(Circulation. 2000;102:1388.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Lisinopril-Mediated Regression of Myocardial Fibrosis in Patients With Hypertensive Heart Disease
From the Division of Cardiology, Philipps University of Marburg, Marburg, Germany.
Correspondence to Prof Dr Christian Brilla, Philipps University of Marburg, Division of Cardiology, Baldingerstr, 35033 Marburg, Germany.
Background—In arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial.
Methods and Results—A total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9±0.6% to 6.3±0.6% (P<0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9±0.3 to 8.3±0.4 µg/mg of LV dry weight (P<0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72±0.04 to 0.91±0.06 (P<0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123±9 to 81±5 ms (P<0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22.1±0.6 to 20.7±0.7 µm (P<0.01 versus lisinopril).
Conclusions—In patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function.
Key Words: hypertension • hypertrophy • fibrosis • diastole
This article has been cited by other articles:
 |
|
 |
|
  G W K Yip, M Wang, T Wang, S Chan, J W H Fung, L Yeung, T Yip, S-T Lau, C-P Lau, M-O Tang, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction Heart, May 1, 2008; 94(5): 573 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Goland, L. S.C. Czer, R. M. Kass, R. J. Siegel, J. Mirocha, M. A. De Robertis, J. Lee, S. Raissi, W. Cheng, G. Fontana, et al. Use of Cardiac Allografts With Mild and Moderate Left Ventricular Hypertrophy Can Be Safely Used in Heart Transplantation to Expand the Donor Pool J. Am. Coll. Cardiol., March 25, 2008; 51(12): 1214 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Burstein and S. Nattel Atrial Fibrosis: Mechanisms and Clinical Relevance in Atrial Fibrillation J. Am. Coll. Cardiol., February 26, 2008; 51(8): 802 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Lester, A. J. Tajik, R. A. Nishimura, J. K. Oh, B. K. Khandheria, and J. B. Seward Unlocking the Mysteries of Diastolic Function Deciphering the Rosetta Stone 10 Years Later. J. Am. Coll. Cardiol., February 19, 2008; 51(7): 679 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Casaclang-Verzosa, B. J. Gersh, and T. S.M. Tsang Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J. Am. Coll. Cardiol., January 1, 2008; 51(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. L. Rocha, E. C. Carmo, F. R. Roque, N. Y. Hashimoto, L. V. Rossoni, C. Frimm, I. Aneas, C. E. Negrao, J. E. Krieger, and E. M. Oliveira Anabolic steroids induce cardiac renin-angiotensin system and impair the beneficial effects of aerobic training in rats Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3575 - H3583. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Martos, J. Baugh, M. Ledwidge, C. O'Loughlin, C. Conlon, A. Patle, S. C. Donnelly, and K. McDonald Diastolic Heart Failure: Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction Circulation, February 20, 2007; 115(7): 888 - 895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, K. M. Kurrelmeyer, G. Torre-Amione, and S. F. Nagueh Systolic and Diastolic Dyssynchrony in Patients With Diastolic Heart Failure and the Effect of Medical Therapy J. Am. Coll. Cardiol., October 31, 2006; (2006) j.jacc.2006.10.023v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Knaapen, M. J. W. Gotte, W. J. Paulus, J. J. M. Zwanenburg, P. A. Dijkmans, R. Boellaard, J. T. Marcus, J. W. R. Twisk, C. A. Visser, A. C. van Rossum, et al. Does Myocardial Fibrosis Hinder Contractile Function and Perfusion in Idiopathic Dilated Cardiomyopathy? PET and MR Imaging Study. Radiology, August 1, 2006; 240(2): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Johar, A. C. Cave, A. Narayanapanicker, D. J. Grieve, and A. M. Shah Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase FASEB J, July 1, 2006; 20(9): 1546 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Saeed, G. Guron, A. Oldfors, B. Lindelow, and H. Herlitz Cardiac fibrosis triggered by the kidney: a case report Nephrol. Dial. Transplant., June 1, 2006; 21(6): 1713 - 1715. [Full Text] [PDF]
|
|
|
|
|
|
J. Varagic, E. D. Frohlich, J. Diez, D. Susic, J. Ahn, A. Gonzalez, and B. Lopez Myocardial fibrosis, impaired coronary hemodynamics, and biventricular dysfunction in salt-loaded SHR Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1503 - H1509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D'Ascia, A. Cittadini, M. G. Monti, G. Riccio, and L. Sacca Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-{alpha} expression, and apoptotic death in failing human myocardium Eur. Heart J., January 2, 2006; 27(2): 201 - 206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cuspidi, M. Ciulla, and A. Zanchetti Hypertensive myocardial fibrosis Nephrol. Dial. Transplant., January 1, 2006; 21(1): 20 - 23. [Full Text] [PDF]
|
|
|
|
|
|
L. Brown Cardiac extracellular matrix: a dynamic entity Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H973 - H974. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Haney, D. Sur, and Z. Xu Diastolic Heart Failure: A Review and Primary Care Perspective J Am Board Fam Med, May 1, 2005; 18(3): 189 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S H Poulsen, N H Andersen, L Heickendorff, and C E Mogensen Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension Heart, May 1, 2005; 91(5): 624 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. K. Munagala, C. Y.T. Hart, J. C. Burnett Jr, D. M. Meyer, and M. M. Redfield Ventricular Structure and Function in Aged Dogs With Renal Hypertension: A Model of Experimental Diastolic Heart Failure Circulation, March 8, 2005; 111(9): 1128 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Borbely, J. van der Velden, Z. Papp, J. G.F. Bronzwaer, I. Edes, G. J.M. Stienen, and W. J. Paulus Cardiomyocyte Stiffness in Diastolic Heart Failure Circulation, February 15, 2005; 111(6): 774 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kahan and L. Bergfeldt Left ventricular hypertrophy in hypertension: its arrhythmogenic potential Heart, February 1, 2005; 91(2): 250 - 256. [Full Text] [PDF]
|
|
|
|
|
|
J E Toblli, G Cao, G DeRosa, and P Forcada Reduced cardiac expression of plasminogen activator inhibitor 1 and transforming growth factor {beta}1 in obese Zucker rats by perindopril Heart, January 1, 2005; 91(1): 80 - 86. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Aurigemma and W. H. Gaasch Diastolic Heart Failure N. Engl. J. Med., September 9, 2004; 351(11): 1097 - 1105. [Full Text] [PDF]
|
|
|
|
|
|
R. Querejeta, B. Lopez, A. Gonzalez, E. Sanchez, M. Larman, J. L. Martinez Ubago, and J. Diez Increased Collagen Type I Synthesis in Patients With Heart Failure of Hypertensive Origin: Relation to Myocardial Fibrosis Circulation, September 7, 2004; 110(10): 1263 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Mottram, B. Haluska, R. Leano, D. Cowley, M. Stowasser, and T. H. Marwick Effect of Aldosterone Antagonism on Myocardial Dysfunction in Hypertensive Patients With Diastolic Heart Failure Circulation, August 3, 2004; 110(5): 558 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Ciulla, R. Paliotti, A. Esposito, J. Diez, B. Lopez, B. Dahlof, M. G. Nicholls, R. D. Smith, L. Gilles, F. Magrini, et al. Different Effects of Antihypertensive Therapies Based on Losartan or Atenolol on Ultrasound and Biochemical Markers of Myocardial Fibrosis: Results of a Randomized Trial Circulation, August 3, 2004; 110(5): 552 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Frohlich Left ventricular hypertrophy: a "factor of risk": Mass is reversible, but is the risk? J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2216 - 2218. [Full Text] [PDF]
|
|
|
|
|
|
B. Lopez, R. Querejeta, A. Gonzalez, E. Sanchez, M. Larman, and J. Diez Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure J. Am. Coll. Cardiol., June 2, 2004; 43(11): 2028 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. H. Cingolani, X.-P. Yang, Y.-H. Liu, M. Villanueva, N.-E. Rhaleb, and O. A. Carretero Reduction of Cardiac Fibrosis Decreases Systolic Performance Without Affecting Diastolic Function in Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1067 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Peng, O. A. Carretero, D. R. Brigstock, N. Oja-Tebbe, and N.-E. Rhaleb Ac-SDKP Reverses Cardiac Fibrosis in Rats With Renovascular Hypertension Hypertension, December 1, 2003; 42(6): 1164 - 1170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-H. Cheng, P.-Y. Cheng, N.-L. Shih, I.-B. Chen, D. L. Wang, and J.-J. Chen Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1845 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fraccarollo, P. Galuppo, S. Hildemann, M. Christ, G. Ertl, and J. Bauersachs Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1666 - 1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lombardi, S. Betocchi, M. A. Losi, C. G. Tocchetti, M. Aversa, M. Miranda, G. D'Alessandro, A. Cacace;, Q. Ciampi, and M. Chiariello Myocardial Collagen Turnover in Hypertrophic Cardiomyopathy Circulation, September 23, 2003; 108(12): 1455 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Schlaich, D. M. Kaye, E. Lambert, M. Sommerville, F. Socratous, and M. D. Esler Relation Between Cardiac Sympathetic Activity and Hypertensive Left Ventricular Hypertrophy Circulation, August 5, 2003; 108(5): 560 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Dahlof End-organ damage: does it really matter how we prevent it? Eur. Heart J. Suppl., August 1, 2003; 5(suppl_F): F33 - F39. [Abstract] [PDF]
|
|
|
|
 |
|
 J. K. F. Hon and M. H. Yacoub Bridge to recovery with the use of left ventricular assist device and clenbuterol Ann. Thorac. Surg., June 1, 2003; 75(90060): S36 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Boffa, Y. Lu, S. Placier, A. Stefanski, J.-C. Dussaule, and C. Chatziantoniou Regression of Renal Vascular and Glomerular Fibrosis: Role of Angiotensin II Receptor Antagonism and Matrix Metalloproteinases J. Am. Soc. Nephrol., May 1, 2003; 14(5): 1132 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Backlund, E. Palojoki, A. Saraste, T. Gronholm, A. Eriksson, P. Lakkisto, O. Vuolteenaho, M. S Nieminen, L.-M. Voipio-Pulkki, M. Laine, et al. Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and ventricular remodeling in rat myocardial infarction Cardiovasc Res, March 1, 2003; 57(3): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Cingolani, O. R. Rebolledo, E. L. Portiansky, N. G. Perez, and M. C. Camilion de Hurtado Regression of Hypertensive Myocardial Fibrosis by Na+/H+ Exchange Inhibition Hypertension, February 1, 2003; 41(2): 373 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. F. Bronzwaer, C. Heymes, C. A. Visser, and W. J. Paulus Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H10 - H16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Baicu, J. D. Stroud, V. A. Livesay, E. Hapke, J. Holder, F. G. Spinale, and M. R. Zile Changes in extracellular collagen matrix alter myocardial systolic performance Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H122 - H132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Grandi, D. Imperiale, R. Santillo, E. Barlocco, A. Bertolini, L. Guasti, and A. Venco Aldosterone Antagonist Improves Diastolic Function in Essential Hypertension Hypertension, November 1, 2002; 40(5): 647 - 652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Tzafriri, M. Bercovier, and H. Parnas Reaction Diffusion Model of the Enzymatic Erosion of Insoluble Fibrillar Matrices Biophys. J., August 1, 2002; 83(2): 776 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Lindsay, P. Maxwell, and F. G. Dunn TIMP-1: A Marker of Left Ventricular Diastolic Dysfunction and Fibrosis in Hypertension Hypertension, August 1, 2002; 40(2): 136 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Stroud, C. F. Baicu, M. A. Barnes, F. G. Spinale, and M. R. Zile Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2324 - H2335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diez, R. Querejeta, B. Lopez, A. Gonzalez, M. Larman, and J. L. Martinez Ubago Losartan-Dependent Regression of Myocardial Fibrosis Is Associated With Reduction of Left Ventricular Chamber Stiffness in Hypertensive Patients Circulation, May 28, 2002; 105(21): 2512 - 2517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, D. Li, J.-C. Tardif, and S. Nattel Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure Cardiovasc Res, May 1, 2002; 54(2): 456 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Gonzalez, B Lopez, and J Diezl Myocardial fibrosis in arterial hypertension Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D18 - D22. [Abstract] [PDF]
|
|
|
|
|
|
M. R. Zile and D. L. Brutsaert New Concepts in Diastolic Dysfunction and Diastolic Heart Failure: Part II: Causal Mechanisms and Treatment Circulation, March 26, 2002; 105(12): 1503 - 1508. [Full Text] [PDF]
|
|
|
|
|
|
D. Li, K. Shinagawa, L. Pang, T. K. Leung, S. Cardin, Z. Wang, and S. Nattel Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing-Induced Congestive Heart Failure Circulation, November 20, 2001; 104(21): 2608 - 2614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lopez, A. Gonzalez, N. Varo, C. Laviades, R. Querejeta, and J. Diez Biochemical Assessment of Myocardial Fibrosis in Hypertensive Heart Disease Hypertension, November 1, 2001; 38(5): 1222 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Zannad, B. Dousset, and F. Alla Treatment of Congestive Heart Failure: Interfering the Aldosterone-Cardiac Extracellular Matrix Relationship Hypertension, November 1, 2001; 38(5): 1227 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.G.F. Cleland, K. Thygesen, B.F. Uretsky, P. Armstrong, J.D. Horowitz, B. Massie, M. Packer, P.A. Poole-Wilson, L. Ryden, and on behalf of the ATLAS investigators Cardiovascular critical event pathways for the progression of heart failure; a report from the ATLAS study Eur. Heart J., September 1, 2001; 22(17): 1601 - 1612. [Abstract] [PDF]
|
|
|
|
|
|
K. T. Weber Cardioreparation in Hypertensive Heart Disease Hypertension, September 1, 2001; 38(3): 588 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lopez, R. Querejeta, N. Varo, A. Gonzalez, M. Larman, J. L. Martinez Ubago, and J. Diez Usefulness of Serum Carboxy-Terminal Propeptide of Procollagen Type I in Assessment of the Cardioreparative Ability of Antihypertensive Treatment in Hypertensive Patients Circulation, July 17, 2001; 104(3): 286 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [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]
|
|
|
|
|
|
D.-S. Lim, S. Lutucuta, P. Bachireddy, K. Youker, A. Evans, M. Entman, R. Roberts, and A. J. Marian Angiotensin II Blockade Reverses Myocardial Fibrosis in a Transgenic Mouse Model of Human Hypertrophic Cardiomyopathy Circulation, February 13, 2001; 103(6): 789 - 791. [Abstract] [Full Text] [PDF]
|
|
|
|
|