beta blockers and left ventricular hypertrophy in hypertension

9
Beta blockers and left ventricular hypertrophy in hypertension it is now generally accepted that hypertension-induced left ventricular hypertrophy (LVH) represents a phenomenon of multifactorial origin. Antihypertensive therapy wlth beta-blocking drugs influences most of the factors.involved in the control of left ventricular mass. Therefore, although initial animal experiments yielded conflicting results, it is not surprlsing that a great deal of evidence has been accumulated in clinical studies showing that successful long-term antihypertensive treatment with beta blockers induces regression of LVH in hypertensive subjects. Differences in molecular structure among various beta-blocking agents do not seem to influence this property. On the contrary, the question of whether reversal of LVH represents a beneficial or harmful byproduct of antihypertensive treatment wtth beta blockers is still unanswered. Antmal and clinical studies suggest that left ventricular systolic function is unchanged or even improved after regression of LVH, whereas the ability of the heart to withstand recurrence of hypertension is slightly reduced. Furthermore, development of LVH in hypertensive subjects is associated with abnormalities in diastolic function which are not reduced by reversal of LVH induced by antihypertensive treatment with beta blockers. (AM HEART J 1957;114:975.) Bruno Trimarco, M.D., Nicola De Luca, M.D., Albert.0 Cuocolo, M.D., Bruno Ricciardelli, M.D., Giovanni Rosiello, M.D., Giuseppe Lembo, M.D., and Massimo Volpe, M.D. Nupoli, Italy PATHOGENESIS OF LEFT VENTRICULAR HYPERTROPHY IN ESSENTIAL HYPERTENSION Although hypertension-induced left ventricular hypertrophy (LVH) has long been ascribed exclu- sively to the increased pressure load on the left ventricle, recent reviewers considered LVH to be of multifactorial origin. l-3 In recent years, a consider- able amount of information has been accumulated from large population studies, as well as from pro- spective epidemiologic data, that demonstrates that cardiac enlargement may be directly related to aging, racial, and sexual factors independent of the level of arterial pressure and other hemodynamic alterations.4 In particular, pathologic data have demonstrated that aging is related to increased cardiac mass and ventricular wall thickness.5 Other epidemiologic studies have indicated that the preva- lence of LVH is greater in men than in women and that black patients with hypertension may have more severe cardiac and vascular disease than white patients.4 From the CIiiica Medica, Facolta’ di Medicina, Universita’ di Napoli. Reprint requests: Bruno Trimarco, M.D., CIiiica Medica, Facolta’ di Medicina, via S. Pansini 5, 80131 Napoli, Italy. However, high pressure levels still represent one of the major factors involved in the development of LVH in hypertensive patients, according to some 60-year-old findings describing a close relationship between systolic blood pressure and postmortem left ventricular (LV) mass6 In fact, despite the observa- tion that echocardiographic ventricular weight does not always correlate with casual blood pressure readings, several authors7-g have reported that ambulatory blood pressure monitoring, which is superior to casual blood pressure recording in pre- dicting cardiac hypertrophy, allows an index of determination of LVH of about 30%. The role of neurohumoral factors in favoring the development of LVH in hypertension has been extensively investigated in both animals and humans. In spontaneously hypertensive rats (SHR), it has been reported that the sympathetic nervous system as well as the renin-angiotensin system may be involved in the pathogenesis of LVH.l”-12 In humans, we have demonstrated that changes in sympathetic nervous activity are accompanied by parallel changes in LV massI In particular, we have studied normotensive subjects with two hyperten- sive parents, who underwent three 3-week periods on different sodium and potassium intakes regi- 975

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Beta blockers and left ventricular hypertrophy in hypertension

it is now generally accepted that hypertension-induced left ventricular hypertrophy (LVH) represents a phenomenon of multifactorial origin. Antihypertensive therapy wlth beta-blocking drugs influences most of the factors.involved in the control of left ventricular mass. Therefore, although initial animal experiments yielded conflicting results, it is not surprlsing that a great deal of evidence has been accumulated in clinical studies showing that successful long-term antihypertensive treatment with beta blockers induces regression of LVH in hypertensive subjects. Differences in molecular structure among various beta-blocking agents do not seem to influence this property. On the contrary, the question of whether reversal of LVH represents a beneficial or harmful byproduct of antihypertensive treatment wtth beta blockers is still unanswered. Antmal and clinical studies suggest that left ventricular systolic function is unchanged or even improved after regression of LVH, whereas the ability of the heart to withstand recurrence of hypertension is slightly reduced. Furthermore, development of LVH in hypertensive subjects is associated with abnormalities in diastolic function which are not reduced by reversal of LVH induced by antihypertensive treatment with beta blockers. (AM HEART J 1957;114:975.)

Bruno Trimarco, M.D., Nicola De Luca, M.D., Albert.0 Cuocolo, M.D., Bruno Ricciardelli, M.D., Giovanni Rosiello, M.D., Giuseppe Lembo, M.D., and Massimo Volpe, M.D. Nupoli, Italy

PATHOGENESIS OF LEFT VENTRICULAR HYPERTROPHY IN ESSENTIAL HYPERTENSION

Although hypertension-induced left ventricular hypertrophy (LVH) has long been ascribed exclu- sively to the increased pressure load on the left ventricle, recent reviewers considered LVH to be of multifactorial origin. l-3 In recent years, a consider- able amount of information has been accumulated from large population studies, as well as from pro- spective epidemiologic data, that demonstrates that cardiac enlargement may be directly related to aging, racial, and sexual factors independent of the level of arterial pressure and other hemodynamic alterations.4 In particular, pathologic data have demonstrated that aging is related to increased cardiac mass and ventricular wall thickness.5 Other epidemiologic studies have indicated that the preva- lence of LVH is greater in men than in women and that black patients with hypertension may have more severe cardiac and vascular disease than white patients.4

From the CIiiica Medica, Facolta’ di Medicina, Universita’ di Napoli. Reprint requests: Bruno Trimarco, M.D., CIiiica Medica, Facolta’ di Medicina, via S. Pansini 5, 80131 Napoli, Italy.

However, high pressure levels still represent one of the major factors involved in the development of LVH in hypertensive patients, according to some 60-year-old findings describing a close relationship between systolic blood pressure and postmortem left ventricular (LV) mass6 In fact, despite the observa- tion that echocardiographic ventricular weight does not always correlate with casual blood pressure readings, several authors7-g have reported that ambulatory blood pressure monitoring, which is superior to casual blood pressure recording in pre- dicting cardiac hypertrophy, allows an index of determination of LVH of about 30%.

The role of neurohumoral factors in favoring the development of LVH in hypertension has been extensively investigated in both animals and humans. In spontaneously hypertensive rats (SHR), it has been reported that the sympathetic nervous system as well as the renin-angiotensin system may be involved in the pathogenesis of LVH.l”-12 In humans, we have demonstrated that changes in sympathetic nervous activity are accompanied by parallel changes in LV massI In particular, we have studied normotensive subjects with two hyperten- sive parents, who underwent three 3-week periods on different sodium and potassium intakes regi-

975

976 Trimarco et al. October 1987

American Heart Journal

IVST cm

LVMi

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600 NE rupinc

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3oc-1 Fig. 1. Effects of three different sodium and potassium intakes on interventricular septum thickness (IVST), left Ventricular Mass index (LVMi), and norepinephrine plasma concentrations in supine (NE supine) and upright (NE upright) positions. *Indicates p < 0.01 vs control conditions; n = 10. Control conditions = Na+ 180 mEq/day, K+ 70 mEq/day; Diet A = Na+ 330 mEq/day, K+ 70 mEq/day; diet B = Na+ 80 mEq/day, K+ 70 mEq/day; diet C = Nat 80 mEq/day, K+ 150 mEq/day.

mens. No change in arterial blood pressure was detected throughout the study, an observation that rules out the possibility that blood pressure may mediate, to some extent, possible changes in LV mass. When these subjects were on a high-sodium- normal-potassium regimen (i.e., 330 n&q/day sodi- um and ‘70 mEq/day potassium), there was a decrease in norepinephrine plasma concentration and a decrease in interventricular septum wall thickness as well aa in LV mass as compared to a standard diet (Fig. 1). The low-sodium-normal- potassium intake (30 mEq/day sodium and 70 mEq/ day potassium) raised the plasma catecholamine concentration and increased LV mass (Fig. 1). Changes in the norepinephrine plasma concentra- tion observed during these two study periods were significantly correlated with concurrent changes in interventricular septum thickness as well as with LV

mass index. Furthermore, the observation that the addition of a high-potassium intake (150 mEq/day potassium) to the low-sodium diet was able to prevent changes in both sympathetic activity and LV anatomy induced by the reduction in sodium intake (Fig. 1) supports our conclusion that the sympathetic nervous system is largely responsible for the changes in LV mass induced by the changes in sodium intake. Finally, as shown in Fig. 2, admin- istration of atenolol prevented any effects on LV anatomy of an increase in the noradrenaline plasma level induced by the reduction in dietary sodium intake. This finding suggests that cardiac beta- adrenergic receptors mediate the effects of the sym- pathetic system on LV mass.

On the other hand, LVH in hypertension cannot be considered independently of the structural changes in both the large Windkessel arteries and

Volume 114 Number 4, Part 2

Table I. Effects on LVH of antihypertensive treatment with different types of beta-adrenergic-blocking agents

Drug Effects on LVH Reference

Timolol Rev. Rowlands et a1.22 Nadolol Rev. Hill et al.“l Propranolol Rev. Hill et al.*’ Metoprolol Rev. Wikstrand et al.14 Atenolol Rev. Corea et al.” Acebutolol Rev. Trimarco et al.”

Rev = reversal of LVH.

the small resistance vessels. In this regard, a signifi- cant correlation between changes in LV wall thick- ness and in peripheral vascular resistance has been reported by Wikstrand et al.‘* during reversal of LVH in hypertensive subjects. In addition, Bouthier et all5 found a significant correlation between LV mass to volume ratio and large artery compli- ance.15

EFFECTSOF BETABLOCKERSTHERAPYON MAJOR LV ANATOMY IN PATIENTS WITH LVH

The multifactorial origin of LVH may explain the common finding that patients with comparable blood pressure levels show different degrees of LVH, or the differences in the response to different types of antihypertensive therapy in the same patient, or those in the response of subjects receiving the same therapy.

As far as beta-blocking agents are concerned, their ability to reduce arterial pressure, sympathetic ner- vous tone, and renin activity may account for the finding that, despite some conflicting reports in the initial animal studies,‘O* ~3 l7 clinical evidence is accu- mulating that they are indeed effective in reducing LV mass. The inconsistent results obtained with beta blockers in SHR probably reflect the particular pharmacokinetics of beta-receptor-blocking agents in SHR. For instance, Ljung et a1.18 found that 20 times higher doses of metoprolol are required in SHR than in humans to achieve comparable plasma levels and then antihypertensive efficacy. Lundin and Hallback-Nordlander,ls who used the very high dose of 350 mglkg body weight/day, were able to demonstrate favorable effects on both blood pres- sure and LVH.

In humans, the structural molecular differences existing among various beta-blocking agents do not seem to influence reversable of LVH. In fact, regres- sion of LVH has been demonstrated with beta- l-selective-blocking agents14~20 as well as with non- selective beta blockers.21,22 Similar responses have been obtained with acebutolol,23 which has been

IVST

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Beta blockers and LV hypertrophy 977

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Fig. 2. Effects of low-sodium-normal-potassium diet plus atenolol (100 mg/day by mouth) on interventricular septum thickness (IVST), left ventricular mass index (L VMi), and norepinephrine plasma concentrations in supine (NE supine) and upright (NE upright) positions. *Indicates p < 0.01 vs control conditions; n = 10. Diet B = Na+ 80 mEq/day, K+ 70 mEq/day.

claimed to possess an intrinsic sympathomimetic activity (Table I).

EFFECTS OF BETA BLOCKER THERAPY ON LV SYSTOLIC FUNCTION IN PATIENTS WITH LVH

Whether regression of LVH induced by antihy- pertensive treatment with beta blockers is beneficial or harmful still remains an unanswered question. When pressure overload is the primary stimulus to hypertrophy, the increased LV systolic pressure and wall stress result in the addition of new myofibrils in parallel, increased wall thickness, and concentric hypertrophy. The increase in wall thickness com- pensates for the increased systolic pressure and maintains a constant LV wall stress, thus enabling the left ventricle to eject a normal stroke volume in the presence of high peripheral resistance. Initial studies in experimental animals suggested that in SHR, after reversal of LVH with methyldopa, the pumping action of the heart was improved at rest, probably on account of blood pressure reduction.” The peak cardiac output achievable by rapid blood

97% Trimarco et al. October 1987

American Heart Journal

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Fig. 3. Effects of l-year antihypertensive treatment in 18 hypertensive patients who responded favorably to acebutolol. *or **indicates p < 0.05 and p < 0.01, respectively, vs baseline.

infusion was higher in normotensive rats and SHR, whose LVH was reversed by methyldopa, than in untreated SHR.% However, in response to phenyl- ephrine infusion, the level of peak achievable output fell more in SHR with reversed LVH than in untreated SHR.24

On the other hand, the hypertrophied heart can- not sustain the increased pressure load indefinitely since, unlike the hypertrophy caused by endurance training, which is associated with normal or increased contractility26p 26 and adaptive morphologic and biochemical changes,27-31 LVH in systemic arte- rial hypertension may result in impaired cardiac function and increased mortality rates from conges- tive heart failure and coronary artery disease.32 The biochemical factors and structural changes that contribute to the reduced contractility and frequent deterioration in overall function observed in pres- sure-overloaded hypertrophied hearts are not fully understood. Recent evidence suggests that a&era- tions in the properties of cellular membranes occur in pressure-overloaded hearts, as evidenced by

reductions in rates of calcium binding to the sarco- plasmic reticulum,33,” calcium uptake by the sarco- plasmic reticulum,34~ 36 and sarcolemmal calcium infl~.36 Alterations in beta-receptor number37p38 associated with altered in vitro methylation of phos- phatidylethanolamine3g have also been observed in pressure-overloaded hearts. Lipid and. protein com- ponents are necessary for these membrane func- tions, and it has been demonstrated that the content and fatty acyl of individual phospholipids are altered in the hypertrophied rat hearta Specific factors mediating fatty acyl modification in hyper- trophied hearts are not known. However, alterations in the hormonal status of animals subjected to pressure overload may play a role. In this regard, catecholamines have been demonstrated to induce profound changes in fatty acyl composition of cardi- ac phospholipids in the rat.41 Therefore, it seems reasonable to speculate that reversal of LVH induced by beta blockers may offer further advan- tages beyond those described by Capasso et al.@ in papillary muscle from hypertrophied left ventricles

V0lom0 114 Number 4, Part 2

of renal hypertensive rats after regression of LVH following nephrectomy.

In humans, we have observedz3 that the regression of LVH induced by long-term antihypertensive treatment with acebutolol was accompanied by an improvement in left ventricular function, as assess- ed by LV circumferential fiber shortening velocity and ejection fraction (Fig. 3). When interpreting this type of result, it is essential to consider the effects of alterations in afterload on changes in cardiac func- tion before drawing conclusions regarding the conse- quences of reduction in ventricular mass. To over- come this obstacle, Fouad et aI.& suggested the use of the correlation between LV end-systolic stress and LV performance, as estimated from LV percent- age shortening, to determine whether any alteration in cardiac performance concomitant with changes in LV mass during treatment was appropriate or went beyond changes in LV wall stress. However, to our knowledge, there has been no study in which the different influences on LV performance of regres- sion of hypertrophy and blood pressure control with beta blockers have been clearly separated. The study of the responses to a rapidly developing increase in afterload would also have been desirable to evaluate the ability of the heart to withstand the stresses of recurrence of hypertension.

The separate effects of the decrease in blood pressure and the reversal of LVH on the LV pump- ing function during long-term antihypertensive treatment with beta blockers is currently being studied in our laboratory. Preliminary data have been obtained in seven patients with mild or moder- ate essential hypertension, who satisfied the echo- cardiographic criteria of LVH.” In these patients, we performed two-dimensional and M-mode echo- cardiography and radionuclide angiography under control conditions (phase 1) after stable blood pres- sure reduction, that is, after about 2 weeks with blood pressure less than 140/90 mm Hg, induced by antihypertensive treatment with beta blockers (ate- nolo1 100 mg/day by mouth) (phase 2), and after reversal of LVH (about 15% of the basal value) either during effective treatment with beta blockers (phase 3) or after withdrawal of the antihyperten- sive treatment, when blood pressure rose again (phase 4). In phase 2, there was a decrease in blood pressure and no change in LV mass; consequently, LV end-systolic wall stress decreased (Fig. 4). About 20 weeks was required to obtain a 15% reduction in LV mass. In phase 3, despite the reduction in LV mass, the end-systolic wall stress did not increase significantly, probably also on account of another small and not statistically significant reduction in

MAP m*g

LVM sv

200 1

0’

LVWS dyne/cm2

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Beta blockers and LV hypertrophy 979

E/s 3-

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Fig. 4. Effects of antihypertensive treatment with beta blockers on mean arterial pressure (MAP), echocardio- graphic left ventricular mass (LVM), left ventricular systolic wall stress (LVWS), ejection fraction (EF), and peak filling rate (PFR) assessed by radionuclide angiogra- phy. I = Control conditions; 2 = after stable blood pres- sure reduction; 3 = after reversal of LVH with normal blood pessure levels; 4 = after reversal of LVH with high blood pressure levels; N = 7; statistical analysis performed by analysis of variance and Duncan’s test. * = p < 0.05 vs 1; A = p < 0.05 vs 2 and 3; l = p < 0.05 vs 1 and 2; n = p < 0.05 vs 1, 2, and 4.

blood pressure (Fig. 4). Finally, in phase 4 there was a marked increase in blood pressure and, conse- quently, in LV end-systolic wall stress, while LV mass was substantially unchanged (Fig. 4). LV systolic function was assessed by ejection fraction measured by radionuclide angiography. This tech- nique seems to allow a reliable assessment of LV performance. In particular, in our laboratory we have found a strong correlation between ejection

980 Trimarco et al.

r 42 n=4!5 p4Ol

0 SO 100

ANGIOEF %

Fig. 5. Relationship between ejection fraction assessed by radionuclide angiography (RNAEF) and contrast angi- ography (ANGIOEF).

fractions obtained by radionuclide angiography and those measured invasively (Fig. 5).

In control conditions, our patients showed a mean ejection fraction value which was significantly lower than that obtained in normal subjects in our labora- tory. In phase 2, we found no change in radionuclide ejection fraction as compared to phase 1 of our study protocol (Fig. 4). These results may be explained by speculating that the positive effect on LV perfor- mance exerted by the reduction in the afterload was counterbalanced by the negative inotropic effect of the beta-blocking agent administered, that is, ateno- 101, so that the net result was no change in LV systolic function. In phase 3, we observed an increase in LV ejection fraction as compared to both of the previous phases. The observation that blood pressure and LV end-systolic stress was unchanged, whereas LV mass was significantly reduced as com- pared to the first two phases of the study, seems to indicate that the increase in ejection fraction should be ascribed to an improvement in LV pumping function induced by the reversal of LVH. Our data do not allow any speculation on the mechanisms underlying this phenomenon. Although the observa- tions of Capasso et al.*2 on the effect of regression of hypertrophy on papillary muscle contractility in renal hypertertensive rats and the previously report- ed observations on the possible role of metabolic changes in the genesis of impaired contractility in LWP sugge&ed some possible explanations, other abrnative hypotheses cannot be ruled out.

Finally, the observation that in phase 4 the increase in blood pressure and, therefore, in LV end-systolic stress was associated with a significant decrease in ejection fraction suggests that the rever-

October 1997 Amsrlcan Heart Journal

sal of LVH inhibits, to some extent, the recurrence of hypertension in the left ventricle. In fact, while in phase 2 there was a complete balance between the positive effect of the reduction in afterload and the negative effect of beta blockers on LV inotropism, in phase 4 the abolition of the negative inotropic effect of beta blockers could not completely counterbal- ance the increase in LV end-systolic wall stress and, consequently, the ejection fraction was significantly reduced. This finding may correspond to the obser- vation of Ferrario et a1.,24 in SHR, that the peak output achievable during phenylephrine infusion fell more after reversal of LVH. However, it should be stressed that the ejection fraction recorded in phase 4 was similar to that measured in phases 1 and 2. Therefore, recurrence of hypertension did not impair LV performance absolutely but only induced the loss of improvement in ejection fraction observed after regression of LVH.

EFFECTSOF BETABLOCKERTHERAPYONLV DIASTOLIC FUNCTION IN PATIENTS WITH LVH

Abnormalities in LV compliance and diastolic filling have been described in patients with various forms of primary and secondary hypertrophy. Dia- stolic properties have been found to become abnor- mal before systolic function is impaired.45-47 Slowing of ventricular filling, therefore, may represent an early marker of heart disease. In particular, it has been suggested that abnormal diastolic function in the hypertrophied ventricle is closely associated with the degree of interstitial fibrosis4 and wall thickness.& However, diastolic function represents an interaction of multiple factors including those that govern isovolumic relaxation, compliance, and filling.4g LV filling which depends, in part, on load- ing conditions of the left ventricle and on events leading to inactivation of contractio# has been shown to be influenced by LV geometry, wall thick- ness, systolic function, heart rate, age, systolic blood pressure, LV filling pressure, chamber and myocar- dial stiffness, and myocardial ischemia.51p52 Adrener- gic factors have been found to markedly influence the diastolic function by their effect on ventricular relaxation.63 On the contrary, most studies on the cardiac effects of beta-adrenergic-blocking agents have dealt with their effects on the systolic phase of the cardiac cycle. M-57 Only recently, Fouad et al.& found a significant difference in the effect of beta blockade on LV filling rate in patients whose blood pressure was reduced by treatment and those who showed no appreciable blood pressure response. The cardiac effects of beta blockade were more subtle than the systemic hemodynamic effects, and their characteristics were markedly influenced by the

vohm* 114 Numb4r 4, Part 2 Beta blockers and LV hypertrophy 981

:

4

3

2

c

&B w 1

r-.41 n40 p&l

60 100 140 180 LIfMi g/m’

Fig. 8. Relationship between peak filling rate assessed by radionuclide angiography (PFR) and echocardiographic left ventricular mass index (L VMi).

behavior of the arterial pressure. Thus, peak LV ejection rate was reduced by beta blockade when blood pressure was unchanged. On the other hand, negative dV/dt was not significantly changed, despite beta-adrenergic blockade, when pressure was reduced, possibly because this reduction coun- terbalanced the negative inotropic effect of the blockade, Similar changes were seen in ventricular filling; LV fast filling fraction increased in respond- ers but decreased in nonresponders. Since no factor other than blood pressure differed significantly in responders and nonresponders, these results suggest that beta blockade, per se, can improve the abnor- malities in cardiac dynamics observed in hyperten- sive patients. On the contrary, the reduction in pressure load influences the diastolic function, according to the experimental observation that relaxation is load dependent, with greater loads delaying relaxation.“*68 Subsequently, Inouye et al.tg while confirming that diastolic filling is abnor- mal in patients with uncomplicated hypertension, failed to observe any improvement in the diastolic filling indexes during short-term hypotensive thera- py with beta blockers also in patients showing a satisfactory blood pressure response. To explain the discrepancy between these findings and those of Fouad, et al@ these authors speculated that in some of Fouad’s patients, who were previously untreated, there could have been some regression in LVH, which might have induced an improvement in dia- stolic function. This possibility seems to be support- ed by experimental and clinicaI data showing that LVH is accompanied by impaired diastolic func-

tions2 and that myocardial relaxation is also impaired in isolated muscle from hypertrophied hearts, suggesting an abnormality of the muscle itseKW These abnormalities decrease or disappear as the hypertrophy is reversed.42 However, as shown in Fig. 4, in our preliminary results there was no change in peak filling rate throughout the study. The observation that blood pressure control alone is unable to improve LV diastolic function is in keep- ing with the data of Inouye et a15’ and suggests, according to the hypothesis of Fouad et al.,43 that the reduction of afterload and blockade of cardiac beta- adrenergic receptors exert opposite influences on LV filling parameters so that the algebraic sum is no change in the diastolic indexes. On the contrary, the lack of change in diastolic function after partial reversal of LVH is more surprising, since previous investigator# have reported a statistically signifi- cant relationship between LV mass and peak filling rate, and we confirmed this finding in a larger population (Fig. 6). However, it is well known that the increase in wall thickness in hypertensive patients is the result of both cellular hypertrophy and fibrosis.% This finding differentiates LVH asso- ciated with chronic hemodynamic overloading from myocardial hypertrophy secondary to endurance training, which is associated with increased actomy- osin adenosine triphosphatase activity28 and slight or no increase in collagen,6263 and may account for the observation that physiologic hypertrophy is not accompanied by slowed LV diastolic filling.64 Fur- thermore, anatomic and biochemical studies indi- cate that fibrosis and an excessive amount of colla-

982 Trimarco et al. October 1997

American Heart Journal

gen may remain after regression of LVH.65-68 Conse- quently, impaired diastolic compliance is virtually irreversible. Finally, the finding that peak and mean filling rates remained unchanged when treatment was stopped and blood pressure rose may be consid- ered the opposite of the phenomenon observed in phase 2, when the decrease in the afterload counter- balanced the negative inotropic effect of the phar- macologic treatment.

CLINICAL IMPLICATIONS

The first conclusion supported by all of the previous considerations is that antihypertensive treatment should be aimed in primis at lowering blood pressure in order to prevent LVH. However, regression of LVH also appears to be a desirable end point of antihypertensive therapy. In fact, although regression of LVH obviously needs more precise answers, particularly with regard to the parallelism or the divergence between cardiac hypertrophy and structural changes in large and small vessels, the results obtained thus far indicate that, after regres- sion of LVH induced by beta blockers, LV systolic function is improved when blood pressure is normal, and it returns to initial values with recurrence of hypertension.

Furthermore, Marcus et al.6s have shown that coronary vascular reserve can be significantly reduced in hypertrophied hearts. This flow reserve was found to be related to the ratio of coronary perfusion pressure to LV mass.‘O Tarazi2 suggested that coronary vascular reserve remained mostly within normal limits in those conditions in which the pressure load on the heart, the degree of LVH, and coronary perfusion pressure were maintained. However, when a dissociation between the level of systemic arterial pressure and LV mass occurred, coronary flow reserve was altered significantly; blood pressure control achieved without concomi- tant reduction in LV mass in hypertensive rats was associated with a reduction in “maximal” coronary fl0w.7~ In humans, regression of LVH may reverse the tendency of ventricular muscle to become ische- mic under stress and, therefore, may contribute to a reduction in the coronary mortality rate among treated hypertensive patients as observed by Ber- glund et al.‘l

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Development and regression of left ventricular hvpertrophv. J Am Co11 Cardiol 1984;3:1309.

_. __

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14. Wikstrand J, Trimarco B, Buzzetti G, Ricciardelli B, De Luca N, Volpe M, Condorelli M. Increased cardiac output and lowered peripheral resistance during metoprolol treatment. Acta Med Stand 1983;672 (suppl):105.

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20. Corea L, Bentivoglio M, Verdecchia P. Echocardiographic left ventricular hypertrophy as related to arterial pressure and plasma norepinephrine concentration in arterial hyper- tension. Reversal by atenolol treatment. Hypertension 1983;5:837.

21. Hill LS, Monaghan M, Richardson PJ. Regression of left ventricular hypertrophy during treatment with anti- hypertensive agents. Br J Clin Pharmacol 1979;7(suppl 2):255s.

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