Review Article | Published:

Animal models of arrhythmia: classic electrophysiology to genetically modified large animals


Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies.

Key points

  • Millions of patients have arrhythmias and are at increased risk of morbidity and death, including atrial fibrillation and sudden cardiac death; however, insufficient therapies are currently available in clinical practice.

  • Understanding the complexity of electrophysiology and arrhythmogenesis is necessary to develop innovative treatment options and requires disease modelling in animals.

  • Despite marked differences in electrophysiology compared with humans, fundamental mechanisms can potentially be identified in rodents and translated into clinical practice; however, validation in larger animals is required.

  • Rabbits should be considered to study ion channel function, repolarization and re-entrant ventricular tachycardia.

  • Dogs have traditionally been widely used in arrhythmia research, but legal restrictions, societal considerations and the lack of genetically engineered models restrict their future use.

  • Pig models could close this translational gap because their use is more accepted in modern societies, pig cardiac anatomy and electrophysiology are similar to those of humans and pigs can be genetically modified.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Chugh, S. S. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837–847 (2014).

  2. 2.

    Krijthe, B. P. et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur. Heart J. 34, 2746–2751 (2013).

  3. 3.

    Schnabel, R. B. et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 386, 154–162 (2015).

  4. 4.

    Zoni-Berisso, M., Lercari, F., Carazza, T. & Domenicucci, S. Epidemiology of atrial fibrillation: European perspective. Clin. Epidemiol. 6, 213–220 (2014).

  5. 5.

    Bogle, B. M., Ning, H., Mehrotra, S., Goldberger, J. J. & Lloyd-Jones, D. M. Lifetime risk for sudden cardiac death in the community. J. Am. Heart Assoc. 5, e002398 (2016).

  6. 6.

    Andersson, T. et al. All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study. Eur. Heart J. 34, 1061–1067 (2013).

  7. 7.

    Benjamin, E. J. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98, 946–952 (1998).

  8. 8.

    Gillum, R. F. Geographic variation in sudden coronary death. Am. Heart J. 119, 380–389 (1990).

  9. 9.

    Stewart, S., Hart, C. L., Hole, D. J. & McMurray, J. J. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 113, 359–364 (2002).

  10. 10.

    Kaab, S. Genetics of sudden cardiac death — an epidemiologic perspective. Int. J. Cardiol. 237, 42–44 (2017).

  11. 11.

    Martens, E. et al. Incidence of sudden cardiac death in Germany: results from an emergency medical service registry in Lower Saxony. Europace 16, 1752–1758 (2014).

  12. 12.

    Kirchhof, P. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur. Heart J. 37, 2893–2962 (2016).

  13. 13.

    Krahn, A. D., Manfreda, J., Tate, R. B., Mathewson, F. A. & Cuddy, T. E. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 98, 476–484 (1995).

  14. 14.

    Wang, T. J. et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 107, 2920–2925 (2003).

  15. 15.

    Wolf, P. A., Abbott, R. D. & Kannel, W. B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22, 983–988 (1991).

  16. 16.

    Priori, S. G. & Blomstrom-Lundqvist, C. 2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. Eur. Heart J. 36, 2757–2759 (2015).

  17. 17.

    Cosedis Nielsen, J. et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N. Engl. J. Med. 367, 1587–1595 (2012).

  18. 18.

    Mont, L. et al. Catheter ablation versus antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur. Heart J. 35, 501–507 (2014).

  19. 19.

    Roskell, N. S., Samuel, M., Noack, H. & Monz, B. U. Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: a systematic review of randomized and observational studies. Europace 15, 787–797 (2013).

  20. 20.

    Clauss, S., Sinner, M. F., Kaab, S. & Wakili, R. The role of microRNAs in antiarrhythmic therapy for atrial fibrillation. Arrhythm. Electrophysiol. Rev. 4, 146–155 (2015).

  21. 21.

    Nattel, S. New ideas about atrial fibrillation 50 years on. Nature 415, 219–226 (2002).

  22. 22.

    Wakili, R., Voigt, N., Kaab, S., Dobrev, D. & Nattel, S. Recent advances in the molecular pathophysiology of atrial fibrillation. J. Clin. Invest. 121, 2955–2968 (2011).

  23. 23.

    Tomaselli, G. F. et al. Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90, 2534 (1994).

  24. 24.

    Qu, J. & Robinson, R. B. Cardiac ion channel expression and regulation: the role of innervation. J. Mol. Cell. Cardiol. 37, 439–448 (2004).

  25. 25.

    Zhang, H. & Vassalle, M. Mechanisms of adrenergic control of sino-atrial node discharge. J. Biomed. Sci. 10, 179–192 (2003).

  26. 26.

    Nattel, S., Burstein, B. & Dobrev, D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ. Arrhythm. Electrophysiol. 1, 62–73 (2008).

  27. 27.

    Schotten, U., Verheule, S., Kirchhof, P. & Goette, A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol. Rev. 91, 265–325 (2011).

  28. 28.

    Voigt, N. et al. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 125, 2059–2070 (2012).

  29. 29.

    Landstrom, A. P., Dobrev, D. & Wehrens, X. H. T. Calcium signaling and cardiac arrhythmias. Circ. Res. 120, 1969–1993 (2017).

  30. 30.

    Jalife, J. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu. Rev. Physiol. 62, 25–50 (2000).

  31. 31.

    Bossu, A. et al. Selective late sodium current inhibitor GS-458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia. Br. J. Pharmacol. 175, 2470–2482 (2018).

  32. 32.

    Liu, W. et al. Mechanisms linking T-wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome. J. Physiol. 596, 1341–1355 (2018).

  33. 33.

    Tomaselli, G. F. & Marban, E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc. Res. 42, 270–283 (1999).

  34. 34.

    Nabauer, M. & Kaab, S. Potassium channel down-regulation in heart failure. Cardiovasc. Res. 37, 324–334 (1998).

  35. 35.

    Marionneau, C. et al. Distinct cellular and molecular mechanisms underlie functional remodeling of repolarizing K+ currents with left ventricular hypertrophy. Circ. Res. 102, 1406–1415 (2008).

  36. 36.

    De Jong, A. M. et al. Atrial remodeling is directly related to end-diastolic left ventricular pressure in a mouse model of ventricular pressure overload. PLOS ONE 8, e72651 (2013).

  37. 37.

    Zhang, C. et al. Blockade of angiotensin II type 1 receptor improves the arrhythmia morbidity in mice with left ventricular hypertrophy. Circ. J. 70, 335–341 (2006).

  38. 38.

    Jin, H. et al. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy. FASEB J. 24, 451–463 (2010).

  39. 39.

    Liu, T. et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ. Res. 115, 44–54 (2014).

  40. 40.

    Wang, Y. et al. beta2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure. Sci. Rep. 5, 7681 (2015).

  41. 41.

    Pogwizd, S. M., Qi, M., Yuan, W., Samarel, A. M. & Bers, D. M. Upregulation of Na+/Ca2+ exchanger expression and function in an arrhythmogenic rabbit model of heart failure. Circ. Res. 85, 1009–1019 (1999).

  42. 42.

    Desantiago, J. et al. Arrhythmogenic effects of beta2-adrenergic stimulation in the failing heart are attributable to enhanced sarcoplasmic reticulum Ca load. Circ. Res. 102, 1389–1397 (2008).

  43. 43.

    Pogwizd, S. M., Schlotthauer, K., Li, L., Yuan, W. & Bers, D. M. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ. Res. 88, 1159–1167 (2001).

  44. 44.

    Yarbrough, W. M. et al. Progressive induction of left ventricular pressure overload in a large animal model elicits myocardial remodeling and a unique matrix signature. J. Thorac. Cardiovasc. Surg. 143, 215–223 (2012).

  45. 45.

    Ishikawa, K. et al. Increased stiffness is the major early abnormality in a pig model of severe aortic stenosis and predisposes to congestive heart failure in the absence of systolic dysfunction. J. Am. Heart Assoc. 4, e001925 (2015).

  46. 46.

    Gyongyosi, M. et al. Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension. J. Transl Med. 15, 202 (2017).

  47. 47.

    Bossu, A. et al. Short-term variability of repolarization is superior to other repolarization parameters in the evaluation of diverse antiarrhythmic interventions in the chronic AV block dog. J. Cardiovasc. Pharmacol. 69, 398–407 (2017).

  48. 48.

    Oros, A., Beekman, J. D. & Vos, M. A. The canine model with chronic, complete atrio-ventricular block. Pharmacol. Ther. 119, 168–178 (2008).

  49. 49.

    Volders, P. G. et al. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation 98, 1136–1147 (1998).

  50. 50.

    Vos, M. A. et al. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation 98, 1125–1135 (1998).

  51. 51.

    de Groot, S. H. et al. Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization-dependent ventricular arrhythmias. Circulation 102, 2145–2151 (2000).

  52. 52.

    Sipido, K. R. et al. Enhanced Ca2+ release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis. Circulation 102, 2137–2144 (2000).

  53. 53.

    Volders, P. G. et al. Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation 100, 2455–2461 (1999).

  54. 54.

    Vos, M. A., Verduyn, S. C., Gorgels, A. P., Lipcsei, G. C. & Wellens, H. J. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation 91, 864–872 (1995).

  55. 55.

    van Opstal, J. M. et al. Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block. Cardiovasc. Res. 50, 354–361 (2001).

  56. 56.

    Neuberger, H.-R. et al. Development of a substrate of atrial fibrillation during chronic atrioventricular block in the goat. Circulation 111, 30 (2005).

  57. 57.

    Tsuji, Y. et al. Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block. Circulation 106, 2012–2018 (2002).

  58. 58.

    Bignolais, O. et al. Early ion-channel remodeling and arrhythmias precede hypertrophy in a mouse model of complete atrioventricular block. J. Mol. Cell. Cardiol. 51, 713–721 (2011).

  59. 59.

    Remes, J. et al. Persistent atrial fibrillation in a goat model of chronic left atrial overload. J. Thorac. Cardiovasc. Surg. 136, 1005–1011 (2008).

  60. 60.

    Benes, J. Jr et al. Myocardial morphological characteristics and proarrhythmic substrate in the rat model of heart failure due to chronic volume overload. Anat. Rec. 294, 102–111 (2011).

  61. 61.

    Scheuermann-Freestone, M. et al. A new model of congestive heart failure in the mouse due to chronic volume overload. Eur. J. Heart Fail. 3, 535–543 (2001).

  62. 62.

    Boyden, P. A. & Hoffman, B. F. The effects on atrial electrophysiology and structure of surgically induced right atrial enlargement in dogs. Circ. Res. 49, 1319–1331 (1981).

  63. 63.

    Mitchell, M. A., McRury, I. D. & Haines, D. E. Linear atrial ablations in a canine model of chronic atrial fibrillation: morphological and electrophysiological observations. Circulation 97, 1176–1185 (1998).

  64. 64.

    Julian, F. J., Morgan, D. L., Moss, R. L., Gonzalez, M. & Dwivedi, P. Myocyte growth without physiological impairment in gradually induced rat cardiac hypertrophy. Circ. Res. 49, 1300–1310 (1981).

  65. 65.

    Swynghedauw, B., Courtault, D. & Wanstok, F. Experimental cardiac hypertrophy in rats [French]. Pathol. Biol. 16, 691–694 (1968).

  66. 66.

    Alderman, E. L. & Harrison, D. C. Myocardial hypertrophy resulting from low dosage isoproterenol administration in rats. Proc. Soc. Exp. Biol. Med. 136, 268–270 (1971).

  67. 67.

    Hickson, R. C., Hammons, G. T. & Holoszy, J. O. Development and regression of exercise-induced cardiac hypertrophy in rats. Am. J. Physiol. 236, H268–H272 (1979).

  68. 68.

    Doggrell, S. A. & Brown, L. Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc. Res. 39, 89–105 (1998).

  69. 69.

    Dunnink, A. et al. Anesthesia and arrhythmogenesis in the chronic atrioventricular block dog model. J. Cardiovasc. Pharmacol. 55, 601–608 (2010).

  70. 70.

    Beiert, T. et al. Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties. Int. J. Cardiol. 250, 21–28 (2018).

  71. 71.

    Boixel, C. et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J. Am. Coll. Cardiol. 42, 336–344 (2003).

  72. 72.

    Curtis, M. J., Macleod, B. A. & Walker, M. J. Models for the study of arrhythmias in myocardial ischaemia and infarction: the use of the rat. J. Mol. Cell. Cardiol. 19, 399–419 (1987).

  73. 73.

    Gehrmann, J. et al. Electrophysiological characterization of murine myocardial ischemia and infarction. Basic Res. Cardiol. 96, 237–250 (2001).

  74. 74.

    Hundahl, L. A., Tfelt-Hansen, J. & Jespersen, T. Rat models of ventricular fibrillation following acute myocardial infarction. J. Cardiovasc. Pharmacol. Ther. 22, 514–528 (2017).

  75. 75.

    Kolossov, E. et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J. Exp. Med. 203, 2315–2327 (2006).

  76. 76.

    Rucker-Martin, C. et al. Chronic hemodynamic overload of the atria is an important factor for gap junction remodeling in human and rat hearts. Cardiovasc. Res. 72, 69–79 (2006).

  77. 77.

    Zhang, Y. et al. Thyroid hormone replacement therapy attenuates atrial remodeling and reduces atrial fibrillation inducibility in a rat myocardial infarction-heart failure model. J. Card Fail. 20, 1012–1019 (2014).

  78. 78.

    Mertz, T. E. & Kaplan, H. R. Pirmenol hydrochloride (CI-845) and reference antiarrhythmic agents: effects on early ventricular arrhythmias after acute coronary artery ligation in anesthetized rats. J. Pharmacol. Exp. Ther. 223, 580–586 (1982).

  79. 79.

    Spear, J. F. & Moore, E. N. The importance of the electrophysiologic substrates in the development of ventricular tachyarrhythmias. P. R. Health Sci. J. 4, 73–78 (1985).

  80. 80.

    Tan, M. Y. et al. Development of a new model for acute myocardial infarction in rabbits. J. Vet. Med. Sci. 79, 467–473 (2017).

  81. 81.

    Miyauchi, Y. et al. Altered atrial electrical restitution and heterogeneous sympathetic hyperinnervation in hearts with chronic left ventricular myocardial infarction: implications for atrial fibrillation. Circulation 108, 360–366 (2003).

  82. 82.

    Ohara, K. et al. Downregulation of immunodetectable atrial connexin40 in a canine model of chronic left ventricular myocardial infarction: implications to atrial fibrillation. J. Cardiovasc. Pharmacol. Ther. 7, 89–94 (2002).

  83. 83.

    Damiano, B. P. et al. Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates. J. Pharmacol. Toxicol. Methods 72, 72–84 (2015).

  84. 84.

    Aggarwal, R. & Boyden, P. A. Diminished Ca2+ and Ba2+ currents in myocytes surviving in the epicardial border zone of the 5-day infarcted canine heart. Circ. Res. 77, 1180–1191 (1995).

  85. 85.

    Dun, W. & Boyden, P. A. Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart. Am. J. Physiol. Heart Circ. Physiol. 289, H667–H673 (2005).

  86. 86.

    Jiang, M., Cabo, C., Yao, J., Boyden, P. A. & Tseng, G. Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle. Cardiovasc. Res. 48, 34–43 (2000).

  87. 87.

    Abriel, H., Rougier, J. S. & Jalife, J. Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death. Circ. Res. 116, 1971–1988 (2015).

  88. 88.

    Kaufman, E. S. Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Heart Rhythm 6, S51–S55 (2009).

  89. 89.

    Wagner, S., Maier, L. S. & Bers, D. M. Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death. Circ. Res. 116, 1956–1970 (2015).

  90. 90.

    Echt, D. S. et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 324, 781–788 (1991).

  91. 91.

    Fukuda, K. et al. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circ. Res. 97, 1262–1269 (2005).

  92. 92.

    Dun, W., Danilo, P. Jr., Mohler, P. J. & Boyden, P. A. Microtubular remodeling and decreased expression of Nav1.5 with enhanced EHD4 in cells from the infarcted heart. Life Sci. 201, 72–80 (2018).

  93. 93.

    Vegh, A., Gonczi, M., Miskolczi, G. & Kovacs, M. Regulation of gap junctions by nitric oxide influences the generation of arrhythmias resulting from acute ischemia and reperfusion in vivo. Front. Pharmacol. 4, 76 (2013).

  94. 94.

    Adamson, P. B. & Vanoli, E. Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction. J. Am. Coll. Cardiol. 37, 1741–1748 (2001).

  95. 95.

    Issa, Z. F., Rosenberger, J., Groh, W. J., Miller, J. M. & Zipes, D. P. Ischemic ventricular arrhythmias during heart failure: a canine model to replicate clinical events. Heart Rhythm 2, 979–983 (2005).

  96. 96.

    Schwartz, P. J., Billman, G. E. & Stone, H. L. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death. Circulation 69, 790–800 (1984).

  97. 97.

    Sridhar, A. et al. Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1463–R1472 (2008).

  98. 98.

    Eldar, M. et al. A closed-chest pig model of sustained ventricular tachycardia. Pacing Clin. Electrophysiol. 17, 1603–1609 (1994).

  99. 99.

    Biondi-Zoccai, G. et al. A novel closed-chest porcine model of chronic ischemic heart failure suitable for experimental research in cardiovascular disease. Biomed. Res. Int. 2013, 410631 (2013).

  100. 100.

    Lancaster, L. D., Kern, K. B., Morrison, D. A., Olajos, M. & Goldman, S. Changes in right ventricular relaxation during acute anterior myocardial infarction in pigs. Cardiovasc. Res. 23, 46–52 (1989).

  101. 101.

    Indik, J. H. et al. Predictors of resuscitation in a swine model of ischemic and nonischemic ventricular fibrillation cardiac arrest: superiority of amplitude spectral area and slope to predict a return of spontaneous circulation when resuscitation efforts are prolonged. Crit. Care Med. 38, 2352–2357 (2010).

  102. 102.

    Niemann, J. T., Rosborough, J. P., Youngquist, S. T. & Shah, A. P. Transthoracic defibrillation potential gradients in a closed chest porcine model of prolonged spontaneous and electrically induced ventricular fibrillation. Resuscitation 81, 477–480 (2010).

  103. 103.

    Cherry, B. H., Nguyen, A. Q., Hollrah, R. A., Olivencia-Yurvati, A. H. & Mallet, R. T. Modeling cardiac arrest and resuscitation in the domestic pig. World J. Crit. Care Med. 4, 1–12 (2015).

  104. 104.

    Sasano, T., Kelemen, K., Greener, I. D. & Donahue, J. K. Ventricular tachycardia from the healed myocardial infarction scar: validation of an animal model and utility of gene therapy. Heart Rhythm 6, S91–S97 (2009).

  105. 105.

    Greener, I. D. et al. Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J. Am. Coll. Cardiol. 60, 1103–1110 (2012).

  106. 106.

    Hegyi, B. et al. Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc. Natl Acad. Sci. USA 115, E3036–E3044 (2018).

  107. 107.

    Sinno, H. et al. Atrial ischemia promotes atrial fibrillation in dogs. Circulation 107, 1930–1936 (2003).

  108. 108.

    Rivard, L. et al. The pharmacological response of ischemia-related atrial fibrillation in dogs: evidence for substrate-specific efficacy. Cardiovasc. Res. 74, 104–113 (2007).

  109. 109.

    Nishida, K. et al. Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation 123, 137–146 (2011).

  110. 110.

    Li, Y. et al. Development of human-like advanced coronary plaques in low-density lipoprotein receptor knockout pigs and justification for statin treatment before formation of atherosclerotic plaques. J. Am. Heart Assoc. 5, e002779 (2016).

  111. 111.

    Wijffels, M. C., Kirchhof, C. J., Dorland, R. & Allessie, M. A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92, 1954–1968 (1995).

  112. 112.

    Ausma, J. et al. Dedifferentiation of atrial cardiomyocytes as a result of chronic atrial fibrillation. Am. J. Pathol. 151, 985–997 (1997).

  113. 113.

    Greiser, M. et al. Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation. J. Mol. Cell. Cardiol. 46, 385–394 (2009).

  114. 114.

    Allessie, M. A., Wijffels, M. C. & Dorland, R. Mechanisms of pharmacologic cardioversion of atrial fibrillation by class I drugs. J. Cardiovasc. Electrophysiol. 9, S69–S77 (1998).

  115. 115.

    Morillo, C. A., Klein, G. J., Jones, D. L. & Guiraudon, C. M. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation 91, 1588–1595 (1995).

  116. 116.

    Yamamoto, W. et al. Effects of the selective KACh channel blocker NTC-801 on atrial fibrillation in a canine model of atrial tachypacing: comparison with class Ic and III drugs. J. Cardiovasc. Pharmacol. 63, 421–427 (2014).

  117. 117.

    Fareh, S., Villemaire, C. & Nattel, S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation 98, 2202–2209 (1998).

  118. 118.

    Anne, W. et al. Self-terminating AF depends on electrical remodeling while persistent AF depends on additional structural changes in a rapid atrially paced sheep model. J. Mol. Cell. Cardiol. 43, 148–158 (2007).

  119. 119.

    Filgueiras-Rama, D. et al. Long-term frequency gradients during persistent atrial fibrillation in sheep are associated with stable sources in the left atrium. Circ. Arrhythm. Electrophysiol. 5, 1160–1167 (2012).

  120. 120.

    Zhao, Y., Gu, T. X., Zhang, G. W., Liu, H. G. & Wang, C. Losartan affects the substrate for atrial fibrillation maintenance in a rabbit model. Cardiovasc. Pathol. 22, 383–388 (2013).

  121. 121.

    Lin, J. L. et al. Electrophysiological mapping and histological examinations of the swine atrium with sustained (> or = 24 h) atrial fibrillation: a suitable animal model for studying human atrial fibrillation. Cardiology 99, 78–84 (2003).

  122. 122.

    Bauer, A., McDonald, A. D. & Donahue, J. K. Pathophysiological findings in a model of persistent atrial fibrillation and severe congestive heart failure. Cardiovasc. Res. 61, 764–770 (2004).

  123. 123.

    Bauer, A. et al. The new selective I(Ks)-blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation. Basic Res. Cardiol. 100, 270–278 (2005).

  124. 124.

    Chen, C. L. et al. Upregulation of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases in rapid atrial pacing-induced atrial fibrillation. J. Mol. Cell. Cardiol. 45, 742–753 (2008).

  125. 125.

    Bikou, O. et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc. Res. 92, 218–225 (2011).

  126. 126.

    Igarashi, T. et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125, 216–225 (2012).

  127. 127.

    Schmidt, C. et al. Cloning, functional characterization, and remodeling of K2P3.1 (TASK-1) potassium channels in a porcine model of atrial fibrillation and heart failure. Heart Rhythm 11, 1798–1805 (2014).

  128. 128.

    Lugenbiel, P. et al. Atrial fibrillation complicated by heart failure induces distinct remodeling of calcium cycling proteins. PLOS ONE 10, e0116395 (2015).

  129. 129.

    Kazui, T. et al. The impact of 6 weeks of atrial fibrillation on left atrial and ventricular structure and function. J. Thorac. Cardiovasc. Surg. 150, 1602–1608 (2015).

  130. 130.

    Schwarzl, M. et al. A porcine model of early atrial fibrillation using a custom-built, radio transmission-controlled pacemaker. J. Electrocardiol. 49, 124–131 (2016).

  131. 131.

    Spinale, F. G. et al. Chronic supraventricular tachycardia causes ventricular dysfunction and subendocardial injury in swine. Am. J. Physiol. 259, H218–H229 (1990).

  132. 132.

    Yarbrough, W. M. & Spinale, F. G. Large animal models of congestive heart failure: a critical step in translating basic observations into clinical applications. J. Nucl. Cardiol. 10, 77–86 (2003).

  133. 133.

    Jia, X. et al. MicroRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model. PLOS ONE 8, e85639 (2013).

  134. 134.

    Nuss, H. B. et al. Reversal of potassium channel deficiency in cells from failing hearts by adenoviral gene transfer: a prototype for gene therapy for disorders of cardiac excitability and contractility. Gene Ther. 3, 900–912 (1996).

  135. 135.

    Kaab, S. et al. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ. Res. 78, 262–273 (1996).

  136. 136.

    Pak, P. H. et al. Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy. J. Am. Coll. Cardiol. 30, 576–584 (1997).

  137. 137.

    Kaab, S. et al. Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98, 1383–1393 (1998).

  138. 138.

    O’Rourke, B. et al. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies. Circ. Res. 84, 562–570 (1999).

  139. 139.

    Nuss, H. B., Kaab, S., Kass, D. A., Tomaselli, G. F. & Marban, E. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am. J. Physiol. 277, H80–H91 (1999).

  140. 140.

    Balaji, S. et al. Inducible lethal ventricular arrhythmias in swine with pacing-induced heart failure. Basic Res. Cardiol. 94, 496–503 (1999).

  141. 141.

    Chow, E., Woodard, J. C. & Farrar, D. J. Rapid ventricular pacing in pigs: an experimental model of congestive heart failure. Am. J. Physiol. 258, H1603–H1605 (1990).

  142. 142.

    Lacroix, D. et al. Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy. Cardiovasc. Res. 54, 42–50 (2002).

  143. 143.

    Finckh, M. et al. Enhanced cardiac angiotensinogen gene expression and angiotensin converting enzyme activity in tachypacing-induced heart failure in rats. Basic Res. Cardiol. 86, 303–316 (1991).

  144. 144.

    Mulla, W. et al. Prominent differences in left ventricular performance and myocardial properties between right ventricular and left ventricular-based pacing modes in rats. Sci. Rep. 7, 5931 (2017).

  145. 145.

    Nishida, K., Michael, G., Dobrev, D. & Nattel, S. Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace 12, 160–172 (2010).

  146. 146.

    Shinagawa, K., Shi, Y. F., Tardif, J. C., Leung, T. K. & Nattel, S. Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs. Circulation 105, 2672–2678 (2002).

  147. 147.

    Cha, T. J., Ehrlich, J. R., Zhang, L. & Nattel, S. Atrial ionic remodeling induced by atrial tachycardia in the presence of congestive heart failure. Circulation 110, 1520–1526 (2004).

  148. 148.

    Li, D., Fareh, S., Leung, T. K. & Nattel, S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100, 87–95 (1999).

  149. 149.

    Li, D. et al. Effects of experimental heart failure on atrial cellular and ionic electrophysiology. Circulation 101, 2631–2638 (2000).

  150. 150.

    Burstein, B. et al. Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure. Circ. Res. 105, 1213–1222 (2009).

  151. 151.

    Cardin, S. et al. Marked differences between atrial and ventricular gene-expression remodeling in dogs with experimental heart failure. J. Mol. Cell. Cardiol. 45, 821–831 (2008).

  152. 152.

    Kaab, S. et al. Global gene expression in human myocardium-oligonucleotide microarray analysis of regional diversity and transcriptional regulation in heart failure. J. Mol. Med. 82, 308–316 (2004).

  153. 153.

    Barth, A. S. et al. Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature. Circ. Res. 96, 1022–1029 (2005).

  154. 154.

    Dawson, K. et al. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 127, 1466–1475 (2013).

  155. 155.

    Chen, Y. et al. Detailed characterization of microRNA changes in a canine heart failure model: relationship to arrhythmogenic structural remodeling. J. Mol. Cell. Cardiol. 77, 113–124 (2014).

  156. 156.

    Luo, X. et al. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Invest. 123, 1939–1951 (2013).

  157. 157.

    Bessissow, A., Khan, J., Devereaux, P. J., Alvarez-Garcia, J. & Alonso-Coello, P. Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview. J. Thromb. Haemost. 13 (Suppl. 1), 304–312 (2015).

  158. 158.

    Bruins, P. et al. Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia. Circulation 96, 3542–3548 (1997).

  159. 159.

    Chung, M. K. et al. C-Reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation. Circulation 104, 2886–2891 (2001).

  160. 160.

    Pagé, P. L., Plumb, V. J., Okumura, K. & Waldo, A. L. A new animal model of atrial flutter. J. Am. Coll. Cardiol. 8, 872–879 (1986).

  161. 161.

    Tselentakis, E. V., Woodford, E., Chandy, J., Gaudette, G. R. & Saltman, A. E. Inflammation effects on the electrical properties of atrial tissue and inducibility of postoperative atrial fibrillation. J. Surg. Res. 135, 68–75 (2006).

  162. 162.

    Zhang, Y. et al. Role of inflammation in the initiation and maintenance of atrial fibrillation and the protective effect of atorvastatin in a goat model of aseptic pericarditis. Mol. Med. Rep. 11, 2615–2623 (2015).

  163. 163.

    Kumagai, K., Nakashima, H. & Saku, K. The HMG-CoA reductase inhibitor atorvastatin prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model. Cardiovasc. Res. 62, 105–111 (2004).

  164. 164.

    Song, Y. B. et al. The effects of atorvastatin on the occurrence of postoperative atrial fibrillation after off-pump coronary artery bypass grafting surgery. Am. Heart J. 156, 373 (2008).

  165. 165.

    Fu, X. X. et al. Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis. Int. J. Mol. Med. 36, 83–92 (2015).

  166. 166.

    Yu, G., Yu, Y., Li, Y. N. & Shu, R. Effect of periodontitis on susceptibility to atrial fibrillation in an animal model. J. Electrocardiol. 43, 359–366 (2010).

  167. 167.

    Fung, G., Luo, H., Qiu, Y., Yang, D. & McManus, B. Myocarditis. Circ. Res. 118, 496–514 (2016).

  168. 168.

    Grabmaier, U. et al. Soluble vascular cell adhesion molecule-1 (VCAM-1) as a biomarker in the mouse model of experimental autoimmune myocarditis (EAM). PLOS ONE 11, e0158299 (2016).

  169. 169.

    Tang, Q. et al. Antiarrhythmic effect of atorvastatin on autoimmune myocarditis is mediated by improving myocardial repolarization. Life Sci. 80, 601–608 (2007).

  170. 170.

    Ohmae, M., Kishimoto, C. & Tomioka, N. Complete atrioventricular block in experimental murine myocarditis. J. Electrocardiol. 38, 230–234 (2005).

  171. 171.

    Terasaki, F. et al. Arrhythmias in Coxsackie B3 virus myocarditis. Continuous electrocardiography in conscious mice and histopathology of the heart with special reference to the conduction system. Heart Vessels Suppl. 5, 45–50 (1990).

  172. 172.

    Steinke, K. et al. Coxsackievirus B3 modulates cardiac ion channels. FASEB J. 27, 4108–4121 (2013).

  173. 173.

    Izumi, T., Kodama, M. & Shibata, A. Experimental giant cell myocarditis induced by cardiac myosin immunization. Eur. Heart J. 12, D166–D168 (1991).

  174. 174.

    Radhakrishnan, V. V. Experimental myocarditis in the guinea-pig. Cardiovasc. Res. 31, 651–654 (1996).

  175. 175.

    Gwathmey, J. K. et al. An experimental model of acute and subacute viral myocarditis in the pig. J. Am. Coll. Cardiol. 19, 864–869 (1992).

  176. 176.

    Kamiyama, K. et al. Modulation of glucocorticoid receptor expression, inflammation, and cell apoptosis in septic guinea pig lungs using methylprednisolone. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L998–L1006 (2008).

  177. 177.

    Aoki, Y. et al. Role of ion channels in sepsis-induced atrial tachyarrhythmias in guinea pigs. Br. J. Pharmacol. 166, 390–400 (2012).

  178. 178.

    Chen, P. S., Chen, L. S., Fishbein, M. C., Lin, S. F. & Nattel, S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ. Res. 114, 1500–1515 (2014).

  179. 179.

    Guasch, E. et al. Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model. J. Am. Coll. Cardiol. 62, 68–77 (2013).

  180. 180.

    Allessie, M. A., Lammers, W. J., Bonke, I. M. & Hollen, J. Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog. Circulation 70, 123–135 (1984).

  181. 181.

    Wang, Z., Page, P. & Nattel, S. Mechanism of flecainide’s antiarrhythmic action in experimental atrial fibrillation. Circ. Res. 71, 271–287 (1992).

  182. 182.

    Hayashi, H., Fujiki, A., Tani, M., Usui, M. & Inoue, H. Different effects of class Ic and III antiarrhythmic drugs on vagotonic atrial fibrillation in the canine heart. J. Cardiovasc. Pharmacol. 31, 101–107 (1998).

  183. 183.

    Aidonidis, I., Poyatzi, A., Stamatiou, G., Lymberi, M. & Molyvdas, P. A. Assessment of local atrial repolarization in a porcine acetylcholine model of atrial flutter and fibrillation. Acta Cardiol. 64, 59–64 (2009).

  184. 184.

    Lee, A. M. et al. Importance of atrial surface area and refractory period in sustaining atrial fibrillation: testing the critical mass hypothesis. J. Thorac. Cardiovasc. Surg. 146, 593–598 (2013).

  185. 185.

    Carneiro, J. S. et al. The selective cardiac late sodium current inhibitor GS-458967 suppresses autonomically triggered atrial fibrillation in an intact porcine model. J. Cardiovasc. Electrophysiol. 26, 1364–1369 (2015).

  186. 186.

    Frame, L. H., Page, R. L. & Hoffman, B. F. Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter. Circ. Res. 58, 495–511 (1986).

  187. 187.

    Rosenblueth, A. & Garcia Ramos, J. Studies on flutter and fibrillation; the influence of artificial obstacles on experimental auricular flutter. Am. Heart J. 33, 677–684 (1947).

  188. 188.

    Feld, G. K. & Shahandeh-Rad, F. Activation patterns in experimental canine atrial flutter produced by right atrial crush injury. J. Am. Coll. Cardiol. 20, 441–451 (1992).

  189. 189.

    Janse, M. J., Opthof, T. & Kléber, A. G. Animal models of cardiac arrhythmias. Cardiovasc. Res. 39, 165–177 (1997).

  190. 190.

    Brunner, S. et al. Alcohol consumption, sinus tachycardia, and cardiac arrhythmias at the Munich Octoberfest: results from the Munich Beer Related Electrocardiogram Workup Study (MunichBREW). Eur. Heart J. 38, 2100–2106 (2017).

  191. 191.

    Rich, E. C., Siebold, C. & Campion, B. Alcohol-related acute atrial fibrillation. A case-control study and review of 40 patients. Arch. Intern. Med. 145, 830–833 (1985).

  192. 192.

    Anadon, M. J. et al. Alcohol concentration determines the type of atrial arrhythmia induced in a porcine model of acute alcoholic intoxication. Pacing Clin. Electrophysiol. 199, 1962–1967 (1996).

  193. 193.

    Bruner, L. H., Hilliker, K. S. & Roth, R. A. Pulmonary hypertension and ECG changes from monocrotaline pyrrole in the rat. Am. J. Physiol. 245, H300–H306 (1983).

  194. 194.

    Rosenberg, H. C. & Rabinovitch, M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am. J. Physiol. 255, H1484–H1491 (1988).

  195. 195.

    Guihaire, J. et al. Experimental models of right heart failure: a window for translational research in pulmonary hypertension. Semin. Respir. Crit. Care Med. 34, 689–699 (2013).

  196. 196.

    Temple, I. P. et al. Atrioventricular node dysfunction and ion channel transcriptome in pulmonary hypertension. Circ. Arrhythm. Electrophysiol. 9, e003432 (2016).

  197. 197.

    Rocchetti, M. et al. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovasc. Res. 104, 37–48 (2014).

  198. 198.

    Gami, A. S. et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 110, 364–367 (2004).

  199. 199.

    Haugan, K., Lam, H. R., Knudsen, C. B. & Petersen, J. S. Atrial fibrillation in rats induced by rapid transesophageal atrial pacing during brief episodes of asphyxia: a new in vivo model. J. Cardiovasc. Pharmacol. 44, 125–135 (2004).

  200. 200.

    Iwasaki, Y. K. et al. Determinants of atrial fibrillation in an animal model of obesity and acute obstructive sleep apnea. Heart Rhythm 9, 1409–1416 (2012).

  201. 201.

    Iwasaki, Y. K. et al. Atrial fibrillation promotion with long-term repetitive obstructive sleep apnea in a rat model. J. Am. Coll. Cardiol. 64, 2013–2023 (2014).

  202. 202.

    Channaveerappa, D. et al. Atrial electrophysiological and molecular remodelling induced by obstructive sleep apnoea. J. Cell. Mol. Med. 21, 2223–2235 (2017).

  203. 203.

    Linz, D. et al. Low-level but not high-level baroreceptor stimulation inhibits atrial fibrillation in a pig model of sleep apnea. J. Cardiovasc. Electrophysiol. 27, 1086–1092 (2016).

  204. 204.

    Linz, D., Schotten, U., Neuberger, H. R., Bohm, M. & Wirth, K. Negative tracheal pressure during obstructive respiratory events promotes atrial fibrillation by vagal activation. Heart Rhythm 8, 1436–1443 (2011).

  205. 205.

    Linz, D. et al. Effect of renal denervation on neurohumoral activation triggering atrial fibrillation in obstructive sleep apnea. Hypertension 62, 767–774 (2013).

  206. 206.

    Liu, Y. B. et al. Sympathetic nerve sprouting, electrical remodeling, and increased vulnerability to ventricular fibrillation in hypercholesterolemic rabbits. Circ. Res. 92, 1145–1152 (2003).

  207. 207.

    Wiegerinck, R. F. et al. Transmural dispersion of refractoriness and conduction velocity is associated with heterogeneously reduced connexin43 in a rabbit model of heart failure. Heart Rhythm 5, 1178–1185 (2008).

  208. 208.

    Maruyama, M. et al. Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles. Heart Rhythm 11, 697–706 (2014).

  209. 209.

    Gerhardy, A., Scholtysik, G., Schaad, A., Haltiner, R. & Hess, T. Generating and influencing Torsades de Pointes—like polymorphic ventricular tachycardia in isolated guinea pig hearts. Basic Res. Cardiol. 93, 285–294 (1998).

  210. 210.

    Janse, M. J., van Capelle, F. J., Freud, G. E. & Durrer, D. Circus movement within the AV node as a basis for supraventricular tachycardia as shown by multiple microelectrode recording in the isolated rabbit heart. Circ. Res. 28, 403–414 (1971).

  211. 211.

    Ravelli, F. & Allessie, M. Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation 96, 1686–1695 (1997).

  212. 212.

    Choy, L., Yeo, J. M., Tse, V., Chan, S. P. & Tse, G. Cardiac disease and arrhythmogenesis: mechanistic insights from mouse models. Int. J. Cardiol. Heart Vasc. 12, 1–10 (2016).

  213. 213.

    Huang, C. L. Murine electrophysiological models of cardiac arrhythmogenesis. Physiol. Rev. 97, 283–409 (2017).

  214. 214.

    Riley, G., Syeda, F., Kirchhof, P. & Fabritz, L. An introduction to murine models of atrial fibrillation. Front. Physiol. 3, 296 (2012).

  215. 215.

    Brunner, M. et al. Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome. J. Clin. Invest. 118, 2246–2259 (2008).

  216. 216.

    Polejaeva, I. A. et al. Increased susceptibility to atrial fibrillation secondary to atrial fibrosis in transgenic goats expressing transforming growth factor-beta1. J. Cardiovasc. Electrophysiol. 27, 1220–1229 (2016).

  217. 217.

    Park, D. S. et al. Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. J. Clin. Invest. 125, 403–412 (2015).

  218. 218.

    Lumb, G. D. in Swine in Biochemical Research (eds Busiad, L. K. & McClellan, R. O.) (Frayn Prontong Co, Seattle, 1966).

  219. 219.

    Chan, J. L. et al. Encouraging experience using multi-transgenic xenografts in a pig-to-baboon cardiac xenotransplantation model. Xenotransplantation 24, e12330 (2017).

  220. 220.

    McGregor, C. G. A. & Byrne, G. W. Porcine to human heart transplantation: is clinical application now appropriate? J. Immunol. Res. 2017, 2534653 (2017).

  221. 221.

    Abicht, J. M. et al. Multiple genetically modified GTKO/hCD46/HLA-E/hbeta2-mg porcine hearts are protected from complement activation and natural killer cell infiltration during ex vivo perfusion with human blood. Xenotransplantation 25, e12390 (2018).

  222. 222.

    Hill, A. J. & Iaizzo, P. A. in Handbook of Cardiac Anatomy, Physiology, and Devices (ed. Iaizzo, P. A.) 81–91 (Humana Press, Totowa, NJ, 2005).

  223. 223.

    Sahni, D., Kaur, G. D., Jit, H. & Jit, I. Anatomy and distribution of coronary arteries in pig in comparison with man. Indian J. Med. Res. 127, 564–570 (2008).

  224. 224.

    Hughes, G. C., Post, M. J., Simons, M. & Annex, B. H. Translational physiology: porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis. J. Appl. Physiol. 94, 1689–1701 (2003).

  225. 225.

    Hearse, D. J. The elusive coypu: the importance of collateral flow and the search for an alternative to the dog. Cardiovasc. Res. 45, 215–219 (2000).

  226. 226.

    Bode, G. et al. The utility of the minipig as an animal model in regulatory toxicology. J. Pharmacol. Toxicol. Methods 62, 196–220 (2010).

  227. 227.

    Podesser, B. et al. Epicardial branches of the coronary arteries and their distribution in the rabbit heart: the rabbit heart as a model of regional ischemia. Anat. Rec. 247, 521–527 (1997).

  228. 228.

    Kaese, S. et al. The ECG in cardiovascular-relevant animal models of electrophysiology. Herzschrittmacherther Elektrophysiol. 24, 84–91 (2013).

  229. 229.

    Bharati, S. et al. The conduction system of the swine heart. Chest 100, 207–212 (1991).

  230. 230.

    Lelovas, P. P., Kostomitsopoulos, N. G. & Xanthos, T. T. A comparative anatomic and physiologic overview of the porcine heart. J. Am. Assoc. Lab. Anim. Sci. 53, 432–438 (2014).

  231. 231.

    Li, J. et al. Three-dimensional computer model of the right atrium including the sinoatrial and atrioventricular nodes predicts classical nodal behaviours. PLOS ONE 9, e112547 (2014).

  232. 232.

    Such, L. et al. Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart. J. Appl. Physiol. 92, 225–229 (2002).

  233. 233.

    Bordas, R. et al. Rabbit-specific ventricular model of cardiac electrophysiological function including specialized conduction system. Prog. Biophys. Mol. Biol. 107, 90–100 (2011).

  234. 234.

    Bowman, T. A. & Hughes, H. C. Swine as an in vivo model for electrophysiologic evaluation of cardiac pacing parameters. Pacing Clin. Electrophysiol. 7, 187–194 (1984).

  235. 235.

    Santana, L. F., Cheng, E. P. & Lederer, W. J. How does the shape of the cardiac action potential control calcium signaling and contraction in the heart? J. Mol. Cell. Cardiol. 49, 901–903 (2010).

  236. 236.

    Varro, A., Lathrop, D. A., Hester, S. B., Nanasi, P. P. & Papp, J. G. Ionic currents and action potentials in rabbit, rat, and guinea pig ventricular myocytes. Basic Res. Cardiol. 88, 93–102 (1993).

  237. 237.

    Mow, T., Arlock, P., Laursen, M. & Ganderup, N. Major ion currents except ito are present in the ventricle of the Göttingen minipig heart. J. Pharmacol. Toxicol. Methods 58, 165 (2008).

  238. 238.

    Li, G. R. et al. Calcium-activated transient outward chloride current and phase 1 repolarization of swine ventricular action potential. Cardiovasc. Res. 58, 89–98 (2003).

  239. 239.

    Yue, L., Melnyk, P., Gaspo, R., Wang, Z. & Nattel, S. Molecular mechanisms underlying ionic remodeling in a dog model of atrial fibrillation. Circ. Res. 84, 776–784 (1999).

  240. 240.

    Fedida, D., Shimoni, Y. & Giles, W. R. Alpha-adrenergic modulation of the transient outward current in rabbit atrial myocytes. J. Physiol. 423, 257–277 (1990).

  241. 241.

    Chang, K. et al. Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer. BMC Biotechnol. 2, 5 (2002).

  242. 242.

    Kurome, M., Ueda, H., Tomii, R., Naruse, K. & Nagashima, H. Production of transgenic-clone pigs by the combination of ICSI-mediated gene transfer with somatic cell nuclear transfer. Transgen. Res. 15, 229–240 (2006).

  243. 243.

    Nottle, M. B. et al. Effect of DNA concentration on transgenesis rates in mice and pigs. Transgen. Res. 10, 523–531 (2001).

  244. 244.

    Renner, S. et al. Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59, 1228–1238 (2010).

  245. 245.

    Wu, Z. et al. Pig transgenesis by piggyBac transposition in combination with somatic cell nuclear transfer. Transgen. Res. 22, 1107–1118 (2013).

  246. 246.

    Renner, S. et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 62, 1505–1511 (2013).

  247. 247.

    Hinkel, R. et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J. Am. Coll. Cardiol. 69, 131–143 (2017).

  248. 248.

    Blutke, A. et al. The Munich MIDY Pig Biobank — a unique resource for studying organ crosstalk in diabetes. Mol. Metab. 6, 931–940 (2017).

  249. 249.

    Gaj, T., Gersbach, C. A. & Barbas, C. F. 3rd. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31, 397–405 (2013).

  250. 250.

    Carlson, D. F. et al. Efficient TALEN-mediated gene knockout in livestock. Proc. Natl Acad. Sci. USA 109, 17382–17387 (2012).

  251. 251.

    Christian, M. et al. Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186, 757–761 (2010).

  252. 252.

    Fernandez, A., Josa, S. & Montoliu, L. A history of genome editing in mammals. Mamm. Genome 28, 237–246 (2017).

  253. 253.

    Kim, Y. G., Cha, J. & Chandrasegaran, S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc. Natl Acad. Sci. USA 93, 1156–1160 (1996).

  254. 254.

    Klymiuk, N. et al. Homologous recombination contributes to the repair of zinc-finger-nuclease induced double strand breaks in pig primary cells and facilitates recombination with exogenous DNA. J. Biotechnol. 177, 74–81 (2014).

  255. 255.

    Motta, B. M., Pramstaller, P. P., Hicks, A. A. & Rossini, A. The impact of CRISPR/Cas9 technology on cardiac research: from disease modelling to therapeutic approaches. Stem Cells Int. 2017, 8960236 (2017).

  256. 256.

    Pattanayak, V., Guilinger, J. P. & Liu, D. R. Determining the specificities of TALENs, Cas9, and other genome-editing enzymes. Methods Enzymol. 546, 47–78 (2014).

  257. 257.

    Yang, D. et al. Generation of PPARgamma mono-allelic knockout pigs via zinc-finger nucleases and nuclear transfer cloning. Cell Res. 21, 979–982 (2011).

  258. 258.

    Yao, J., Huang, J. & Zhao, J. Genome editing revolutionize the creation of genetically modified pigs for modeling human diseases. Hum. Genet. 135, 1093–1105 (2016).

  259. 259.

    Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

  260. 260.

    Wiedenheft, B., Sternberg, S. H. & Doudna, J. A. RNA-guided genetic silencing systems in bacteria and archaea. Nature 482, 331–338 (2012).

  261. 261.

    Heigwer, F., Kerr, G. & Boutros, M. E-CRISP: fast CRISPR target site identification. Nat. Methods 11, 122–123 (2014).

  262. 262.

    Labun, K., Montague, T. G., Gagnon, J. A., Thyme, S. B. & Valen, E. CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering. Nucleic Acids Res. 44, W272–W276 (2016).

  263. 263.

    Hsu, P. D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827–832 (2013).

  264. 264.

    Whitworth, K. M. et al. Use of the CRISPR/Cas9 system to produce genetically engineered pigs from in vitro-derived oocytes and embryos. Biol. Reprod. 91, 78 (2014).

  265. 265.

    Huang, L. et al. CRISPR/Cas9-mediated ApoE−/− and LDLR−/− double gene knockout in pigs elevates serum LDL-C and TC levels. Oncotarget 8, 37751–37760 (2017).

  266. 266.

    Niu, D. et al. Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 357, 1303–1307 (2017).

  267. 267.

    Kaab, S. & Näbauer, M. Diversity of ion channel expression in health and disease. Eur. Heart J. Suppl. 3, K31–K40 (2001).

  268. 268.

    Macianskiene, R. et al. Action potential changes associated with a slowed inactivation of cardiac voltage-gated sodium channels by KB130015. Br. J. Pharmacol. 139, 1469–1479 (2003).

  269. 269.

    Tsuchida, K., Kaneko, K. & Aihara, H. Electrophysiological effects of CD-349, a dihydropyridine-type calcium antagonist, on goat cardiac Purkinje fibers. J. Cardiovasc. Pharmacol. 18, 769–776 (1991).

  270. 270.

    Hume, J. R. & Uehara, A. Ionic basis of the different action potential configurations of single guinea-pig atrial and ventricular myocytes. J. Physiol. 368, 525–544 (1985).

  271. 271.

    Anumonwo, J. M., Tallini, Y. N., Vetter, F. J. & Jalife, J. Action potential characteristics and arrhythmogenic properties of the cardiac conduction system of the murine heart. Circ. Res. 89, 329–335 (2001).

  272. 272.

    Freudig, D. Lexikon der Biologie (Spektrum Akademischer Verlag, Heidelberg, 1999).

  273. 273.

    Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

  274. 274.

    Groenen, M. A. et al. Analyses of pig genomes provide insight into porcine demography and evolution. Nature 491, 393–398 (2012).

  275. 275.

    Jones, R. D., Stuart, B. P., Greufe, N. P. & Landes, A. M. Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent animal model for regulatory and mechanistic toxicology studies. Lab Anim. 33, 356–365 (1999).

  276. 276.

    Paslawska, U. et al. Normal electrocardiographic and echocardiographic (M-mode and two-dimensional) values in Polish Landrace pigs. Acta Vet. Scand. 56, 54 (2014).

  277. 277.

    Stubhan, M. et al. Evaluation of cardiovascular and ECG parameters in the normal, freely moving Gottingen Minipig. J. Pharmacol. Toxicol. Methods 57, 202–211 (2008).

  278. 278.

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

  279. 279.

    Macfarlane, P. et al. Comprehensive Electrocardiology (Springer Verlag London Ltd, London, 2010).

  280. 280.

    Carneiro, M. et al. Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication. Science 345, 1074–1079 (2014).

  281. 281.

    Lord, B., Boswood, A. & Petrie, A. Electrocardiography of the normal domestic pet rabbit. Vet. Rec. 167, 961–965 (2010).

  282. 282.

    Weiss, J., Becker, K., Bernsmann, E., Dietrich, H. & Nebendahl, K. Tierpflege in Forschung und Klinik (Enke, 2008).

  283. 283.

    Wolfensohn, S. & Llyod, M. Handbook of Laboratory Animal Management and Welfare (Wiley, 2003).

  284. 284.

    Dhein, S., Mohr, F. & Delmar, M. Practical Methods in Cardiovascular Research (Springer-Verlag Berlin Heidelberg, 2005).

  285. 285.

    Gnerre, S. et al. High-quality draft assemblies of mammalian genomes from massively parallel sequence data. Proc. Natl Acad. Sci. USA 108, 1513–1518 (2011).

  286. 286.

    Knollmann, B. C., Schober, T., Petersen, A. O., Sirenko, S. G. & Franz, M. R. Action potential characterization in intact mouse heart: steady-state cycle length dependence and electrical restitution. Am. J. Physiol. Heart Circ. Physiol. 292, H614–H621 (2007).

  287. 287.

    EMBL-EBI. Ensembl genome browser 95. (2019).

  288. 288.

    Nerbonne, J. M. Mouse models of arrhythmogenic cardiovascular disease: challenges and opportunities. Curr. Opin. Pharmacol. 15, 107–114 (2014).

  289. 289.

    Gussak, I., Chaitman, B. R., Kopecky, S. L. & Nerbonne, J. M. Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J. Electrocardiol. 33, 159–170 (2000).

  290. 290.

    Liu, G. et al. In vivo temporal and spatial distribution of depolarization and repolarization and the illusive murine T wave. J. Physiol. 555, 267–279 (2004).

  291. 291.

    Mitchell, G. F., Jeron, A. & Koren, G. Measurement of heart rate and Q-T interval in the conscious mouse. Am. J. Physiol. 274, H747–H751 (1998).

  292. 292.

    Bers, D. M., Lederer, W. J. & Berlin, J. R. Intracellular Ca transients in rat cardiac myocytes: role of Na-Ca exchange in excitation-contraction coupling. Am. J. Physiol. 258, C944–C954 (1990).

  293. 293.

    De Carvalho, C. A. M. & Thomazini, J. A. Study of Wistar rats heart at different stages in the evolutionary cycle. Int. J. Morphol. 32, 614–617 (2014).

  294. 294.

    Busch, A. E. et al. The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels expressed in Xenopus oocytes and IKs in guinea pig cardiac myocytes. Biochem. Biophys. Res. Commun. 202, 265–270 (1994).

  295. 295.

    Webster, S. H. & Liljegren, E. J. Organ:body weight ratios for certain organs of laboratory animals. II. Guinea pig. Am. J. Anat. 85, 199–230 (1949).

  296. 296.

    Kijtawornrat, A., Sawangkoon, S., Simonetti, O. & Hamlin, R. Body surface potentials generated by the heart of normal guinea pigs. Thai J. Vet. Med. 41, 463–470 (2011).

  297. 297.

    Stengl, M. Experimental models of spontaneous ventricular arrhythmias and of sudden cardiac death. Physiol. Res. 59 (Suppl. 1), 25–31 (2010).

  298. 298.

    Farkas, A., Batey, A. J. & Coker, S. J. How to measure electrocardiographic QT interval in the anaesthetized rabbit. J. Pharmacol. Toxicol. Methods 50, 175–185 (2004).

  299. 299.

    Dosdall, D. J. et al. Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs. Am. J. Physiol. Heart Circ. Physiol. 305, H725–H731 (2013).

  300. 300.

    Lipovetsky, G., Fenoglio, J. J., Gieger, M., Srinivasan, M. R. & Dobelle, W. H. Coronary artery anatomy of the goat. Artif. Organs 7, 238–245 (1983).

  301. 301.

    Ahmed, J. A. & Sanyal, S. Electrocardiographic studies in Garol sheep and black Bengal goats. Res. J. Cardiol. 1, 1–8 (2008).

  302. 302.

    Upadhyay, R. C. & Sud, S. C. Electrocardiogram of the goat. Indian J. Exp. Biol. 15, 359–362 (1977).

  303. 303.

    Donahue, J. K. in Clinical Cardiac Pacing, Defibrillation & Resynchronization Therapy 4th edn (eds Ellenbogen, K. A., Kay, G. N., Lau, C.-P. & Wilkoff, B. L.) 191–194 (Elsevier/Saunders, 2011).

  304. 304.

    Hamlin, R. L., Smith, C. R. & Smetzer, D. L. Sinus arrhythmia in the dog. Am. J. Physiol. 210, 321–328 (1966).

  305. 305.

    Lunney, J. K. Advances in swine biomedical model genomics. Int. J. Biol. Sci. 3, 179–184 (2007).

  306. 306.

    Swindle, M. M., Makin, A., Herron, A. J., Clubb, F. J. Jr & Frazier, K. S. Swine as models in biomedical research and toxicology testing. Vet. Pathol. 49, 344–356 (2011).

  307. 307.

    Wolf, E., Braun-Reichhart, C., Streckel, E. & Renner, S. Genetically engineered pig models for diabetes research. Transgen. Res. 23, 27–38 (2014).

  308. 308.

    Renner, S. et al. Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research. Theriogenology 86, 406–421 (2016).

  309. 309.

    Kleinert, M. et al. Animal models of obesity and diabetes mellitus. Nat. Rev. Endocrinol. 14, 140–162 (2018).

  310. 310.

    Aigner, B. et al. Transgenic pigs as models for translational biomedical research. J. Mol. Med. 88, 653–664 (2010).

  311. 311.

    Rehbinder, C. et al. FELASA recommendations for the health monitoring of breeding colonies and experimental units of cats, dogs and pigs: Report of the Federation of European Laboratory Animal Science Associations (FELASA) Working Group on Animal Health. Lab. Anim. 32, 1–17 (1998).

  312. 312.

    Wolf, E. et al. Transgenic technology in farm animals — progress and perspectives. Exp. Physiol. 85, 615–625 (2000).

Download references


The authors received support from the German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK); 81Z4600241, 81X3600208 and 81X2600249), the Förderprogramm für Forschung und Lehre (FöFoLe; 962; 29/2017), the German Centre for Diabetes Research (Deutsches Zentrum für Diabetes-Forschung (DZD)) and the German Research Council (DFG; TRR127, SFB1123 and SFB914).

Reviewer information

Nature Reviews Cardiology thanks M. A. Vos and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

S.C., C.B., D.S. and P.T. researched data for the article and wrote the manuscript. All the authors discussed its content and reviewed and edited the manuscript before submission.

Correspondence to Sebastian Clauss.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Animal models for arrhythmia research.
Fig. 2: Cardiac action potentials in different species.
Fig. 3: A practical trio of animal models for translational research.
Fig. 4: Generation of genetically modified pigs by CRISPR–Cas.