(Circulation. 1997;95:1349-1351.)
© 1997 American Heart Association, Inc.
Articles |
On Variations in the Cardiac Hypertrophic Response to Pressure Overload
the Division of Cardiology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, Calif.
Correspondence to John Ross, Jr, MD, UCSD School of Medicine 0613B, 9500 Gilman Dr, BSB Room 5026, La Jolla, CA 92093-0613. E-mail jross{at}ucsd.edu
Key Words: Editorials • hypertrophy • pressure • contractility • heart diseases • ventricles
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Introduction |
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This issue of Circulation contains an interesting and provocative study concerning the prediction of differences in cardiac hypertrophy and function in response to pressure overload. Koide et al,1 using a canine model of controlled, progressive ascending aortic constriction over an 8-week period, report that 5 dogs having a relatively high left ventricular (LV) mass to body weight ratio (LVM/BW) before constriction (calculated by angiography) as well as a high mean normalized systolic ejection rate and low systolic wall stress developed compensatory hypertrophy and maintained normal LV function. The remaining 10 dogs with aortic constriction had a lower initial LVM/BW, developed significantly less hypertrophy, and evidenced late LV dysfunction with decreased contractility; the presence of intrinsic myocardial depression in the latter group at the end of the study also was documented by studies of function of isolated myocytes taken from these ventricles. Studies performed under anesthesia with ß-adrenergic blockade showed higher levels of afterload (mean systolic wall stress) and lower mean systolic ejection rates both before and after aortic constriction in the group developing LV dysfunction, although both groups fell within the normal range of the inverse relation between afterload and ejection rate before aortic constriction. In a subsequent group of animals, the presence of a higher wall stress (a preselected value
115 kdyne/cm2) before aortic constriction was associated with the late development of LV dysfunction in 75% of animals, whereas an initial LV wall stress below that value was associated with normal LV function at the final study in 90% of animals, although the data were not analyzed statistically.1 The authors suggest that their findings mimic the wide variations in LV hypertrophic responses observed in patients with chronic aortic stenosis or hypertension and may indicate that in some individuals there is a lower set point (perhaps genetically determined) for maintaining a physiologically higher LV weight under normal conditions and for developing a greater compensatory hypertrophic response to pressure overload. With experimental aortic banding in many mammalian species, there is generally a good correlation between the LVM/BW and the pressure gradient or the LV peak systolic pressure but with considerable scatter, as we have observed, for example, in mice.2 There also is a linear relation between the LVM/body mass index (BMI) ratio and the peak LV systolic wall stress in patients without and with LV hypertrophy due to hypertension.3 Thus, before accepting genetic factors and excluding basal differences in the afterload as the cause of the initial variation in LVM/BW and wall stress in the study by Koide et al,1 several factors bear scrutiny. The population of dogs was by no means uniform in this study; although they were purpose-bred mongrel dogs, which should eliminate major differences in diet and exercise, the group included both sexes, body weights varied by up to 45%, and the ages ranged from 1 to 5 years. The blood pressure measured under anesthesia may not reflect that in the unanesthetized animal, particularly throughout a 24-hour period, and it seems possible that the true arterial pressure may have been higher under conscious conditions in some animals rather than low, as observed in the 5 dogs that developed hypertrophy without LV dysfunction; if this were the case, it might lead to a form of "physiological hypertrophy," and a low blood pressure under anesthesia could account for the low systolic wall stress calculated in these dogs. The production of mild hypertrophy by temporary aortic constriction to lower initial wall stress in 3 dogs with low LVM/BW values before aortic constriction does not necessarily mimic this group of 5 dogs, since the mild hypertrophy was artificially and acutely induced. In addition, despite the same average pressure gradients in the two groups (reaching a severe level of about 120 mm Hg at 6 weeks), the gradient (assessed without autonomic blockade) does not necessarily directly reflect loading conditions on the left ventricle, since the gradient depends both on the degree of stenosis and the stroke volume. Finally, the afterload was clearly different in the two groups throughout the study, and the rapidly increasing and relatively excessive afterload in the group developing LV dysfunction might have acted to limit the hypertrophic response. Thus, the hypothesis that the same mechanical stress on the left ventricle can induce different hypertrophic responses might have been more clearly tested had the systolic wall stress been maintained at the same level in the two groups during aortic constriction. Nevertheless, the observation that increased relative LV mass before constriction appears to confer an advantage in developing a compensatory hypertrophic response is of considerable significance.
Aoyagi et al,4 in a study of 9 conscious sheep in which progressive ascending aortic constriction was performed in steps over a 6-week period to increase the LV systolic pressure from an average of 117 to 163 mm Hg, maintained the systolic wall stress constant as the stenosis progressed. Although LV mass values were not available before and after the development of stenosis, these animals responded with initial compensation of LV function followed by significant depression of myocardial contractility at 6 weeks; in that study performed in unanesthetized animals, subgroups with different responses were not described.4
The findings in both of these experimental studies1 4 may not be representative of the variations in cardiac hypertrophy observed in humans. The increased load in both experiments was applied in steps over 6 to 8 weeks and therefore constitutes an acute overload when compared with that occurring in patients with hypertension or aortic stenosis, in whom the overload develops gradually over many years. Also, in the clinical setting there is not necessarily a constant progression of overload; in aortic stenosis, LV dysfunction often occurs when the degree of stenosis becomes critical, with a small change in orifice size resulting in a large change in afterload, and in hypertension there may be a relatively sudden increase in blood pressure after many years of stability (as with discontinuation of medications or the development of a malignant hypertensive phase). Thus, variations in the severity, duration, and rate of load development may be important in causing the variability in degree of hypertrophy observed in human disease. Other factors also may be important, such as age, level of physical activity, blood pressure and basal heart rate, and sex (women with aortic stenosis are reported to have lower systolic wall stress and better LV function than men with comparable degrees of valve stenosis5 ), as well as potential genetic factors that might affect the LVM/BMI before the onset of disease. Therefore, although the results of the present experiments are intriguing in suggesting that individual differences exist in the response of cardiac mass to similar basal hemodynamic conditions, as well as in the response to a pressure overload, whether multiple environmental factors, differences in loading, or genetic factors are dominant in determining the variability cannot be stated with certainty.
If Koide et al1 are correct in the extrapolation of their experimental results to explain the variability in the degree of hypertrophy in response to overload in the clinical setting, are there practical implications? The presence of what might be called "physiological cardiac hypertrophy" in some individuals, perhaps on a genetic basis, could lead to a more prolonged stage of compensation in aortic stenosis before the onset of depressed LV myocardial contractility, although the rate of development of critical narrowing of the valve seems more likely to determine the onset of LV dysfunction, since there is an important component of afterload mismatch in that setting that is partially or completely reversible after operation.6 On the other hand, in chronic hypertension, such individuals might develop a highly favorable initial compensatory hypertrophic response and never develop LV dysfunction or heart failure, particularly if treatment were maintained.
What might be done to provide stronger theoretical and practical bases for the authors' hypothesis? A population approach would seem useful to study the degree of variability in LV mass and systolic wall stress (determined noninvasively by echocardiography and sphygmomanometry) relative to body weight or BMI in normal subjects of similar age and activity level, as well as in patients with mild to moderate hypertension, to determine whether or not these variables exhibit bimodal, normal, or other distributions. Two clinical studies have some relevance to this topic. Lutas et al7 reported a bimodal distribution of endocardial LV fractional shortening relative to end-systolic wall stress in mildly hypertensive patients compared with normal subjects, with 23% showing above normal LV performance and cardiac index; however, in that subgroup, LV mass was reduced and diastolic LV dimension was increased. In a subsequent larger study by the same investigators in 474 unselected hypertensive patients and 140 normal subjects,8 the above finding was confirmed, but when midwall instead of endocardial LV fractional shortening was determined, only 4% had an increased LV fractional shortening relative to end-systolic wall stress (suggesting increased myocardial contractility). In 16% of hypertensive patients the fractional shortening was reduced, and in that subgroup LV mass and wall thickness were increased (with normal LV chamber size) compared with hypertensive subjects having normal LV function.8 Thus, the second clinical study8 (as well as the study in animals by Koide et al1 ) did not demonstrate an unusual distribution of LV performance relative to wall stress in normal subjects, but since LV mass calculations were made in the clinical study,8 it would be of interest to determine whether or not there was a population within the normal human subject group that had increased LVM/BMI and relatively low wall stress, as in the experimental study. The population of hypertensive patients with depressed LV function had a higher LVM/BMI value than those with normal function,8 and here again it would be useful to know the LVM/BMI and wall stress distributions to assess whether or not there was a subpopulation with an inadequate hypertrophic response.
There are potential problems with experimental methods and design and unmeasured environmental factors that could have played a role in the study of Koide et al1 ; the authors' interpretation of their data appears plausible, however. Certainly, this work provides a basis for further experimental and clinical observations in larger populations, which might confirm variations in the basal LVM/BW and in the response to cardiac loading. These, in turn, if present, might reflect differences in the signaling pathways for cardiac hypertrophy,9 10 11 12 which involve a variety of receptors, early response genes, kinase cascades, and intranuclear transacting factors that determine the character of the hypertrophic response to altered cardiac load at the cellular level and might be influenced by genetic factors.
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Acknowledgments |
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This study was supported in part by SCOR grant HL-53773 awarded by the National Heart, Lung, and Blood Institute and an endowed chair awarded to Dr Ross by the San Diego Division of the American Heart Association, California Affiliate.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Koide M, Ngatsu M, Zile MR, Hamawaki M, Swindle MM, Keech G, DeFreyte G, Tagawa H, Cooper G IV, Carabello BA. Premorbid determinants of left ventricular dysfunction in a novel model of gradually induced pressure overload in the adult canine. Circulation. 1997;95:1601-1610.
2.
Rockman HA, Wachhorst S, Mao L, Ross J Jr. Angiotensin II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. Am J Physiol. 1994;266:H2468-H2475.
3.
Ganau A, Devereux RB, Pickering TG, Roman MJ, Schnall PL, Santucci S, Spitzer MC, Laragh JH. Relation of left ventricular hemodynamic load and contractile performance to left ventricular mass in hypertension. Circulation. 1990;81:25-36.
4.
Aoyagi T, Fujii AM, Flanagan MF, Arnold LW, Brathwaite KW, Colan SD, Mirsky I. Transition from compensated hypertrophy to intrinsic myocardial dysfunction during development of left ventricular pressure-overload hypertrophy in conscious sheep: systolic dysfunction precedes diastolic dysfunction. Circulation. 1993;88:2415-2425.
5.
Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D, Karp RB. Sex-associated differences in left ventricular contractile dysfunction in experimental canine mitral regurgitation. Circ Res. 1992;70:131-147.
6. Ross J Jr. Afterload mismatch in aortic and mitral valve disease: implications for surgical therapy. J Am Coll Cardiol. 1985;5:811-826.[Abstract]
7.
Lutas EM, Devereux RB, Reis G, Alderman MH, Pickering TG, Borer JS, Laragh JH. Increased cardiac performance in mild essential hypertension: left ventricular mechanics. Hypertension. 1985;7:979-988.
8. De Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH, Laragh JH. Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol. 1994;23:1444-1451.[Abstract]
9.
Schneider MD, Parker TG. Cardiac myocytes as targets for the action of peptide growth factors. Circulation. 1990;81:1443-1456.
10.
Izumo S, Nadal-Ginard B, Mahdavi V. Proto-oncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci U S A. 1988;85:339-343.
11. Simpson PC. Proto-oncogenes and cardiac hypertrophy. Annu Rev Physiol. 1989;51:189-202.[Medline] [Order article via Infotrieve]
12. Chien KR, Zhu H, Knowlton KU, Miller-Hance W, van-Bilsen M, O'Brien TX, Evans SM. Transcriptional regulation during cardiac growth and development. Annu Rev Physiol. 1993;55:77-95.[Medline] [Order article via Infotrieve]
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