Cardiac atrophy is the most common complication of prolonged application of the left ventricle (LV) assist device (LVAD) in patients with advanced heart failure (HF). Our aim was to evaluate the course of unloading-induced cardiac atrophy in rats with failing hearts, and to examine if increased isovolumic loading obtained by intraventricular implantation of an especially designed spring expander would attenuate this process. Heterotopic abdominal heart transplantation (HTx) was used as a rat model of heart unloading. HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart (HW) to the control heart. Isovolumic loading was increased by intraventricular implantation of a stainless steel three-branch spring expander. The course of cardiac atrophy was evaluated on days 7, 14, 21, and 28 after HTx Seven days unloading by HTx in failing hearts sufficed to substantially decrease the HW (-59 ± 3%), the decrease progressed when measured on days 14, 21, and 28 after HTx Implantation of the spring expander significantly reduced the decreases in whole HW at all the time points (-39 ± 3 compared with -59 ± 3, -52 ± 2 compared with -69 ± 3, -51 ± 2 compared with -71 ± 2, and -44 ± 2 compared with -71 ± 3%, respectively; P<0.05 in each case). We conclude that the enhanced isovolumic heart loading obtained by implantation of the spring expander attenuates the development of unloading-induced cardiac atrophy in the failing rat heart.

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

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

Department of Cardiovascular Surgery Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Pathophysiology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Renal and Body Fluid Physiology Mossakowski Medical Research Centre Polish Academy of Sciences Warsaw Poland

ELLA CS Ltd Hradec Králové Czech Republic

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Braunwald E. (2015) The war against heart failure. Lancet 385, 812–824 10.1016/S0140-6736(14)61889-4 PubMed DOI

Udelson J.E. and Stevenson L.W. (2016) The future of heart failure diagnosis, therapy and management. Circulation 133, 2671–2686 10.1161/CIRCULATIONAHA.116.023518 PubMed DOI

Moayedi Y. and Ross H.J. (2017) Advances in heart failure: a review of biomarkers, emerging pharmacological therapies, durable mechanical support and telemonitoring. Clin. Sci. 131, 553–566 10.1042/CS20160196 PubMed DOI

Ibrahim M., Nader A., Yacoub M.H. and Terracciano C. (2015) Manipulation of sarcoplasmic reticulum Ca2+ release in heart failure through mechanical intervention. J. Physiol. 593, 3253–3259 10.1113/JP270446 PubMed DOI PMC

Chaggar P.S., Williams S.G., Yonan N., Fildes J., Venkateswaran R. and Shaw S.M. (2016) Myocoardial recovery with mechanical circulatory support. Eur. J. Heart Fail. 18, 1220–1227 10.1002/ejhf.575 PubMed DOI

Birks EJ. (2013) Molecular changes after left ventricular assist device support for heart failure. Circ. Res. 113, 777–791 10.1161/CIRCRESAHA.113.301413 PubMed DOI

Soppa G.K.R., Barton P.J.R., Terracciano C.M.N. and Yacoub M.H. (2008) Left ventricle assist device-induced molecular changes in the failing myocardium. Curr. Opin. Cardiol. 23, 206–218 10.1097/HCO.0b013e3282fc7010 PubMed DOI

Ibrahim M., Terracciano C. and Yacoub M.H. (2012) Can bridge to recovery help to reveal the secrets of the failing heart? Curr. Cardiol. Rep. 14, 392–396 10.1007/s11886-012-0282-x PubMed DOI

Xydas S., Rosen R.S., Ng C., Mercando M., Cohen J., DiTullio M. et al. (2006) Mechanical unloading leads to echocardiographic, electrocardiographic, neurohormonal, and histological recovery. J. Heart Lung Transplant. 25, 7–15 10.1016/j.healun.2005.08.001 PubMed DOI

Drakos S.G., Kfoury A.G., Stehlik J., Selzman C.H., Reid B.B., Terrovitis J.V. et al. (2012) Bridge to recovery. Understanding the disconnect between clinical and biological outcomes. Circulation 126, 230–241 10.1161/CIRCULATIONAHA.111.040261 PubMed DOI PMC

Pokorný M., Červenka L., Netuka I., Pirk J., Koňařík M. and Malý J. (2014) Ventricular assist devices in heart failure: how to support the heart but prevent atrophy? Phys. Res. 63, 147–156 PubMed

Drakos S.G. and Mehra M.R. (2016) Clinical myocardial recovery during long-term mechanical support in advanced heart failure: insights into moving the field forward. J. Heart Lung Transplant. 35, 413–420 10.1016/j.healun.2016.01.001 PubMed DOI

Bruggink A.H., van Oosterhout M.F.M., de Joge N., Ivangh B., van Kuik J., Voorbij R.H. et al. (2006) Reverse remodelling of the myocardial extracellular matrix after prolonged left ventricle assist device support follows a biphasic pattern. J. Heart Lung Transplant. 25, 1091–1098 10.1016/j.healun.2006.05.011 PubMed DOI

Brinks H., Tevaearai H., Muhlfeld C., Bertschi D., Gahl B., Carrel T. et al. (2009) Contractile function is preserved in unloaded hearts despite atrophic remodelling. J. Thorac. Cardiovasc. Surg. 137, 742–746 10.1016/j.jtcvs.2008.09.020 PubMed DOI

Heckle M.R., Flatt D.M., Sun Y., Mancarella S., Marion T.N., Gerling I.C. et al. (2016) Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function. Heart Fail. Rev. 21, 191–198 10.1007/s10741-016-9535-x PubMed DOI

Brinks H., Giraud M.N., Segiser A., Ferrié C., Longnus S., Ullrich N.D. et al. (2014) Dynamic patterns of ventricular remodelling and apoptosis in hearts unloaded by heterotopic transplantation. J. Heart Lung Transplant. 33, 203–210 10.1016/j.healun.2013.10.006 PubMed DOI PMC

Geenen D.L., Malhotra A., Buttrick P.M. and Scheuer J. (1994) Ventricular pacing attenuates but does not reverse cardiac atrophy and an isomyosin shift in the rat heart. Am. J. Physiol. 267, H2149–H2154 PubMed

Navaratnarajah M., Siedlecka U., Ibrahim M., van Doorn C., Soppa G., Gandhi A. et al. (2014) Impact of combined clenbuterol and metoprolol therapy on reverse remodelling during mechanical unloading. PLoS ONE 9, e92909 10.1371/journal.pone.0092909 PubMed DOI PMC

Didié M., Biermann D., Buchert R., Hess A., Wittkopper K., Christalla P. et al. (2013) Preservation of left ventricle function and morphology in volume-loaded versus volume-unloaded heterotopic heart transplants. Am. J. Physiol. 305, H533–H541 PubMed

Liu Y., Maureira P., Gauchotte G., Falanga A., Marie V., Olivier A. et al. (2015) Effect of chronic left ventricular unloading on myocardial remodeling: multimodal assessment of two heterotopic heart transplantation techniques. J. Heart Lung Transplant. 34, 594–603 10.1016/j.healun.2014.11.015 PubMed DOI

Schena S., Kurimoto Y., Fukada J., Tack I., Ruiz P., Pang M. et al. (2004) Effects of ventricular unloading on apoptosis and atrophy of cardiac myocytes. J. Surg. Res. 120, 119–126 10.1016/j.jss.2003.10.006 PubMed DOI

Oriyanhan W., Tsuneyoshi H., Nishina T., Matsuoka S., Ikeda T. and Komeda M. (2007) Determination of optimal duration of mechanical unloading for failing hearts to achieve bridge to recovery in a rat heterotopic heart transplantation model. J. Heart Lung Transplant. 26, 16–23 10.1016/j.healun.2006.10.016 PubMed DOI

Klein I., Hong C. and Schreiber S.S. (1991) Isovolumic loading prevents atrophy of the heterotopically transplanted rat heart. Circ. Res. 69, 1421–1425 10.1161/01.RES.69.5.1421 PubMed DOI

Tsuneyoshi H., Oriyanhan W., Kanemitsu H., Shiina R., Nishina T., Ikeda T. et al. (2005) Heterotopic transplantation of the failing rat heart as a model of left ventricular mechanical unloading toward recovery. ASAIO. J. 51, 116–120 10.1097/01.MAT.0000150325.05589.8B PubMed DOI

Takaseya T., Ishimatsu M., Tayama E., Nishi A., Akasu T. and Aoyagi S. (2004) Mechanical unloading improves intracellular Ca2+ regulation in rats with doxorubicin-induced cardiomyopathy. J. Am. Coll. Cardiol. 44, 2239–2246 10.1016/j.jacc.2004.08.057 PubMed DOI

Soppa G.K., Lee J., Stagg M.A., Siedlecka U., Youssef S., Yacoub M.H. et al. (2008) Prolonged mechanical unloading reduces myofilament sensitivity to calcium and sarcoplasmatic reticulum calcium uptake leading to contractile dysfunction. J. Heart Lung Transplant. 27, 882–889 10.1016/j.healun.2008.05.005 PubMed DOI

Muranaka H., Marui A., Tsukashita M., Wang J., Nakano J., Ikeda T. et al. (2010) Prolonged mechanical unloading preserves myocardial contractility and impairs relaxation in rat heart of dilated cardiomyopathy accompanied by myocardial stiffness and apoptosis. J. Thorac. Cardiovasc. Surg. 140, 916–922 10.1016/j.jtcvs.2010.02.006 PubMed DOI

Ito K., Nakayama M., Hasan F., Yan X., Schneider M.D. and Lorell B.H. (2003) Contractile reserve and calcium regulation are depressed in myocytes from chronically unloaded hearts. Circulation 107, 1176–1182 10.1161/01.CIR.0000051463.72137.96 PubMed DOI

Rakusan K., Heron M.I., Kolar F. and Korecky B. (1997) Transplantation-induced atrophy of normal and hypertrophic rat hearts: effects on cardiac myocytes and capillaries. J. Mol. Cell Cardiol. 29, 1045–1054 10.1006/jmcc.1996.0350 PubMed DOI

Fu X., Segiser A., Carrel T.P., Tevaerai Sthael H.T. and Most H. (2016) Rat heterotopic heart transplantation model to investigate unloading-induced myocardial remodelling. Front. Cardiovas. Med. 3, 34 10.3389/fcvm.2016.00034 PubMed DOI PMC

Depre C., Davies P.J. and Taegtmeyer H. (1999) Transcriptional adaptation of the heart to mechanical unloading. Am. J. Cardiol. 83, 58H–63H 10.1016/S0002-9149(99)00260-X PubMed DOI

Razehi P. and Taegtmeyer H. (2006) Hypertrophy and atrophy of the heart. The other side of remodelling. Ann. N.Y. Acad. Sci. 1080, 110–119 10.1196/annals.1380.011 PubMed DOI

Taegtmeyer H., Sen S. and Vela D. (2010) Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann. N.Y. Acad. Sci. 1188, 191–198 10.1111/j.1749-6632.2009.05100.x PubMed DOI PMC

Ono K. and Lidnsey E.S. (1969) Improved technique of heart transplantation in rats. J. Thorac. Cardiovasc. Surg. 57, 225–229 PubMed

Kolář F., MacNaughton C., Papoušek F. and Korecky B. (1993) Systolic mechanical performance of heterotopically transplanted hearts in rats treated with cyclosporine. Cardiovasc. Res. 27, 1244–1247 10.1093/cvr/27.7.1244 PubMed DOI

Garcia R. and Diebold S. (1990) Simple, rapid, and effective method of producing aorto-caval shunts in the rat. Cardiovasc. Res. 24, 430–432 10.1093/cvr/24.5.430 PubMed DOI

Abassi Z., Goltsmna I., Karram T., Winaver J. and Horrman A. (2011) Aortocaval fistula in rat: a unique model of volume-overload congestive heart failure and cardiac hypertrophy. J. Biomed. Biotechnol. 729497 PubMed PMC

Oliver-Dussault C., Ascah A., Marcil M., Matas J., Picard S., Pibarot P. et al. (2010) Early predictors of cardiac decompensation in experimental volume overload. Mol. Cell. Biochem. 338, 271–281 10.1007/s11010-009-0361-5 PubMed DOI

Beneš J., Melenovský V., Škaroupková P., Pospíšilová J., Petrák J., Cervenka L. et al. (2011) Myocardial morphological characteristics and proarrhytmic substrate in the rat model of heart failure due to chronic volume overload. Anat. Rec. 294, 102–111 10.1002/ar.21280 PubMed DOI

Melenovsky V., Skaroupkova P., Benes J., Torresova V., Kopkan L. and Cervenka L. (2012) The course of heart failure development and mortality in rats with volume overload due to aorto-caval fistula. Kidney Blood Press. Res. 35, 167–173 10.1159/000331562 PubMed DOI

Lossef S.V., Lutz R.J., Mudorf J. and Barth K.H. (1994) Comparison of mechanical deformation properties of metallic stents with use of stress-strain analysis. J. Vasc. Interv. Radiol. 5, 341–349 10.1016/S1051-0443(94)71499-8 PubMed DOI

Kolář F., Papoušek F., MacNaughton C., Pelouch V., Milerová M. and Korecký B. (1996) Myocardial fibrosis and right ventricular function of heterotopically transplanted hearts in rats treated with cyclosporine. Mol. Cell. Biochem. 164, 253–260 10.1007/BF00408666 PubMed DOI

Hampl V., Herget J., Bíbová J., Baňasová A., Husková Z., Vaňourková Z. et al. (2015) Intrapulmonary activation of the angiotensin-converting enzyme type 2/angiotensin 1-7/G-protein-coupled Mas receptor axis attenuates pulmonary hypertension in Ren-2 transgenic rats exposed to chronic hypoxia. Physiol. Res. 64, 25–38 PubMed

Pokorný M., Mrázová I., Malý J., Pirk J., Netuka I., Vaňourková Z. et al. (2018) Effects of increased myocardial tissue concentration of myristic, paltmic and palmitoleic acids on the course of cardiac atrophy of the failing heart unloaded by heterotopic transplantation. Physiol. Res. 67, 13–30 PubMed

Jíchová Š, Doleželová Š, Kopkan L., Kompanowska-Jezierska E., Sadowski J. and Červenka L. (2016) Fenofibrate attenuates malignant hypertension by suppression of the renin-angioensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am. J. Med. Sci. 352, 618–630 10.1016/j.amjms.2016.09.008 PubMed DOI

Taegtmeyer H., Lam T. and Davogussto G. (2016) Cardiac metabolism in perspective. Compr. Physiol. 6, 1675–1699 10.1002/cphy.c150056 PubMed DOI

Lee L.C., Kassab G.S. and Guccione J.M. (2016) Mathematical modelling of cardiac growth and remodelling. Wiley Interdiscip. Rev. Syst. Biol. Med. 8, 211–226 10.1002/wsbm.1330 PubMed DOI PMC

Maybaum S., Mancini D., Xydas S., Starling R.C., Aaronson K., Pagani F.D. et al. (2007) Cardiac improvement during mechanical support: a prospective multicentre study of the LVAD working group. Circulation 115, 2497–2505 10.1161/CIRCULATIONAHA.106.633180 PubMed DOI

El-Armouche A., Schwoerer A.P., Neuber C., Emmons J., Biermann D., Christalla T. et al. (2010) Common microRNA signature in cardiac hypertrophic and atrophic remodelling induced by changes in hemodynamic load. PLoS ONE 5, e14263 10.1371/journal.pone.0014263 PubMed DOI PMC

Korecky B. and Rakusan K. (1983) Morphological and physiological aspects of cardiac atrophy. In Myocardial Hypertrophy and Failure. Perspectives in Cardiovascular Research, vol. 7, pp. 293–309, Raven Press, New York

Benke K., Sayour A.A., Mátyás C., Ágg B., Némeht B.T., Oláh A. et al. (2017) Heterotopic abdominal rat heart transplantation as a model to investigate volume dependency of myocardial remodelling. Transplantation 101, 498–505 10.1097/TP.0000000000001585 PubMed DOI

Birks E.J., George R.S., Hedger M., Bahrami T., Wilton P., Bowles C.T. et al. (2011) Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacological therapy: a prospective study. Circulation 123, 381–390 10.1161/CIRCULATIONAHA.109.933960 PubMed DOI

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