The aim of the present study was to evaluate the role of the left ventricle (LV) remodeling in the process of the transition from the compensation to the decompensation phase of cardiorenal syndrome. Ren-2 transgenic rats (TGR) with aorto-caval fistula (ACF) were used as the model of cardiorenal syndrome. Two weeks after ACF creation or sham operation, heart morphological parameters, cardiac structure and function were assessed by echocardiography and invasive pressure-volume analysis. This time point was chosen because two weeks after ACF the TGR still exhibit 100% survival rate and are in the transition phase from the compensation to the decompensation of cardiorenal syndrome. Our results at this stage show: (i) ACF TGR have already fully developed eccentric LV hypertrophy as compared with sham-operated TGR which exhibited signs of LV concentric hypertrophy; (ii) the increase in whole heart weight in ACF TGR was dominantly mediated by right ventricle (RV) hypertrophy, whereas the increase in the LV mass was minimal; (iii) ACF TGR displayed, besides bilateral ventricular dilatation, significant impairment of LV systolic functions whereas RV systolic functions were not impaired as compared with sham-operated TGR. Based on our present results, we propose that the inability of the LV to develop an appropriate hypertrophic response leads to maladaptive ventricular remodeling, which is likely a crucial factor in the process of the transition from the compensation to the decompensation phase of cardiorenal syndrome.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Center of Experimental Medicine Institute for Heart Research Slovak Academy of Sciences Bratislava Slovakia

Department of Cardiology České Budějovice Hospital České Budějovice Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiology Motol University Hospital and 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University Prague Czech Republic

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Boulpaep EL. Integrative control of the cardiovascular system. In: Walter FB and Emile LB Medical Physiology: A Cellular and Molecular Approach, third edition. Saunders Elsevier; 2016, pp. 593–609.

Giebisch G, Windhager E. Integration of salt and water balance. In: Walter FB and Emile LB: Medical Physiology: A Cellular and Molecular Approach, third edition. Saunders Elsevier; 2016, pp. 866–80.

Pappano AJ. Integrated control of the cardiovascular system. In: Bern and Levy: Physiology, edited by Koeppen BM, Stanton BA, Hall JM, Swiatecka-Urban A, Eighth edition. Elsevier; 2023, pp. 393–413.

Bright R. Cases and observations illustrative of renal disease accompanied by the secretion of albuminous urine. Med Chir Rev. 1836;25:23–35.

Barger AC, Muldowney FP, Liebowitz MR. Role of the kidney in the pathogenesis of congestive heart failure. Circulation. 1959;20:273–85. PubMed DOI

Authors/Task Force Members, McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2024;26:5–17. DOI

Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023;118:3272–87. PubMed DOI

Khan MS, Shahid I, Bennis A, Rakisheva A, Metra M, Butler J. Global epidemiology of heart failure. Nat Rev Cardiol. 2024;21:717–34. PubMed DOI

Patel KP, Katsurada K, Zheng H. Cardiorenal Syndrome: The Role of Neural Connections Between the Heart and the Kidneys. Circ Res. 2022;130:1601–17. PubMed DOI PMC

McCullough PA, Amin A, Pantalone KM, Ronco C. Cardiorenal Nexus: A Review With Focus on Combined Chronic Heart and Kidney Failure, and Insights From Recent Clinical Trials. J Am Heart Assoc. 2022;11:e024139. PubMed DOI PMC

Mullens W, Martens P, Testani JM, Tang WHW, Skouri H, Verbrugge FH, et al. Renal effects of guideline-directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2022;24:603–19. PubMed DOI

Young JB, Eknoyan G. Cardiorenal Syndrome: An Evolutionary Appraisal. Circ Heart Fail. 2024;17:e011510. PubMed DOI

Ronco C, House AA, Haapio M. Cardiorenal and renocardiac syndromes: the need for a comprehensive classification and consensus. Nat Clin Pr Nephrol. 2008;4:310–1. DOI

Rangawwami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, et al. American Heart Asssociation Council on the Kidney in Cardiovascular Disease and Council on Clinical Cardiology. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies. A scientific statement from the American Heart Association. Circulation. 2019;139:e840–e878.

Mullens W, Verbrugge FH, Nijst P, Tang WHW. Renal sodium avidity in heart failure: from pathophysiology to treatment strategies. Eur Heart J. 2017;38:1872–82. PubMed DOI

Ciccarelli M, Dawson D, Falcao-Pires I, Giacca M, Hamdani N, Heymans S, et al. Reciprocal organ interactions during heart failure: a position paper from the ESC Working Group on Myocardial Function. Cardiovasc Res. 2021;117:2416–33. PubMed DOI PMC

Pontremoli R, Borghi C, Perrone Filardi P. Renal protection in chronic heart failure: focus on sacubitril/valsartan. Eur Heart J Cardiovasc Pharmacother. 2021;7:445–52. PubMed DOI PMC

Van den Eynde J, Verbrugge FH. Renal Sodium Avidity in Heart Failure. Cardiorenal Med. 2024;14:270–80. PubMed

Zoccali C, Mallamaci F, Halimi JM, Rossignol P, Sarafidis P, De Caterina R, et al. Chronic cardiovascular-kidney disorder: a new conceptual Framework. Nat Rev Nephrol. 2024;20:201–2. PubMed DOI

Hatamizadeh P. From cardiorenal syndrome to nephrocardiology: The journey of exploring the interconnection between nephrology and cardiovascular medicine. Trends Cardiovasc Med. 2024;34:541–6. PubMed DOI

Damman K, Testani J. Cardiorenal interactions in heart failure: insights from recent therapeutic advances. Cardiovasc Res. 2024;120:1372–84. PubMed DOI

Zoccali C, Zannad F. Refocusing cardio-renal problems: the cardiovascular-kidney-metabolic syndrome and the chronic cardiovascular-kidney disorder. Nephrol Dial Transpl. 2024;39:1378–80. DOI

Kanbay M, Guldan M, Ozbek L, Copur S, Covic AS, Covic A. Exploring the nexus: The place of kidney diseases within the cardiovascular-kidney-metabolic syndrome spectrum. Eur J Intern Med. 2024;127:1–14. PubMed DOI

Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, et al. A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation. 2023;148:1636–64. PubMed DOI

Trivedi MV, Jadhav HR, Gaikwad AB. Novel therapeutic targets for cardiorenal syndrome. Drug Discov Today. 2025;30:104285. PubMed DOI

Blazquez-Bermejo Z, Quiroga B, Casado J, de la Espriella R, Trullàs JC, Romero-González G, et al. Practical Approaches to the Management of Cardiorenal Disease beyond Congestion. Cardiorenal Med. 2024;14:235–50. PubMed

Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022;387:1185–95. PubMed DOI

Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature. 1990;344:541–4. PubMed DOI

Kopkan L, Kramer HJ, Huskova Z, Vaňourková Z, Škaroupková P, Thumová M, et al. The role of intrarenal angiotensin II in the development of hypertension in Ren-2 transgenic rats. J Hypertens. 2005;23:1531–9. PubMed DOI

Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248–54. PubMed DOI

Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol. 2017;14:30–38. PubMed DOI

Mann DL, Felker GM. Mechanisms and Models in Heart Failure: A Translational Approach. Circ Res. 2021;128:1435–50. PubMed DOI PMC

Červenka L, Melenovský V, Husková Z, Škaroupková P, Nishiyama A, Sadowski J. Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Clin Exp Pharm Physiol. 2015;42:795–807. DOI

Vacková Š, Kikerlová S, Melenovský V, Kolář F, Imig JD, Kompanovska-Jezierska E, et al. Altered renal vascular responsiveness in rats with angiotensin II-dependent hypertension and congestive heart failure. Kidney Blood Press Res. 2019;44:792–809. PubMed DOI

Honetschlagerová Z, Škaroupková P, Kikerlová S, Vaňourková Z, Husková Z, Melenovský V, et al. Renal sympathetic denervation attenuates congestive heart failure in angiotensin II-dependent hypertension: studies with Ren-2 transgenic hypertensive rats with aorto-caval fistula. Kidney Blood Press Res. 2021;46:95–113. PubMed DOI

Honetschlägerová Z, Sadowski J, Kompanowska-Jezierska E, Táborský M, Červenka L. Impaired renal autoregulation and pressure-natriuresis: any role in the development of heart failure in normotensive and angiotensin II-dependent hypertensive rats?. Hypertens Res. 2023;46:2340–55. PubMed DOI PMC

Honetschlägerová Z, Husková Z, Kikerlová S, Sadowski J, Kompanowska-Jezierska E, Táborský M, et al. Renal sympathetic denervation improves pressure-natriuresis relationship in cardiorenal syndrome: insight from studies with Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula. Hypertens Res. 2024;47:998–1016. PubMed DOI PMC

Miklovič M, Gawryś O, Honetschlägerová Z, Kala P, Husková Z, Kikerlová S, et al. Renal denervation improves cardiac function independently of afterload and restores myocardial norepinephrine levels in a rodent heart failure model. Hypertens Res. 2024;47:2718–30. PubMed DOI PMC

Russell WMS, Burch RL The Principles of Humane Experimental Technique. (Methuen, London, 1959).

Lauwereyns J, Bajramovic J, Bert B, Camenzind S, De Kock J, Elezović A, et al. Toward a common interpretation of the 3Rs principles in animal research. Lab Anim. 2024;53:347–50. DOI

Havlenova T, Skaroupkova P, Miklovic M, Behounek M, Chmel M, Jarkovska D, et al. Right versus left ventricular remodeling in heart failure due to chronic volume overload. Sci Rep. 2021;11:17136. PubMed DOI PMC

Tykvartova T, Miklovic M, Kotrc M, Skaroupkova P, Kazdova L, Trnovska J, et al. The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload. Pharmacol Res Perspect. 2024;12:e1172. PubMed DOI PMC

Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DC. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharm Pharmacother. 2010;2:94–99. DOI

Kala P, Gawrys O, Miklovič M, Vaňourková Z, Škaroupková P, Jíchová Š, et al. Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension. J Hypertens. 2023;41:99–114. PubMed DOI

Gawrys O, Jíchová Š, Miklovič M, Husková Z, Kikerlová S, Sadowski J, et al. Characterization of a new model of chemotherapy-induced heart failure with reduced ejection fraction and nephrotic syndrome in Ren-2 transgenic rats. Hypertens Res. 2024;47:3126–46. PubMed DOI PMC

Pacher P, Nagayama T, Mukhopadhyay P, Bátkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc. 2008;3:1422–34. PubMed DOI PMC

Miklovic M, Kala P, Melenovsky V Simultaneous biventricular pressure-volume analysis in rats. J Physiol Pharmacol. 2023;74: https://doi.org/10.26402/jpp.2023.2.02 .

Honetschlagerová Z, Škaroupková P, Kikerlová S, Husková Z, Maxová H, Melenovský V, et al. Effects of renal sympathetic denervation on the course of congestive heart failure combined with chronic kidney disease: insight from studies with fawn-hooded hypertensive rats with volume overload induced using aorto-caval fistula. Clin Exp Hypertens. 2021;43:522–35. PubMed DOI

Kratky V, Kopkan L, Kikerlova S, Huskova Z, Taborsky M, Sadowski J, et al. The role of renal vascular reactivity in the development of renal dysfunction in compensated and decompensated congestive heart failure. Kidney Blood Press Res. 2018;43:1730–41. PubMed DOI

Melenovsky V, Skaroupkova P, Benes J, Torresova V, Kopkan L, Cervenka L. The course of heart failure development and mortality in rats with volume overload due to aorto-caval fistula. Kidney Blood Press Res. 2012;35:167–73. PubMed DOI

Wearing OH, Chesler NC, Colebank MJ, Hacker TA, Lorenz JN, Simpson JA, et al. Guidelines for assessing ventricular pressure-volume relationships in rodents. Am J Physiol Heart Circ Physiol. 2025;328:H120–H140. PubMed DOI

Weiss JL, Frederiksen JW, Weisfeldt ML. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest. 1976;58:751–60. PubMed DOI PMC

Gawrys O, Husková Z, Škaroupková P, Honetschlägerová Z, Vaňourková Z, Kikerlová S, et al. The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula. Naunyn Schmiedebergs Arch Pharm. 2023;396:3757–73. DOI

Obayashi M, Yano M, Kohno M, Kobayashi S, Tanigawa T, Hironaka K, et al. Dose-dependent effect of ANG II-receptor antagonist on myocyte remodeling in rat cardiac hypertrophy. Am J Physiol. 1997;273:H1824–H1831. PubMed

Pokorný M, Mrázová I, Šochman J, Melenovský V, Malý J, Pirk J, et al. Isovolumic loading of the failing heart by intraventricular placement of a spring expander attenuates cardiac atrophy after heterotopic heart transplantation. Biosci Rep. 2018;38:BSR20180371. PubMed DOI PMC

Whittaker P, Kloner RA, Boughner DR, Pickering JG. Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol. 1994;89:397–410. PubMed DOI

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8. PubMed DOI

Sporková A, Čertíková Chábová V, Doleželová Š, Jíchová Š, Kopkan L, Vaňourková Z, et al. Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20-Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney. Am J Med Sci. 2017;353:568–79. PubMed DOI

Kala P, Bartušková H, Piťha J, Vaňourková Z, Kikerlová S, Jíchová Š, et al. Deleterious Effects of Hyperactivity of the Renin-Angiotensin System and Hypertension on the Course of Chemotherapy-Induced Heart Failure after Doxorubicin Administration: A Study in Ren-2 Transgenic Rat. Int J Mol Sci. 2020;21:9337. PubMed DOI PMC

Jíchová Š, Gawryś O, Kompanowska-Jezierska E, Sadowski J, Melenovský V, Hošková L, et al. Kidney Response to Chemotherapy-Induced Heart Failure: mRNA Analysis in Normotensive and Ren-2 Transgenic Hypertensive Rats. Int J Mol Sci. 2021;22:8475. PubMed DOI PMC

Bas A, Forsberg G, Hammarström S, Hammarström ML. Utility of the housekeeping genes 18S rRNA, beta-actin and glyceraldehyde-3-phosphate-dehydrogenase for normalization in real-time quantitative reverse transcriptase-polymerase chain reaction analysis of gene expression in human T lymphocytes. Scand J Immunol. 2004;59:566–73. PubMed DOI

Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55:611–22. PubMed DOI

Liu HM, Yang D, Liu ZF, Hu SZ, Yan SH, He XW. Density distribution of gene expression profiles and evaluation of using maximal information coefficient to identify differentially expressed genes. PLoS ONE. 2019;14:e0219551. PubMed DOI PMC

Kala P, Sedláková L, Škaroupková P, Kopkan L, Vaňourková Z, Táborský M, et al. Effect of angiotensin-converting enzyme blockade, alone or combined with blockade of soluble epoxide hydrolase, on the course of congestive heart failure and occurrence of renal dysfunction in Ren-2 transgenic hypertensive rats with aorto-caval fistula. Physiol Res. 2018;67:401–15. PubMed

Legault F, Rouleau JL, Juneau C, Rose C, Rakusan K. Functional and morphological characteristics of compensated and decompensated cardiac hypertrophy in dogs with chronic infrarenal aorto-caval fistulas. Circ Res. 1990;66:846–59. PubMed DOI

Gerdes AM, Clark LC, Capasso JM. Regression of cardiac hypertrophy after closing an aortocaval fistula in rats. Am J Physiol. 1995;268:H2345–H2351. PubMed

Brower GL, Henegar JR, Janicki JS. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload. Am J Physiol. 1996;271:H2071–H2078. PubMed

Brower GL, Janicki JS. Contribution of ventricular remodeling to pathogenesis of heart failure in rats. Am J Physiol. 2001;280:H674–H683.

Wang X, Ren B, Liu S, Sentex E, Tappia PS, Dhalla NS. Characterization of cardiac hypertrophy and heart failure due to volume overload in the rat. J Appl Physiol. 2003;94:752–63. PubMed DOI

Oliver-Dussault C, Ascah A, Marcil M, Matas J, Picard S, Pibarot B, et al. Early predictors of cardiac decompensation in experimental volume overload. Mol Cell Biochem. 2010;338:271–81. PubMed DOI

Hutchinson KR, Guggilam A, Cismowski MJ, Galantowics ML, West TA, Stewart JA, et al. Temporal pattern of left ventricle structural and functional remodeling following reversal of volume overload heart failure. J Appl Physiol. 2011;111:1778–88. PubMed DOI PMC

Linzbach AJ. Heart failure from the point of view of quantitative anatomy. Am J Cardiol. 1960;5:370–82. PubMed DOI

Sugishita Y, Iida K, Ohtsuka S, Yamaguchi I. Ventricular wall stress revisited. A keystone of cardiology. Jpn Heart J. 1994;35:577–87. PubMed DOI

Gerdes AM, Capasso JM. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J Mol Cell Cardiol. 1995;27:849–56. PubMed DOI

Gerdes AM. Cardiac myocyte remodeling in hypertrophy and progression to failure. J Card Fail. 2002;8:S264–S268. PubMed DOI

Taegtmeyer H, Sen S, Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci. 2010;1188:191–8. PubMed DOI PMC

van der Pol A, Hoes MF, de Boer RA, van der Meer P. Cardiac foetal reprogramming: a tool to exploit novel treatment targets for the failing heart. J Intern Med. 2020;288:491–506. PubMed DOI PMC

Lindsey ML, LeBlanc AJ, Ripplinger CM, Kassiri Z, Kirk JA, Kleinbongard P, et al. Progress on incorporating sex as a biological variable in cardiovascular research. Am J Physiol. 2025;329:H309–H310.

Lee MA, Böhm M, Paul M, Bader M, Ganten U, Ganten D. Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27. Am J Physiol. 1996;270:E919–E929. PubMed

Rauchová H, Hojná S, Kadlecová M, Vaněčková I, Chao YM, Chan J, et al. Sex differences in blood pressure, free radicals and plasma cholesterol fractions in Ren-2 transgenic rats of various ages. Physiol Res. 2023;72:167–75. PubMed DOI PMC

Kala P, Červenka L, Škaroupková P, Táborský M, Kompanowska-Jezierska E, Sadowski J. Sex-linked differences in the mortality in Ren-2 transgenic hypertensive rats with aorto-caval fistula: effects of treatment with angiotensin converting enzyme alone and combined with inhibitor of soluble epoxide hydrolase. Physiol Res. 2019;68:589–601. PubMed DOI

Červenka L, Škaroupková P, Kompanowska-Jezierska E, Sadowski J. Sex-linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula. Clin Exp Pharm Physiol. 2016;43:883–95. DOI