This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thürmann, P. A. Articles by Rietbrock, N. Search for Related Content PubMed PubMed Citation Articles by Thürmann, P. A. Articles by Rietbrock, N.

(Circulation. 1998;98:2037-2042.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension

Petra A. Thürmann, MD; Peter Kenedi, MD; Andor Schmidt, MD; Sebastian Harder, MD; ; Norbert Rietbrock, MD

From the Philipp Klee-Institute of Clinical Pharmacology, Hospital Wuppertal GmbH, Clinical Pharmacology, University Witten/Herdecke, Wuppertal (P.A.T.); Institute of Clinical Pharmacology, University Hospital, Frankfurt (S.H., N.R.); Department of Internal Medicine, Diakonissenkrankenhaus, Frankfurt (P.K.); and General Practice, Offenbach/Main (A.S.), Germany.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background—Left ventricular hypertrophy (LVH) represents an independent risk factor in patients with essential hypertension. Because reversal of LVH may be associated with an improvement of prognosis, the influence of new antihypertensive compounds, such as angiotensin II AT₁ receptor antagonists, on LVH should be determined.

Methods and Results—In a randomized, double-blind trial, 69 predominantly previously untreated hypertensive patients with echocardiographically proven LVH, ie, left ventricular mass index (LVMI) >134 g/m² in men and >110 g/m² in women and/or end-diastolic septal thickness >12 mm, received either the angiotensin II antagonist valsartan or atenolol for 8 months. Echocardiographic data of 58 patients were available. After 8 months of valsartan treatment (n=29), LVMI decreased from 127±23 to 106±25 g/m² (ratio [R]=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). Under atenolol (n=29), LVMI decreased to a smaller extent, from 127±25 to 117±27 g/m² (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline). The mean reduction of LVMI came to 21 g/m² under valsartan and only to 10 g/m² under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol). Baseline mean blood pressure values were determined to be 163±12/101±6 mm Hg before treatment with valsartan and 160±14/103±6 mm Hg before atenolol treatment. After 8 months of treatment, mean blood pressure decreased to 146±13/90±7 mm Hg with valsartan and to 147±18/90±7 mm Hg with atenolol. Nine patients in the valsartan group and 8 patients in the atenolol group required additional medication with hydrochlorothiazide.

Conclusions—Antihypertensive treatment with the angiotensin II antagonist valsartan for 8 months produced a significant regression of LVH in predominantly previously untreated patients with essential hypertension. The drug may be safely administered in this subset of hypertensive patients; however, the long-term benefit in terms of risk reduction has still to be evaluated in further trials.

Key Words: hypertension • hypertrophy • ventricles • angiotensin

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
In hypertensive patients, left ventricular hypertrophy (LVH) represents a powerful predictor for cardiovascular morbidity and mortality independent of other cardiovascular risk factors, even blood pressure itself.^{1 2} Regression of LVH may be associated with an improvement of prognosis.^{3 4} Meta-analyses^{5 6} and a recently published trial⁷ comparing the effects of different drug classes on LVH have suggested that ACE inhibitors are currently the most powerful drugs in this regard. In contrast, recently published prospective trials comparing the effects of different drug classes revealed no relevant differences in terms of LVH reduction,^{7 8} and the question of whether antihypertensive drugs differ in their ability to regress LVH was put forward.⁹ Considering the importance of LVH as an independent risk factor, the safety and efficacy of new antihypertensive drugs in patients with LVH have to be studied.

In addition to a chronic increase in pressure and/or volume overload, an elevation in plasma ACE activity, plasma aldosterone levels,¹⁰ and angiotensin II (Ang II) concentrations play a major role in the development of LVH.¹¹ Reduction of Ang II levels after ACE inhibition may be responsible for the beneficial effects of ACE inhibitors beyond the blood pressure–lowering activity. Apart from cleavage of Ang I by ACE, alternative pathways exist for the formation of Ang II, and despite ACE inhibition, a considerable amount of Ang II may be present, particularly in the heart.¹² Because almost all known actions of Ang II are mediated via the AT₁ receptor subtype,¹³ the recently introduced specific Ang II AT₁ receptor antagonists could also be useful drugs in terms of LVH regression.¹⁴ Experimental data suggest a considerable effect of this class of drugs on myocardial hypertrophy and fibrosis.^{15 16}

The antihypertensive efficacy of the selective Ang II antagonist valsartan¹⁷ in essential hypertensive patients was shown earlier.¹⁸ We investigated the influence of 8 months of antihypertensive treatment with this Ang II antagonist on LVH versus the ß-adrenergic receptor antagonist atenolol. ß-Adrenergic receptor antagonists are included as first-line treatment in the recommendations of most national and international committees for the treatment of high blood pressure. Atenolol has recently been shown to be at least equally tolerable and to ensure blood pressure control comparable to that with enalapril, hydrochlorothiazide (HCTZ), and nitrendipine.¹⁹ We enrolled predominantly untreated patients to avoid the effects of previous drug treatment.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patients and Study Design
The trial followed a randomized, double-blind, actively controlled, parallel-group design.²⁰ The study protocol was approved by the ethics committee of the University Hospital in Frankfurt, and all study participants gave written informed consent before participation in the trial. Patients were recruited and treated by 14 general practitioners, whereas echocardiographic readings and analyses were performed at 1 central laboratory (P.K.).

One hundred seventeen previously untreated, white, hypertensive patients or those who had been treated (1) for <4 weeks during the previous 12 months or (2) with diuretics only were screened. Secondary forms of hypertension were excluded. Pretreatment with diuretics was considered acceptable, because their effect on left ventricular mass and especially wall thickness parameters has been shown to be negligible.^{6 21} Normal renal and liver function tests as well as blood counts were confirmed in 1 central laboratory.

The inclusion criterion was a diastolic blood pressure between 95 and 115 mm Hg and systolic blood pressure between 150 and 180 mm Hg determined after a single-blind, 3-week placebo run-in period. All blood pressure measurements were performed in duplicate with a standard cuff sphygmomanometer after 10 minutes in the sitting position. During the run-in period, the presence of LVH was established by echocardiography and defined as left ventricular mass index (LVMI) >134 g/m² body surface area for men and >110 g/m² for women and/or septal thickness >12 mm at end diastole.²²

Randomized patients received, in a double-blind manner, either valsartan 80 mg/d or atenolol 50 mg/d for the following 4 weeks. If blood pressure was not adequately controlled, ie, sitting diastolic blood pressure measured in the morning before drug intake >95 mm Hg, the dose of both drugs was doubled. After an additional 4 weeks, HCTZ could be added in those patients in whom diastolic blood pressure still exceeded 95 mm Hg. After 3 months, the second echocardiogram was performed; regular visits were then at 8-week intervals. The final visit and third echocardiogram were performed after 8 months of double-blind treatment.

Echocardiography
All echocardiographic recordings were performed by 1 experienced investigator using a Hewlett Packard Sonos 1000 system with a 2.5-MHz transducer according to recommendations of the American Society of Echocardiography.²³ M-mode recordings were guided by 2-dimensional views. LVMI was calculated according to the formula of Devereux et al.²² Left ventricular end-diastolic and end-systolic volumes were determined by 2-dimensional echocardiography, and left ventricular ejection and fractional shortening were calculated with standard formulas. Pulsed-wave Doppler recordings of transmitral flow velocity were performed to calculate the areas under the velocity/time curves E and A.

Values from at least 3 beats were measured and averaged, and intraobserver variability was determined to be 6.8%, 6.2%, 3.8%, and 13% for end-diastolic septal thickness, end-diastolic posterior wall thickness, left ventricular internal diameter, and V_maxE/V_maxA, respectively.²⁴

Statistical Analysis
For primary efficacy analysis, baseline and final LVMIs were compared within treatment groups. To detect a clinically relevant change of 15% with 80% power, 26 patients were required in each treatment group, assuming a coefficient of variation of 29% and using Student's t test on logarithmically transformed data. The level of significance was set to 5%. To compare the change in LVMI between groups, the 90% CI of the 2 ratios could be calculated with a precision of ±13%.

For the intention-to-treat analysis, all randomized patients having at least 1 postbaseline echocardiogram were included. The primary efficacy variable LVMI and secondary variables were analyzed after logarithmic transformation of the data by the paired t test (SAS), and the corresponding 95% CIs were calculated.

Between-treatment differences were analyzed by ANCOVA, and 95% CIs were derived. Data are given as mean±SD; if appropriate, the median value is quoted.

A correlation analysis (Kendall) was performed between percent reduction in systolic and diastolic blood pressures, respectively, and change in LVMI. Kendall correlation coefficients () and corresponding P values are given.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patients
One hundred seven patients underwent a baseline echocardiogram; 69 met the inclusion criteria (Table 1). The known duration of hypertension was maximally 8 years (median, 17 months). Two patients were pretreated with diuretics, and 11 patients had received other blood pressure–lowering drugs for <4 weeks in the 12 months before the study. Concomitant diagnoses and medications are given in Table 2. In addition, 9 patients received acetylsalicylic acid and paracetamol for relief of common cold symptoms.

View this table: [in this window] [in a new window]   Table 1. Demographic Data of 69 Randomized Patients

View this table: [in this window] [in a new window]   Table 2. Number of Patients With Concomitant Chronic Diseases and Number of Patients Receiving Chronic Concomitant Medication

Three patients in each treatment group discontinued the study because of adverse events: under valsartan, 1 female patient developed a probably drug-induced bilateral dermatitis of the breast, 1 patient had a subarachnoid hemorrhage, and in 1 patient a brain tumor was diagnosed. Under atenolol, 2 patients experienced angina and 1 patient dyspnea, the latter possibly associated with atenolol. Safety blood chemistry parameters revealed no variations in the mean and median values, especially for serum creatinine and urea, as well as blood lipid profiles, with the exception of 1 patient receiving atenolol 100 mg/d plus HCTZ, in whom a clinically relevant increase of serum uric acid, creatinine, and urea occurred.

Fifty-eight patients (n=29 in each treatment group) were evaluable for the intention-to-treat analysis of LVH; echocardiographic data and blood pressure values for these patients are presented.

Blood Pressure Control
In the valsartan treatment group, a dose increment to 160 mg/d was required in 14 patients, and 9 patients required additional medication with HCTZ. In the atenolol group, 16 patients received 100 mg/d, and in 8 patients, addition of HCTZ was necessary to achieve a satisfactory blood pressure control.

After 8 months of valsartan treatment, systolic blood pressure decreased from 163±12 to 146±13 mm Hg (mean, –17 mm Hg; 95% CI, –21 to 13 mm Hg; P<0.0001), diastolic blood pressure decreased from 101±6 to 90±7 mm Hg (mean, –11 mm Hg; 95% CI, –14 to 8 mm Hg; P<0.0001). Treatment with atenolol resulted in a decrease of systolic blood pressure from 160±14 to 147±18 mm Hg (mean, –13 mm Hg; 95% CI, –18 to 7 mm Hg; P<0.0001), and diastolic blood pressure was reduced from 103±6 to 90±7 mm Hg (mean, –12 mm Hg; 95% CI, –15 to 9 mm Hg; P<0.0001).

Heart rate remained almost unchanged under valsartan treatment at 76 bpm (median value) before treatment and 73 bpm after 8 months of treatment, whereas under atenolol, an expected marked decrease from 76 to 64 bpm was observed.

Echocardiographic Data
After 3 months of valsartan therapy, LVMI decreased slightly, from 127±23 to 119±23 g/m², whereas a significant decrease could be observed after 8 months to 106±25 g/m² (R=0.83; 95% CI, 0.79 to 0.87; P<0.0001 versus baseline). In the atenolol group, LVMI decreased from 127±25 to 119±23 g/m² during the first 3 months; after 8 months, LVMI was determined to be 117±27 g/m² (R=0.92; 95% CI, 0.86 to 0.98; P=0.0082 versus baseline; Figure 1). Covariate analyses revealed no influence of sex and age on treatment effects.

View larger version (32K): [in this window] [in a new window]   Figure 1. LVMI before and after 3 and 8 months of treatment with valsartan and atenolol (n=58 patients).

The mean reduction of LVMI was 21 g/m² under valsartan and 10 g/m² under atenolol (R=0.91; 90% CI, 0.85 to 0.97 versus atenolol), suggesting a tendency toward a more pronounced treatment effect with valsartan.

Septal and posterior wall thicknesses were reduced by both drugs, valsartan being slightly more effective (Table 3). Left ventricular internal diameters and volumes and their derived parameters ejection fraction and fractional shortening remained almost constant (Table 3).

View this table: [in this window] [in a new window]   Table 3. M-Mode and 2-Dimensional Echocardiographic Parameters (mean±SD) Obtained During the Study (Intention-to-Treat Analysis, n=29 in Each Treatment Group)

No relevant changes were observed for Doppler echocardiographic parameters (Table 4); the ratio E/A showed a small but significant increase after atenolol treatment (R=1.18; 95% CI, 1.05 to 1.33; P<0.01 versus baseline).

View this table: [in this window] [in a new window]   Table 4. Doppler Echocardiographic Parameters (mean±SD) Obtained During the Study (Intent-to-Treat Analysis, n=29 in Each Treatment Group)

No significant correlation could be found between the changes in blood pressure and in LVMI (Table 5) for either valsartan or atenolol treatment.

View this table: [in this window] [in a new window]   Table 5. Correlation Coefficients Between Percent Reduction of Blood Pressure and Decrease in LVMI (Kendall Correlation Coefficient, )

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The prevalence of LVH has recently been estimated to be 62% in essential hypertensive patients with a sitting diastolic blood pressure between 100 and 115 mm Hg,²⁵ which is in accordance with our screening results. In contrast to 3 previous studies in patients with LVH^{26 27 28} who were given the Ang II antagonist losartan, we observed a significant reduction in left ventricular mass after 8 months of treatment with the Ang II antagonist valsartan. As in our study, Cheung²⁶ included only previously untreated patients, but as in the investigation by Himmelmann et al,²⁷ treatment duration was only 12 weeks. However, the most marked effect on LVMI, and especially the difference versus atenolol, occurred between 3 and 8 months of treatment with valsartan. Baseline values of LVMI were comparable between our study and these 2 studies; however, in the long-term (29-month) study reported by Himmelmann and coworkers,²⁸ patients were pretreated and had a normal baseline LVMI of 97 g/m². One should consider that in the other investigations,^{26 27 28} the number of patients enrolled ranged between 12 and 24 patients.

The overall extent of reduction in LVMI observed in our trial is comparable to that of other studies.^{5 6} In a comparative trial between the ACE inhibitor ramipril and atenolol,²⁹ 6 months of treatment with atenolol induced only a minor regression of LVMI, from 139 to 133 g/m²; in contrast, ramipril produced a significant reduction, from 136 to 117 g/m². The reduction of 19 g/m² obtained with the ACE inhibitor appears to be comparable to our results with an AT₁ antagonist.

We found no significant correlation between blood pressure reduction and decrease in left ventricular mass, possibly because of the sample size and the large variability of findings. However, there was a trend for a positive correlation for valsartan, but not for atenolol. In 206 essential hypertensive patients receiving lisinopril and additional HCTZ, no correlation could be demonstrated between change in clinic sitting blood pressure and change in LVMI, whereas a close correlation was found between decrease in average 24-hour ambulatory blood pressure values and reduction in LVMI.³⁰

In renovascular hypertensive rats, Zierhut et al¹⁵ observed a significant decrease of LVMI after 12 weeks of treatment with valsartan, comparable to the effect induced by an ACE inhibitor. Treatment with the Ang II antagonist TCV-116 prevented the development of LVH in the spontaneously hypertensive rat model by reducing left ventricular wall thickness and weight and also interstitial fibrosis.³¹

It has been suggested that AT₁ antagonists, like ACE inhibitors, possess a pharmacological effect beyond blood pressure reduction,¹⁴ in which blockade of the AT₁ receptor may lead to an attenuation of the growth-promoting actions of Ang II.

However, little is known about the presence and role of the AT₂ receptor subtype (and other subtypes) in patients with LVH.³² Liu and coworkers³³ showed, in rats after myocardial infarction, that a considerable share of the beneficial effects of an Ang II AT₁ receptor antagonist could be attenuated by additional treatment with an AT₂ antagonist. These findings indicate that stimulation of the AT₂ receptor plays an important role in the mechanism of action of selective AT₁ receptor antagonists. Irrespective of the mechanism of action, the ELITE trial³⁴ demonstrated that the Ang II antagonist losartan is at least as effective as an ACE inhibitor with regard to prevention of heart failure–related hospital admissions and reduction of total mortality.

Some aspects of our study may be considered to be shortcomings. First, treatment duration was restricted to 8 months. Liebson and coworkers⁸ described an additional decrease of left ventricular mass after 12 months of treatment with different antihypertensive drug classes.

The addition of HCTZ was required equally in both our treatment groups, and a beneficial influence of this diuretic on LVMI cannot be ruled out. According to Liebson et al⁸ and others,^{5 7} the major influence of a diuretic was confined predominantly to the left ventricular internal diameters rather than wall thickness parameters. We did not observe a decrease of left ventricular internal diameters or left ventricular volumes.

The method of measuring LVMI by echocardiography requires some comment. The reproducibility of 2-dimensional and M-mode echocardiography has been validated in our echocardiography laboratory, and variability²⁴ is in accordance with recently published data on the quality of echocardiographic readings.^{35 36}

Confirming experimental data, a considerable regression of LVH was obtained after 8 months of treatment with the Ang II antagonist valsartan in essential hypertensive patients, indicating that valsartan may safely be given to patients with LVH. The long-term clinical benefit of the LVH reduction obtained after chronic treatment with Ang II antagonists has to be elucidated in clinical studies using end points such as cardiovascular events and mortality.³⁷

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Participating General Practitioners
K. Albrecht, S. Mörchen (Undenheim); E. Bakker (Gründau); F. Criveanu (Frankfurt); A. Faust (Mainz); F. Frohnapfel (Ludwigshafen); G. Härter, V. Rudie (Reilingen); V. Janekovic (Frankfurt); E. Reichwein (Villmar); R. Santo (Lahnau); A. Schmidt (Offenbach); R. Schneider (Wetzlar); M. Stoll, A. Dietz (Dreieich); R. Will (Frankfurt); W. Oldenburg (Frankfurt), Germany.

	Acknowledgments

 
We thank Florence Botteri, PhD, Novartis Pharma AG, Switzerland, for her advice and Doris Bach, PhD, Novartis Pharma AG, Switzerland, for statistical evaluations.

	Footnotes

 
Reprint requests to Prof Dr med Petra A. Thürmann, Philipp Klee-Institute of Clinical Pharmacology, Klinikum Wuppertal GmbH, Arrenberger Straße 20, 42117 Wuppertal, Germany.

Received April 13, 1998; revision received June 19, 1998; accepted June 25, 1998.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med. 1990;322:1561–1566.[Abstract]
   
2. Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Gattobigio R, Zampi I, Santucci A, Santucci C, Reboldi G, Porcellati C. Prognostic value of left ventricular mass and geometry in systemic hypertension with left ventricular hypertrophy. Am J Cardiol. 1996;78:197–202.[Medline] [Order article via Infotrieve]
   
3. Levy D, Salomon M, D'Agostino RB, Belanger AJ, Kannel WB. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left ventricular hypertrophy. Circulation. 1994;90:1786–1793.[Abstract/Free Full Text]
   
4. Muiesan ML, Salvetti M, Rizzoni D, Castellano M, Donato F, Agabiti-Rosei E. Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment. J Hypertens. 1995;13:1091–1095.[Medline] [Order article via Infotrieve]
   
5. Schmieder RE, Martus P, Klingbeil A. Reversal of left ventricular hypertrophy in essential hypertension: meta-analysis of randomized double-blind studies. JAMA. 1996;275:1507–1513.[Abstract]
   
6. Dahlöf B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy in hypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens. 1992;5:95–110.[Medline] [Order article via Infotrieve]
   
7. Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW, Anderson RJ, the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Effect of single-drug therapy on reduction of left ventricular mass in mild to moderate hypertension: comparison of six antihypertensive agents. Circulation. 1997;95:2007–2014.[Abstract/Free Full Text]
   
8. Liebson PR, Grandits GA, Dianzumba S, Prineas RJ, Grimm RH, Neaton JD, Stamler J. 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.[Abstract/Free Full Text]
   
9. Devereux RB. Do antihypertensive drugs differ in their ability to regress left ventricular hypertrophy? Circulation. 1997;95:1983–1985.[Free Full Text]
   
10. Schunkert H, Hense HW, Muscholl M, Luchner A, Kürzinger S, Danser AHJ, Riegger GAJ. Associations between circulating components of the renin-angiotensin-aldosterone system and left ventricular mass. Heart. 1997;77:24–31.[Abstract/Free Full Text]
    
11. Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Circulation. 1993;73:413–423.
    
12. Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265:2348–2357.
    
13. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996;334:1649–1654.[Free Full Text]
    
14. Dahlöf B. Effect of angiotensin II blockade on cardiac hypertrophy and remodelling: a review. J Hum Hypertens. 1995;9(suppl 5):37–44.
    
15. Zierhut W, Studer R, Laurent D, Kästner S, Allegrini P, Whitebread S, Cumin F, Baum H, de Gasparo M, Drexler H. Left ventricular wall stress and sarcoplasmatic reticulum Ca²⁺-ATPase gene expression in renal hypertensive rats: dose-dependent effects of ACE inhibition and AT₁-receptor blockade. Cardiovasc Res. 1996;31:758–768.[Medline] [Order article via Infotrieve]
    
16. Nicoletti A, Heudes D, Hinglais N, Appay M-D, Philippe M, Sassy-Prigent C, Bariety J, Michel J-B. Left ventricular fibrosis in renovascular rats: effect of losartan and spironolactone. Hypertension. 1995;26:101–111.[Abstract/Free Full Text]
    
17. Criscione L, de Gasparo M, Bühlmayer P, Whitebread S, Ramjoue H-PR, Wood J. Pharmacological profile of valsartan: a potent, orally active nonpeptide antagonist on the angiotensin II AT₁-receptor subtype. Br J Pharmacol. 1993;110:761–771.[Medline] [Order article via Infotrieve]
    
18. Corea L, Cardoni O, Fogari R, Innocenti P, Porcellati C, Provvidenza M, Meilenbrock S, Sullivan J, Bodin F. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. Clin Pharmacol Ther. 1996;60:341–346.[Medline] [Order article via Infotrieve]
    
19. Philipp T, Anlauf M, Distler A, Holzgreve H, Michaelis J, Wellek S. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: results of the HANE study. BMJ. 1997;315:154–159.[Abstract/Free Full Text]
    
20. Devereux RB, Dahlöf B. Criteria for an informative trial of left ventricular hypertrophy regression. J Hum Hypertens. 1994;8:735–739.[Medline] [Order article via Infotrieve]
    
21. Dahlöf B, Hansson L. Regression of left ventricular hypertrophy in previously untreated essential hypertension: different effects of enalapril and hydrochlorothiazide. J Hypertens. 1992;10:1513–1524.[Medline] [Order article via Infotrieve]
    
22. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–458.[Medline] [Order article via Infotrieve]
    
23. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072–1083.[Abstract/Free Full Text]
    
24. Thürmann PA, Stephens N, Heagerty AM, Kenedi P, Weidinger G, Rietbrock N. Influence of isradipine and spirapril on left ventricular hypertrophy and resistance arteries. Hypertension. 1996;28:450–456.[Abstract/Free Full Text]
    
25. Zabalgoitia M. Left ventricular mass and function in primary hypertension. Am J Hypertens. 1996;9:55S–59S.
    
26. Cheung B. Increased left-ventricular mass after losartan treatment. Lancet. 1997;349:1743–1744.[Medline] [Order article via Infotrieve]
    
27. Himmelmann A, Svensson A, Dahlöf B, Bergbrant A, Hansson L. Losartan in essential hypertension: effects on blood pressure and left ventricular mass. High Blood Pressure. 1995;4:242–248.
    
28. Himmelmann A, Svensson A, Bergbrant A, Hansson L. Long-term effects of losartan on blood pressure and left ventricular structure in essential hypertension. J Hum Hypertens. 1996;10:729–734.[Medline] [Order article via Infotrieve]
    
29. Agabiti-Rosei E, Ambrosioni E, Dal Palu C, Muiesan ML, Zanchetti A. ACE inhibitor ramipril is more effective than the ß-blocker atenolol in reducing left ventricular mass in hypertension: results of the RACE (ramipril cardioprotective evaluation) study. J Hypertens. 1995;13:1325–1334.[Medline] [Order article via Infotrieve]
    
30. Mancia G, Zanchetti A, Agebiti-Rosei E, Benemio G, De Cesaris R, Fogari R, Pessino A, Porcellati C, Salvetti A, Trimarco B. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation. 1997;95:1464–1470.[Abstract/Free Full Text]
    
31. Kojima M, Shiojima I, Yamazaki T, Komura I, Yunzeng Z, Ying W, Mizuno T, Ueki K, Tobe K, Kadowaki T, Nagai R, Yazaki Y. Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro. Circulation. 1994;89:2204–2211.[Abstract/Free Full Text]
    
32. Brink M, de Gasparo M, Rogg H, Schmid A, Stulz P, Bullock G. Localization of the angiotensin II receptor subtypes in the human atrium. J Mol Cell Cardiol. 1996;28:1789–1799.[Medline] [Order article via Infotrieve]
    
33. Liu Y-H, Yang X-P, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. J Clin Invest. 1997;99:1926–1935.[Medline] [Order article via Infotrieve]
    
34. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI, on behalf of the ELITE Study Investigators. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747–752.[Medline] [Order article via Infotrieve]
    
35. Otterstad JE, Froeland G, St John Sutton M, Holme I. Accuracy and reproducibility of biplane two-dimensional echocardiographic measurements of left ventricular dimensions and function. Eur Heart J. 1997;18:507–513.[Abstract/Free Full Text]
    
36. Gardin JM, Siscovick D, Anton-Culver H, Lynch JC, Smith VE, Klopfenstein HS, Bommer WJ, Fried L, O'Leary D, Manolio TA. Sex, age, and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly: the Cardiovascular Health Study. Circulation. 1995;91:1739–1748.[Abstract/Free Full Text]
    
37. Dahlöf B, Devereux R, deFaire U, Fyhrquist F, Hedner T, Ibsen H, Julius S, Kjeldsen S, Kristianson K, Lederalle-Pedersen O, Lindholm L, Nieminen M, Omvik P, Oparil S, Wedel H, for the LIFE Study Group. Baseline characteristics of the LIFE (Losartan Intervention For Endpoint Reduction) in hypertension study. J Hypertens. 1997;15(suppl 4):S35.
    

This article has been cited by other articles:

				Authors/Task Force Members:, G. Mancia, G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, G. Grassi, A. M. Heagerty, S. E. Kjeldsen, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur. Heart J., June 11, 2007; (2007) ehm236v1. [Full Text] [PDF]

				J. L. Grobe, A. P. Mecca, H. Mao, and M. J. Katovich Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2417 - H2423. [Abstract] [Full Text] [PDF]

				A. Prasad and A. A. Quyyumi Renin-Angiotensin System and Angiotensin Receptor Blockers in the Metabolic Syndrome Circulation, September 14, 2004; 110(11): 1507 - 1512. [Full Text] [PDF]

				M. P. Schneider, A. U. Klingbeil, C. Delles, M. Ludwig, R. E. Kolloch, M. Krekler, K. O. Stumpe, and R. E. Schmieder Effect of Irbesartan Versus Atenolol on Left Ventricular Mass and Voltage: Results of the CardioVascular Irbesartan Project Hypertension, July 1, 2004; 44(1): 61 - 66. [Abstract] [Full Text] [PDF]

				G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]

				K. Yasunari, K. Maeda, T. Watanabe, M. Nakamura, J. Yoshikawa, and A. Asada Comparative effects of valsartan versus amlodipine on left ventricular mass and reactive oxygen species formation by monocytes in hypertensive patients with left ventricular hypertrophy J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2116 - 2123. [Abstract] [Full Text] [PDF]

				B. L. Metcalfe, M. J. Huentelman, L. D. Parilak, D. G. Taylor, M. J. Katovich, H. J. Knot, C. Sumners, and M. K. Raizada Prevention of Cardiac Hypertrophy by Angiotensin II Type-2 Receptor Gene Transfer Hypertension, June 1, 2004; 43(6): 1233 - 1238. [Abstract] [Full Text] [PDF]

				S. Julius Bringing VALUE to LIFE Eur. Heart J. Suppl., April 1, 2003; 5(suppl_C): C5 - C8. [Abstract] [PDF]

				W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]

				L. Sironi, A. M. Calvio, L. Arnaboldi, A. Corsini, A. Parolari, M. de Gasparo, E. Tremoli, and L. Mussoni Effect of Valsartan on Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells Hypertension, March 1, 2001; 37(3): 961 - 966. [Abstract] [Full Text] [PDF]

				M. Burnier Angiotensin II Type 1 Receptor Blockers Circulation, February 13, 2001; 103(6): 904 - 912. [Full Text] [PDF]

				M. Schafer, K. Ponicke, I. Heinroth-Hoffmann, O.-E. Brodde, H. M. Piper, and K.-D. Schluter Beta-adrenoceptor stimulation attenuates the hypertrophic effect of alpha-adrenoceptor stimulation in adult rat ventricular cardiomyocytes J. Am. Coll. Cardiol., January 1, 2001; 37(1): 300 - 307. [Abstract] [Full Text] [PDF]

				R. Rocha, C. T. Stier Jr., I. Kifor, M. R. Ochoa-Maya, H. G. Rennke, G. H. Williams, and G. K. Adler Aldosterone: A Mediator of Myocardial Necrosis and Renal Arteriopathy Endocrinology, October 1, 2000; 141(10): 3871 - 3878. [Abstract] [Full Text] [PDF]

				M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]

				E. Grossman, F. H. Messerli, and J. M. Neutel Angiotensin II Receptor Blockers: Equal or Preferred Substitutes for ACE Inhibitors? Arch Intern Med, July 10, 2000; 160(13): 1905 - 1911. [Full Text] [PDF]

				E. L. Schiffrin, J. B. Park, H. D. Intengan, and R. M. Touyz Correction of Arterial Structure and Endothelial Dysfunction in Human Essential Hypertension by the Angiotensin Receptor Antagonist Losartan Circulation, April 11, 2000; 101(14): 1653 - 1659. [Abstract] [Full Text] [PDF]

				P. Paradis, N. Dali-Youcef, F. W. Paradis, G. Thibault, and M. Nemer Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling PNAS, January 18, 2000; 97(2): 931 - 936. [Abstract] [Full Text] [PDF]

				J. S. Gottdiener, P. A. Thurmann, P. Kenedi, A. Schmidt, S. Harder, and N. Rietbrock Influence of the Angiotensin II Antagonist Valsartan on Left Ventricular Hypertrophy in Patients With Essential Hypertension • Response Circulation, August 10, 1999; 100(6): 685 - 688. [Full Text] [PDF]

				B. Pitt Regression of Left Ventricular Hypertrophy in Patients With Hypertension : Blockade of the Renin-Angiotensin-Aldosterone System Circulation, November 10, 1998; 98(19): 1987 - 1989. [Full Text] [PDF]

				W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]

< This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thürmann, P. A. Articles by Rietbrock, N. Search for Related Content PubMed PubMed Citation Articles by Thürmann, P. A.