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(Circulation. 2000;102:253.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Reverse Remodeling of Cardiac Myocyte Hypertrophy in Hypertension and Failure by Targeting of the Renin-Angiotensin System

Tetsutaro Tamura, MD; Suleman Said, MS; Jennifer Harris, BS; Wenyan Lu, MD; A. Martin Gerdes, PhD

From the South Dakota Health Research Foundation, Cardiovascular Research Institute, Sioux Falls, SD 57105.

Correspondence to A. Martin Gerdes, PhD, South Dakota Health Research Foundation, Cardiovascular Research Institute, 1400 W 22nd St, Sioux Falls, SD 57105-1570. E-mail mgerdes{at}usd.edu

	Abstract

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Background—ACE inhibitors (ACEIs) and angiotensin II type 1 (AT₁) receptor blockers are effective in reducing left ventricular mass in hypertension and heart failure. However, the ability of these drugs to reverse excessive myocyte lengthening and transverse growth in heart failure is unknown.

Methods and Results—L-158,809 (an AT₁ blocker; AT₁), enalapril (an ACEI), and hydralazine (a vasodilator) were administered to spontaneously hypertensive heart failure rats between 6 and 10 months of age (early treatment) and between 18 and 22 months of age (late treatment). After 4 months of treatment, hemodynamics and chamber dimensions were collected before left ventricular myocyte isolation and subsequent analysis of myocyte shape. Each drug reduced systolic blood pressures to normal values. In the early and late studies, the ACEI reduced myocyte volume. Myocyte length was also reduced in the late study. However, the AT₁ was most effective in reversing myocyte dimensions to near-normal values in both studies. Hydralazine was ineffective in reducing cell size but arrested progression of myocyte lengthening in the late study. Changes in myocyte shape reflected alterations in chamber dimensions and wall thickness.

Conclusions—Reversal of myocyte hypertrophy was produced in hypertensive/heart failure rats with an AT₁. The ACEI was effective but to a lesser extent. Results indicate that it is possible to significantly reverse myocyte remodeling pharmacologically even if therapy is initiated near the onset of failure. Further work is needed to determine whether similar results can be obtained in humans.

Key Words: hypertension • drugs • heart failure • remodeling • myocytes

	Introduction

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It is estimated that 4 to 5 million individuals living in the United States have heart failure. Hypertension is one of the major underlying diseases leading to heart failure. For >20 years, regression of hypertrophy has been a major goal of clinical trials and of hypertension research.^{1 2 3} Among other factors, the renin-angiotensin system plays an important role in the regulation of cardiac myocyte growth. ACE inhibitors have been shown to reduce left ventricular (LV) weight significantly.^{1 4 5} For the past decade, efforts have been made to develop new angiotensin II receptor blockers and to investigate their effectiveness on hypertrophy reversal and chamber dilatation.^{6 7 8 9} Some reports have demonstrated a reduction of heart weight or LV weight after treatment with angiotensin II type 1 receptor (AT₁) blockers.^{6 7 8 9} It is important, however, to know the effects of AT₁ blockers at the myocyte level. Our previous study,¹⁰ using lean female spontaneously hypertensive heart failure rats (SHHF; a genetic model predisposed to hypertension and failure), showed that the cross-sectional area (CSA) of myocytes was approximately twice normal by 3 months of age but did not change after this age. Myocyte lengthening, which underlies chamber dilatation, was detected by 12 months of age and continued until failure at 22 to 24 months of age.^{10 11} Although the temporal development of these important cellular changes in humans is not known, it was shown that LV myocyte dimensions in hypertensive patients with compensated hypertrophy and failure are identical to those observed in SHHF rats at similar stages of the disease.¹¹ Thus, the SHHF rat should represent a relevant animal model to test the efficacy of various drugs on hypertension and associated ventricular remodeling. In this study, L-158,809, enalapril, and hydralazine were administered to SHHF rats with early compensated hypertrophy (treatment from 6 to 10 months of age) and also just before rats developed symptoms of failure (18 to 22 months of age). The primary objective was to determine the effects of these drugs on cardiac myocyte remodeling and whether echo data on chamber dimensions and wall thickness reflect underlying myocyte remodeling.

	Methods

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Experimental Animals and Drugs
Lean female 6-month-old SHHF rats were obtained from Genetic Models Inc (Indianapolis, Ind). Body weight and systolic blood pressures (tail-cuff method) were collected from all rats before initiation of drug treatment. The early-treatment study had 6- and 10-month-old untreated groups, plus 6-month-old rats treated for 4 months with hydralazine, enalapril, or an AT₁ blocker. The late-treatment study had a similar design with 18- and 22-month-old untreated groups plus 18-month-old rats treated for 4 months with the same 3 drugs. In both the early and late studies, mean body weights and mean blood pressures for each group were matched initially as closely as possible. L-158,809 (AT₁ blocker) and enalapril were provided as a gift from Merck & Co, Inc (Rahway, NJ), and hydralazine was obtained from Sigma Chemical Co (St Louis, Mo). Each drug was dissolved in drinking water. Concentrations of the drugs were 1 mg · kg^-1 · d^-1 for L-158,809, 15 mg · kg^-1 · d^-1 for enalapril (initial dose of 3 mg · kg^-1 · d^-1 was raised to the higher dose after 1-month treatment in the early study to reduce blood pressure to the same level as in other treatment groups), and 20 mg · kg^-1 · d^-1 for hydralazine. Systolic blood pressure was collected at baseline and after 1, 2, and 3 months of treatment with an RTBP1001 Rat Tail Blood Pressure System (Kent Scientific Corp).

Echocardiography and Hemodynamics
The animals were anesthetized with an intramuscular injection of ketamine HCl (30 mg/kg) and xylazine (5 mg/kg) at the time of terminal experiments. Standard echocardiography techniques¹² were used to obtain M-mode echocardiograms from short-axis views of the left ventricle below the tip of the mitral valve leaflets with a General Electric RT5000 echo machine with a 7-MHz transducer. LV hemodynamics were collected by catheterization during terminal experiments as described previously.¹³

Myocyte Isolation and Morphometry
The hearts were quickly removed, trimmed of excess tissue, blotted, and weighed. The procedure for isolating myocytes by use of retrograde aortic perfusion with collagenase has been described previously.¹⁴ Myocyte volume was measured with a Coulter Channelyzer (model Z2, Coulter Corp). Myocyte length, defined as the longest length parallel to the longitudinal axis of the myocyte, was measured in 50 cells from each sample with a Jandel Video Analysis System (Jandel Scientific). CSA was calculated from myocyte volume/myocyte length.

Data Analysis
Results are presented as mean±SD for animal data and mean±SEM for cellular data. ANOVA was used to compare data in each group. The Bonferroni test was used to examine statistically significant differences observed with the ANOVA.¹⁵

	Results

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There were no significant differences in body weights and blood pressures between each group before the treatments were started (Table 1). Because the initial dosage of enalapril (3 mg · kg^-1 · d^-1) failed to decrease blood pressure significantly, the dosage was increased to 15 mg · kg^-1 · d^-1 for the final 3 months of treatment. This higher dosage was used throughout the late treatment study and quickly lowered pressures to the same extent as hydralazine and the AT₁ blocker. The dose adjustment for enalapril in the early study should not affect remodeling data, because we have found that maximum reversal in cell size is achieved within 1 month after therapy is begun (A.M.G., unpublished data, 1999). In the late-treatment study, blood pressure was also normal in untreated rats because of the onset of congestive heart failure.

View this table: [in this window] [in a new window]   Table 1. Body Weight and Blood Pressure

Table 2, top, shows comparative echocardiographic and systolic wall stress data from the early treatment study. Enalapril and the AT₁ blocker significantly reduced the thickness of both the anterior and posterior walls in diastole and systole. Although hydralazine reduced systolic blood pressure and LV systolic wall stress to the same extent as the other drugs, it failed to reduce wall thickness significantly. Table 2, bottom, shows echo and wall stress data from the late-treatment groups. Hydralazine prevented the progressive chamber dilatation between 18 and 22 months of age. Enalapril significantly reversed LV diastolic diameter to values lower than those in untreated 18-month-old rats. Diastolic wall thickness was less than that observed in 22-month-old untreated rats in failure. The AT₁ blocker, however, significantly reduced most wall thickness and chamber diameter values below those found in 18-month-old untreated rats.

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Data

Figure 1A shows heart weight/body weight ratios of animals from each group. There were no significant differences in body weight at the time of terminal experiments. Compared with untreated SHHF controls, enalapril and the AT₁ blocker decreased heart weight/body weight ratios, whereas hydralazine did not affect heart mass.

View larger version (51K): [in this window] [in a new window]   Figure 1. Early-treatment study. A, Changes in heart weight/body weight ratios (HW/BW). Both enalapril (ENAL) and AT1 blocker (AT1) significantly reduced HW/BW compared with 10-month-old untreated SHHF rats (10M). AT1 blocker significantly decreased HW/BW below that of 6-month-old untreated SHHF rats (6M). B through D, Changes in LV myocyte volume, length, and CSA. AT1 blocker was most effective in reducing LV myocyte volume and CSA. P<0.05 vs 6M (*), 10M (), hydralazine (HYD, ), and ENAL (§).

LV isolated myocyte data from the early-treatment study are shown in Figure 1, B through D. Cell volume was significantly less than in 10-month-old but not 6-month-old untreated SHHF rats after enalapril treatment. The AT₁ blocker, however, reduced cell volume and CSA to values significantly lower than those of 6-month-old untreated SHHF rats. In the hydralazine group, neither cell volume nor CSA was significantly reduced. Cell length values were within the range of values typically found in normal rats.

Changes in heart weight/body weight ratios in the late-treatment study are shown in Figure 2A. L-158,809 reversed heart weight/body weight ratios to values significantly lower than those in 18-month-old untreated rats. Heart weight/body weight ratio with enalapril treatment was less than in 18-month-old untreated rats but did not reach statistical significance. Hydralazine prevented the progressive increase in heart mass between 18 and 22 months of age.

View larger version (57K): [in this window] [in a new window]   Figure 2. Late-treatment study. A, Changes in heart weight/body weight ratios (HW/BW). AT1 blocker (AT1) reduced HW/BW below those observed in 18-month-old untreated SHHF rats (18M). Hydralazine (HYD) arrested progression of cardiac hypertrophy. B through D, Changes in LV myocyte volume, length, and CSA. Enalapril (ENAL) and AT1 blocker reduced cell volume and length significantly below values in 18M. Hydralazine prevented progressive increase in myocyte volume and length observed in untreated SHHF rats between 18 and 22 months of age (22M). Only AT1 blocker reduced myocyte CSA below values at 18M. P<0.05 vs 18M (*), 22M (), and hydralazine ().

Changes in LV myocyte dimensions in the late-treatment study are shown in Figure 2, B through D. The AT₁ blocker reversed myocyte volume, length, and CSA to values lower than those of 18-month-old untreated rats. Enalapril reversed myocyte volume and length to values lower than those of 18-month-old untreated rats. CSA was also reduced but not to the extent found with the AT₁ blocker. Hydralazine was able to prevent the progressive myocyte lengthening and cell volume increase from 18 to 22 months of age but did not reduce myocyte CSA. Regression analyses revealed a significant (P<0.001) correlation between myocyte length versus diastolic chamber diameter and myocyte diameter versus diastolic wall thickness (data not shown). To visually illustrate the extent of reverse remodeling with late therapy, confocal images of -actinin–labeled myocytes from an untreated rat and an AT₁ blocker–treated rat are shown in Figure 3. It should also be noted that myocyte cytoplasm is packed in a similar manner with myofibrils (-actinin label) in treated and untreated rats.

View larger version (118K): [in this window] [in a new window]   Figure 3. LV myocyte remodeling after late treatment with AT1 blocker. Reduction in myocyte diameter and length after late treatment with AT1 blocker is readily apparent. Confocal images of -actinin–labeled myocytes from untreated SHHF rat (A) and SHHF rat treated with AT1 blocker (B).

	Discussion

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The most important finding from this study was that administration of L-158,809, a nonpeptide AT₁ receptor–selective blocker,^{16 17} to hypertensive rats just before the development of symptomatic heart failure produced significant reverse remodeling of myocyte volume, length, and CSA. Myocyte dimensions were reduced below pretreatment values. Thus, true reverse remodeling, rather than simply arrested progression of myocyte hypertrophy, was shown. To the best of our knowledge, these are the first comprehensive data demonstrating that a noninvasive treatment initiated just before the onset of symptoms of heart failure was able to dramatically reverse the maladaptive changes in cardiac myocyte dimensions to near-normal values. To date, the most significant reversal of myocyte shape alterations due to heart failure was reported in patients on LV assist devices awaiting heart transplants.¹⁸ Because recent data suggest that excessive series sarcomere addition can account for most of the chamber dilatation in the progression to failure,¹⁹ this mechanism is of considerable importance. The extent of reverse remodeling shown in the present study was so impressive after AT₁ blockade that values were indistinguishable from those found in normal adult male rats (which typically have larger myocytes than females).²⁰ Enalapril was as effective as the AT₁ blocker in reversing LV myocyte length but was not as effective in reversing CSA. Hydralazine was able to prevent progressive myocyte lengthening and chamber dilatation when administered late. In general, echocardiographically derived changes in chamber diameter and wall thickness accurately reflected changes in myocyte length and myocyte thickness (CSA), respectively. This observation suggests that noninvasive imaging may be helpful in predicting underlying cellular remodeling.

Clinical studies have demonstrated that increased LV mass predicts an adverse outcome in patients with hypertension.^{21 22} In addition, treatment that reduces cardiac mass in these patients has been shown to improve outcome.²³ It has not been clear, however, which drugs or drug combinations are most effective in reducing cardiac mass, improving chamber geometry, and reversing maladaptive myocyte remodeling. Although a new technique allows accurate assessment of myocyte length from cardiac biopsies,²⁴ the inherent limitations of such studies in humans make it difficult to assess the effects of antihypertensive drugs on patients at the cardiac myocyte level.

The results of the early-treatment study demonstrated that the AT₁ blocker produced the greatest reduction in LV myocyte volume and CSA in adult SHHF rats with compensated hypertrophy. These data confirm the findings of Kojima et al,²⁵ who noted a good correlation between a crude measure of myocyte diameter and wall thickness after administering an AT₁ blocker to spontaneously hypertensive rats. Myocyte length and volume changes were not examined in that study. As expected, none of the drugs affected myocyte length in the early-treatment study, which is normal during this phase of the disease process.¹⁰ Cumulative data from the early and late studies suggest that hypertrophy regression may be more complete if treatment is initiated earlier. Although a good normotensive control for SHHF rats has not been clearly identified, it should be noted that the AT₁ blocker reduced LV myocyte dimensions in the early-treatment study to values typically found in normal female rats.²⁰ Such comparisons can be readily made with the techniques used here. In fact, data collected with these methods have shown that LV myocyte dimension in normal rats, cats, guinea pigs, hamsters, and humans are virtually indistinguishable.²⁶

Angiotensin II has been reported to accelerate the hypertrophy of myocytes as well as the development of interstitial fibrosis.²⁷ Miyata and Haneda²⁸ reported that losartan inhibits increases in the protein-to-DNA and RNA-to-DNA ratios, rates of protein synthesis, and activity of protein kinase C in cultured neonatal cardiac myocytes. It is likely that angiotensin II–induced hypertrophic growth is, at least in part, mediated through AT₁ receptors. Results from these studies suggest that blocking the growth-promoting effects of angiotensin II at the AT₁ receptor level may be more effective than reducing its production by inhibition of converting enzyme.

The role of AT₂ receptors in cardiac hypertrophy and hypertension is poorly understood. Recent data suggest that these receptors may have a growth-inhibitory effect on cardiac myocytes.^{29 30} Thus, it is possible that some of the reverse remodeling observed with AT₁ receptor blockade may be due to growth inhibition through the AT₂ receptor. Antigrowth effects mediated through the AT₂ receptor may result from ACE inhibition and subsequent effects on kinin levels.^{30 31} Human and animal studies also suggest that potentiation of bradykinin may mediate part of the beneficial effects of ACE inhibitors in heart disease.^{30 32 33} It is clear from recent publications, however, that much more work is needed to fully understand the contributions of bradykinin in ACE inhibitor and AT₁ blocker therapy.^{34 35}

Although hydralazine, an arteriolar dilator, reduced systolic blood pressure and wall stress to an extent similar to that of the other drugs, it failed to reduce myocyte CSA. The basis for this discrepancy between load and mass reduction is not clear. Unlike drugs targeting the renin-angiotensin system, hydralazine does not affect the increased collagen content in spontaneously hypertensive rats, a strain closely related to the SHHF rats used here.³⁶ Thus, it is possible that mechanical signaling mediated through extracellular matrix–integrin pathways remains in an activated state with hydralazine treatment. An alternative possibility is that hydralazine does not correct the AT₁ signaling defect that may maintain myocyte hypertrophy in this model. Further work will be needed to clarify these issues. It should be noted that hydralazine-treated rats did not develop a reflex tachycardia, so this can be excluded as a possible means of maintaining mechanical drive and myocyte hypertrophy (data not shown). Although AT₁ receptor stimulation is not mandatory for mechanically induced myocyte hypertrophy,^{37 38} the relative contributions of load and angiotensin II–mediated cellular hypertrophy have not been completely resolved in hypertension.

The degree of heart failure in the 22-month-old "failure" group was not as severe as that reported in 24-month-old SHHF rats in our previous study.¹¹ Although LV pressure had declined to normal values and 22-month-old untreated animals had symptoms of heart failure (eg, dyspnea, lethargy, orthopnea), dP/dt_max (not reported here) had not yet declined as in the previous 24-month-old group. It should be pointed out that female SHHF rats were used in this study, and they tend to have better preservation of function than males with heart failure.³⁹ This sex difference is also true in humans with heart failure, in whom ejection fraction is normal in a much greater percentage of women than men.^{40 41} Although systolic function was better preserved in the female SHHF rats used in our studies, more recently we have detected significant diastolic dysfunction in 22-month-old female SHHF by echo-Doppler methods (A.M.G., unpublished data, 1999). Considering the importance of better understanding diastolic dysfunction in patients with heart failure and apparent similarities in SHHF rats, it may prove helpful to characterize pharmacologically related changes in diastolic function more thoroughly in future studies. Although data reported here are promising, further work is needed to determine whether AT₁ blockers can produce similar beneficial myocyte remodeling in humans.

	Acknowledgments

 
This work was supported by grant HL-30696 from the National Institutes of Health. Support was also provided by the South Dakota Health Research Foundation, which is a partnership between the University of South Dakota School of Medicine and Sioux Valley Hospitals and Health System in Sioux Falls, SD. We would like to acknowledge technical support provided by Susan Andersen.

Received November 22, 1999; revision received February 1, 2000; accepted February 7, 2000.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Pfeffer JM, Pfeffer MA, Mirsky I, et al. Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat. Proc Natl Acad Sci U S A. 1982;79:3310–3314.[Abstract/Free Full Text]
   
2. Eichhorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart: a new era in the treatment of heart failure. Circulation. 1996;94:2285–2296.[Abstract/Free Full Text]
   
3. Francis GS. Changing the remodeling process in heart failure: basic mechanisms and laboratory results. Curr Opin Cardiol. 1998;13:156–161.[Medline] [Order article via Infotrieve]
   
4. Bohm M, Castellano M, Agabiti-Rosei E, et al. Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, cardiac hypertrophy, and ß-adrenergic signal transduction. Circulation. 1995;92:3006–3013.[Abstract/Free Full Text]
   
5. Ennis IL, Alvarez BV, Camilion de Hurtado MC, et al. Enalapril induces regression of cardiac hypertrophy and normalization of pH_i regulatory mechanisms. Hypertension. 1998;31:961–967.[Abstract/Free Full Text]
   
6. Nunez E, Hosoya K, Susic D, et al. Enalapril and losartan reduced cardiac mass and improved coronary hemodynamics in SHR. Hypertension. 1997;29:519–524.[Abstract/Free Full Text]
   
7. Kai T, Sugimura K, Shimada S, et al. Inhibitory effects of a subdepressor dose of L-158,809, an angiotensin II type 1 receptor antagonist, on cardiac hypertrophy and nephropathy via the activated human renin-angiotensin system in double transgenic mice with hypertension. Jpn Circ J. 1998;62:599–603.[Medline] [Order article via Infotrieve]
   
8. Kaneko K, Susic D, Nunez E, et al. Losartan reduces cardiac mass and improves coronary flow reserve in the spontaneously hypertensive rat. J Hypertens. 1996;14:645–653.[Medline] [Order article via Infotrieve]
   
9. Brodsky S, Gurbanov K, Abassi Z, et al. Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure. Hypertension. 1998;32:746–752.[Abstract/Free Full Text]
   
10. Onodera T, Tamura T, Said S, et al. Maladaptive remodeling of cardiac myocyte shape begins long before failure in hypertension. Hypertension. 1998;32:753–757.[Abstract/Free Full Text]
    
11. Gerdes AM, Onodera T, Wang X, et al. Myocyte remodeling during the progression to failure in rats with hypertension. Hypertension. 1996;28:609–614.[Abstract/Free Full Text]
    
12. Litwin SE, Katz SE, Weinberg EO, et al. Serial echocardiographic Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy: chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure. Circulation. 1995;91:2642–2654.[Abstract/Free Full Text]
    
13. Zierhut W, Zimmer HG, Gerdes AM. Effects of angiotensin-converting enzyme inhibition on pressure-induced left ventricular hypertrophy in rats. Circ Res. 1991;69:609–617.[Abstract/Free Full Text]
    
14. Gerdes AM, Moore JA, Hines JM, et al. Regional differences in myocyte size in normal rat heart. Anat Rec. 1986;215:420–426.[Medline] [Order article via Infotrieve]
    
15. Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res. 1980;47:1–9.[Abstract/Free Full Text]
    
16. Siegl PK, Chang RS, Mantlo NB, et al. In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist. J Pharmacol Exp Ther. 1992;262:139–144.[Abstract/Free Full Text]
    
17. Chang RS, Siegl PK, Clineschmidt BV, et al. In vitro pharmacology of L-158,809, a new highly potent and selective angiotensin II receptor antagonist. J Pharmacol Exp Ther. 1992;262:133–138.[Abstract/Free Full Text]
    
18. Zafeiridis A, Jeevanandam V, Houser SR, et al. Regression of cellular hypertrophy after left ventricular assist device support. Circulation. 1998;98:656–662.[Abstract/Free Full Text]
    
19. Tamura T, Onodera T, Said S, et al. Correlation of myocyte lengthening to chamber dilation in the spontaneously hypertensive heart failure (SHHF) rat. J Mol Cell Cardiol.. 1998;30:2175–2181.[Medline] [Order article via Infotrieve]
    
20. Bai S, Campbell SE, Moore JA, et al. Influence of age, growth, and sex on cardiac myocyte size and number in rats. Anat Rec. 1990;226:207–212.[Medline] [Order article via Infotrieve]
    
21. Agabiti-Rosei E, Muiesan ML. Left ventricular hypertrophy: how to influence an important risk factor in hypertension. J Hypertens. 1998;16(suppl 1):S53–S58.
    
22. Haider AW, Larson MG, Benjamin EJ, et al. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol. 1998;32:1454–1459.[Abstract/Free Full Text]
    
23. Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic significance of serial changes in left ventricular mass in essential hypertension. Circulation. 1998;97:48–54.[Abstract/Free Full Text]
    
24. Gerdes AM, Onodera T, Tamura T, et al. New method to evaluate myocyte remodeling from formalin-fixed biopsy and autopsy material. J Card Fail. 1998;4:343–348.[Medline] [Order article via Infotrieve]
    
25. Kojima M, Shiojima I, Yamazaki T, et al. 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]
    
26. Gerdes AM, Capasso JM. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J Mol Cell Cardiol. 1995;27:849–856.[Medline] [Order article via Infotrieve]
    
27. Kato H, Suzuki H, Tajima S, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991;9:17–22.[Medline] [Order article via Infotrieve]
    
28. Miyata S, Haneda T. Hypertrophic growth of cultured neonatal rat heart cells mediated by type 1 angiotensin II receptor. Am J Physiol. 1994;266:H2443–H2451.[Abstract/Free Full Text]
    
29. Bartunek J, Weinberg EO, Tajima M, et al. Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts. Circulation. 1999;99:22–25.[Abstract/Free Full Text]
    
30. Liu YH, Yang XP, Sharov VG, et al. 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]
    
31. Siragy HM, Inagami T, Ichiki T, et al. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A. 1999;96:6506–6510.[Abstract/Free Full Text]
    
32. McDonald KM, Mock J, D’Aloia A, et al. Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis. Circulation. 1995;91:2043–2048.[Abstract/Free Full Text]
    
33. Zhu YC, Zhu YZ, Gohlke P, et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II AT1 receptor antagonism on cardiac parameters in left ventricular hypertrophy. Am J Cardiol. 1997;80:110A–117A.[Medline] [Order article via Infotrieve]
    
34. Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting enzyme inhibitors in normotensive and hypertensive subjects. N Engl J Med. 1998;339:1285–1292.[Abstract/Free Full Text]
    
35. Davie AP, Dargie HJ, McMurray JJV. Role of bradykinin in the vasodilator effects of losartan and enalapril in patients with heart failure. Circulation. 1999;100:268–273.[Abstract/Free Full Text]
    
36. Mukherjee D, Sen S. Alteration of cardiac collagen phenotypes in hypertensive hypertrophy: role of blood pressure. J Mol Cell Cardiol. 1993;25:185–196.[Medline] [Order article via Infotrieve]
    
37. Hamawaki M, Coffman TM, Lashus A, et al. Pressure-overload hypertrophy is unabated in mice devoid of AT1A receptors. Am J Physiol. 1998;274:H868–H873.
    
38. Kudoh S, Komuro I, Hiroi Y, et al. Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J Biol Chem. 1998;273:24037–24043.[Abstract/Free Full Text]
    
39. Tamura T, Said S, Gerdes AM. Gender-related differences in myocyte remodeling in progression to heart failure. Hypertension. 1999;33:676–680.[Abstract/Free Full Text]
    
40. Vasan RS, Larson MG, Benjamin EJ, et al. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction. J Am Coll Cardiol. 1999;33:1948–1955.[Abstract/Free Full Text]
    
41. Aronow WS, Ahn C, Kronzon I. Normal left ventricular ejection fraction in older persons with congestive heart failure. Chest. 1998;113:867–869.[Abstract/Free Full Text]
    

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				T. Walther, A. Schubert, V. Falk, C. Binner, C. Walther, N. Doll, A. Fabricius, S. Dhein, J. Gummert, and F. W. Mohr Left Ventricular Reverse Remodeling After Surgical Therapy for Aortic Stenosis: Correlation to Renin-Angiotensin System Gene Expression Circulation, September 24, 2002; 106(12_suppl_1): I-23 - I-26. [Abstract] [Full Text] [PDF]

				M. J. Radin, B. J. Holycross, L. C. Sharkey, L. Shiry, and S. A. McCune Gender modulates activation of renin-angiotensin and endothelin systems in hypertension and heart failure J Appl Physiol, March 1, 2002; 92(3): 935 - 940. [Abstract] [Full Text] [PDF]

				D. Li, H. Chen, and J. L. Mehta Angiotensin II via Activation of Type 1 Receptor Upregulates Expression of Endoglin in Human Coronary Artery Endothelial Cells Hypertension, November 1, 2001; 38(5): 1062 - 1067. [Abstract] [Full Text] [PDF]

				F. C. Barone, R. W. Coatney, S. Chandra, S. K. Sarkar, A. H. Nelson, L. C. Contino, D. P. Brooks, W. G. Campbell Jr., E. H. Ohlstein, and R. N. Willette Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats Cardiovasc Res, June 1, 2001; 50(3): 525 - 537. [Abstract] [Full Text] [PDF]

				M.H. Yacoub A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery Eur. Heart J., April 1, 2001; 22(7): 534 - 540. [PDF]

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