Reversal of cardiac and vascular hypertrophy by antihypertensive therapy

Volume Number

121 3, Part 2

Cardiovascular

as you infer, on HDL cholesterol. There has been some argument that alcohol raises HDL3, although it may be HDLz that is more protective. I have had some discussions with Lars Carlson at the Karolinska Institute who has quoted to me some studies on ultracentrifugation of plasma. These studies show that alcohol turns the plasma pattern on ultracentrifugation more towards that of premenopausal women. So it may be that it is a rather complex interaction, but the evidence, I think, is really solid that it is a good

risk and intervention

interaction. I know that not everybody believes this. Gerry Schaper, in London, thinks that this J-shaped curve showing two or three drinks a day to be beneficial is an artifact. He thinks that the group that have zero intake comprise reformed alcoholic types, but I do not think that is the explanation myself. I think that all the epidemiologic evidence so strongly supports alcohol as being protective that we can stop being entirely negative about it to patients. They have a hard enough time anyway.

Reversal of cardiac and vascular antihypertensive therapy

hypertrophy

by

Cardiovascular hypertrophy, such as left ventricular hypertrophy, and arteriolar hypertrophic changes are common in established hypertension. Left ventricular hypertrophy, in particular, markedly increases the risk of cardiovascular complications and death. The ability of an antihypertensive agent to reverse hypertrophic changes could, therefore, be greatly advantageous. Clinical studies with @-blockers have shown them able to substantially reduce left ventricular hypertrophy. For reversal of arteriolar hypertrophy, vasodilatory j3-blockers have been shown to be preferable to ordinary &blockers, possibly because vasodilation reduces vascular smooth-muscle tone, which may facilitate reversal of hypertrophy. Theoretically, a vasodilatory B-blocker, such as celiprolol, would therefore appear to offer advantages because of its ability to reverse left ventricular and arteriolar hypertrophy in addition to its antihypertensive action. The practical and clinical effects of cardiovascular hypertrophy reversal remain to be fully evaluated; however, it is logical to assume that they would be of considerable benefit to the hypertensive patient. (AM HEART J 1991;121:995-8.)

Lennart

Hansson, MD GGteborg, Sweden

Arterial hypertension is associated with a number of adaptive structural changes in the cardiovascular system, and left ventricular hypertrophy (LVH) is a common c0nsequence.l Similarly, structural arteriolar changes, for example in the wall/lumen ratio in the precapillary resistance vessels, are also common in established hypertension.2 The following is a brief review of some of the consequences associated with these structural changes, Special emphasis is given to studies that have shown reversal of such changes with long-term antihypertensive treatment. From

the Department

Reprint requests: GGteborg, dstra

4/O/26250

of Medicine,

University

of CBteborg.

L. Hansson, MD, Department of Medicine, Hospital, 41685 GBteborg, Sweden.

University

of

LEFT

VENTRICULAR

HYPERTROPHY

Cardiac involvement is common in essential hypertension, and increased left ventricular muscle mass has been reported by numerous investigators. LVH has several important clinical implications. Even when the rather nonspecific method of ECG evaluation of LVH is used, its sequelae are ominous and resemble those of overt coronary disease. Findings in the Framingham study based on ECG diagnosis show that about 20 % of men and 13 % of women with hypertension have LVH.3 Of all the elderly (aged 70 years or more) in this study, LVH was found in 33% of men and 49% of women. Although the principal risk factors for LVH are hypertension and obesity,4 age also seems to be important.

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1. Increase in cardiovascular risk in patients with ECG-verified LVH in the Framingham Heart Study

Table

Times risk increased

Morbidity

3-5 2-5 1-6 6-10 6-17

Coronary heart disease Myocardial infarction Angina pectoris Stroke Congestive heart failure Cardiovascular disease Data

frum

Levy

D. Drugs

1988;:35(suppl

factor by

4-8 5):l

The increased risks of cardiovascular complications and even death associated with LVH are marked. Depending on age and sex, some groups with LVH in the Framingham study were associated with up to a 17-times greater risk of developing certain complications (Table Q3 Using echocardiography, which is more reliable than ECG for evaluation of LVH 5+fi these risks can be predicted with even greater accuracy. Data from various centers around the world, therefore, confirm that LVH, assessed either by ECG or echocardiography, is a powerful predictor of risks, not only for the heart itself but for the entire cardiovascular system. ARTERIOLAR

HYPERTROPHY

Flow resistance (R) in a cylindrical tube, such as a blood vessel, can be calculated by Poiseuille’s formula: R = L xVlr4, where L is the length of the vessel, V is the viscosity of the fluid, and r is the inner radius of the vessel. From this simple formula it is evident that r is most important and that even minute changes in r will have marked effects on R. In virtually all forms of hypertension, experimental as well as clinical, the hemodynamic hallmark is increased systemic vascular resistance. To a large extent this is caused by increased resistance in the precapillary arterioles, often referred to as the resistance vessels.2 A structural alteration in these vessels, consisting of increased wall thickness and thereby a reduction in the inner radius, will have profound effects on resistance. Experiments in hypertensive animals using both histologic and physiologic techniques have indicated an increased wall/lumen ratio. This means that even at maximum dilation, vascular resistance is higher in a blood vessel from an individual with hypertension than in one with normal blood pressure. With increasing degrees of contraction in the vascular smooth muscle cells, this difference in vascular resistance between the two groups becomes even more striking.2

Heart

lSS1 Journal

The pathophysiologic implications of such structural changes are numerous. First, they act as a structural amplifier of all stimuli that raise blood pressure. Second, they form the basis for a vicious circle by which hypertension may arise and be maintained even if the initial trigger mechanisms have ceased to be active.2 REVERSAL

OF

LEFT

VENTRICULAR

HYPERTROPHY

In view of the major cardiovascular risks associated with LVH, it appears logical that one of the aims of antihypertensive treatment should be LVH reversal. A recent review has stressed that although reduction of blood pressure appears to be the most important factor in LVH reversal, there appears to be some dissociation between the antihypertensive effect and LVH reversal with at least some antihypertensive agents7 In particular, direct-acting vasodilators such as hydralazine and minoxidil, which are effective antihypertensive agents, have not been shown to cause LVH reversal.8-11 In fact, minoxidil, although markedly reducing blood pressure, has been shown to increase ventricular mass.l’ This effect is probably the result of a reflex increase in sympathetic activity and a release of sympathetically mediated catecholamines. In addition, trophic factors such as angiotensin II and insulin may also play a role. Such factors have been implicated after a study in which the vasodilator dihydralazine effectively lowered blood pressure but did not prevent the development of structural cardiovascular changes in young, spontaneously hypertensive rats.13 Antihypertensive compounds, such as angiotensinconverting enzyme inhibitors,14 cy-methyldopa,15 and P-blockers, I6 which do not elicit a reflex increase in the release of various trophic factors, have all been shown to reverse LVH concomitantly with their lowering of arterial blood pressure. Obviously, all agents of the same class are not equipotent in this regard. In a large comparative trial using echocardiographic determinations of LVH, the effects of propranolol, atenolol, metoprolol, pindolol, and celiprolol were evaluated in 145 patients with essential hypertension, randomly allocated to each treatment group. I7 All five of these ,&blockers significantly reduced blood pressure, but LVH was not reversed with propranolol, whereas some reversal was seen with atenolol, metoprolol, and pindolol, and the greatest reduction was obtained with celiprolol.17 In a study of LVH and its reversal with long-term antihypertensive therapy, ketanserin and celiprolol were compared in 60 patients over 55 years of age. Patients receiving ketanserin or celiprolol monother-

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121 3, Pert 2

apy were studied for 18 months, and both drugs were found to reduce blood pressure significantly. Both these therapeutic regimens caused reversal of LVH, although this was significantly more marked with celiprolol treatment after both 6 and 18 months.18 In another study, the antihypertensive and LVH regression effects of celiprolol and the calcium antagonist, nicardipine, were compared in 32 elderly patients with hypertension (Rhbne-Poulenc Rorer Inc., data on file). Both drugs were found to reduce blood pressure to approximately the same extent, but only celiprolol caused reversal of left ventricular mass. These few examples illustrate that the antihypertensive effect of some drugs may be dissociated from their ability to normalize left ventricular mass. Undoubtedly, the pharmacodynamic profile of a compound such as celiprolol appears favorable in this regard, combining effective lowering of blood pressure with reversal of hypertension-induced LVH. It still remains to be shown, however, that reversal of LVH leads to a reduction in LVH-associated cardiovascular morbidity. Several studies are currently assessing this possibility, but so far only a reduced incidence of cardiac arrhythmias has been described as a result of LVH reversal.lg REVERSALOFSTRUCTURALVASCULARCHANGES

The effects of antihypertensive therapy on reversal of structural cardiovascular changes, with special emphasis on the precapillary blood vessels, have been reviewed elsewhere. 2o In brief, reversibility appears to differ between different vascular beds; no reversal at all has been demonstrated in the calf vascular bed, irrespective of the type of treatment used. In the vascular beds of the forearm and hand, reversal has been described after treatment with either monotherapy or combinations of antihypertensive drugs.20 In a direct comparison between two ,&blockers, pindolol and metoprolol, only pindolol (which has additional vasodilatory properties), reversed structural vascular changes. 21 Both therapeutic regimens, however, were equally effective at reducing blood pressure; hence it is reasonable to assume that the active vasodilatory effect of pindolol may have contributed to the desired reversal of hypertrophy, perhaps by actively reducing vascular smooth-muscle tone. It would be logical to assume that a compound such as celiprolol, which shows some similarities with pindolol in its pharmacodynamics, would have a similar beneficial effect. The practical implications of the reversal of structural vascular changes remain to be fully evaluated.

Cardiac

and

vascuZar

hypertrophy

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Undoubtedly, interruption of the vicious circle, discussed earlier, would be expected if the aforementioned structural amplifier could be prevented from exerting its influence: every stimulus that increases blood pressure would, therefore, cause a less marked rise in blood pressure. REFERENCES

1. Devereaux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55:613. 2. Folkow B, Hansson L, Sivertsson R. Structural vascular factors in the pathogenesis of hypertension. In: Robertson JIS, ed. Handbook of hypertension, vol 1: clinical aspects of essential hvnertension. Amsterdam: Elsevier, 1983:133. 3. Levy “D. Left ventricular hypertrophy: Epidemiological insights from theFramingham Heart Study. Drugs 1988;35(suppl 5):l. 4. Levy D, Anderson KM, Savage DD, et al. Echocardiographitally detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988;108:7. RB, Lutas EM, Casale PN, et al. Standardization 5. Devereaux of M-mode echocardiographic left ventricular anatomic measurements. J Am Co11 Cardiol 1984;4:1222. RJ, et al. Echocardiographic 6. Levy D, Savage DD, Garrison criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987;59:956. 7. Moser M, Setano JF. Antihypertensive drug therapy and the regression of left ventricular hypertrophy: is there a preferred medication? (Submitted for publication.) FM. Biochemical changes associ8. Sen S, Tarazi RC, Bumpus ated with development and reversal of cardiac hypertrophy in spontaneously hypertensive rats. Cardiovasc Res 1976;lO: 254. JIM, Gardin JM, Weber MA, Aronow WS. Cardiac 9. Drayer muscle mass during vasodilatation therapy of hypertension. Clin Pharmacol Ther 1983:33:727. 10. Leenen FH, Smith DL, Farkas RM, et al. Vasodilators and regression of left ventricular hypertrophy: hydralazine versus urazosin in hvnertensive humans. Am J Med 1987;82:969. 11. Tarazi RC, Fouad FM. Reversal of cardiac hypertrophy by medical treatment. Annu Rev Med 1985;36:407. 12. Connor G, Wilburn RL, Bennet CM. Double blind comparison of minoxidil and hydralazine in severe hypertension. Clin Sci 1976;51(suppl 3):593s. JF. Comnared mvocardial and vascular 13. Freslon JL. Giudicelli effects of captopril and dihydralazine during hypertension development in spontaneously hypertensive rats. Br J Pharmacol 1983;80:533. 14. Frohlich ED, Tarazi RC. Is arterial pressure the sole factor responsible for cardiac hypertrophy? Am J Cardiol 1979;44:959. 15. Fouad F:M, Nakashima Y, Tarazi RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa. Am J Cardiol 1982;49:795. 16. Fouad-Tarazi FM. Structural cardiac and vascular changes in hypertension: response to treatment. Curr Opin Cardiol 1987;2:782. 17. Vyssoulis GP, Karpanou EA, Pitsavos CE, et al. Left ventricular hypertrophy regression with beta-blocker antihypertensive therapy. (Submitted for publication.) 18. Vyssoulis GP, Karpanou EQ, Pitsavos CE, et al. Effects of Ketanserin and celiprolol on left ventricular structure and function in older hypertensive% (Submitted for publication.) R. Reversal of LVH in hypertension causes re19. Schmieder duction in cardiac arrhythmias. Clin Exp Hypertens. (In press.)

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20. Hansson L, Sivertsson R. Regression of structural cardiovascular changes by antihypertensive therapy. Hypertension 1984;6(suppl 111):147. 21. Hansson L, Svensson A, Gudbrandsson T, Sivertsson R. Treatment of hypertension with beta-blockers with and without intrinsic sympathomimetic activity. J Cardiovasc Pharmacol 1983;5(suppl 1):26.

DISCUSSION Question. Do you believe that structural

changes in the muscles in the smaller resistance vessels in the coronary beds can play a role as a risk factor in patients with hypertension, and that the different antihypertensive drugs used in past trials can at least partially explain the failure in preventing coronary events? Dr. Hansson. I think that the small precapillary arterioles in the coronary circulation are probably of great importance. I am not aware of any clinical studies in this field, but Peter Friberg, Margareta Nordlander, and a few others have done studies in spontaneously hypertensive rats where they have shown reversal of these changes with antihypertensive treatment. I assume that this is beneficial, but that is an assumption and of course I cannot prove this.

American

March 1991 Heart Journal

Dr. De Champlain. This is pure speculation, but I wonder if you think that the same trophic factors are involved in hypertrophy of the vessels and hypertrophy of the heart, and which would you suspect as the worst, based on current knowledge? Dr. Hansson. In principle, I think that the same trophic factors would be of importance both for the myocardium and for the blood vessels. Delegate comment. We have studied the relationship between left ventricular hypertrophy and minimal vascular resistance taken as an index of vasculature changes. What we have found is that there is an association between these two processes: patients with left ventricular hypertrophy show an increased minimal vascular resistance whereas patients without left ventricular hypertrophy show a reduced minimal vascular resistance. Dr. Hansson. Yes, but there may be limited association in the ability of causing reversal of these changes. We have data that would indicate this association, and it may be caused by different degrees of irreversible changes, like collagen and fibrous changes, which may occur much more easily in the blood vessels than in the heart, or vice versa.