In 2023, six decades have elapsed since the first experimental work on the heart muscle was published, in which a member of the Institute of Physiology of the Czech Academy of Sciences participated as an author; Professor Otakar Poupa was the founder and protagonist of this research domain. Sixty years - more than half of the century - is certainly significant enough anniversary that is worth looking back and reflecting on what was achieved during sometimes very complicated periods of life. It represents the history of an entire generation of experimental cardiologists; it is possible to learn from its successes and mistakes. The objective of this review is to succinctly illuminate the scientific trajectory of an experimental cardiological department over a 60-year span, from its inaugural publication to the present. The old truth - historia magistra vitae - is still valid. Keywords: Heart, Adaptation, Development, Hypoxia, Protection.

Laboratory of Developmental Cardiology Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

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Kolar F, Ostadal B. Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia. Physiol Res. 2004;53:S3–S13. doi: 10.33549/physiolres.930000.53.S3. PubMed DOI

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Kolar F, MacNaughton C, Papousek F, Korecky B, Rakusan K. Changes in calcium handling in atrophic heterotopically isotransplanted rat hearts. Basic Res Cardiol. 1995;90:475–481. doi: 10.1007/BF00788540. PubMed DOI

Kolar F, Papousek F, MacNaughton C, Pelouch V, Milerova M, Korecky B. Myocardial fibrosis and right ventricular function of heterotopically transplanted hearts in rats treated with cyclosporin. Mol Cell Biochem. 1996;163/164:253–260. doi: 10.1007/BF00408666. PubMed DOI

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Deindl E, Kolar F, Neubauer E, Vogel S, Schaper W, Ostadal B. Effect of intermittent high altitude hypoxia on gene expression in rat heart and lung. Physiol Res. 2003;52:147–157. doi: 10.33549/physiolres.930295. PubMed DOI

Kolar F, Seppet EK, Vetter R, Prochazka J, Grünermel J, Zilmer K, Ostadal B. Thyroid control of contractile function and calcium handling in neonatal rat heart. Pflügers Arch. 1992;421:26–31. doi: 10.1007/BF00374729. PubMed DOI

Vetter R, Studer R, Reinecke H, Kolar F, Ostadalova I, Drexler H. Reciprocal changes in the postnatal expression of the sarcolemmal Na+-Ca2+-exchanger and SERCA2 in rat heart. J Mol Cell Cardiol. 1995;27:1689–1701. doi: 10.1016/S0022-2828(95)90788-2. PubMed DOI

Cernohorsky J, Kolar F, Pelouch V, Korecky B, Vetter R. Thyroid control of sarcolemmal Na+-Ca2+ exchanger and SR Ca2+-ATPase in developing rat heart. Am J Physiol Heart Circ Physiol. 1998;275:H264–H273. doi: 10.1152/ajpheart.1998.275.1.H264. PubMed DOI

Wibo M, Kolar F, Zheng L, Godfraind T. Influence of thyroid status on postnatal maturation of calcium channels, beta-adrenoceptors and cation transport ATPases in rat ventricular tissue. J Mol Cell Cardiol. 1995;27:1731–1743. doi: 10.1016/S0022-2828(95)90887-0. PubMed DOI

Zheng L, Wibo M, Kolar F, Godfraind T. Calcium channels and cation transport ATPases in cardiac hypertrophy induced by aortic constriction in newborn rats. Mol Cell Biochem. 1996;163/164:23–29. doi: 10.1007/BF00408637. PubMed DOI

Wibo M, Feron O, Zheng L, Maleki M, Kolar F, Godfraind T. Thyroid status and postnatal changes in subsarcolemmal distribution and isoform expression of rat cardiac dihydropyridine receptors. Cardiovasc Res. 1998;37:151–159. doi: 10.1016/S0008-6363(97)00228-9. PubMed DOI

Ostadalova I, Ostadal B, Kolar F, Parratt JR, Wilson S. Tolerance to ischaemia and ischaemic preconditioning in neonatal rat heart. J Mol Cell Cardiol. 1998;30:857–865. doi: 10.1006/jmcc.1998.0653. PubMed DOI

Oliviero P, Chassagne C, Kolar F, Adamy C, Marotte F, Samuel J-L, Rappaport L, Ostadal B. Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life. J Mol Cell Cardiol. 2000;32:1631–1645. doi: 10.1006/jmcc.2000.1198. PubMed DOI

Ratajczak P, Oliviero P, Marotte F, Kolar F, Ostadal B, Samuel J-L. Expression and localization of caveolins during postnatal development in rat heart: implication of thyroid hormone. J Appl Physiol. 2005;99:244–251. doi: 10.1152/japplphysiol.01292.2004. PubMed DOI

Ravingerova T, Neckar J, Kolar F, Stetka R, Volkovova K, Ziegelhöffer A, Styk J. Ventricular arrhythmias following coronary artery occlusion in rats: is the diabetic heart less or more sensitive to ischaemia? Basic Res Cardiol. 2001;96:160–168. doi: 10.1007/s003950170066. PubMed DOI

Ravingerova T, Neckar J, Kolar F. Ischemic tolerance of rat hearts in acute and chronic phases of experimental diabetes. Mol Cell Biochem. 2003;249:167–174. doi: 10.1023/A:1024751109196. PubMed DOI

Hrbasova M, Novotny J, Hejnova L, Kolar F, Neckar J, Svoboda P. Altered myocardial Gs protein and adenylyl cyclase signaling in rats exposed to chronic hypoxia and normoxic recovery. J Appl Physiol. 2003;94:2423–2432. doi: 10.1152/japplphysiol.00958.2002. PubMed DOI

Neckar J, Borchert GH, Hlouskova P, Micova P, Novakova O, Novak F, Hroch M, Papousek F, Ostadal B, Kolar F. Brief daily episode of normoxia inhibits cardioprotection conferred by chronic continuous hypoxia. Role of oxidative stress and BKCa channels. Curr Pharm Des. 2013;19:6880–6889. doi: 10.2174/138161281939131127115154. PubMed DOI

Waskova-Arnostova P, Kasparova D, Elsnicova B, Novotny J, Neckar J, Kolar F, Zurmanova J. Chronic hypoxia enhances expression and activity of mitochondrial creatine kinase and hexokinase in the rat ventricular myocardium. Cell Physiol Biochem. 2014;33:310–320. doi: 10.1159/000356671. PubMed DOI

Chytilova A, Borchert GH, Mandikova-Alanova P, Hlavackova M, Kopkan L, Hye Khan A, Imig JD, Kolar F, Neckar J. Tumour necrosis factor α contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia. Acta Physiol. 2015;214:97–108. doi: 10.1111/apha.12489. PubMed DOI

Waskova-Arnostova P, Elsnicova B, Kasparova D, Hornikova D, Kolar F, Novotny J, Zurmanova J. Cardioprotective adaptation of rats to intermittent hypobaric hypoxia is accompanied by the increased association of hexokinase with mitochondria. J Appl Physiol. 2015;119:1487–1493. doi: 10.1152/japplphysiol.01035.2014. PubMed DOI

Alanova P, Chytilova A, Neckar J, Hrdlicka J, Micova P, Holzerova K, Hlavackova M, Machackova K, Papousek F, Vasinova J, Benak D, Novaková O, Kolar F. Myocardial ischemic tolerance in rats subjected to endurance exercise training during adaptation to chronic hypoxia. J Appl Physiol. 2017;122:1452–1461. doi: 10.1152/japplphysiol.00671.2016. PubMed DOI

Kohutova J, Elsnicova B, Holzerova K, Neckar J, Sebesta O, Jezkova J, Vecka M, Vebr P, Hornikova D, Szeiffova-Bacova B, Egan Benova T, Hlavackova M, Tribulova T, Kolar F, Novakova O, Zurmanova JM. Anti-arrhythmic cardiac phenotype elicited by chronic intermittent hypoxia is associated with alterations in connexin-43 expression, phosphorylation and distribution. Front Endocrinol. 2019;9:789. doi: 10.3389/fendo.2018.00789. PubMed DOI PMC

Neckar J, Kopkan L, Huskova Z, Kolar F, Papousek F, Kramer HJ, Hwang SH, Hammock BD, Imig JD, Maly J, Netuka I, Ostadal B, Cervenka L. Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension. Clin Sci. 2012;122:513–525. doi: 10.1042/CS20110622. PubMed DOI PMC

Neckar J, Svatonova A, Weissova R, Drahota Z, Zajickova P, Brabcova I, Kolar D, Alanova P, Vasinova J, Silhavy J, Hlavackova M, Tauchmannova K, Milerova M, Ostadal B, Cervenka L, Zurmanova J, Kalous M, Novakova O, Novotny J, Pravenec M, Kolar F. Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats. Clin Sci. 2017;131:865–881. doi: 10.1042/CS20170083. PubMed DOI

Neckar J, Alanova P, Olejnickova V, Papousek F, Hejnova L, Silhavy J, Behuliak M, Bencze M, Hrdlicka J, Vecka M, Jarkovska D, Sviglerova J, Mistrova E, Stengl M, Novotny J, Ostadal B, Pravenec M, Kolar F. Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats. Clin Sci. 2021;135:2143–2163. doi: 10.1042/CS20210648. PubMed DOI

Nedvedova I, Kolar D, Elsnicova B, Hornikova D, Novotny J, Kalous M, Pravenec M, Neckar J, Kolar F, Zurmanova J. Mitochondrial genome modulates myocardial Akt/GLUT/HK salvage pathway in spontaneously hypertensive rats adapted to chronic hypoxia. Physiol Genomics. 2018;50:532–541. doi: 10.1152/physiolgenomics.00040.2017. PubMed DOI

Nedvedova I, Kolar D, Neckar J, Kalous M, Pravenec M, Silhavy J, Korenkova V, Kolar F, Zurmanova JM. Cardioprotective regimen of adaptation to chronic hypoxia diversely alters myocardial gene expression in SHR and SHR-mtBN conplastic rat strains. Front Endocrinol. 2019;9:809. doi: 10.3389/fendo.2018.00809. PubMed DOI PMC

Kolesova H, Bartos M, Hsieh WC, Olejnickova V, Sedmera D. Novel approaches to study coronary vasculature development in mice. Dev Dyn. 2018;247:1018–1027. doi: 10.1002/dvdy.24637. PubMed DOI

Kvasilova A, Olejnickova V, Jensen B, Christoffels VM, Kolesova H, Sedmera D, Gregorovicova M. The formation of the atrioventricular conduction axis is linked in development to ventricular septation. J Exp Biol. 2020;223:jeb229278. doi: 10.1242/jeb.229278. PubMed DOI

Olejnickova V, Kocka M, Kvasilova A, Kolesova H, Dziacky A, Gidor T, Gidor L, Sankova B, Gregorovicova M, Gourdie RG, Sedmera D. Gap junctional communication via connexin43 between Purkinje fibers and working myocytes explains the epicardial activation pattern in the postnatal mouse left ventrikle. Int J Mol Sci. 2021;22:2475. doi: 10.3390/ijms22052475. PubMed DOI PMC

Neffeova K, Olejnickova V, Nanka O, Kolesova H. Development and diseases of the coronary microvasculature and its communication with the myocardium. WIREs Mech Dis. 2022:e1560. doi: 10.1002/wsbm.1560. PubMed DOI

Skarka L, Bardova K, Brauner P, Flachs P, Jarkovska D, Kopecky J, Ostadal B. Expression of mitochondrial uncoupling protein 3 and adenine nucleotide translocase 1 genes in developing rat heart: putative involvement in control of mitochondrial membrane potential. J Mol Cell Cardiol. 2003;35:321–330. doi: 10.1016/S0022-2828(03)00016-6. PubMed DOI

Netuka I, Szarszoi O, Maly J, Besik J, Neckar J, Kolar F, Ostadalova I, Pirk J, Ostadal B. Effect of perinatal hypoxia on cardiac tolerance to acute ischaemia in adult male and female rats. Clin Exp Pharmacol Physiol. 2006;33:714–719. doi: 10.1111/j.1440-1681.2006.04423.x. PubMed DOI

Ostadal B, Netuka I, Maly J, Besik J, Ostadalova I. Gender differences in cardiac ischemic injury and protection-experimental aspects. Exp Biol Med. 2009;234:1011–1019. doi: 10.3181/0812-MR-362. PubMed DOI

Netuka I, Szarszoi O, Maly J, Riha H, Turek D, Ostadalova I, Ostadal B. Late effect of early hypoxic disturbance in the rat heart: Gender differences. Physiol Res. 2010;59:127–31. doi: 10.33549/physiolres.931833. PubMed DOI

Milerova M, Charvatova Z, Skarka L, Ostadalova I, Drahota Z, Fialova M, Ostadal B. Neonatal cardiac mitochondria and ischemia/reperfusion injury. Mol Cell Biochem. 2010;335:147–153. doi: 10.1007/s11010-009-0251-x. PubMed DOI

Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. Br J Pharmacol. 2014;171:541–554. doi: 10.1111/bph.12270. PubMed DOI PMC

Ostadal P, Ostadal B. Women and the management of acute coronary syndrome. Can J Physiol Pharmacol. 2012;90:1151–1159. doi: 10.1139/y2012-033. PubMed DOI

Milerova M, Drahota Z, Chytilova A, Tauchmannova K, Houstek J, Ostadal B. Sex difference in the sensitivity of cardiac mitochondrial permeability transition pore to calcium load. Mol Cell Biochem. 2016;412:147–154. doi: 10.1007/s11010-015-2619-4. PubMed DOI

Ostadal B, Drahota Z, Houstek J, Milerova M, Ostadalova I, Hlavackova M, Kolar F. Developmental and sex differences in cardiac tolerance to ischemia-reperfusion injury: the role of mitochondria. Can J Physiol Pharmacol. 2019;97:808–814. doi: 10.1139/cjpp-2019-0060. PubMed DOI

Ostadal B, Ostadalova I, Szarszoi O, Netuka I, Olejnickova V, Hlavackova M. Sex-dependent effect of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults. Can J Physiol Pharmacol. 2021;99:1–8. doi: 10.1139/cjpp-2020-0310. PubMed DOI

Alanova P, Huskova Z, Kopkan L, Sporkova A, Jichova S, Neckar J, Imig JD, Klevstig M, Kolar F, Reddy NR, Falck JR, Sadowski J, Nishiyama A, Kramer HJ, Melenovsky V, Cervenkova L, Kujal P, Vernerova Z, Cervenka L. Orally active epoxyeicosatrienoic acid analog does not exhibit antihypertensive and reno- or cardioprotective actions in two-kidney, one-clip Goldblatt hypertensive rats. Vasc Pharmacol. 2015;73:45–56. doi: 10.1016/j.vph.2015.08.013. PubMed DOI

Neckar J, Hsu A, Md Hye Khan A, Gross G, Nithipatikom K, Cyprova M, Benak D, Hlavackova M, Sotaova-Kasparova D, Falck J, Sedmera D, Kolar F, Imig J. Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia inducible factor-1α via down regulation of prolyl hydroxylase 3. Am J Physiol Heart Circ Physiol. 2018;315:H1148–H1158. doi: 10.1152/ajpheart.00726.2017. PubMed DOI PMC

Neckar J, Md Hye Khan A, Gross GJ, Cyprova M, Hrdlicka J, Kvasilova A, Falck JR, Campbell WB, Sedlakova L, Skutova S, Olejnickova V, Gregorovicova M, Sedmera D, Kolar F, Imig JD. Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats. Clin Sci. 2019;133:936–951. doi: 10.1042/CS20180728. PubMed DOI PMC

Hrdlicka J, Neckar J, Papousek F, Huskova Z, Kikerlova S, Vanourkova Z, Vernerova Z, Akat F, Vasinova J, Hammock BD, Hwang SH, Imig JD, Falck JR, Cervenka L, Kolar F. Epoxyeicosatrienoic acid-based therapy attenuates the progression of postischemic heart failure in normotensive Sprague-Dawley but not in hypertensive Ren-2 transgenic rats. Front Pharmacol. 2019;10:159. doi: 10.3389/fphar.2019.00159. PubMed DOI PMC

Bohuslavova R, Kolar F, Kuthanova L, Neckar J, Tichopad A, Pavlinkova G. Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia. J Appl Physiol. 2010;109:1195–1202. doi: 10.1152/japplphysiol.00366.2010. PubMed DOI

Cerychova R, Bohuslavova R, Papousek F, Sedmera D, Abaffy P, Benes V, Kolar F, Pavlinkova G. Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart. Cardiovasc Diabetol. 2018;17:68. doi: 10.1186/s12933-018-0713-0. PubMed DOI PMC

Bohuslavova R, Cerychova R, Papousek F, Olejnickova V, Bartos M, Gorlach A, Kolar F, Sedmera D, Semenza GL, Pavlinkova G. HIF-1 α is required for development of the sympathetic nervous system. Proc Natl Acad Sci USA. 2019;116:13414–13423. doi: 10.1073/pnas.1903510116. PubMed DOI PMC

Hrabalova P, Bohuslavova R, Matejkova K, Papousek F, Sedmera D, Abaffy P, Kolar F, Pavlinkova G. Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy. Cardiovasc Diabetol. 2023;22:88. doi: 10.1186/s12933-023-01824-5. PubMed DOI PMC

Adameova A, Hrdlicka J, Szobi A, Farkasova V, Kopaskova K, Murarikova M, Neckar J, Kolar F, Ravingerova T, Dhalla NS. Evidence of necroptosis in hearts subjected to various forms of ischemic insults. Can J Physiol Pharmacol. 2017;95:1163–1169. doi: 10.1139/cjpp-2016-0609. PubMed DOI

Lichy M, Szobi A, Hrdlicka J, Horvath C, Kormanova V, Rajtik T, Neckar J, Kolar F, Adameova A. Different signaling in infarcted and non-infarcted areas of rat failing hearts: a role of necroptosis and inflammation. J Cell Mol Med. 2019;23:6429–6441. doi: 10.1111/jcmm.14536. PubMed DOI PMC

Lichy M, Szobi A, Hrdlicka J, Neckar J, Kolar F, Adameova A. Programmed cell death in the left and right ventricle of the late phase of post-infarction heart failure. Int J Mol Sci. 2020;21:7782. doi: 10.3390/ijms21207782. PubMed DOI PMC

Semenovykh D, Benak D, Holzerova K, Cerna B, Telensky P, Vavrikova T, Kolar F, Neckar J, Hlavackova M. Myocardial m6A regulators in postnatal development: effect of sex. Physiol Res. 2022;71:877–882. doi: 10.33549/physiolres.934970. PubMed DOI PMC

Benak D, Kolar F, Zhang L, Devaux Y, Hlavackova M. RNA modification m6Am: the role in cardiac biology. Epigenetics. 2023;18:2218771. doi: 10.1080/15592294.2023.2218771. PubMed DOI PMC

Benak D, Benakova S, Plecita-Hlavata L, Hlavackova M. The role of m6A and m6Am RNA modifications in the pathogenesis of diabetes mellitus. Front Endocrinol. 2023;14:1223583. doi: 10.3389/fendo.2023.1223583. PubMed DOI PMC

Benak D, Holzerova K, Hrdlicka J, Kolar F, Olsen M, Karelson M, Hlavackova M. Epitranscriptomic regulation in fasting hearts: implications for cardiac health. RNA Biol. 2024;21:1–14. doi: 10.1080/15476286.2024.2307732. PubMed DOI PMC

50 years of the Czech and Slovak Society of Experimental Cardiology - historical background and scientific benefit