The importance of hypertensive left ventricular hypertrophy

Transcription

1 AJH 2001; 14: Review Left Ventricular Hypertrophy and Angiotensin II Antagonists Bjorn Dahlöf Left ventricular hypertrophy in patients with hypertension is an important condition. It is associated with significant mortality and carries increased risk for developing nonfatal cardiovascular complications, including coronary heart disease. The pathogenesis of left ventricular hypertrophy is linked to activation of the renin-angiotensin system, with excessive production of angiotensin II believed to be responsible. The therapeutic benefit of blocking angiotensin II at the receptor with selective angiotensin II antagonists, a relatively new class of antihypertensive agents, is therefore considered for regression of left ventricular hypertrophy. Clinical evidence shows significant efficacy in reversing left ventricular hypertrophy in hypertensive patients after treatment with angiotensin II antagonists. Published data include open-label and randomized studies with losartan treatment for left ventricular hypertrophy, with fewer studies investigating the effects of valsartan, irbesartan, and candesartan. Am J Hypertens 2001;14: American Journal of Hypertension, Ltd. Key Words: Left ventricular hypertrophy, renin-angiotensin system, angiotensin II antagonists, losartan. FIG. 1. Unadjusted change in percentage of LV mass and 95% confidence intervals. (Based on Reference 7.) The importance of hypertensive left ventricular hypertrophy (LVH) relates to the significant mortality associated with this remodeling process in patients with hypertension, 1 and to the higher risk for the development of coronary heart disease, myocardial infarction, stroke, heart failure, and other cardiovascular complications independent of blood pressure (BP). 2 Blood pressure is the strongest independent risk factor for LVH. It has been observed in normotensive individuals as well as in all stages of hypertension, 3,4 and the degree of hypertension is far from explaining the variance in LV mass. 5 Although lowering of BP produces a beneficial effect on LVH per se, 6 meta-analyses of clinical trials have indicated that angiotensin-converting enzyme (ACE) inhibitors decrease LV mass more effectively than do other antihypertensives 7 9 (Fig. 1). This suggests that the reversal of LVH may be more strongly related to changes in the renin-angiotensin system (RAS) than to reductions in BP. 10 Reversal of LVH has been associated with reduced arrhythmias, improved diastolic dysfunction, preservation of systolic function, and an improvement in coronary reserve. 11 Although the prognostic implications of the regression of LVH are far from established, 12 the risk for cardiovascular events in individuals with persistent LVH has been shown to be greater than in subjects in whom LVH has resolved. 13 Thus, the primary goal of antihypertensive treatment in patients with hypertensive LVH should be to normalize BP and to reverse target organ change (including cardiac hypertrophy and fibrosis, vascular hypertrophy and dysfunction, and atherosclerosis) to reduce the risk of cardiovascular events. Angiotensin II (AII) antagonists (AIIA) are a relatively new class of Received March 13, Accepted July 11, From the Clinical Experimental Research Laboratory, Sahlgrenska University Hospital, Östra, Göteborg, Sweden. Address correspondence and reprint requests to Bjorn Dahlöf, MD, PhD, Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital, Östra, S Göteborg, Sweden; bjorn.dahlof@swipnet.se /01/$ by the American Journal of Hypertension, Ltd. PII S (00) Published by Elsevier Science Inc.

2 AJH February 2001 VOL. 14, NO. 2 LVH AND ANG II ANTAGONISTS 175 antihypertensive agents that specifically block the action of AII at the receptor. This article reviews preclinical and emerging clinical evidence relating to the effects of AIIA on LVH. From these data it is clear that AII has a pathologic role in cardiovascular hypertrophy, and that blocking AII synthesis or blocking the actions of AII at the receptor antagonize these effects. The RAS and LVH The Pathogenesis of LVH There are two types of LVH that occur in response to hemodynamic load. In concentric LVH there is a relative increase in LV wall size, whereas in eccentric LVH an increase in LV wall size as well as diameter is observed. The increase in LV mass is due not only to anatomical transverse and longitudinal enlargement of muscle cells, but also to alterations in vasculature and intercellular matrix Hemodynamic stress, both pressure and volume overload, is fundamental to the development of LVH; however, a host of nonhemodynamic factors contribute, with the RAS implicated strongly in the hypertrophic response. Within the last few years, there has been increasing interest in the contribution of nonhemodynamic factors in addition to the RAS; the sympathetic nervous system and genetic factors, as well as a number of other factors, have been implicated in the development of LVH. The RAS was initially viewed as a hormonal system predominately involved in BP and volume regulation via vasoconstrictor and aldosterone-stimulating effects and, thus, the short-term management of cardiovascular homeostasis. More recently, RAS activation has been understood to be an important inducer of tissue hypertrophy and interstitial fibrosis, with AII acting as a potent growth factor in vascular smooth muscle cells and cardiac myocytes. 10,17 19 In humans, AII (but not plasma renin activity, aldosterone, or angiotensin I) correlate with LV structural parameters such as posterior wall thickness and relative wall thickness in patients with hypertension. 20 Human studies have shown that patients with high AII concentrations in relation to sodium excretion have a greater LV mass, posterior wall thickness, and septal wall thickness than those with relatively low AII levels in relation to sodium excretion, and have added weight to the link between AII and LVH. 21 Other studies that have found that AII concentrations at high salt intake correlates with LV mass independently of ambulatory BP have corroborated this link. 22 Myocardial Fibrosis in LVH In hypertensive LVH, fibrotic changes are often observed. These result from an imbalance between the synthesis and degradation of extracellular matrix, composed mainly of types I and III collagen and synthesized by fibroblasts. It can be described as interstitial, pericoronary, or replacement fibrosis (myocyte death leading to fibrotic microscars). 14 In contrast to replacement fibrosis, the pathophysiology and sensitivity of interstitial and pericoronary fibrosis to treatment is less well documented. 14 The function of the heart is thought to be predicted in part by the amount of collagen present in the ventricle. However, recently it has been suggested that the quality, rather than quantity, of the collagen present in the heart is more important in determining cardiac function. 23,24 Animal studies have provided evidence that supports the importance of AII in the fibrous tissue response. 14 Blocking of the RAS not only has important quantitative effects on myocyte hypertrophy, but also has cardioprotective and cardioreparative properties that affect the development and reversal of pathologic fibrosis. 14,15 AT 1 Versus AT 2 Receptors The cloning of AII receptors and the development of selective antagonists of the two major receptor subtypes, AT 1 and AT 2, have led to increased understanding of the biology of AII. However, much of what is known about AII relates to the AT 1 -receptor, with this subtype mediating virtually all of the well known short- and long-term negative effects of AII, including vasoconstriction, aldosterone release, inhibition of renin release, enhancement of norepinephrine release, and cardiovascular hypertrophy. 25,26 Interestingly, the AT 2 -receptor appears to down-modulate actions mediated by the AT 1 -receptor and results in decreased cellular proliferation, decreased levels of serum arginine vasopressin, or decreased vasoconstrictor responses. 27 In addition, stimulation of the AT 2 -receptor may affect potassium currents, nitric oxide production neuronal growth and differentiation, and coronary endothelial growth. 28,29 Investigators testing the hypothesis that the AT 2 -receptor can modulate the growth of vascular smooth muscle cells, transfected an AT 2 -receptor expression vector into rats with balloon-injured carotid arteries and observed that over-expression of the AT 2 -receptor attenuated neointimal formation. 30 Masaki and coworkers 31 have shown that murine cardiac-specific overexpression of the AT 2 -gene in atria and ventricles results in decreased sensitivity to AT 1 - mediated pressor and chronotropic actions. In these mice, ratios of AT 2 to AT 1 were 40% to 50% in atria and ventricles, compared to undetectable levels of AT 2 in wild-type mice. Although there was no obvious morphologic change in the myocardium and no significant difference in cardiac development or in the ratio of heart to body weight observed between wild-type and transgenic mice, transgenic mice had a significantly attenuated increase in BP in response to infusion of AII. 31 Although the function of the AT 2 -receptor is less well understood than that of the AT 1 -receptor, studies such as those detailed above and evidence of up-regulation of AT 2 -receptors in pathologic cardiovascular conditions 32,33

3 176 LVH AND ANG II ANTAGONISTS AJH February 2001 VOL. 14, NO. 2 Table 1. baseline) Open studies evaluating the effects of losartan on left ventricular (LV) mass (P values versus Author, Reference suggest a function of the AT 2 -receptor to counteract the growth-promoting effects of the AT 1 -receptor. Mode of Action of ACE Inhibitors and AIIA Angiotensin converting enzyme inhibitors prevent the conversion of angiotensin I to AII and thus inhibit the action of AII at the AT 1 - and AT 2 -receptors, while at the same time blocking the degradation of various peptides (most notably, bradykinin). Angiotensin II is, however, also formed through non ACE-dependent pathways (such as via chymase), and therefore the formation of AII is not completely blocked by ACE inhibition. 34 In contrast to ACE inhibitors, which lower the levels of AII, AIIA increase concentrations of the peptide via inhibition of the negative feedback mechanisms through blockade of the AT 1 -receptor. Thus, AIIA directly prevent binding of AII to the AT 1 -receptor irrespective of origin and consequently completely inhibit the proliferative effects mediated via this receptor. However, AIIAs do not inhibit binding of AII to the AT 2 -receptor, and thus the AT 2 - receptor is stimulated through excessive AII. AIIAs, therefore, may have greater effects on LVH regression compared with ACE inhibitors because of the more complete inhibition of the AT 1 -receptor and the indirect stimulation of the AT 2 -receptor via the increased concentration of AII. AIIA and LVH: Clinical Evidence Study Population A number of trials have determined the effects of AIIAs on LV mass, with the majority using losartan the first of this class of drugs to be developed. Valsartan, irbesartan, and Patients With LVH (%) Study Duration (months) LVH Regression Himmelmann et al Patients with MM HT 5 29 No Lukman et al 36 7 Diabetic patients with HT Yes (P.001) Bignotti et al Patients with MM HT Yes (P.001) Acarturk et al Patients with MM HT Yes (P.001) Almazov et al Patients with HT Not reported 6 Yes* Arinsov et al Patients with MM HT 5 3 Yes (P.001) Kilavuz et al Patients with MM HT Yes (P.05) Cottone et al Patients with MM HT, 25 6 Yes (P.05) 25 Normotensive controls Tan et al Male diabetic patients Yes* with MM HT Caruso et al Patients with MM HT Yes (P.001) Grassos et al Patients with MM HT Yes (P.01) Karakoç et al Patients with MM HT Yes (P.0001) Paraskeupoulou et al Patients with HT Yes (P.001) LVH left ventricular hypertrophy; MM mild to moderate; HT hypertension. * P value not reported. candesartan are the only other AIIA to have published data in LVH so far. There have been 22 studies reporting LV mass at baseline and after treatment with losartan that have published up to October 1999; the earlier of these consist mostly of open uncontrolled studies, whereas the later trials use a controlled and randomized design. Review of Open Studies Thirteen open-label studies have evaluated the effects of losartan on LV mass in hypertensive patients (Table 1). Of the 13 studies, only one early study failed to report significant effects on LV mass regression with losartan. 35 In this open-label extension study, 19 patients with mildto-moderate hypertension were treated with losartan 50 mg/day. Patients received additional treatment with hydrochlorothiazide (6.25 to 12.5 mg/day, with or without a dihydropyridine calcium channel blocker) if diastolic blood pressure (DBP) did not decrease to 90 mm Hg. After 29 months of follow-up, although systolic (SBP) and DBP decreased by 24.3 and 20.7 mm Hg, respectively (achieved with monotherapy in only five patients, the addition of hydrochlorothiazide in eight patients, and triple therapy in six patients), the change in the LV mass index over the study period was not significant (P.16). The investigators stressed a number of limitations of the trial, which included the need for combination therapy, the small sample size, and evidence of LVH in only one patient at the start of the study; the LV mass index in this patient actually fell from g/m 2 to g/m 2,as would be expected. 35 The remaining 12 of these open-label studies all reported significant improvements in LV dimensions or mass. In another early study, Lukman et al 36 reported significant regression (P.01) of LVH from baseline in

4 AJH February 2001 VOL. 14, NO. 2 LVH AND ANG II ANTAGONISTS 177 seven hypertensive patients after 3 months of losartan 50 mg/day. The LV dimensions approached normal at 6 months (P.001 compared with baseline). A larger study followed up 50 patients with mild-to-moderate hypertension and LVH. 37 Patients were evaluated after 1 year of treatment with losartan 50 mg/day, and LV mass index significantly decreased from g/m 2 to g/m 2 (P.001). The study performed by Cottone et al 42 was a 6-month study that determined the effects of losartan in 16 hypertensive male patients (blood pressure 160/95 mm Hg) and 25 normotensive male control subjects. After 3 months of therapy, there was a nonsignificant reduction in both the interventricular septum thickness (from to mm) and the posterior wall thickness (from to mm) in hypertensive patients. After 6 months, these values had both fallen significantly (P.05) compared with baseline (to and mm, respectively). The decreases in posterior wall and interventricular thickness were accompanied by a significant reduction in SBP and DBP; however, there were no significant changes in BP or LV dimensions in the normotensive patients. 42 One study has examined the effect of losartan in 12 hypertensive men with recent myocardial infarction ( 3 months) and LVH. 43 After the addition of losartan 50 mg/day to postinfarction medication, regression in LVH became significant within 4 months, with concomitant improvement in cardiac ejection fraction. The effect of losartan on the structural characteristics of the left ventricle has also been investigated in 65 hypertensive patients. 47 Administration of losartan for 6 months significantly reduced the thickness of the interventricular septum and posterior wall by 6.5% and 3.8%, respectively (P.0001). The LV mass index was also lowered (from 142 to 130 g/m 2 ; P.0001). Controlled Studies With Losartan Following evidence from preclinical experiments and open-label studies that indicated that AIIA were able to reduce LV mass, randomized, mostly double-blind trials comparing losartan to placebo or other non-aiia antihypertensive agents have been performed (Table 2). Eight of these nine studies have documented a reduction in LV mass with losartan. The smallest of the three placebo-controlled studies failed to demonstrate a reduction in LV mass with losartan. 48 However, the results of this particular 3-month study should not significantly influence the otherwise consistent finding of LV regression, given that the 12 patients recruited did not appear to have LVH at baseline, and the negative results could be explained by the inherent variability of echocardiographic measurements compounded by the small sample size. 49 The other placebo-controlled studies 50,51 were larger in size (40 and 50 patients, respectively), longer in duration (2 and 3 years, respectively), Table 2. Randomized studies evaluating the effects of losartan on left ventricular (LV) mass (P values versus baseline) LVH Regression Study Duration (Months) Patients With LVH (%) Author, Reference Study Design Comparator Study Population Cheung et al 48 Placebo-controlled Placebo 12 Patients with mild HT Not reported 3 No De Rosa et al 50 Single-blind, placebocontrolled Placebo 40 Patients with MM HT Yes (P.01) De Rosa et al 51 Placebo-controlled Placebo 50 Elderly patients with Yes (P.01) hypertension Himmelmann et al 52 Double-blind Atenolol 24 Patients with MM HT Yes* Cuspidi et al 53 Double-blind Verapamil 17 Patients with MM HT 35 6 Yes (P.01) Villatico-Campbell et al 54 Placebo-controlled Fosinopril, placebo 44 Patients with MM HT Yes (P.01) Tedesco et al 55 Double-blind Hydrochlorothiazide 89 Patients with essential HT Yes (P.04) Tedesco et al 56 Double-blind Hydrochlorothiazide 77 Patients with MM HT Yes (P.02) Martina et al 57 Double-blind, controlled Amlodipine 25 Patients with MM HT Yes (P.003) Abbreviations as in Table 1. * P value not reported.

5 178 LVH AND ANG II ANTAGONISTS AJH February 2001 VOL. 14, NO. 2 and specifically recruited hypertensive patients with LVH. Both studies noted a significant (P.01) decrease in LV mass index after either 2 or 3 years of treatment with losartan. Six randomized studies have compared the effects of losartan with other antihypertensive agents and found the LVH regression produced by losartan to be numerically larger. A 3-month study compared the effects of losartan 50 to 100 mg/day and atenolol 50 to 100 mg/day on LV mass in 24 patients with mild-to-moderate hypertension (diastolic blood pressure 95 to 115 mm Hg). Half of them had LVH, defined as 131 g/m 2 in men and 100 g/m 2 in women. 52 The data showed a small decrease with losartan (from 126 to 124 g/m 2 ) compared with a small increase with atenolol (from 125 to 129 g/m 2 ). Cuspidi et al 53 performed a 6-month study in 40 patients with mild-tomoderate hypertension (diastolic blood pressure 95 to 115 mm Hg), some of whom had LVH (LV mass 125 g/m 2 in men and 110 g/m 2 in women). At the end of this study, the reduction in LV mass index from baseline with losartan (from to g/m 2 ; P.01) tended to be greater than with verapamil (from to g/m 2 ; P NS). The reduction by losartan in LVH was primarily driven by significant decreases in interventricular septal thickness and posterior wall thickness. 53 Another recent study compared the effects of losartan on LV mass with those of an ACE inhibitor in a doubleblind, placebo-controlled, randomized study. 54 The study population included 44 patients with mild-to-moderate hypertension (diastolic blood pressure 95 to 115 mm Hg) and LVH (LV mass index 125 g/m 2 ); 24 were treated with losartan 50 mg/day, 20 were treated with fosinopril 20 mg/day, and 24 hypertensive patients were randomized to a placebo-control group. After a follow-up of 12 months, both the ACE inhibitor and AIIA improved LV geometry (with decreases in LV internal diameter, intraventricular septal thickness and posterior wall thickness) and decreased the LV mass index compared with placebo. However, the investigators reported that improvements in LVH were more pronounced with losartan than with fosinopril after 6 and 12 months. 54 Tedesco et al have published two large double-blind studies 55,56 evaluating the effects of losartan on LV mass. They initially randomized patients with essential hypertension to 10 months of double-blind treatment with losartan 50 mg/day (n 49) or hydrochlorothiazide 25 mg (n 40). 55 A significant reduction in LV mass index was obtained with losartan (P.004), with baseline LV mass index reduced from to g/m 2. After this, Tedesco et al 56 published results from a longer double-blind study of 77 patients with hypertension randomized to receive either losartan 50 mg/day or hydrochlorothiazide 25 mg/day for 22 months (Fig. 2). In all, 63% patients randomized to losartan and 65% randomized to hydrochlorothiazide were found to have LVH ( 130 g/m 2 in men and 110 g/m 2 in women) at baseline. After a mean 22 months of follow-up, LV mass index had decreased significantly with losartan from g/m 2 at baseline to g/m 2 after 10 months (P.04) and g/m 2 after 22 months (P.02). This was achieved mainly by a decrease in the interventricular septum thickness (from to and after 10 and 22 months, respectively), and posterior wall thickness (from to and , respectively). In the patients randomized to hydrochlorothiazide, a significant decrease in the LV mass index was not observed ( v g/m 2 at baseline). Patients with mild-to-moderate hypertension (n 25) were randomized to receive either losartan titrated to losartan 50 mg/hydrochlorothiazide 12.5 mg (n 11) or amlodipine 5 mg titrated to 10 mg (n 14). 57 After 16 weeks of active treatment, LV mass in the losartan group was significantly reduced from a mean baseline of g to g(p.003) after 16 weeks of active treatment, whereas the reduction in LV mass seen in the amlodipine group was not significantly different from mean baseline. This indicates that LVM can be decreased significantly as early as 16 weeks into treatment with losartan. Overall, 22 studies (13 open-label and nine randomized) have evaluated the effects of losartan on the left ventricle. Of these, only two smaller studies (one randomized and comparative, and one open-label) have failed to show a significant effect of the AIIA on LV mass. The remainder of the studies have shown significant reductions in LV mass, LV mass index, and improvements in LV geometry in patients treated with losartan. Other AIIA Irbesartan, Valsartan, and Candesartan Other AIIA also appear to be effective in reducing LVH, although limited evidence has so far been published. Two studies, one with valsartan 58 and the other with irbesartan, 59 have reported a therapeutic effect on LV mass in patients with mild-to-moderate hypertension and LVH. In a randomized, double-blind trial in hypertensive patients with LVH, valsartan 80 mg/day or atenolol 50 mg/day was compared over 8 months. 58 Although both active treatments produced a significant regression in LVH, the mean reduction of LV mass index was 21 g/m 2 after 8 months of valsartan treatment (n 29) compared with only 10 g/m 2 under atenolol (n 29). The long-term benefit of valsartan has yet to be evaluated. Malmqvist et al 59 compared the effect of irbesartan treatment with atenolol over 12 months in hypertensive patients with LVH. Patients were randomized in a doubleblind manner to receive irbesartan 150 mg/day (n 57) or atenolol 50 mg/day (n 58). Although no correlation was reported between antihypertensive effects (expressed as pulse pressure) and LV mass index reduction in the atenolol group, a significant correlation existed between

6 AJH February 2001 VOL. 14, NO. 2 LVH AND ANG II ANTAGONISTS 179 FIG. 2. Effect of losartan ( SD) on (A) LV mass index, (B) interventricular septal thickness, (C) posterior wall thickness, and (D) LV internal-diastolic diameter in hypertensive patients with LVH. *P.04; **P.03; ***P.02; P.001 v baseline. (Based on Reference 56.) the changes in pulse pressure and LV mass index in the irbesartan group (P.0007). Thus, although similar reductions were seen in BP with the two active treatments, LVH regressed to a greater extent after treatment with irbesartan compared with atenolol. An article reporting the study protocol of a new trial investigating the effects of irbesartan compared with felodipine over a 1-year period in patients with mild to moderate hypertension and LVH has recently been published, 60 but no data are yet available from this study. One study with candesartan cilexetil has also reported a therapeutic effect on LV mass index in patients with essential hypertension. 61 Ten patients received candesartan cilexetil 2 to 8 mg daily for 8 to 12 weeks, and a significant decrease in LV mass index was recorded at the end of the study period (magnetic resonance imaging: P.0484; electrocardiography: P.0316), suggesting candesartan to be beneficial in the regression of cardiac hypertrophy in patients with essential hypertension. Limitations of the Current Evidence Individual studies do not conclusively offer a firm basis for determining the extent to which regression of LVH can be obtained. Although it is fair to say that pooling of results from the literature (as done in meta-analyses) is less satisfactory than adequate-sized single studies, meta-analyses are helpful for increasing statistical power, resolving uncertainty when results differ between studies, and improving accurate estimations of the magnitude of effect. The reliability of the resulting conclusions of metaanalyses depends on the quality of the original studies, and therefore the methodology of studies to be combined is

7 180 LVH AND ANG II ANTAGONISTS AJH February 2001 VOL. 14, NO. 2 Table 3. in LVH Design criteria necessary for all studies Randomized, double-blind design Comparison of active agents or active agent and placebo with 20 patients per treatment arm for a pilot study and patients for a definitive study Inclusion of hypertensive patients of both genders Minimum study duration of 6 months Use of anatomically validated echocardiographic (or other imaging method) determination of LVH Based on Reference 63. Abbreviation as in Tables 1 and 2. critical. 62 Many studies included in reviews and metaanalyses on LVH regression thus far have had one or more serious limitations that should be considered. Stringent criteria that should be met by any trial designed to provide useful information on LVH regression have been defined (Table 3) 63 ; however, in the meta-analysis performed by Dahlöf et al, 7 only 18 of 109 studies fulfilled even the first of these criteria (randomized, double-blind trials). In a subsequent larger meta-analysis, 8 only 33 of 412 studies were randomized, double-blind, parallel-group comparative trials performed in patients with hypertension. Although five of the 22 published studies evaluating the effect of losartan on LV mass in hypertensive patients are double-blind, randomized studies, the more stringent criteria are met by only two of the trials. A meta-analysis of the currently available information seems inappropriate at this stage. Nevertheless, there seems to be a very consistent message emerging across the different studies: namely, that treatment with an AIIA is capable of inducing significant regression of existing LVH. The Possibility of Reduced Mortality and Morbidity As outlined by Devereux et al, 64 studies have shown consistently higher risks of morbid events in subjects with LVH compared with subjects without the condition. Also, morbid events occur in a higher proportion of subjects in whom LVH progresses, compared with those in whom it regresses. As yet, however, no quantitative relationships between change in LVH and subsequent morbidity and mortality have been defined. Although a number of studies have reported the relationship between LVH and adverse prognosis, only a few have provided information on the relationship between LVH regression and subsequent morbidity and mortality There are a number of ongoing studies in which the comparative effects of different antihypertensive treatments, or different goal blood pressures, on morbidity and mortality and LVH regression are being determined. 64 It has been suggested that for trials to provide valid information as to whether reversal of LVH improves prognosis over and above reductions in blood pressure, their design should incorporate a large study population ( 1200 patients) and long-term ( 4 years duration) follow-up. 63 The Losartan Interventional For Endpoint (LIFE) trial is the only one that has recruited a study population of sufficient size, and that is following patients for a relatively long duration of time. 69 The LIFE trial is a double-blind, prospective, parallel group study that will compare the effects of losartan with those of the -blocker atenolol on cardiovascular mortality and morbidity in patients with hypertension and LVH. 69 A total of 9194 patients have been recruited into this study. Those eligible include men or women aged 55 to 80 years with either previously untreated or treated hypertension and electrocardiographically determined LVH. Patients will be randomized to losartan 50 mg/day or atenolol 50 mg/day, and followed for 4 years and until 1040 primary cardiovascular events have occurred. The LIFE study is the first to evaluate the effect of antagonizing the RAS with complete AT 1 -receptor blockade on prevention of complications in hypertension. It will be the first study with the defined optimal study design to have the power to address whether LVH regression in hypertensive patients is associated with a reduction in cardiovascular mortality and morbidity, independently of lowering of BP. Summary Although it stands to reason that if the stimulus for hypertrophy is removed, regression of LV mass will occur, it remains to be proved beyond doubt whether such a reduction in LVH will result in a concomitant improvement in prognosis independent of a change in blood pressure. The independent contribution of LVH to cardiovascular morbidity and mortality makes it mandatory, however, to consider the potential regression of LVH when managing patients with hypertension. Currently available data suggest that treatment with AIIA does reduce LV mass in patients with hypertension, and does so over and above the LVH regression associated with lowering of BP per se. Studies are required with the power to demonstrate conclusively 1) whether AIIA reduce LVH, and 2) whether regression of LVH is directly associated with a decrease in cardiovascular mortality and morbidity, independent of BP reduction. 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