood pressure with some drugs is not followed by regression of cardiac hypertrophy.29*30 On the other hand, it can be achieved with drugs that do not normalize arterial blood pressure9rm (Fig. 1). During cardiac hypertrophy the left ventricular contractile response to &stimulation is blunted, whereas ventricular distensibility may not be altered. Regression of cardiac hypertrophy is not always an advantage in cardiac function. More studies are needed to evaluate the mechanisms underlying either the systolic or diastolic function in this situation. REFEReNCES
1. Zak R. Factors controlling cardiac growth. In: Zak R, ed. Growth of the heart in health and disease. New York: R.aven Press, 1964:165. 2. Frohlich ED. The heart in hypertension. In: Genest J, ed. Physiopatbology of hypertension. 2nd ed. New York: McGraw Hill, 1983:791. 3. De Gaudemaris R, Camaleonte A, Dimitriou R, Debru JL,
Mallion JM. Interest of ambulatory test recordings, and echocardiographic derline arterial 1985;A7:371. 4. Parati G, Pomidossi
hypertension. G, Albini
blood pressure, exercise Clin
measurements in borExp Hypertens
F, Malaspina
D, Mancia
G.
610
5.
6.
I.
8.
9.
10.
11. 12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
Tuquini
American
Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5:93. Szakacs JE, Mehlman B. Pathologic changes induced by L-norepinephrine: quantitative aspects. Am J Cardiol 1972;5:619. Gordon AL, Inchiosa MA, Leher D. Isoproterenol induced cardiomegaly: assessment of myocardial protein content, actomyosin ATPase and heart rate. J Mol Cell Cardiol 1972;4:543. Laks DM, Morady F, Swan JJC. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in dogs. Chest 1973;64:75. Yamori Y, Tarzai RC, Ooshima A. Effect of beta-receptor blocking agents on cardiovascular structural changes in spontaneousand noradrenaline-induced hypertension in rats. Clin Sci 1981;59:457. Tomanek RJ, Davis JR, Anderson SC. The effect of alpha methyldopa on cardiac hypertrophy in SHR. Cardiovasc Res 197%11:427. Sen S, Khairallah PA, Tarazi RC, Bumpus FM. Effect of chronic administration of Sar 1 Ileu 8 angiotensin II in rats [Abstract]. Circulation 1975;51,52-98. Sen S, Tarazi RC, Bumpus FM. Cardiac effect of angiotensin antagonist in normotensive rats. Clin Sci 1979;56:439. Khairallah PA, Sen S, Tarazi RC. Angiotensin protein biosynthesis and cardiovascular hypertrophy in SHR [Abstract]. Am J Cardiol 1976;37:145. Cutilleta AF, Erinoff L, Heller A, Low J, Oparil S. Development of left ventricular hypertrophy in young spontaneously hypertensive rats after peripheral sympathectomy. Circ Res 1977;40:428. Page sympathectomy on left - E, --Oparil S. Effect of peripheral ventricular ultra structure in young spontaneously hypertensive rata. J Mol Cell Cardiol 1978:10:301. Lindpainter K, Sen S. Role of sodium in hypertensive cardiac hypertrophy. Circ Res 1985;57:610. Ferrans VJ. Cardiac hypertrophy: morphological aspects. In: Zak R, ed. Growth of the heart in health and disease. New York: Raven Press 1984;187. Meerson FZ, Breger AM. The common mechanism of heart’s adaptation and deadaptation. Hypertrophy and atrophy of the heart muscle. Basic Res Cardiol 1977;72:228. Smith VE, Schullman P, Karimeddini MK, Withe WW, Meeran MK. Katz AM. Rauid ventricular filling in left ventricular hypertrophy: II. Pathologic hypertrophy. J Am Coll Cardiol 1985;5:869. Hanrath P, Mathey DG, Siegert R, Bleifeld W. Left ventricular relaxation and filling pattern in different form of left ventricular hypertrophy: an echocardiographic study. Am J Cardiol 1980;45:15. Motz W, Strauer BE. Regression of structural cardiovascular changes by antihypertensive therapy. Hypertension 1984; G(supp1 IIi):133. Gomez Llambi H. Fontan M. Taauini CM, Taauini AC. Function ventricular en etapas precoces de hipertension renal experimental [Abstract]. Medicina (B Aires) 1983; 43760.
ia
August 1999 Heart Journal
MA, Tarazi RC. Left ventricular hypertrophy in 22. Saragoca rata with renovascular hypertension alterations in cardiac function and adrenergic responses. Hypertension 1981; __ 3(suppl 11):11771. 23. Kuwajima I, Kardon MB, Pegram BL, Sesoko S, Frohlich ED. Regression of left ventricular h.vpertrophy in two kidney, one clip Golblatt hypertension. Hypertension 1981;4(suppl 11):113. 24. Sen S, Tarazi RC, Khairallah PA, Bumpus FM. Cardiac hypertrophy in SHR. Circ Res 1974;35:775. 25. Marcus ML, Mueller TM, Gascho JA, Kerber RE. Effects of cardiac hypertrophy secondary to hypertension on coronary circulation. Am J Cardiol 1979;44:1023. CR, Bordeau-Martini J. Extravascular component of 26. Honing oxygen transport in normal and hypertrophied hearts with special reference to oxygen therapy. Circ Res 1974;3435(suppl II): 97. A, Camilion MC, Pedroni P, Taquini 27. Gende OA, Mattiazzi CM; Gomez Llambi H, Cingolani HE. Renal hypertension impairs inotropic isoproterenol effect without beta-receptor changes. Am J Physiol 1985;245:H 814. 28. Ayobe H, Tarazi RC. Reversal of changes in myocardial beta receptors and inotropic responsiveness with regression of cardiac hypertrophy in renal hypertensive rats (RHR). Circ Res 1984;54-2:125. 29. Ishise S, Pegram BL, Frohlich ED. Disparate effects of methyldopa and clonidine on cardiac mass and hemodynamits in rata. Clin Sci 1980;59(suppl):449s. FHH, Prause S. Time-course of changes in cardiac 30. Leenen hypertrophy in two kidney, one clip hypertensive rata during treatment with minoxidil, enalapril or after uninephrectomy. J Hype&ens 1987;5:73. M, Kuraja I, Gallo A, Gomez Llambi H, Taquini CM. 31. Fontan Rapid normalization of blood pressure by unclipping induces regression of cardiac hypertrophy in renal hypertensive rats [Abstract]. Hypertension 1987;9:559. H. Taauini CM. Massadi A. Acute effects of 32. Gomez Llambi unclipping (U) on cardiac hypertrophy and left ventricular inotropic response to isoproterenol in renal hypertensive rats [Abstract]. Hypertension 1987;9:558. CM, Spech MM, Tarazi RC, Doi Y. Cardiac pumping 33. Ferrario ability in rats with experimental renal and genetic hypertension. Am J Cardiol 1979;44:979. RC, Sen S, Fouad FM, Wicker P. Regression of 34. Tarazi myocardial hypertrophy: conditions and sequelae of reversal in hypertensive heart disease. In: Alpert NP, ed. Perspective in cardiovascular research: myocardial hypertrophy and failure. New York: Raven Press, 1983637. 35. Kuraja I, Gal10 A, Fontan M, Gomez Llambi H, Taquini CM. Regression of cardiac hypertrophy and beta receptors in two kidney, one clip rats: enalapril versus surgical therapy. J Hype&&s 198%5(suppl5):S419. CM. Gomez Llambi H. Massadi A, Kuraia I, Gallo A. 36. Taauini Efectos de1 enalapril sobre la hipertrofia cardiac;, la respuesta contractil y 10s beta receptores en la hipertension renal 2R-1C [Abstract]. Medicina (B Aires) 1987;47:615.
function
Carlos M. Taquini,
in experimental
MD Buenos Aires, Argentina
Cardiac growth is controlled by two sets of factors. The first set includes factors that are time dependent and not related to functional demands, which occur mainly in the embryogenic period. The second set is related to the contractile activity of the heart, which depends on the hemodynamic load.’ Despite the different underlying pathophysiologies, pressure or volume overload of the ventricles increases left ventricular systolic or diastolic circumferential wall stress. As defined by the Laplace equation, this is a function of the product of intracavitary pressure (P) times the chamber radius (R) divided by myocardial wall thickness (h): Stress = P . R/2h. In response to the increased stress caused by pressure overload, a rapid biochemical response of the myocardium with increased protein synthesis is induced.2 The intimate mechanism of the induced activation of protein synthesis is presently unresolved. Many factors responsible for the development and maintenance of hypertension may play a role in the stimulation of left ventricular hypertropb. It is known that in hypertensive patients, as well as in different models of experimental hypertension, the extent of cardiac enlargement is not always proportionate to the level of arterial pressure. Moreover, it has been established that at the same level of mean blood pressure, the observed target organ damage is also related to the variability of arterial pressure.3t * PATiOGENESiS HYPERTROPHY
OF LEFT VENTRICULAR IN HYPERTENSION
Because of the previously mentioned poor correlation between cardiac hypertrophy and blood pressure, other factors have been implicated in the pathogenesis of myocardial hypertrophy in hypertension. Among them, the sympathetic nervous sysFrom
Institute
de Investigaciones
hypertension
Cardiologicae.
Reprint requests: Carloe M. Taquini, MD, Instituto de Investigsciones Cardiologicas, Marcel0 T. de Alvear 2270 (1122). Buenos Aires, Argentina.
tern and catecholamines have important roles since it is known that suppressor doses of norepinephrine or synthetic catecholamines will similarly produce ventricular hypertrophy,5-7 each independent of hemodynamic alteration. Moreover, Yamori et al.S have demonstrated that norepinephrine infusion induces cardiac hypertrophy in rate, but an increase in blood pressure is prevented with cw-blockers. On the other hand, Tomanek et al.9 have shown that regardless of blood pressure control, the use of a-methyldopa, a drug that has a sympatholitic effect on the heart, reverses hypertrophy in spontaneously hypertensive rate (SHR). There is also evidence that the renin-angiotensin system could be involved in the development of cardiac hypertrophy. In fact, angiotensin II can exert a direct or indirect growth action on myocardial tissue. Sen et a1.‘osl1 demonstrated that in rats treated with an angiotensin II antagonist, cardiac hypertrophy developed that was associated with an increase in catecholamine concentration. When bilateral adrenalectomy was performed, cardiac hypertrophy was prevented.lOT” Moreover, it was reported that angiotensin II increases the myocardial protein synthesis.12 Genetic factors have been implicated in cardiac hypertrophy in some models of hypertension. Prevention of hypertension in SHR with neonatal administration of nerve-growth factor antiserum does not alter the development of cardiac hypertrophy.13, l4 Sodium may also modulate cardiac hypertrophy. In experimental two kidney, one clip hypertension, a low-sodium diet led to a reduced cardiac mass when compared with rats fed a normal diet.15 Still other factors such as aging, race, and sexual hormones must be taken into consideration as modulating factors in the cardiac hypertrophy process.14 CARDIAC FUNCTION IN HYPERTENSIVE VENTRICULARHYPERTROPHY
LEFT
Structurally, cardiac hypertrophy involves (1) an increase in the size and sometimes in the number of cardiac muscle cells, (2) an increase in the number of 6D7
606
Taquini
connective tissue cells, and (3) the deposition of connective tissue proteins in the interstitial space.16 From a functional point of view, Meerson and Breger17 described the following three different stages in the evolution of left ventricular hypertrophy: (1) phase I, development of hypertrophy, which was characterized by increased protein synthesis and energy production; (2) phase II, stable hyperfunction or compensated hypertrophy, and (3) phase III, contractility depression caused by failure of a mitochondrial renovation with myofibrillar damage and cellular atrophy. l7 According to this, the analysis of data related to the performance of the heart during cardiac hypertrophy must consider in which of these periods the studies were performed. Early in hypertension, diastolic heart function is impaired in humans. Signs of reduced ventricular distensibility have been registered during the passive filling phase in the form of a reduced left ventricular filling rate, as measured by radioisotopic techniques16 and echocardiography.lg In experimental hypertension in SHR, it has also been found that cardiac distensibility is alteredzO and that the pressure-volume curve is shifted to the pressure axis. However, in renal hypertensive rats with 3 weeks of hypertension, Gomez et a1.21 found no difference in the pressure-volume curve of hypertensive rats with already developed hypertrophy when compared with control animals. This could be attributed to the short period of hypertension. However, similar results were obtained by Saragoca et al.22 after 6 weeks of hypertension in the same model. Thus changes in distensibility are not always present in cardiac hypertrophy in hypertension, and they cannot be solely attributed to the increase in the thickness of the ventricle. Other mechanisms for diastolic abnormalities are probably involved in different models of hypertension. Accordingly, because essential hypertension is a multifactorial disease, the changes in ventricular compliance are not necessarily present in all hypertensive patients. In agreement with previous observations, Gomez et a1.21found an increase in the end-diastolic pressure in renal hypertension. Since distensibility is not altered, this indicates, as has been postulated, that this model demonstrates an increase in the enddiastolic volume and that the heart is more dependent on Starling’s mechanism to generate the adequate force to cope with the increased pressure.22 Despite the normal cardiac output observed in the two kidney, one clip model during early periods of inotropic response to hypertension,23 an impaired &adrenergic stimulation was described in renovas-
cular hypertensive rate as well as in the SHR model.2*s22*24 In fact, our observations after 3 weeks of hypertension, as well as those of other investigators at different periods of hypertension, indicate that hypertensive rate have a blunted response of cardiac contractility to isoproterenol infusion, which is measured by dP/dt. Since coronary reserve is decreased during cardiac hypertrophy, it was suggested that this impaired response could be caused by an insufficient coronary flow.25926To test this possibility, we measured the maximal rate of tension development (+T) by papillary muscles of hypertrophied ventricles from animals with the same period of hypertension to different doses of isoproterenol. Once more, the +T response was decreased in papillary muscles of hypertensive rats when compared with those from control rate, thereby discarding the participation of the coronary flo~.~~ Because the concentration in &receptors from these hearts are similar to that of the control rats, mechanisms related to alteration at the postreceptor adenyl cyclase level could be related to the diminished response.27 In summary, the contractile response of the ventricle to ,&stimulation is limited during cardiac hypertrophy. This alteration occurs in the early stages of hypertension and is probably related to postreceptor alteration. Whether this blunted response is responsible for the dependence of the heart on the Frank-Starling mechanism remains speculation. REGRESSION
OF HYPERTROPHY
Normalization of blood pressure by surgery or medical treatment of hypertension with some drugs is accompanied by regression of cardiac hypertropk. 9.2840 It has been shown that regression of cardiac mass with different maneuvers is followed by normalization of the contractile response to isoproterenol.28 These results suggest that regression of cardiac mass toward normal is followed by normalization of the contractile response to isoproterenol. However, we have shown that 24 hours after unclipping, normalization of blood pressure is followed by a regression of cardiac mass and a decrease in cardiac protein content without changes in the water concentration of the ventricles.31 This regression of cardiac mass is not followed by normalization of the contractile resnonse to &stimulation. since the maxima! rate of tension development of the papillary muscles from these hearts is not different from that of hypertrophic ventricles.32 This indicates that the impaired cardiac response to isoproterenol is not exclusively
vohlma Number
116 2, Part 2
Cardiac function
CARDIAC
Blood
Fig.
diagram
Other
of cardiac
609
HYPERTROPHY
Pressure
1. Schematic
in hypertension
hypertrophy
related to the muscle hypertrophy and that its recovery lags behind the normalization of the cardiac mass. Some drugs, such as a-methyldopa, can produce regression of cardiac hypertrophy even without complete normalization of arterial blood pressure.* In either SHR or renovascular hypertensive rats, the reversal of hypertrophy with this drug led to higher cardiac output for the same end-diastolic pressure. Although the ventricles were reduced in mass, this did not impair their ability to sustain increased volume 1oads.23,33This improvement in cardiac ability was probably related to the lower afterload. On the other hand, the increase in blood pressure by an infusion of phenylephrine led to a greater reduction of peak output in hearts with reversed hypertrophy than in either untreated hypertensive rats or untreated control rats.33 Other drugs, such as captopril, in either SHR or renovascular hypertension, normalize the ventricular weight and the left ventricular function.28~34 In the two kidney, one clip model we also found that enalapril lowers the arterial blood pressure and regress cardiac hypertrophy.36 However, the contractile response to isoproterenol stimulation of papiliary muscles from treated hypertensive rats remained diminished after normalization of cardiac mass, Moreover, the maximal tension development of the papillary muscles (+T) from treated normotensive control animals is blunted when compared with those of untreated control rats.% Regression of hypertrophy with captopril is followed by normalization of the number of &receptors,28 whereas with enalapril p-receptors remain elevated.36 This suggests that this drug could interfere with the sympathetic drive to the heart or may produce postrecep-
and regression
tor alterations, to &stimulation.
Factors
in hypertension.
which alter the contractile
response
CONCLUSION
Although other mentioned mechanisms may also be involved, cardiac hypertrophy caused by arterial hypertension is a result of increased blood pressure, which modulates the response of the cardiac cells to the increased afterload. On the one hand, to obtain regression of cardiac hypertrophy, these other mechanisms must be suppressed, since simple normalization of blood pressure with some drugs is not followed by regression of cardiac hypertrophy.29*30 On the other hand, it can be achieved with drugs that do not normalize arterial blood pressure9rm (Fig. 1). During cardiac hypertrophy the left ventricular contractile response to &stimulation is blunted, whereas ventricular distensibility may not be altered. Regression of cardiac hypertrophy is not always an advantage in cardiac function. More studies are needed to evaluate the mechanisms underlying either the systolic or diastolic function in this situation. REFEReNCES
1. Zak R. Factors controlling cardiac growth. In: Zak R, ed. Growth of the heart in health and disease. New York: R.aven Press, 1964:165. 2. Frohlich ED. The heart in hypertension. In: Genest J, ed. Physiopatbology of hypertension. 2nd ed. New York: McGraw Hill, 1983:791. 3. De Gaudemaris R, Camaleonte A, Dimitriou R, Debru JL,
Mallion JM. Interest of ambulatory test recordings, and echocardiographic derline arterial 1985;A7:371. 4. Parati G, Pomidossi
hypertension. G, Albini
blood pressure, exercise Clin
measurements in borExp Hypertens
F, Malaspina
D, Mancia
G.
610
5.
6.
I.
8.
9.
10.
11. 12.
13.
14.
15. 16.
17.
18.
19.
20.
21.
Tuquini
American
Relationship of 24-hour blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5:93. Szakacs JE, Mehlman B. Pathologic changes induced by L-norepinephrine: quantitative aspects. Am J Cardiol 1972;5:619. Gordon AL, Inchiosa MA, Leher D. Isoproterenol induced cardiomegaly: assessment of myocardial protein content, actomyosin ATPase and heart rate. J Mol Cell Cardiol 1972;4:543. Laks DM, Morady F, Swan JJC. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepinephrine in dogs. Chest 1973;64:75. Yamori Y, Tarzai RC, Ooshima A. Effect of beta-receptor blocking agents on cardiovascular structural changes in spontaneousand noradrenaline-induced hypertension in rats. Clin Sci 1981;59:457. Tomanek RJ, Davis JR, Anderson SC. The effect of alpha methyldopa on cardiac hypertrophy in SHR. Cardiovasc Res 197%11:427. Sen S, Khairallah PA, Tarazi RC, Bumpus FM. Effect of chronic administration of Sar 1 Ileu 8 angiotensin II in rats [Abstract]. Circulation 1975;51,52-98. Sen S, Tarazi RC, Bumpus FM. Cardiac effect of angiotensin antagonist in normotensive rats. Clin Sci 1979;56:439. Khairallah PA, Sen S, Tarazi RC. Angiotensin protein biosynthesis and cardiovascular hypertrophy in SHR [Abstract]. Am J Cardiol 1976;37:145. Cutilleta AF, Erinoff L, Heller A, Low J, Oparil S. Development of left ventricular hypertrophy in young spontaneously hypertensive rats after peripheral sympathectomy. Circ Res 1977;40:428. Page sympathectomy on left - E, --Oparil S. Effect of peripheral ventricular ultra structure in young spontaneously hypertensive rata. J Mol Cell Cardiol 1978:10:301. Lindpainter K, Sen S. Role of sodium in hypertensive cardiac hypertrophy. Circ Res 1985;57:610. Ferrans VJ. Cardiac hypertrophy: morphological aspects. In: Zak R, ed. Growth of the heart in health and disease. New York: Raven Press 1984;187. Meerson FZ, Breger AM. The common mechanism of heart’s adaptation and deadaptation. Hypertrophy and atrophy of the heart muscle. Basic Res Cardiol 1977;72:228. Smith VE, Schullman P, Karimeddini MK, Withe WW, Meeran MK. Katz AM. Rauid ventricular filling in left ventricular hypertrophy: II. Pathologic hypertrophy. J Am Coll Cardiol 1985;5:869. Hanrath P, Mathey DG, Siegert R, Bleifeld W. Left ventricular relaxation and filling pattern in different form of left ventricular hypertrophy: an echocardiographic study. Am J Cardiol 1980;45:15. Motz W, Strauer BE. Regression of structural cardiovascular changes by antihypertensive therapy. Hypertension 1984; G(supp1 IIi):133. Gomez Llambi H. Fontan M. Taauini CM, Taauini AC. Function ventricular en etapas precoces de hipertension renal experimental [Abstract]. Medicina (B Aires) 1983; 43760.
ia
August 1999 Heart Journal
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