Volume 121 Number 3, Part 2 Cardiovascular risk and intervention

as you infer, on HDL cholesterol. There has been interaction. I know that not everybody believes this. some argument that alcohol raises HDL3, although it Gerry Schaper, in London, thinks that this J-shaped may be HDLz that is more protective. I have had curve showing two or three drinks a day to be bene- some discussions with Lars Carlson at the Karolinska ficial is an artifact. He thinks that the group that have Institute who has quoted to me some studies on ul- zero intake comprise reformed alcoholic types, but I tracentrifugation of plasma. These studies show that do not think that is the explanation myself. I think alcohol turns the plasma pattern on ultracentrifuga- that all the epidemiologic evidence so strongly sup- tion more towards that of premenopausal women. So ports alcohol as being protective that we can stop be- it may be that it is a rather complex interaction, but ing entirely negative about it to patients. They have the evidence, I think, is really solid that it is a good a hard enough time anyway.

Reversal of cardiac and vascular hypertrophy by

antihypertensive therapy

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 arterio- lar 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 of Medicine, University of CBteborg.

Reprint requests: L. Hansson, MD, Department of Medicine, University of GGteborg, dstra Hospital, 41685 GBteborg, Sweden.

4/O/26250

LEFT VENTRICULAR HYPERTROPHY

Cardiac involvement is common in essential hy- pertension, 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. Find- ings in the Framingham study based on ECG diag- nosis 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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American Heart Journal

Table 1. Increase in cardiovascular risk in patients with The pathophysiologic implications of such struc- ECG-verified LVH in the Framingham Heart Study tural changes are numerous. First, they act as a

Times risk factor structural amplifier of all stimuli that raise blood Morbidity increased by pressure. Second, they form the basis for a vicious

Coronary heart disease circle by which hypertension may arise and be main-

3-5

Myocardial infarction 2-5 tained even if the initial trigger mechanisms have

Angina pectoris 1-6 ceased to be active.2 Stroke 6-10 Congestive heart failure 6-17

Cardiovascular disease 4-8

Data frum Levy D. Drugs 1988;:35(suppl 5):l

The increased risks of cardiovascular complica- tions 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 for- mula: R = L xVlr4, where L is the length of the ves- sel, 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, experimen- tal as well as clinical, the hemodynamic hallmark is increased systemic vascular resistance. To a large ex- tent this is caused by increased resistance in the pre- capillary arterioles, often referred to as the resistance vessels.2 A structural alteration in these vessels, con- sisting of increased wall thickness and thereby a re- duction 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 individ- ual 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

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 dis- sociation 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 catechola- mines. In addition, trophic factors such as angioten- sin II and insulin may also play a role. Such factors have been implicated after a study in which the va- sodilator dihydralazine effectively lowered blood pressure but did not prevent the development of structural cardiovascular changes in young, sponta- neously hypertensive rats.13

Antihypertensive compounds, such as angiotensin- converting 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 low- ering 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 signif- icantly reduced blood pressure, but LVH was not re- versed 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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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 ce- liprolol treatment after both 6 and 18 months.18

In another study, the antihypertensive and LVH regression effects of celiprolol and the calcium an- tagonist, 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 antihyper- tensive effect of some drugs may be dissociated from their ability to normalize left ventricular mass. Un- doubtedly, the pharmacodynamic profile of a com- pound such as celiprolol appears favorable in this re- gard, 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 cardiovascu- lar 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 rever- sal 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 mono- therapy or combinations of antihypertensive drugs.20 In a direct comparison between two ,&blockers, pin- dolol and metoprolol, only pindolol (which has addi- tional vasodilatory properties), reversed structural vascular changes. 21 Both therapeutic regimens, how- ever, were equally effective at reducing blood pres- sure; 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 pin- dolol in its pharmacodynamics, would have a similar beneficial effect.

The practical implications of the reversal of struc- tural vascular changes remain to be fully evaluated.

Cardiac and vascuZar hypertrophy 997

Undoubtedly, interruption of the vicious circle, dis- cussed earlier, would be expected if the aforemen- tioned 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 fac- tors in the pathogenesis of hypertension. In: Robertson JIS, ed. Handbook of hypertension, vol 1: clinical aspects of essen- tial hvnertension. Amsterdam: Elsevier, 1983:133.

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Levy “D. Left ventricular hypertrophy: Epidemiological in- sights from theFramingham Heart Study. Drugs 1988;35(suppl 5):l. Levy D, Anderson KM, Savage DD, et al. Echocardiographi- tally detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988;108:7. Devereaux RB, Lutas EM, Casale PN, et al. Standardization of M-mode echocardiographic left ventricular anatomic mea- surements. J Am Co11 Cardiol 1984;4:1222. Levy D, Savage DD, Garrison RJ, et al. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol 1987;59:956. Moser M, Setano JF. Antihypertensive drug therapy and the regression of left ventricular hypertrophy: is there a preferred medication? (Submitted for publication.) Sen S, Tarazi RC, Bumpus FM. Biochemical changes associ- ated with development and reversal of cardiac hypertrophy in spontaneously hypertensive rats. Cardiovasc Res 1976;lO: 254. Drayer JIM, Gardin JM, Weber MA, Aronow WS. Cardiac muscle mass during vasodilatation therapy of hypertension. Clin Pharmacol Ther 1983:33:727. Leenen FH, Smith DL, Farkas RM, et al. Vasodilators and re- gression of left ventricular hypertrophy: hydralazine versus urazosin in hvnertensive humans. Am J Med 1987;82:969. Tarazi RC, Fouad FM. Reversal of cardiac hypertrophy by medical treatment. Annu Rev Med 1985;36:407. Connor G, Wilburn RL, Bennet CM. Double blind comparison of minoxidil and hydralazine in severe hypertension. Clin Sci 1976;51(suppl 3):593s. Freslon JL. Giudicelli JF. Comnared mvocardial and vascular effects of captopril and dihydralazine during hypertension development in spontaneously hypertensive rats. Br J Phar- macol 1983;80:533. Frohlich ED, Tarazi RC. Is arterial pressure the sole factor re- sponsible for cardiac hypertrophy? Am J Cardiol 1979;44:959. 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. Fouad-Tarazi FM. Structural cardiac and vascular changes in hypertension: response to treatment. Curr Opin Cardiol 1987;2:782. Vyssoulis GP, Karpanou EA, Pitsavos CE, et al. Left ventric- ular hypertrophy regression with beta-blocker antihyperten- sive therapy. (Submitted for publication.) 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.) Schmieder R. Reversal of LVH in hypertension causes re- duction in cardiac arrhythmias. Clin Exp Hypertens. (In press.)

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20.

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Hansson L, Sivertsson R. Regression of structural cardiovas- cular changes by antihypertensive therapy. Hypertension 1984;6(suppl 111):147. Hansson L, Svensson A, Gudbrandsson T, Sivertsson R. Treatment of hypertension with beta-blockers with and with- out intrinsic sympathomimetic activity. J Cardiovasc Phar- macol 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 pa- tients 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 ar- terioles in the coronary circulation are probably of great importance. I am not aware of any clinical stud- ies in this field, but Peter Friberg, Margareta Nord- lander, and a few others have done studies in spon- taneously hypertensive rats where they have shown reversal of these changes with antihypertensive treat- ment. I assume that this is beneficial, but that is an assumption and of course I cannot prove this.

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 hypertro- phy 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 relation- ship between left ventricular hypertrophy and min- imal vascular resistance taken as an index of vascu- lature 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 with- out left ventricular hypertrophy show a reduced minimal vascular resistance.

Dr. Hansson. Yes, but there may be limited associ- ation in the ability of causing reversal of these changes. We have data that would indicate this asso- ciation, 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.