Advertisement

Transgenic Animal Models of Cardiac Channelopathies: Benefits and Limitations

  • Katja E. Odening
  • David Ziupa
Chapter
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)

Abstract

Ideally, studies investigating pathophysiological mechanisms of human arrhythmia disorders should be performed in human subjects, their hearts, tissue, and cells. Human cardiac tissues, however, are not easily accessible to experimental electrophysiologists. Therefore, transgenic animal models (mouse, rabbit, and pig) mimicking (several aspects of) the human disease phenotype have been generated and utilized to gather mechanistic insight into cardiac channelopathies.

In this overview, we summarize advantages, limitations, and translational value of the different available genetic animal models (mouse, rabbit, and pig) for potassium channelopathies (long QT syndromes), sodium channelopathies (LQT3, Brugada syndrome, cardiac conduction disease, and overlap syndrome), and catecholaminergic polymorphic ventricular tachycardia (CPVT).

Notes

Compliance with Ethical Standards

Sources of Funding

None.

Conflict of Interest

Katja E. Odening and David Ziupa declare that they have no conflict of interest.

Ethical Approval

All animal studies summarized and reviewed in this article were conducted based on international, national, and/or institutional guidelines for the care and use of animals.

References

  1. Antzelevitch C, Brugada R. Fever and Brugada syndrome. Pacing Clin Electrophysiol. 2002;25(11):1537–9.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005;111(5):659–70.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Babij P, Askew GR, Nieuwenhuijsen B, Su CM, Bridal TR, Jow B, Argentieri TM, Kulik J, DeGennaro LJ, Spinelli W, Colatsky TJ. Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice. Circ Res. 1998;83(6):668–78.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Baczkó I, Jost N, Virág L, Bősze Z, Varró A. Rabbit models as tools for preclinical cardiac electrophysiological safety testing: importance of repolarization reserve. Prog Biophys Mol Biol. 2016;121(2):157–68.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Baker LC, London B, Choi BR, Koren G, Salama G. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circ Res. 2000;86(4):396–407.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Balasubramaniam R, Grace AA, Saumarez RC, Vandenberg JI, Huang CL. Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1. J Physiol. 2003;552(Pt 2):535–46.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Barry DM, Xu H, Schuessler RB, Nerbonne JM. Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. Circ Res. 1998;83(5):560–7.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Belardinelli L, Liu G, Smith-Maxwell C, Wang WQ, El-Bizri N, Hirakawa R, Karpinski S, Li CH, Hu L, Li XJ, Crumb W, Wu L, Koltun D, Zablocki J, Yao L, Dhalla AK, Rajamani S, Shryock JC. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013;344(1):23–32.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Bősze Z, Major P, Baczkó I, Odening KE, Bodrogi L, Hiripi L, Varró A. The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases. Prog Biophys Mol Biol. 2016;121(2):123–30.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Boukens BJ, Sylva M, de Gier-de Vries C, Remme CA, Bezzina CR, Christoffels VM, Coronel R. Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. Circ Res. 2013;113(2):137–41.PubMedCrossRefGoogle Scholar
  11. Brunner M, Guo W, Mitchell GF, Buckett PD, Nerbonne JM, Koren G. Characterization of mice with a combined suppression of I(to) and I(K,slow). Am J Physiol Heart Circ Physiol. 2001;281(3):H1201–9.PubMedCrossRefGoogle Scholar
  12. Brunner M, Peng X, Liu GX, Ren XQ, Ziv O, Choi BR, Mathur R, Hajjiri M, Odening KE, Steinberg E, Folco EJ, Pringa E, Centracchio J, Macharzina RR, Donahay T, Schofield L, Rana N, Kirk M, Mitchell GF, Poppas A, Zehender M, Koren G. Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. J Clin Invest. 2008;118(6):2246–59.PubMedPubMedCentralGoogle Scholar
  13. Calvillo L, Spazzolini C, Vullo E, Insolia R, Crotti L, Schwartz PJ. Propranolol prevents life-threatening arrhythmias in LQT3 transgenic mice: implications for the clinical management of LQT3 patients. Heart Rhythm. 2014;11(1):126–32.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, Pfeifer K. Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen syndrome. Proc Natl Acad Sci U S A. 2001;98(5):2526–31.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cerrone M, Colombi B, Santoro M, di Barletta MR, Scelsi M, Villani L, Napolitano C, Priori SG. Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. Circ Res. 2005;96(10):e77–82.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cerrone M, Noujaim SF, Tolkacheva EG, Talkachou A, O’Connell R, Berenfeld O, Anumonwo J, Pandit SV, Vikstrom K, Napolitano C, Priori SG, Jalife J. Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2007;101(10):1039–48.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Charpentier F, Merot J, Riochet D, Le Marec H, Escande D. Adult KCNE1-knockout mice exhibit a mild cardiac cellular phenotype. Biochem Biophys Res Commun. 1998;251(3):806–10.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Charpentier F, Bourgé A, Mérot J. Mouse models of SCN5A-related cardiac arrhythmias. Prog Biophys Mol Biol. 2008;98(2–3):230–7.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Choy L, Yeo JM, Tse V, Chan SP, Tse G. Cardiac disease and arrhythmogenesis: mechanistic insights from mouse models. Int J Cardiol Heart Vasc. 2016;12:1–10.PubMedPubMedCentralGoogle Scholar
  20. Davisson MT. Genetic and phenotypic definition of laboratory mice and rats. National Research Council (US) International Committee of the Institute for Laboratory Animal Research, 1999.Google Scholar
  21. Demolombe S, Lande G, Charpentier F, van Roon MA, van den Hoff MJ, Toumaniantz G, Baro I, Guihard G, Le Berre N, Corbier A, de Bakker J, Opthof T, Wilde A, Moorman AF, Escande D. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: phenotypic characterisation. Cardiovasc Res. 2001;50(2):314–27.PubMedCrossRefGoogle Scholar
  22. Derangeon M, Montnach J, Baró I, Charpentier F. Mouse models of SCN5A-related cardiac arrhythmias. Front Physiol. 2012;3:210.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Drici MD, Arrighi I, Chouabe C, Mann JR, Lazdunski M, Romey G, Barhanin J. Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circ Res. 1998;83(1):95–102.PubMedCrossRefGoogle Scholar
  24. Fabritz L, Kirchhof P, Franz MR, Nuyens D, Rossenbacker T, Ottenhof A, Haverkamp W, Breithardt G, Carmeliet E, Carmeliet P. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice. Cardiovasc Res. 2003;57(4):1085–93.PubMedCrossRefGoogle Scholar
  25. Fabritz L, Damke D, Emmerich M, Kaufmann SG, Theis K, Blana A, Fortmüller L, Laakmann S, Hermann S, Aleynichenko E, Steinfurt J, Volkery D, Riemann B, Kirchhefer U, Franz MR, Breithardt G, Carmeliet E, Schäfers M, Maier SK, Carmeliet P, Kirchhof P. Autonomic modulation and antiarrhythmic therapy in a model of long QT syndrome type 3. Cardiovasc Res. 2010;87(1):60–72.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Fernandez-Velasco M, Rueda A, Rizzi N, Benitah JP, Colombi B, Napolitano C, Priori SG, Richard S, Gomez AM. Increased Ca2+ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic ventricular tachycardia. Circ Res. 2009;104:201–9.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Goddard CA, Ghais NS, Zhang Y, Williams AJ, Colledge WH, Grace AA, Huang CL. Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts. Acta Physiol (Oxf). 2008;194:123–40.CrossRefGoogle Scholar
  28. Guo W, Li H, London B, Nerbonne JM. Functional consequences of elimination of I(to,f) and i(to,s): early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit. Circ Res. 2000;87(1):73–9.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Guo W, Jung WE, Marionneau C, Aimond F, Xu H, Yamada KA, Schwarz TL, Demolombe S, Nerbonne JM. Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ Res. 2005;97(12):1342–50.PubMedCrossRefGoogle Scholar
  30. Haugaa KH, Smedsrud MK, Steen T, Kongsgaard E, Loennechen JP, Skjaerpe T, Voigt JU, Willems R, Smith G, Smiseth OA, Amlie JP, Edvardsen T. Mechanical dispersion assessed by myocardial strain in patients after myocardial infarction for risk prediction of ventricular arrhythmia. JACC Cardiovasc Imaging. 2010;3(3):247–56.PubMedCrossRefGoogle Scholar
  31. Head CE, Balasubramaniam R, Thomas G, Goddard CA, Lei M, Colledge WH, Grace AA, Huang CL. Paced electrogram fractionation analysis of arrhythmogenic tendency in DeltaKPQ Scn5a mice. J Cardiovasc Electrophysiol. 2005;16(12):1329–40.PubMedCrossRefGoogle Scholar
  32. Hoekstra M, Mummery CL, Wilde AA, Bezzina CR, Verkerk AO. Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias. Front Physiol. 2012;3:346.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Hondeghem LM. Disturbances of cardiac wavelength and repolarization precede torsade de pointes and ventricular fibrillation in Langendorff perfused rabbit hearts. Prog Biophys Mol Biol. 2016;121(1):3–10.PubMedCrossRefGoogle Scholar
  34. Hwang HS, Hasdemir C, Laver D, Mehra D, Turhan K, Faggioni M, Yin H, Knollmann BC. Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2011;4(2):128–35.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Jung B, Odening KE, Dall’Armellina E, Foll D, Menza M, Markl M, Schneider JE. A quantitative comparison of regional myocardial motion in mice, rabbits and humans using in-vivo phase contrast CMR. J Cardiovasc Magn Reson. 2012;14:87.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Kannankeril PJ, Mitchell BM, Goonasekera SA, Chelu MG, Zhang W, Sood S, Kearney DL, Danila CI, De Biasi M, Wehrens XH, Pautler RG, Roden DM, Taffet GE, Dirksen RT, Anderson ME, Hamilton SL. Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy. Proc Natl Acad Sci USA. 2006;103:12179–84.PubMedCrossRefPubMedCentralGoogle Scholar
  37. Katz G, Khoury A, Kurtzwald E, Hochhauser E, Porat E, Shainberg A, Seidman JG, Seidman CE, Lorber A, Eldar M, Arad M. Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice. Heart Rhythm. 2010;7(11):1676–82.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kim TY, Kunitomo Y, Pfeiffer Z, Patel D, Hwang J, Harrison K, Patel B, Jeng P, Ziv O, Lu Y, Peng X, Qu Z, Koren G, Choi B-R. Complex excitation dynamics underlie polymorphic ventricular tachycardia in a transgenic rabbit model of long QT syndrome type 1. Heart Rhythm. 2015;12(1):220–8.PubMedCrossRefGoogle Scholar
  39. Knollmann BC, Chopra N, Hlaing T, Akin B, Yang T, Ettensohn K, Knollmann BE, Horton KD, Weissman NJ, Holinstat I, Zhang W, Roden DM, Jones LR, Franzini-Armstrong C, Pfeifer K. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2006;116:2510–20.PubMedPubMedCentralGoogle Scholar
  40. Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M. Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S/+) knock-in mouse model. Circ J. 2010;74(12):2579–84.PubMedCrossRefGoogle Scholar
  41. Kodirov SA, Brunner M, Nerbonne JM, Buckett P, Mitchell GF, Koren G. Attenuation of I(K,slow1) and I(K,slow2) in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias. Am J Physiol Heart Circ Physiol. 2004;286(1):368–74.CrossRefGoogle Scholar
  42. Koren G. Electrical remodeling and arrhythmias in long-QT syndrome: lessons from genetic models in mice. Ann Med. 2004;36(Suppl 1):22–7.PubMedCrossRefGoogle Scholar
  43. Kuo H-C, Cheng C-F, Clark RB, Lin JJ-C, Lin JL-C, Hoshijima M, Nguyêñ-Trân VTB, Yusu G, Ikeda Y, Chu P-H, Jr JR, Giles WR, Chien KR. A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell. 2001;107(6):801–13.PubMedCrossRefGoogle Scholar
  44. Kupershmidt S, Yang T, Anderson ME, Wessels A, Niswender KD, Magnuson MA, Roden DM. Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circ Res. 1999;84(2):146–52.PubMedCrossRefGoogle Scholar
  45. Kurtzwald-Josefson E, Hochhauser E, Bogachenko K, Harun-Khun S, Katz G, Aravot D, Seidman JG, Seidman CE, Eldar M, Shainberg A, Arad M. Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice. Heart Rhythm. 2014;11(8):1471–9.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Lahat H, Pras E, Olender T, Avidan N, Ben-Asher E, Man O, Levy-Nissenbaum E, Khoury A, Lorber A, Goldman B, Lancet D, Eldar M. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet. 2001;69(6):1378–84.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Lande G, Demolombe S, Bammert A, Moorman A, Charpentier F, Escande D. Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part II: Pharmacological profile. Cardiovasc Res. 2001;50(2):328–34.PubMedCrossRefGoogle Scholar
  48. Lang CN, Menza M, Jochem S, Franke G, Perez Feliz S, Brunner M, Koren G, Zehender M, Bugger H, Jung BA, Foell D, Bode C, Odening KE. Electro-mechanical dysfunction in long QT syndrome. Prog Biophys Mol Biol. 2016a;120(1–3):255–69.PubMedCrossRefGoogle Scholar
  49. Lang CN, Koren G, Odening KE. Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome. Prog Biophys Mol Biol. 2016b;121(2):142–56.PubMedCrossRefGoogle Scholar
  50. Lau E, Kossidas K, Kim TY, Kunitomo Y, Ziv O, Zhen S, Taylor C, Schofield L, Yammine J, Liu G, Peng X, Qu Z, Koren G, Choi B-R. Spatially discordant alternans and arrhythmias in tachypacing-induced cardiac myopathy in transgenic LQT1 rabbits: the importance of IKs and Ca2+ cycling. PLoS One. 2015;10(5):e0122754.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Lee MP, Ravenel JD, Hu RJ, Lustig LR, Tomaselli G, Berger RD, Brandenburg SA, Litzi TJ, Bunton TE, Limb C, Francis H, Gorelikow M, Gu H, Washington K, Argani P, Goldenring JR, Coffey RJ, Feinberg AP. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest. 2000;106(12):1447–55.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lees-Miller JP, Guo J, Somers JR, Roach DE, Sheldon RS, Rancourt DE, Duff HJ. Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia. Mol Cell Biol. 2003;23(6):1856–62.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Leren IS, Hasselberg NE, Saberniak J, Håland TF, Kongsgård E, Smiseth OA, Edvardsen T, Haugaa KH. Cardiac mechanical alterations and genotype specific differences in subjects with long QT syndrome. JACC Cardiovasc Imaging. 2015;8(5):501–10.PubMedCrossRefGoogle Scholar
  54. Li H, Guo W, Yamada KA, Nerbonne JM. Selective elimination of I(K,slow1) in mouse ventricular myocytes expressing a dominant negative Kv1.5alpha subunit. Am J Physiol Heart Circ Physiol. 2004;286(1):H319–28.PubMedCrossRefGoogle Scholar
  55. Liu GX, Choi BR, Ziv O, Li W, de Lange E, Qu Z, Koren G. Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. J Physiol. 2012;590(5):1171–80.PubMedCrossRefGoogle Scholar
  56. Liu Y, Wang R, Sun B, Mi T, Zhang J, Mu Y, Chen J, Bround MJ, Johnson JD, Gillis AM, Chen SR. Generation and characterization of a mouse model harboring the exon-3 deletion in the cardiac ryanodine receptor. PLoS One. 2014;9:e95615.PubMedPubMedCentralCrossRefGoogle Scholar
  57. London B, Jeron A, Zhou J, Buckett P, Han X, Mitchell GF, Koren G. Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proc Natl Acad Sci U S A. 1998a;95(6):2926–31.PubMedPubMedCentralCrossRefGoogle Scholar
  58. London B, Wang DW, Hill JA, Bennett PB. The transient outward current in mice lacking the potassium channel gene Kv1.4. J Physiol. 1998b;509(Pt 1):171–82.PubMedPubMedCentralCrossRefGoogle Scholar
  59. London B, Guo W, Pan X, Lee JS, Shusterman V, Rocco CJ, Logothetis DA, Nerbonne JM, Hill JA. Targeted replacement of KV1.5 in the mouse leads to loss of the 4-aminopyridine-sensitive component of I(K,slow) and resistance to drug-induced qt prolongation. Circ Res. 2001;88(9):940–6.PubMedCrossRefGoogle Scholar
  60. London B, Baker LC, Petkova-Kirova P, Nerbonne JM, Choi B-R, Salama G. Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT. J Physiol. 2007;578(Pt 1):115–29.PubMedCrossRefGoogle Scholar
  61. Major P, Baczkó I, Hiripi L, Odening KE, Juhász V, Kohajda Z, Horváth A, Seprényi G, Kovács M, Virág L, Jost N, Prorok J, Ördög B, Doleschall Z, Nattel S, Varró A, Bősze Z. A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene. Br J Pharmacol. 2016;173(12):2046–61.PubMedPubMedCentralCrossRefGoogle Scholar
  62. McLerie M, Lopatin AN. Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol. 2003;35(4):367–78.PubMedCrossRefGoogle Scholar
  63. Moreno JD, Clancy CE. Pathophysiology of the cardiac late Na current and its potential as a drug target. J Mol Cell Cardiol. 2012;52(3):608–19.PubMedCrossRefGoogle Scholar
  64. Morita H, Wu J, Zipes DP. The QT syndromes. Lancet. 2008;372(9640):750–63.PubMedCrossRefGoogle Scholar
  65. Moshal KS, Zhang Z, Roder K, Kim TY, Cooper L, Patedakis Litvinov B, Lu Y, Reddy V, Terentyev D, Choi BR, Koren G. Progesterone modulates SERCA2a expression and function in rabbit cardiomyocytes. Am J Physiol Cell Physiol. 2014;307(11):C1050–7.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Moss AJ. Sex hormones and ventricular tachyarrhythmias in LQTS: new insights regarding antiarrhythmic therapy. Heart Rhythm. 2012;9(5):833–4.PubMedCrossRefGoogle Scholar
  67. Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, Severski P, Rosero S, Daubert JP, Qi M, Cieciorka M, Manalan AS. Safety and efficacy of flecainide in subjects with long QT-3 syndrome (DeltaKPQ mutation): a randomized, double-blind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005;10(4 Suppl):59–66.PubMedCrossRefGoogle Scholar
  68. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008;19(12):1289–93.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Nador F, Beria G, De Ferrari GM, Stramba-Badiale M, Locati EH, Lotto A, Schwartz PJ. Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Circulation. 1991;84(4):1530–42.PubMedCrossRefGoogle Scholar
  70. Nakata T, Hearse DJ. Species differences in vulnerability to injury by oxidant stress: a possible link with calcium handling? Cardiovasc Res. 1990;24(10):857–64.PubMedCrossRefGoogle Scholar
  71. Nattel S, Duker G, Carlsson L. Model systems for the discovery and development of antiarrhythmic drugs. Prog Biophys Mol Biol. 2008;98(2–3):328–39.PubMedCrossRefGoogle Scholar
  72. Nerbonne JM. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol. 2000;525(Pt 2):285–98.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005;85(4):1205–53.PubMedCrossRefGoogle Scholar
  74. Nerbonne JM, Nichols CG, Schwarz TL, Escande D. Genetic manipulation of cardiac K(+) channel function in mice: what have we learned, and where do we go from here? Circ Res. 2001;89(11):944–56.PubMedCrossRefGoogle Scholar
  75. Nuyens D, Stengl M, Dugarmaa S, Rossenbacker T, Compernolle V, Rudy Y, Smits JF, Flameng W, Clancy CE, Moons L, Vos MA, Dewerchin M, Benndorf K, Collen D, Carmeliet E, Carmeliet P. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med. 2001;7(9):1021–7.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Odening KE, Kohl P. Follow the white rabbit: experimental and computational models of the rabbit heart provide insights into cardiac (patho-) physiology. Prog Biophys Mol Biol. 2016;121(2):75–6.PubMedCrossRefPubMedCentralGoogle Scholar
  77. Odening KE, Koren G, Kirk M. Normalization of QT interval duration in a long QT syndrome patient during pregnancy and the postpartum period due to sex hormone effects on cardiac repolarization. Heart Rhythm Case Rep. 2016;2(3):223–7.CrossRefGoogle Scholar
  78. Odening KE, Koren G. How do sex hormones modify arrhythmogenesis in long QT syndrome? Sex hormone effects on arrhythmogenic substrate and triggered activity. Heart Rhythm. 2014;11(11):2107–15.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Odening KE, Hyder O, Chaves L, Schofield L, Brunner M, Kirk M, Zehender M, Peng X, Koren G. Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization. Am J Physiol Heart Circ Physiol. 2008;295(6):H2264–72.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Odening KE, Kirk M, Brunner M, Ziv O, Lorvidhaya P, Liu GX, Schofield L, Chaves L, Peng X, Zehender M, Choi BR, Koren G. Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and his conduction. Am J Physiol Heart Circ Physiol. 2010;299(3):H643–55.PubMedPubMedCentralCrossRefGoogle Scholar
  81. Odening KE, Choi BR, Liu GX, Hartmann K, Ziv O, Chaves L, Schofield L, Centracchio J, Zehender M, Peng X, Brunner M, Koren G. Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm. 2012;9(5):823–32.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Odening KE, Jung BA, Lang CN, Cabrera Lozoya R, Ziupa D, Menza M, Relan J, Franke G, Perez Feliz S, Koren G, Zehender M, Bode C, Brunner M, Sermesant M, Föll D. Spatial correlation of action potential duration and diastolic dysfunction in transgenic and drug-induced LQT2 rabbits. Heart Rhythm. 2013;10(10):1533–41.PubMedCrossRefPubMedCentralGoogle Scholar
  83. Opthof T, Remme CA, Jorge E, Noriega F, Wiegerinck RF, Tasiam A, Beekman L, Alvarez-Garcia J, Munoz-Guijosa C, Coronel R, Cinca J. Cardiac activation-repolarization patterns and ion channel expression mapping in intact isolated normal human hearts. Heart Rhythm. 2017;14(2):265–72.PubMedCrossRefGoogle Scholar
  84. Organ-Darling LE, Vernon AN, Giovanniello JR, Lu Y, Moshal K, Roder K, Li W, Koren G. Interactions between hERG and KCNQ1 alpha-subunits are mediated by their COOH termini and modulated by cAMP. Am J Physiol Heart Circ Physiol. 2013;304(4):H589–99.PubMedCrossRefGoogle Scholar
  85. Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CL, Vandenberg JI, Colledge WH, Grace AA. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc Natl Acad Sci U S A. 2002;99(9):6210–5.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Park DS, Cerrone M, Morley G, Vasquez C, Fowler S, Liu N, Bernstein SA, Liu FY, Zhang J, Rogers CS, Priori SG, Chinitz LA, Fishman GI. Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. J Clin Invest. 2015;125(1):403–12.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Portero V, Casini S, Hoekstra M, Verkerk AO, Mengarelli I, Belardinelli L, Rajamani S, Wilde AAM, Bezzina CR, Veldkamp MW, Remme CA. Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD+/− and human SCN5A-1795insD+/− iPSC-derived cardiomyocytes. Cardiovasc Res. 2017;113(7):829–38.PubMedCrossRefPubMedCentralGoogle Scholar
  88. Priori SG, Bloise R, Crotti L. The long QT syndrome. Europace. 2001a;3:16–27.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001b;103(2):196–200.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002a;105(11):1342–7.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Priori SG, Napolitano C, Memmi M, Colombi B, Drago F, Gasparini M, De Simone L, Coltorti F, Bloise R, Keegan R, Cruz Filho FE, Vignati G, Benatar A, De Logu A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002b;106(1):69–74.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–63.PubMedCrossRefPubMedCentralGoogle Scholar
  93. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36(41):2793–867.PubMedCrossRefPubMedCentralGoogle Scholar
  94. Quinn TA, Kohl P. Rabbit models of cardiac mechano-electric and mechano-mechanical coupling. Prog Biophys Mol Biol. 2016;121(2):110–22.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Rajamani S, Liu G, El-Bizri N, Guo D, Li C, Chen XL, Kahlig KM, Mollova N, Elzein E, Zablocki J, Belardinelli L. The novel late Na+ current inhibitor, GS-6615 (eleclazine) and its anti-arrhythmic effects in rabbit isolated heart preparations. Br J Pharmacol. 2016;173(21):3088–98.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, Wilders R, van Roon MA, Tan HL, Wilde AA, Carmeliet P, de Bakker JM, Veldkamp MW, Bezzina CR. Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation. 2006;114(24):2584–94.PubMedCrossRefGoogle Scholar
  97. Remme CA, Wilde AA, Bezzina CR. Cardiac sodium channel overlap syndromes: different faces of SCN5A mutations. Trends Cardiovasc Med. 2008;18(3):78–87.PubMedCrossRefGoogle Scholar
  98. Remme CA, Scicluna BP, Verkerk AO, Amin AS, van Brunschot S, Beekman L, Deneer VH, Chevalier C, Oyama F, Miyazaki H, Nukina N, Wilders R, Escande D, Houlgatte R, Wilde AA, Tan HL, Veldkamp MW, de Bakker JM, Bezzina CR. Genetically determined differences in sodium current characteristics modulate conduction disease severity in mice with cardiac sodium channelopathy. Circ Res. 2009;104(11):1283–92.PubMedCrossRefPubMedCentralGoogle Scholar
  99. Ren XQ, Liu GX, Organ-Darling LE, Zheng R, Roder K, Jindal HK, Centracchio J, McDonald TV, Koren G. Pore mutants of HERG and KvLQT1 downregulate the reciprocal currents in stable cell lines. Am J Physiol Heart Circ Physiol. 2010;299(5):H1525–34.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Rudic B, Chaykovskaya M, Tsyganov A, Kalinin V, Tülümen E, Papavassiliu T, Dösch C, Liebe V, Kuschyk J, Röger S, El-Battrawy I, Akin I, Yakovleva M, Zaklyazminskaya E, Shestak A, Kim S, Chmelevsky M, Borggrefe M. Simultaneous non-invasive epicardial and endocardial mapping in patients with Brugada syndrome: new insights into arrhythmia mechanisms. J Am Heart Assoc. 2016;5(11):pii: e004095.CrossRefGoogle Scholar
  101. Salama G, London B. Mouse models of long QT syndrome. J Physiol. 2007 Jan 1;578(Pt 1):43–53.PubMedCrossRefGoogle Scholar
  102. Salama G, Baker L, Wolk R, Barhanin J, London B. Arrhythmia phenotype in mouse models of human long QT. J Interv Card Electrophysiol. 2009;24(2):77–87.PubMedCrossRefGoogle Scholar
  103. Salata JJ, Jurkiewicz NK, Jow B, Folander K, Guinosso PJ Jr, Raynor B, Swanson R, Fermini B. IK of rabbit ventricle is composed of two currents: evidence for IKs. Am J Phys. 1996;271(6 Pt 2):H2477–89.Google Scholar
  104. Sanbe A, James J, Tuzcu V, Nas S, Martin L, Gulick J, Osinska H, Sakthivel S, Klevitsky R, Ginsburg KS, Bers DM, Zinman B, Lakatta EG, Robbins J. Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation. 2005;111(18):2330–8.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Sanguinetti MC, Curran ME, Spector PS, Keating MT. Spectrum of HERG K+−channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2208–12.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, Qi M, Goldenberg I, Hobbs JB, Ackerman MJ, Benhorin J, Hall WJ, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49(3):329–37.PubMedCrossRefGoogle Scholar
  107. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89–95.PubMedCrossRefPubMedCentralGoogle Scholar
  108. Shy D, Gillet L, Ogrodnik J, Albesa M, Verkerk AO, Wolswinkel R, Rougier JS, Barc J, Essers MC, Syam N, Marsman RF, van Mil AM, Rotman S, Redon R, Bezzina CR, Remme CA, Abriel H. PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function. Circulation. 2014;130(2):147–60.PubMedCrossRefGoogle Scholar
  109. Song L, Alcalai R, Arad M, Wolf CM, Toka O, Conner DA, Berul CI, Eldar M, Seidman CE, Seidman JG. Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2007 Jul;117(7):1814–23.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M. Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant ca(2)(+)release leading to catecholaminergic polymorphic ventricular tachycardia. Circulation. 2011;124(6):682–94.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Sumitomo N. Current topics in catecholaminergic polymorphic ventricular tachycardia. J Arrhythm. 2016;32:344–51.PubMedCrossRefPubMedCentralGoogle Scholar
  112. Thomas G, Killeen MJ, Gurung IS, Hakim P, Balasubramaniam R, Goddard CA, Grace AA, Huang CL-H. Mechanisms of ventricular arrhythmogenesis in mice following targeted disruption of KCNE1 modelling long QT syndrome 5. J Physiol. 2007;578(Pt 1):99–114.PubMedCrossRefGoogle Scholar
  113. Tian X-L, Yong SL, Wan X, Wu L, Chung MK, Tchou PJ, Rosenbaum DS, van Wagoner DR, Kirsch GE, Wang Q. Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. Cardiovasc Res. 2004;61(2):256–67.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Valentin JP, Hoffmann P, Clerck F, Hammond TG, Hondeghem L. Review of the predictive value of the Langendorff heart model (Screenit system) in assessing the proarrhythmic potential of drugs. J Pharmacol Toxicol Methods. 2004;49(3):171–81.PubMedCrossRefGoogle Scholar
  115. van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, Shimizu W, Sumitomo N, Fish FA, Bhuiyan ZA, Willems AR, van der Veen MJ, Watanabe H, Laborderie J, Haissaguerre M, Knollmann BC, Wilde AA. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57(22):2244–54.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Wan E, Abrams J, Weinberg RL, Katchman AN, Bayne J, Zakharov SI, Yang L, Morrow JP, Garan H, Marx SO. Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J Clin Invest. 2016;126(1):112–22.PubMedCrossRefPubMedCentralGoogle Scholar
  117. Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15(4):380–3.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Watanabe H, Yang T, Stroud DM, Lowe JS, Harris L, Atack TC, Wang DW, Hipkens SB, Leake B, Hall L, Kupershmidt S, Chopra N, Magnuson MA, Tanabe N, Knollmann BC, George AL Jr, Roden DM. Striking in vivo phenotype of a disease-associated human SCN5A mutation producing minimal changes in vitro. Circulation. 2011;124(9):1001–11.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR, Mohler PJ, Sun J, Guatimosim S, Song LS, Rosemblit N, D’Armiento JM, Napolitano C, Memmi M, Priori SG, Lederer WJ, Marks AR. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell. 2003;113:829–40.PubMedCrossRefPubMedCentralGoogle Scholar
  120. Wickenden AD, Lee P, Sah R, Huang Q, Fishman GI, Backx PH. Targeted expression of a dominant-negative K(v)4.2 K(+) channel subunit in the mouse heart. Circ Res. 1999;85(11):1067–76.PubMedCrossRefPubMedCentralGoogle Scholar
  121. Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, Lopes C, Towbin JA, Spazzolini C, Crotti L, Zareba W, Goldenberg I, Kanters JK, Robinson JL, Qi M, Hofman N, Tester DJ, Bezzina CR, Alders M, Aiba T, Kamakura S, Miyamoto Y, Andrews ML, Mc Nitt S, Polonsky B, Schwartz PJ, Ackerman MJ. Clinical aspects of type 3 long-QT syndrome: an international multicenter study. Circulation. 2016;134(12):872–82.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Williams H, Kerr PM, Suleiman MS, Griffiths EJ. Differences in the calcium-handling response of isolated rat and Guinea-pig cardiomyocytes to metabolic inhibition: implications for cell damage. Exp Physiol. 2000;85(5):505–10.PubMedCrossRefPubMedCentralGoogle Scholar
  123. Xu H, Barry DM, Li H, Brunet S, Guo W, Nerbonne JM. Attenuation of the slow component of delayed rectification, action potential prolongation, and triggered activity in mice expressing a dominant-negative Kv2 alpha subunit. Circ Res. 1999;85(7):623–33.PubMedCrossRefPubMedCentralGoogle Scholar
  124. Zareba W, Sattari MN, Rosero S, Couderc JP, Moss AJ. Altered atrial, atrioventricular, and ventricular conduction in patients with the long QT syndrome caused by the DeltaKPQ SCN5A sodium channel gene mutation. Am J Cardiol. 2001;88(11):1311–4.PubMedCrossRefPubMedCentralGoogle Scholar
  125. Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res. 2000;87(2):160–6.PubMedCrossRefPubMedCentralGoogle Scholar
  126. Zhang Y, Wu J, Jeevaratnam K, King JH, Guzadhur L, Ren X, Grace AA, Lei M, Huang CL, Fraser JA. Conduction slowing contributes to spontaneous ventricular arrhythmias in intrinsically active murine RyR2-P2328S hearts. J Cardiovasc Electrophysiol. 2013;24:210–8.PubMedCrossRefPubMedCentralGoogle Scholar
  127. Zhao YT, Valdivia CR, Gurrola GB, Powers PP, Willis BC, Moss RL, Jalife J, Valdivia HH. Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function. Proc Natl Acad Sci USA. 2015;112:E1669–77.PubMedCrossRefPubMedCentralGoogle Scholar
  128. Ziupa D, Beck J, Franke G, Perez Feliz S, Hartmann M, Koren G, Zehender M, Bode C, Brunner M, Odening KE. Pronounced effects of HERG-blockers E-4031 and erythromycin on APD, spatial APD dispersion and triangulation in transgenic long-QT type 1 rabbits. PLoS One. 2014;9(9):e107210.PubMedPubMedCentralCrossRefGoogle Scholar
  129. Ziv O, Morales E, Song YK, Peng X, Odening KE, Buxton AE, Karma A, Koren G, Choi BR. Origin of complex behaviour of spatially discordant alternans in a transgenic rabbit model of type 2 long QT syndrome. J Physiol. 2009;587(Pt 19):4661–80.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cardiology and Angiology IHeart Center University of FreiburgFreiburgGermany
  2. 2.Faculty of MedicineUniversity of FreiburgFreiburgGermany
  3. 3.Institute for Experimental Cardiovascular MedicineHeart Center University of FreiburgFreiburgGermany

Personalised recommendations