Heart, Lung and Circulation

The Role of Extracellular Matrix in the Experimental Acute Aortic Regurgitation Model in Rats

Published:January 13, 2022DOI:


      Mechanisms involved in cardiac remodelling by aortic regurgitation (AR) and the moment when cardiac dysfunction begins are largely unknown. This study aimed to investigate cardiac morphology and function after 1, 4, 8, and 12 weeks of experimental AR in Wistar rats. Extracellular matrix was also investigated as the potential mechanism that underlies the AR remodelling process.


      Male Wistar rats underwent surgical acute AR (AR group, n=51) or a sham surgery (sham group, n=32). After the procedure, serial transthoracic echocardiograms were performed at 1, 4, 8, and 12 weeks. Morphometry of cardiac tissue and the activities of metalloproteinase 2 (MMP-2) and tissue metalloproteinase inhibitor-1 (TIMP-1) were analysed. Statistical analysis was performed by two-way ANOVA. Significance level was 5%.


      The AR group presented an increase in the sphericity index (week 1); an increase in the left atrium, left ventricular mass index, TIMP-1 and MMP-2 activities, and collagen fraction (week 4); an increase in myocyte area (week 8); and a reduction in fraction shortening (week 12). First, the chamber became more spherical; second, MMP-2 and TIMP-1 were activated and this may have contributed to hypertrophy and atrial enlargement, until systolic dysfunction occurred.


      This study showed a sequence of abnormalities that preceded myocardial dysfunction in an experimental model of AR. First, haemodynamic volume overload led to a more spherical left ventricle chamber. Second, MMP-2 and TIMP-1 transitorily increased and may have contributed to atrial enlargement, eccentric hypertrophy, and systolic dysfunction.


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        • Enache R.
        • Popescu B.A.
        • Piazza R.
        • Muraru D.
        • Cãlin A.
        • Beladan C.C.
        • et al.
        Left ventricular shape and mass impact torsional dynamics in asymptomatic patients with chronic aortic regurgitation and normal left ventricular ejection fraction.
        Int J Cardiovasc Imaging. 2015; 31: 1315-1326
        • Carabello B.A.
        Volume overload.
        Heart Failure Clin. 2012; 8: 33-42
        • Barnes J.
        • DelláItalia L.J.
        The multiple mechanistic faces of a pure volume overload: implications for therapy.
        Am J Med Sci. 2014; 348: 337-346
        • Gaasch W.H.
        • Zile M.R.
        Left ventricular structural remodeling in health a disease: with emphasis on volume, mass, and geometry.
        J Am Coll Cardiol. 2011; 58: 1733-1740
        • Roscani M.G.
        • Polegato B.F.
        • Minamoto S.E.T.
        • Lousada A.P.M.
        • Minicucci M.F.
        • Azevedo P.
        • et al.
        Left ventricular sphericity index predicts systolic dysfunction in rats with experimental aortic regurgitation.
        J Appl Physiol. 2014; 116: 1259-1262
        • Nishimura R.A.
        • Otto C.M.
        • Bonow R.O.
        • Carabello B.A.
        • JP3rd Erwin
        • Guyton R.A.
        • et al.
        2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
        Circulation. 2014; 129: 2440-2492
        • Vollema E.M.
        • Singh G.K.
        • Prihadi E.A.
        • Regeer M.V.
        • Ewe S.H.
        • Ng A.C.T.
        • et al.
        Time course of left ventricular remodelling and mechanics after aortic valve surgery: aortic stenosis vs. aortic regurgitation.
        Eur Heart J Cardiovasc Imaging. 2019; 20: 1105-1111
        • Spinale F.G.
        Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function.
        Physiol Rev. 2007; 87: 1285-1342
        • Tomek J.
        • Bub G.
        Hypertension-induced remodelling: on the interactions of cardiac risk factors.
        J Physiol. 2017; 595: 4027-4036
        • Mazzo F.R.
        • de Carvalho Frimm C.
        • Moretti A.I.
        • Guido M.C.
        • Kroike M.K.
        Acute aortocaval fistula: role of low perfusion pressure and subendocardial remodeling on left ventricular function.
        Int J Exp Pathol. 2013; 94: 178-187
        • Kolpakov M.A.
        • Seggat R.
        • Rafiq K.
        • Xi H.
        • Marqulies K.B.
        • Libonati J.R.
        • et al.
        Pleiotropic effects of neutrophils on myocyte apoptosis and left ventricular remodeling during early volume overload.
        J Mol Cell Cardiol. 2009; 47: 634-645
        • Plante E.
        • Couet J.
        • Gaudreau M.
        • Dumas M.P.
        • Drolet M.C.
        • Arsenault M.
        Left ventricular response to sustained volume overload from chronic aortic valve regurgitation in rats.
        J Card Fail. 2003; 9: 128-140
        • Lang R.M.
        • Bierig M.
        • Devereux R.B.
        Recommendations for Chamber quantification: a report from the American Society of Echocardiography’s Guidelines and standard Committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of European Society of Cardiology.
        J Am Soc Echocardiogr. 2005; 18: 1140-1163
        • Zoghbi W.A.
        • Enriquez-Sarano M.
        • Foster E.
        Recommendations for evaluation of the severity of native valvular regurgitation with two dimensional and Doppler echocardiography.
        J Am Soc Echocardiogr. 2006; 16: 777-802
        • Gazzana M.L.
        • Souza J.J.
        • Okoshi M.P.
        • Okoshi K.
        Prospective echocardiographic evaluation of the right ventricle and pulmonary arterial pressure in hyperthyroid patients.
        Heart Lung Circ. 2019; 28: 1190-1196
        • Lustosa B.B.
        • Polegato B.
        • Minicucci M.
        • Rafacho B.
        • Santos P.P.
        • Fernandes A.A.
        • et al.
        Green tea (Cammellia sinensis) attenuates ventricular remodeling after experimental myocardial infarction.
        Int J Cardiol. 2016; 225: 147-153
        • Pereira B.L.B.
        • Reis P.P.
        • Severino F.E.
        • Felix T.F.
        • Braz M.G.
        • Nogueira F.R.
        • et al.
        Tomato (Lycopersicon esculentum) or lycopene supplementation attenuates ventricular remodeling after myocardial infarction through different mechanistic pathways.
        J Nutr Biochem. 2017; 46: 117-124
        • Tyagi S.C.
        • Matsubara L.
        • Weber K.T.
        Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus.
        Clin Biochem. 1993; 26: 191-198
        • Goncalves A.F.
        • Santos P.P.
        • Rafacho B.P.
        • Batista D.F.
        • Azevedo P.S.
        • Minicucci M.F.
        • et al.
        Vitamin D supplementation intensifies cardiac remodeling after experimental myocardial infarction.
        Int J Cardiol. 2014; 176: 1225-1226
        • Borer J.S.
        • Supino P.G.
        • Herrold E.M.
        • Innasimuthu A.
        • Hochreiter C.
        • Krieger K.
        • et al.
        Survival after aortic valve replacement for aortic regurgitation: prediction from preoperative contractility measurement.
        Cardiology. 2018; 140: 204-212
        • Minicucci M.F.
        • Azevedo P.S.
        • Matsubara B.B.
        • Matsubara L.S.
        • Paiva S.A.R.
        • Zornoff L.A.M.
        Association between sphericity, ventricular function and size of the infarction in rats.
        Arq Bras Cardiol. 2010; 94: 645-650
        • Ambale-Venkatesh B.
        • Yoneyama K.
        • Sharma R.K.
        • Ohyama Y.
        • Wu C.O.
        • Burke G.L.
        • et al.
        Left ventricular shape predicts different types of cardiovascular events in the general population.
        Heart. 2017; 103: 499-507
        • Savinova O.V.
        • Gerdes A.M.
        Myocyte changes in heart failure.
        Heart Fail Clin. 2012; 8: 1-6
        • Lamb H.J.
        • Beyerbacht H.P.
        • de Roos A.
        • van der Laase A.
        • Vliegen H.W.
        • Leujes F.
        • et al.
        Left ventricular remodeling early after aortic valve replacement: differential effects on diastolic function in aortic valve stenosis and aortic regurgitation.
        J Am Coll Cardiol. 2002; 40: 2182-2188
        • Gaasch W.H.
        • Delorey D.E.
        • St John Sutton M.G.
        • Zile M.R.
        Patterns of structural and functional remodeling of the left ventricle in chronic heart failure.
        Am J Cardiol. 2008; 102: 459-462
        • Janicki J.S.
        • Brower G.L.
        • Gardner J.D.
        • Chancey A.L.
        • Stewart Jr., J.A.
        The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling.
        Heart Fail Rev. 2004; 9: 33-42
        • Truter S.L.
        • Catanzaro D.F.
        • Supino P.G.
        • Gupta A.
        • Carter J.
        • Herrold E.M.
        • et al.
        Differential expression of matrix metalloproteinases and tissue inhibitors and extracellular matrix remodeling in aortic regurgitant hearts.
        Cardiology. 2009; 113: 161-168
        • Janssens S.
        • Lijnen H.R.
        What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models?.
        Cardiovasc Res. 2006; 69: 585-594
        • Guido M.C.
        • Koike M.K.
        • Frimm C.C.
        Low coronary perfusion pressure is associated with endocardial fibrosis in a rat model of volume overload cardiac hypertrophy.
        Rev Hosp Clín Fac Med S Paulo. 2004; 59: 228-235