Left ventricular hypertrophy (LVH) is an adaptive response of the heart to an increased workload either volume or pressure overload. This compensatory mechanism is an attempt by the heart to maintain near normal hemodynamics. In the long term however, its detrimental effects start manifesting. LVH causes demand supply mismatch both by reducing the coronary flow reserve and an increase in O2 consumption due to hypertrophy of the myocytes. Though not a conventional risk factor, LVH is a direct independent predictor of heart failure, stroke arrhythmia and sudden cardiac death (1).

Population based studies have clearly shown a strong association between hypertension and LVH. In fact in severe forms of hypertension there is a >50% incidence of LVH while in milder forms it is <25% (2). The Framingham studies have also established an age linked prevalence of LVH (3). Regression of LVH improves the prognosis in patients with hypertension. Thus any drug, which effectively reduces LVH, has an important role in the management of hypertension and cardiovascular diseases.

Mechanisms of Left ventricular Hypertrophy

The heart responds to an increased workload by 3 mechanisms (1) increasing cross bridge formation by Frank Starlings method (2) increasing its muscle mass and (3) neurohormonal activation(4) The increase in muscle mass is primarily by compensatory hypertrophy mediated by gene reprogramming. Down regulation of β1 adrenergic receptors, and M2 muscuranic receptors, an increase in the ratio of angiotensin II to angiotensin I receptors and increase in collagen formation in the interstitium are other key changes which occur. Activation of growth factors like angiotensin II, insulin and growth hormones by myocardial stretch also contribute to hypertrophy and fibrosis.

Targeting the mechanisms responsible for LVH could slow and potentially retard the process.  The increased workload on heart is reduced by effectively treating hypertension, reducing the central aortic pressure and correcting the processes responsible for pressure or volume overload on the heart.  This in turn would reduce neurohormonal activation, prevent reprogramming of genes (to cause myocardial hypertrophy) and reduce stimulation of various growth factors and cytokines.

Trials of Betablockers in LVH regression
Betablockers for long have been the mainstay for treatment of hypertension.  By reducing heart rate the cardiac workload is reduced, and neurohormonal activation is prevented thus removing toxic effects of circulating catecholamines. The usefulness of Beta blockers in regressing LVH has always been debated.  Most of the reports on LV regression are based on small nonrandomized trials with only one or two therapeutic arms   The Veterans Affairs Cooperative Study in mild to moderate hypertension was one of the earliest randomized trials which tested the effect of 6 groups of drugs including a placebo on LVH regression(5).  Atenolol was the betablocker of choice given at a dose of 25-100 mg/day.  Periodic echocardiography was performed at baseline, 8 weeks and 1 year.  The study showed a disparate effect of various antihypertensives on LVH regression.  Patients with adequate blood pressure control on captopril, hydrochlorothiazide and atenolol showed regression in LV mass at 1 year while patients on diltiazem, clonidine or prazocin did not.   Interestingly this trial was conducted only in men who had a high prevalence of LVH so data cannot be extrapolated for women or to men with less severe forms of the disease.  One of the other drawbacks was that the study design necessitated adherence to monotherapy so there were dropouts .Of the initial eleven hundred and five patents randomized, only 493 completed one year of maintenance therapy.  Nevertheless regardless of the drawbacks, this was the first major randomized trial, which showed effective LV mass regression with betablockers.

Indian Heart J. 2010; 62:139-142

Hypertensive patients often achieve good BP control with betablockers.  However, regression of LV hypertrophy is also necessary to reduce cardiovascular events.  Few studies have looked at the effects of different classes of betablockers on LV mass regression. Vyssoulis et al(6)  studied 200 patients with mild to moderate hypertension and treated with monotherapy with propranolol, atenolol, metaprolol, pindolol & celiprolol.  Except for propranolol all the other 4 drugs showed regression of LVH.  Celiprolol had the maximum LVH regression effect

The echocardiographic substudy of SHEP trial focused on the LV mass regression by antihypertensive therapy(7).  A total of 94 patients were followed upto 3 years.  80% of participants were on a Chlorthiazide based regimen.  Atenolol as add on therapy was used if there was no adequate BP control.  Aggressive antihypertensive therapy with good BP control was clearly associated with LV mass regression.

TOMHS (Comparison of Five Antihypertensive Monotherapies and Placebo for Change in left ventricular mass in patients receiving nutritional hygienic therapy in the treatment of Mild Hypertension Study) was the first major study, which looked at the effects of different antihypertensive drugs (monotherapy) on LVH regression in patients with mild hypertension (8).  The group noted that even in patients with mild hypertension a significant proportion of patients had a high LV mass compared to normal population.  They decided to analyse effects of a nutrition hygiene therapy & antihypertensive therapy on LV mass. A randomized double blind study on 902 patients was conducted over 4 years.  The LV mass was monitored by several echocardiograms.  Acebutalol was the betablocker used.  The study showed that LV mass regression was seen in both actively treated group as well the group treated with nutritional-hygiene therapy.  Among the antihypertensive groups chlorthalidone based therapy was most effective in reducing LV mass with changes in LV mass near identical in other groups.

The initial studies, which had shown LVH regression by betablockers, used nonselective agents.  A small study (30 hypertensive patients with documented LVH) from Madrid Spain by deTeresa et al looked at the effects of cardioselective betablocker Bisoprolol on LVH regression (9).  Bisoprolol improved diastolic function and significantly reduced LV mass (p value <0.001). Serum lipids were unchanged and tread mill exercise capacity was increased.  Since cardioselective agents like Bisoprolol has distinct advantages over nonselective betablockers vis-à-vis hemodynamic and metabolic effects, this trial is important.

Betablockers vs other antihypertensives in regression of LVH

Left ventricular hypertrophy is associated with hyperplasia of myocytes and increased collagen deposits with fibrosis.  Myocardial fibrosis occurs due to an imbalance between growth factors (Angiotensin II, insulin growth factor, fibroblast growth factor) and inhibitory factors, (prostaglandins, nitric oxide and natriuretic peptides).  Angiotensin II plays a major role and this probably explains the superiority of most ARBs and ACE inhibitors over betablockers in LVH regression.  Consistently all ARBs including Valsartan, ibesartan and losartan are found to be superior to atenolol in all studies in reversing LVH (10).

The echocardiographic substudy of LIFE trial analysed the LV mass regression on patients on losartan and atenolol based regimen(11).  This was a fairly large trial including 960 patients over 4 years and showed superiorly of losartan over atenolol in LVH regression.  The ELSA study was also echocardiography based and looked at effects of Lacidipine and Atenolol on LVH regression (12).Interestingly both trials showed that the regression in LVH was mostly in first 2 years of therapy and thereafter despite good BP control further regression in LVH was inconsistent 

Ciulla et al studied 219 hypertensive patients with echocardiographically documented LVH (13).  Patients were randomized to either losartan or atenolol with or without add on therapy with hydrocholorthiazide. Special software was used to get a colour histogram of reflecting echo’s –in broadband.  This has been previously shown to correlate with collagen content in endomyocardial biopsies.  They showed that losartan reduces myocardial collagen content while atenolol does not, possibly explaining why ARBs are superior to betablockers in regression LVH.

The RACE trial was a multicentre randomized and open labeled study on 193 patients at 16 centres.  Patients were treated with either Atenolol or Ramipril and LV mass was monitored by serial echocardiograms(14).The blood pressure was significantly reduced in both groups and expectedly heart rate was reduced only by atenolol .The trial showed that ramipril was more effective than atenolol in regressing LVH. The drawbacks of the trial were that it was opened labeled and study period was only 6 months. Of the 193 patients only 111 had echocardiograms, which could be qualitatively analyzed.

Thΰrmann and associates in  a randomized double  blind trial studied 69 hypertensive patients with documented LVH on echocardiograms for a period of 8 months(15)    Valsartan was found superior to atenolol in regressing LVH. This study too was of short duration-the implications of long-term therapy with both drugs on LV mass could not be arrived at.

The Swedish SYLVHIA (Swedish irbesartan left ventricular hypertrophy investigation versus atenolol) trial compared atenolol to irbesartan in 115 hypertensive patients for a period of 48 weeks(16). Serial echoes were performed.  Blood pressure reduction was similar in both groups.  However regression of LV mass was better with irbesartan. The Cardiovascular Irbesartan Project was a multicentre trial involving 240 hypertensive patients(17).The trial is important as the study period was longer-18months, and both the ECG and echo criteria were used to document LVH. Regression of LVH was more in patients who had a higher baseline LV mass. Irbesartan caused a significant reduction in LVH by voltage criteria, though the reduction in LV mass by echo was seen only in the group who had a higher baseline LV mass. Atenolol did not cause reduction in LVH either by ECG voltage or echo criteria.
The REASON (Regression of left ventricular mass in hypertensive patients treated with perindopril / indapamide as a first-line combination) echo study compared the perindropil-indapamide combination to atenolol in regressing LVH in 214 hypertensive patients over a period of 1 year(18).Like the Cardiovascular Irbesartan Project the greatest reduction in LV mass was seen in the patients who had a higher baseline LV mass.  The combination of perindropil and indapamide was superior to atenolol in reducing LV mass.

The viscoelastic properties of aorta decline with aging and with comorbid diseases like hypertension and diabetes.  This results in elevation of central aortic pressure and after load of the heart.  Pharmacological reduction of central aortic pressure would reduce afterload and thus the LV hypertrophy.  Medication that reduces peripheral cuff pressure need not regress LVH. The ACE inhibitors and ARBs as well as calcium blockers are superior to betablockers in reducing central aortic pressure.  Both the CAFÉ trial and ASCOT trial support this data (19,20).  A better reduction of central aortic pressure is by ARBs and ACE inhibitors than betablockers result in better LVH regression in the former.

Results of Trials on LV Mass Regression

Meta analysis of various studies show that regression of LV mass was most effective with ACE inhibitors / ARBs, to a lesser extent with calcium channel blockers and least with diuretics and betablockers in that order.  Robert Fagard and colleagues conducted a meta analysis on 75 relevant publications involving 6001 patients (21).  Angiotensin receptor II blockers showed most regression and betablockers showed less regression than other 4 groups of drugs combined.  One

postulate put forward by them was that central aortic pressure is less reduced by betablockers compared to other drugs, so afterload reduction and hence LVH regression is less.  It is to be noted that of the 31 paired comparisons 20 trials were with Atenolol and 8 comparisons with other betablockers.  Atenolol does not have significant reduction in central aortic pressure as noted in CAFE & ASCOT trials and this could be the reason for its inferiority. 

A recent meta analysis by Klingbeil et al on 80 trials with 4000 patients studied the effects of antihypertensive drug therapy on LV mass(22).  LV mass index reduced 13% with ARBs, 11% with calcium blockers, 10% with ace inhibitors, 8% with diuretics and 6% with betablockers.

Adequate control of blood pressure leads to regression of LVH in hypertensive patients. Simpson et al in a prospective study looked at the impact on LVH by reducing blood pressures among hypertensive patients who had normal range blood pressures with treatment.(23 Fifty one subjects with echocardiographic LVH  had  normal range blood pressure on treatment with either an ACE-I or ARB. These patients were given add on therapy with either a placebo or other antihypertensives which included atenolol when required. At 1 year follow up the active treatment group showed further regression of LVH. Whether this leads to reduction in cardiovascular events in the long term is to be seen.

Drawbacks of trials on LVH Regression

Cuspidi etal reviewed 39 trials involving 9,162  hypertensive patients with LVH(24). They found there was no consistency in the criteria used for definition of LVH in all the trials. Pathologically there are 3 varients of LV hypertrophy (concentric hypertrophy,eccentric hypertrophy and concentric remodeling) and each have different risk profiles.  Of the 39 trials analysed only 5 provided clear information on LV geometry types. LV regression depends on adequacy of blood pressure control, only 11 of the 39 trials gave adequate information on rates of normalization of blood pressure.
Most of the trials on LVH regression have been of short duration ranging from forty eight weeks to one year(5,9,13,14,15,16,18).Hence the long term effects on LVH regression and reduction of cardiovascular events cannot be elucidated.The trials involving betablockers used  mostly older generation molecules like atenolol which have a minimal role in reducing central aortic pressure-a key contributor to afterload.Further studies involving newer generation of betablockers would have more relevance in the present scenario.A number of trials we discussed also used add on therapy with other groups of antihypertensives, so benefit for a particular class of drug  cannot be clearly arrived at.

 

central aortic pressure and to lower angiotensin II levels (a known growth factor for myocyte hypertrophy). Betablockers especially older generation have less effect in reducing central aortic pressure, which is the critical determinant for development of LVH. The down regulation of beta receptors in hypertensives would reduce the stimulatory effects that circulatory catecholamines exert on myocyte growth, thus minimizing the role of betablockers in negating this effect.(17). etablockers thus continue to have a role in LVH regression but ace-inhibitors/ARBs and calcium channel blockers are more effective-(Tables 1 and 2) .


Reference:

1) Levy D, Garrison RJ, Savage DD - Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study.
N Engl J Med 1990 ; 322 : 1561-1565

2) Hammond IW, Devereux RB, Alterman MN, et al - The prevalence and correlates of echocardiographic left ventricular hypertrophy among employed patients with uncomplicated hypertension. J Am Coll Cardiol 1986 ; 7 : 639-650

3) Levy D, Anderson KM, Savage DD et al - Echo cardiographially detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988 ; 108 : 7-13

4) Carabello BA, Lorell BH - Left ventricular hypertrophy pathogenesis detection and Prognosis Circulation 200; 102 : 470-79

5) Gottdiener JS. Reda JD, Massie BM et al - Effect of single drug therapy on reduction of left ventricular mass in mild to moderate hypertension. Circulation 1997 ; 95 : 2007 – 2014

6) Vyssoulis GP, Karpanou EA, Pitsavos CE et al-Regression of Left Ventricular Hypertrophy in Systemic Hypertension with Beta Blockers (Propranlol, Atenolol, Metoprolol, Pindolol and Celiprolol). JAMA1998;279:778-780

7) Ofili EO, Cohen JD, St. Vrain JA et al – Effect of treatment of isolated systolic hypertension on left ventricular mass. JAMA 1998 ; 279(10) : 778-780

8) Liebson PR, Grandits GA, Dianzumba S et al - Comparison of Five Antihypertensive Monotherapies and Placebo for Change in left ventricular mass in patients receiving nutritional hygienic therapy in the treatment of Mild Hypertension Study (TOMHS). Circulation 1995 ; 91 : 698-706

9) DeTeresa E, Gonzá.lez M, Camacho-Vázquez C etal:Effects of Bisoprolol on Left Ventricular Hypertrophy in Essential Hypertension.Cardiovascular Drugs and Therapy :1994;8:837-843

10) Cuspidi C Sala C Zanchetti A - Management of hypertension in patients with LV hypertrophy current hypertension reports 2007 ; 9 : 498-505

11) Devereux RB, Dahlof B, Gerdts E etal - Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation 2004 ; 110 : 1456-62.

12) Agabiti Rosei E, Trimarco B, Muiesan ML etal - Cardiac structural & functional changes during long term antihypertensive treatment with lacidipine and atenolol in the European Lacidipine Study on Atherosclerosis (ELSA) J hypertens 2005 ; 23 :1091-98

13) Ciulla MM, Paliotti R, Esposito A etal – Different effects of antihypertensive therapies based on Losartan or Atenolol on Ultrasound and Biochemical Markers of Myocardial Fibrosis Circulation 2004 ; 110 : 552-557

14) Agabiti-Rosei, E; Ambrosioni, E; DalPalùt, C; ACE inhibitor ramipril is more effective than the [beta]-blocker atenolol in reducing left ventricular mass in hypertension. Results of the RACE (ramipril cardioprotective evaluation) study J Hypertens 13(11):1325-1334, November 1995

15) Thu¨rmann P A Kenedi . P, Schmidt A etal - Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension. Circulation. 1998; 98: 2037-2042

16) Malmqvist, K; Kahan, T; Edner, M; Regression of left ventricular hypertrophy in human hypertension with irbesartan J Hypertens. 19(6): 1167-1176, June 2001. Results of the CardioVascular Irbesartan Project. Hypertension. 2004; 44: 61-6

17) Schneider M P; Klingbeil A U, Delles C etal Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage. Results of the CardioVascular Irbesartan Project Hypertension. 2004; 44: 61-66

18) de Luca N, Mallion J-M ,. O'Rourke M F etal Regression of left ventricular mass in hypertensive patients treated with perindopril / indapamide as a first-line combination The reason echocardiography study. Am J Hypertens (2004) 17: 660–667

19) Williams B, Lacy PS, Thom SM etal - Differential impact of blood pressure lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 113(9):1213-25

20) Sever PS, Dahlof B, Poulter NR, etal – Prevention of coronary and stroke events in hypertensive patients who have average or lower than average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arrn (ASCOT-LLA) Lancet 2003; 361 : 1149-58

21) Fagard RH, Celis H, Thijs L etal – Regression of left ventricular mass by antihypertensive treatment. A meta-analysis of randomized comparative studies. Hypertension 2009; 54(5) : 1084-1091.

22) Klingbeil AU, Schneider M, Martus P, etal- A meta-analysis of the efforts of treatment on left ventricular mass in essential hypertension. Am J Med 2003 ; 115 : 41-46.
23) Simpson HJ,Gandy SJ,Houston JG etal.Left Ventricular hypertrophy:Reduction of blood pressure already in the normal range further regresses left ventricular mass.Heart 2010;96:148-152.

24) Cuspidi C,Esposito A,Negri F etal.Studies on Left Ventricular Hypertrophy Regrssion in Arterial Hypertension :A Clear Message for the Clinician? Am J Hypertens 2008; 21:458-463.