Naturally Occurring and Iatrogenic Animal Models of Valvular, Infectious, and Arrhythmic Cardiovascular Disease

  • David R. Gross


Most naturally occurring congenital cardiovascular entities found in humans have been identified in one or more species of animals but the utility of these naturally occurring models as research subjects is not well established. Many of the congenital diseases are associated with noncardiovascular defects and some of these may result in infertility, impotence, and other reproductive problems that preclude the breeding of these animals to obtain adequate numbers for research purposes. The advent of sophisticated genetic testing has made the identification of specific genes responsible for specific defects more practical, and this has led to the creation of specific transgenic animal models, knock-ins and knock-outs, that have advanced our understanding of both congenital defects and genetic predisposition for a variety of cardiovascular diseases.

The order of incidence of congenital cardiac defects diagnosed in all breeds of dogs is patent ductus arteriosus (PDA) > pulmonic stenosis (PS) > ventricular septal defect (VSD) > atrial septal defect (ASD) ≥ Tetralogy of Fallot > persistent right aortic arch > combined PS and PDA and a rare but nearly equal incidence of pericardial, arterial, and venous anomalies, mitral insufficiency, Ebstein’s anomaly of the tricuspid valves, origin of both great vessels from the right ventricle, and partial anomalous pulmonary venous drainage into the right atrium.1 Twenty-two of 52 dogs treated surgically for left-to-right shunting PDA were also found to have mitral valve regurgitation. Twenty-four of the 52 dogs (46.2%) had clinical signs of cardiac insufficiency and 56.3% had left atrial dilatation.2 Boxer dogs exhibiting either a single congenital heart defect (53/105) or multiple defects (52/105) were included in a recent study. In these animals, ASD was most commonly diagnosed (56.2%), followed by mitral valve abnormalities (55.2%), and subaortic stenosis (SAS) (46.7%). Most of the dogs with ASD had a low intensity systolic murmur heard best at he left heart base, i.e., relative PS, while most of the SAS lesions were characterized by a high intensity murmur at the left base.3


Mitral Valve Patent Ductus Arteriosus Atrial Septal Defect Coronary Flow Reserve Mitral Valve Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Gross DR. Animal Models in Cardiovascular Research, 2nd Revised Edition. Boston, MA: Kluwer Academic; 1994.Google Scholar
  2. 2.
    Bureau S, Monnet E, Orton EC. Evaluation of survival rate and prognostic indicators for surgical treatment of left-to-right patent ductus arteriosus in dogs: 52 cases (1995–2003). J Am Vet Med Assoc. 2005;227:1794–1799.PubMedCrossRefGoogle Scholar
  3. 3.
    Chetboul V, Trolle JM, Nicolle A, et al. Congenital heart diseases in the boxer dog: A retrospective study of 105 cases (1998–2005). J Vet Med A Physiol Pathol Clin Med. 2006;53:346–351.PubMedCrossRefGoogle Scholar
  4. 4.
    Gross DR. Unpublished data.Google Scholar
  5. 5.
    Koie H, Sato T, Nakagawa H, Sakai T. Cor triatriatum sinister in a cat. J Small Anim Pract. 2000;41:128–131.PubMedCrossRefGoogle Scholar
  6. 6.
    Fine DM, Tobias AH, Jacob KA. Supravalvular mitral stenosis in a cat. J Am Anim Hosp Assoc. 2002;38:403–406.PubMedGoogle Scholar
  7. 7.
    Rishniw M, Thomas WP. Dynamic right ventricular outflow obstruction: A new cause of systolic murmurs in cats. J Vet Intern Med. 2002;16:547–552.PubMedCrossRefGoogle Scholar
  8. 8.
    Hopper BJ, Richardson JL, Irwin PJ. Pulmonic stenosis in two cats. Aust Vet J. 2004;82:143–148.PubMedCrossRefGoogle Scholar
  9. 9.
    Nilles KM, London B. Knockin animal models of inherited arrhythmogenic diseases: What have we learned from them? J Cardiovasc Electrophysiol. 2007;18:1117–1125.PubMedCrossRefGoogle Scholar
  10. 10.
    Fang H, Howroyd PC, Fletcher AM, et al. Atrioventricular valvular angiectasis in Sprague-Dawley rats. Vet Pathol. 2007;44:407–410.PubMedCrossRefGoogle Scholar
  11. 11.
    Serres F, Chetboul V, Tissier R, et al. Chordae tendineae rupture in dogs with degenerative mitral valve disease: Prevalence, survival, and prognostic factors (114 cases, 2001–2006). J Vet Intern Med. 2007;21:258–264.PubMedGoogle Scholar
  12. 12.
    Kaneshige T, Machida N, Yamamoto S, Nakao S, Yamane Y. A histological study of the cardiac conduction system in canine cases of mitral valve endocardiosis with complete atrioventricular block. J Comp Pathol. 2007;136:120–126.PubMedCrossRefGoogle Scholar
  13. 13.
    Black A, French AT, Dukes-McEwan J, Corcoran BM. Ultrastructural morphologic evaluation of the phenotype of valvular interstitial cells in dogs with myxomatous degeneration of the mitral valve. Am J Vet Res. 2005;66:1408–1414.PubMedCrossRefGoogle Scholar
  14. 14.
    Tarnow I, Kristensen AT, Olsen LH, Pedersen HD. Assessment of changes in hemostatic markers in cavalier King Charles spaniels with myxomatous mitral valve disease. Am J Vet Res. 2004;65:1644–1652.PubMedCrossRefGoogle Scholar
  15. 15.
    Tarnow I, Olsen LH, Jensen MB, Pedersen KM, Pedersen HD. Determinants of weak femoral artery pulse in dogs with mitral valve prolapse. Res Vet Sci. 2004;76:113–120.PubMedCrossRefGoogle Scholar
  16. 16.
    Freeman LM, Rush JE, Markwell PJ. Effects of dietary modification in dogs with early chronic valvular disease. J Vet Intern Med. 2006;20:1116–1126.PubMedCrossRefGoogle Scholar
  17. 17.
    Tou SP, Adin DB, Estrada AH. Echocardiographic estimation of systemic systolic blood pressure in dogs with mild mitral regurgitation. J Vet Intern Med. 2006;20:1127–1131.PubMedCrossRefGoogle Scholar
  18. 18.
    Kanno N, Kuse H, Kawasaki M, Hara A, Kano R, Sasaki Y. Effects of pimobendan for mitral valve regurgitation in dogs. J Vet Med Sci. 2007;69:373–377.PubMedCrossRefGoogle Scholar
  19. 19.
    Borgarelli M, Tarducci A, Zanatta R, Haggstrom J. Decreased systolic function and inadequate hypertrophy in large and small breed dogs with chronic mitral valve insufficiency. J Vet Intern Med. 2007;21:61–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Teshima K, Asano K, Iwanaga K, et al. Evaluation of left ventricular tei index (index of myocardial performance) in healthy dogs and dogs with mitral regurgitation. J Vet Med Sci. 2007;69:117–123.PubMedCrossRefGoogle Scholar
  21. 21.
    Serres FJ, Chetboul V, Tissier R, et al. Doppler echocardiography-derived evidence of pulmonary arterial hypertension in dogs with degenerative mitral valve disease: 86 cases (2001–2005). J Am Vet Med Assoc. 2006;229:1772–1778.PubMedCrossRefGoogle Scholar
  22. 22.
    Teshima K, Asano K, Iwanaga K, et al. Evaluation of right ventricular Tei index (index of myocardial performance) in healthy dogs and dogs with tricuspid regurgitation. J Vet Med Sci. 2006;68:1307–1313.PubMedCrossRefGoogle Scholar
  23. 23.
    Pedersen LG, Tarnow I, Olsen LH, Teerlink T, Pedersen HD. Body size, but neither age nor asymptomatic mitral regurgitation, influences plasma concentrations of dimethylarginines in dogs. Res Vet Sci. 2006;80:336–342.PubMedCrossRefGoogle Scholar
  24. 24.
    Pedersen HD, Falk T, Haggstrom J, et al. Circulating concentrations of insulin-like growth factor-1 in dogs with naturally occurring mitral regurgitation. J Vet Intern Med. 2005;19:528–532.PubMedCrossRefGoogle Scholar
  25. 25.
    Tarnow I, Kristensen AT, Olsen LH, et al. Dogs with heart diseases causing turbulent high-velocity blood flow have changes in platelet function and von Willebrand factor multimer distribution. J Vet Intern Med. 2005;19:515–522.PubMedCrossRefGoogle Scholar
  26. 26.
    Falk T, Jonsson L, Olsen LH, Pedersen HD. Arteriosclerotic changes in the myocardium, lung, and kidney in dogs with chronic congestive heart failure and myxomatous mitral valve disease. Cardiovasc Pathol. 2006;15:185–193.PubMedCrossRefGoogle Scholar
  27. 27.
    Hetyey CS, Manczur F, Dudas-Gyorki Z, et al. Plasma antioxidant capacity in dogs with naturally occurring heart diseases. J Vet Med A Physiol Pathol Clin Med. 2007;54:36–39.PubMedCrossRefGoogle Scholar
  28. 28.
    Rush JE, Lee ND, Freeman LM, Brewer B. C-reactive protein concentration in dogs with chronic valvular disease. J Vet Intern Med. 2006;20:635–639.PubMedCrossRefGoogle Scholar
  29. 29.
    Cote E, Manning AM, Emerson D, Laste NJ, Malakoff RL, Harpster NK. Assessment of the prevalence of heart murmurs in overtly healthy cats. J Am Vet Med Assoc. 2004;225:384–388.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhao L, Wang G, Lu D, et al. Homocysteine, hRIP3 and congenital cardiovascular malformations. Anat Embryol (Berl). 2006;211:203–212.CrossRefGoogle Scholar
  31. 31.
    Yoshioka M, Yuasa S, Matsumura K, et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med. 2006;12:1151–1159.PubMedCrossRefGoogle Scholar
  32. 32.
    Oyama MA, Chittur SV. Genomic expression patterns of mitral valve tissues from dogs with degenerative mitral valve disease. Am J Vet Res. 2006;67:1307–1318.PubMedCrossRefGoogle Scholar
  33. 33.
    Hankes GH, Ardell JL, Tallaj J, et al. Beta1-adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog. Am J Physiol Heart Circ Physiol. 2006;291:H147–H151.PubMedCrossRefGoogle Scholar
  34. 34.
    Nakayama T, Nishijima Y, Miyamoto M, Hamlin RL. Effects of 4 classes of cardiovascular drugs on ventricular function in dogs with mitral regurgitation. J Vet Intern Med. 2007;21:445–450.PubMedCrossRefGoogle Scholar
  35. 35.
    Bernal JM, Garcia I, Morales D, et al. The ‘valve racket’: A new and different concept of atrioventricular valve repair. Eur J Cardiothorac Surg. 2006;29:1026–1029.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoppe H, Pavcnik D, Chuter TA, et al. Percutaneous technique for creation of tricuspid regurgitation in an ovine model. J Vasc Interv Radiol. 2007;18:133–136.PubMedCrossRefGoogle Scholar
  37. 37.
    Gorman JH, III, Gorman RC, Plappert T, et al. Infarct size and location determine development of mitral regurgitation in the sheep model. J Thorac Cardiovasc Surg. 1998;115:615–622.PubMedCrossRefGoogle Scholar
  38. 38.
    Messas E, Bel A, Morichetti MC, et al. Autologous myoblast transplantation for chronic ischemic mitral regurgitation. J Am Coll Cardiol. 2006;47:2086–2093.PubMedCrossRefGoogle Scholar
  39. 39.
    Green GR, Dagum P, Glasson JR, et al. Mitral annular dilatation and papillary muscle dislocation without mitral regurgitation in sheep. Circulation. 1999;100:II95–II102.PubMedGoogle Scholar
  40. 40.
    Drolet MC, Lachance D, Plante E, Roussel E, Couet J, Arsenault M. Gender-related differences in left ventricular remodeling in chronic severe aortic valve regurgitation in rats. J Heart Valve Dis. 2006;15:345–351.PubMedGoogle Scholar
  41. 41.
    Walther T, Schubert A, Wustmann T, et al. Reverse remodeling of cardiac collagen protein expression after surgical therapy for experimental aortic stenosis. J Heart Valve Dis. 2006;15:651–656.PubMedGoogle Scholar
  42. 42.
    Popovic ZB, Martin M, Fukamachi K, et al. Mitral annulus size links ventricular dilatation to functional mitral regurgitation. J Am Soc Echocardiogr. 2005;18:959–963.PubMedCrossRefGoogle Scholar
  43. 43.
    Everett TH, IV, Olgin JE. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm. 2007;4:S24–S27.PubMedCrossRefGoogle Scholar
  44. 44.
    Mekontso-Dessap A, Brouri F, Pascal O, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation. 2006;113:81–89.PubMedCrossRefGoogle Scholar
  45. 45.
    Weiss RM, Ohashi M, Miller JD, Young SG, Heistad DD. Calcific aortic valve stenosis in old hypercholesterolemic mice. Circulation. 2006;114:2065–2069.PubMedCrossRefGoogle Scholar
  46. 46.
    Aikawa E, Nahrendorf M, Sosnovik D, et al. Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease. Circulation. 2007;115:377–386.PubMedCrossRefGoogle Scholar
  47. 47.
    Hanada K, Vermeij M, Garinis GA, et al. Perturbations of vascular homeostasis and aortic valve abnormalities in fibulin-4 deficient mice. Circ Res. 2007;100:738–746.PubMedCrossRefGoogle Scholar
  48. 48.
    Drolet MC, Roussel E, Deshaies Y, Couet J, Arsenault M. A high fat/high carbohydrate diet induces aortic valve disease in C57BL/6J mice. J Am Coll Cardiol. 2006;47:850–855.PubMedCrossRefGoogle Scholar
  49. 49.
    Couet J, Gaudreau M, Lachance D, et al. Treatment of combined aortic regurgitation and systemic hypertension: Insights from an animal model study. Am J Hypertens. 2006;19:843–850.PubMedCrossRefGoogle Scholar
  50. 50.
    Oteo JA, Castilla A, Arosey A, Blanco JR, Ibarra V, Morano LE. Endocarditis due to Bartonella spp. three new clinical cases and Spanish literature review. Enferm Infecc Microbiol Clin. 2006;24:297–301.PubMedCrossRefGoogle Scholar
  51. 51.
    Moody KD, Barthold SW, Terwilliger GA. Lyme borreliosis in laboratory animals: Effect of host species and in vitro passage of borrelia burgdorferi. Am J Trop Med Hyg. 1990;43:87–92.PubMedGoogle Scholar
  52. 52.
    Zeidner NS, Schneider BS, Dolan MC, Piesman J. An analysis of spirochete load, strain, and pathology in a model of tick-transmitted Lyme borreliosis. Vector Borne Zoonotic Dis. 2001;1:35–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Wang G, Ojaimi C, Wu H, et al. Disease severity in a murine model of Lyme borreliosis is associated with the genotype of the infecting borrelia burgdorferi sensu stricto strain. J Infect Dis. 2002;186:782–791.PubMedCrossRefGoogle Scholar
  54. 54.
    Judge DM, La Croix JT, Perine PL. Experimental louse-borne relapsing fever in the grivet monkey, cercopithecus aethiops. II. pathology. Am J Trop Med Hyg. 1974;23:962–968.PubMedGoogle Scholar
  55. 55.
    Saraste A, Arola A, Vuorinen T, et al. Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis. Cardiovasc Pathol. 2003;12:255–262.PubMedCrossRefGoogle Scholar
  56. 56.
    Saraste A, Kyto V, Saraste M, Vuorinen T, Hartiala J, Saukko P. Coronary flow reserve and heart failure in experimental coxsackievirus myocarditis. A transthoracic Doppler echocardiography study. Am J Physiol Heart Circ Physiol. 2006;291:H871–H875.PubMedCrossRefGoogle Scholar
  57. 57.
    Li J, Leschka S, Rutschow S, et al. Immunomodulation by interleukin-4 suppresses matrix metalloproteinases and improves cardiac function in murine myocarditis. Eur J Pharmacol. 2007;554:60–68.PubMedCrossRefGoogle Scholar
  58. 58.
    Lee CK, Kono K, Haas E, et al. Characterization of an infectious cDNA copy of the genome of a naturally occurring, avirulent coxsackievirus B3 clinical isolate. J Gen Virol. 2005;86:197–210.PubMedCrossRefGoogle Scholar
  59. 59.
    Leslie K, Blay R, Haisch C, Lodge A, Weller A, Huber S. Clinical and experimental aspects of viral myocarditis. Clin Microbiol Rev. 1989;2:191–203.PubMedGoogle Scholar
  60. 60.
    Anderson DR, Wilson JE, Carthy CM, Yang D, Kandolf R, McManus BM. Direct interactions of coxsackievirus B3 with immune cells in the splenic compartment of mice susceptible or resistant to myocarditis. J Virol. 1996;70:4632–4645.PubMedGoogle Scholar
  61. 61.
    Beck MA, Chapman NM, McManus BM, Mullican JC, Tracy S. Secondary enterovirus infection in the murine model of myocarditis. pathologic and immunologic aspects. Am J Pathol. 1990;136:669–681.PubMedGoogle Scholar
  62. 62.
    Paque RE, Gauntt CJ, Nealon TJ. Assessment of cell-mediated immunity against coxsackievirus B3-induced myocarditis in a primate model (Papio papio). Infect Immun. 1981;31:470–479.PubMedGoogle Scholar
  63. 63.
    Beck MA. Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice. Biomed Environ Sci. 1997;10:307–315.PubMedGoogle Scholar
  64. 64.
    Levander OA, Beck MA. Interacting nutritional and infectious etiologies of Keshan disease. Insights from Coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E. Biol Trace Elem Res. 1997;56:5–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Zabejinski MM, Ivanova VV, Zaborov AM, Nasirov RA. New animal model of diphtheritic myocarditis. Exp Toxicol Pathol. 2000;52:67–70.PubMedCrossRefGoogle Scholar
  66. 66.
    Monrad ES, Matsumori A, Murphy JC, Fox JG, Crumpacker CS, Abelmann WH. Therapy with cyclosporine in experimental murine myocarditis with encephalomyocarditis virus. Circulation. 1986;73:1058–1064.PubMedCrossRefGoogle Scholar
  67. 67.
    Taylor JA, Havari E, McInerney MF, Bronson R, Wucherpfennig KW, Lipes MA. A spontaneous model for autoimmune myocarditis using the human MHC molecule HLA-DQ8. J Immunol. 2004;172:2651–2658.PubMedGoogle Scholar
  68. 68.
    Wada H, Saito K, Kanda T, et al. Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: A study using mice lacking TNF-alpha. Circulation. 2001;103:743–749.PubMedGoogle Scholar
  69. 69.
    Godsel LM, Leon JS, Engman DM. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in experimental myocarditis. Curr Pharm Des. 2003;9:723–735.PubMedCrossRefGoogle Scholar
  70. 70.
    Szebeni J, Alving CR, Rosivall L, et al. Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J Liposome Res. 2007;17:107–117.PubMedCrossRefGoogle Scholar
  71. 71.
    Horton J, Maass D, White J, Sanders B. Effect of aspiration pneumonia-induced sepsis on post-burn cardiac inflammation and function in mice. Surg Infect (Larchmt). 2006;7:123–135.CrossRefGoogle Scholar
  72. 72.
    Smith CE, Freeman LM, Rush JE, Cunningham SM, Biourge V. Omega-3 fatty acids in boxer dogs with arrhythmogenic right ventricular cardiomyopathy. J Vet Intern Med. 2007;21:265–273.PubMedCrossRefGoogle Scholar
  73. 73.
    Everett TH, 4th, Wilson EE, Verheule S, Guerra JM, Foreman S, Olgin JE. Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: A comparison in canine models of structural and electrical atrial remodeling. Am J Physiol Heart Circ Physiol. 2006;291:H2911–H2923.PubMedCrossRefGoogle Scholar
  74. 74.
    Kaneshige T, Machida N, Itoh H, Yamane Y. The anatomical basis of complete atrioventricular block in cats with hypertrophic cardiomyopathy. J Comp Pathol. 2006;135:25–31.PubMedCrossRefGoogle Scholar
  75. 75.
    Niemann JT, Rosborough JP, Youngquist S, Thomas J, Lewis RJ. Is all ventricular fibrillation the same? A comparison of ischemically induced with electrically induced ventricular fibrillation in a porcine cardiac arrest and resuscitation model. Crit Care Med. 2007;35:1356–1361.PubMedCrossRefGoogle Scholar
  76. 76.
    Zhong JQ, Laurent G, So PP, Hu X, Hennan JK, Dorian P. Effects of rotigaptide, a gap junction modifier, on defibrillation energy and resuscitation from cardiac arrest in rabbits. J Cardiovasc Pharmacol Ther. 2007;12:69–77.PubMedCrossRefGoogle Scholar
  77. 77.
    Spasov AA, Iezhitsa IN, Zhuravleva NV, Gurova NA, Sinolitskii MK, Voronin SP. Comparative study of the antiarrhythmic activity of l-, d- and dl-stereoisomers of potassium magnesium aspartate. Eksp Klin Farmakol. 2007;70:17–21.PubMedGoogle Scholar
  78. 78.
    Clements-Jewery H, Hearse DJ, Curtis MJ. Neutrophil ablation with anti-serum does not protect against phase 2 ventricular arrhythmias in anaesthetised rats with myocardial infarction. Cardiovasc Res. 2007;73:761–769.PubMedCrossRefGoogle Scholar
  79. 79.
    Lorentzon M, Ramunddal T, Bollano E, Soussi B, Waagstein F, Omerovic E. In vivo effects of myocardial creatine depletion on left ventricular function, morphology, and energy metabolism - consequences in acute myocardial infarction. J Card Fail. 2007;13:230–237.PubMedCrossRefGoogle Scholar
  80. 80.
    Fukushima S, Varela-Carver A, Coppen SR, et al. Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation. 2007;115:2254–2261.PubMedCrossRefGoogle Scholar
  81. 81.
    Jardine DL, Charles CJ, Frampton CM, Richards AM. Cardiac sympathetic nerve activity and ventricular fibrillation during acute myocardial infarction in a conscious sheep model. Am J Physiol Heart Circ Physiol. 2007;293:H433–H439.PubMedCrossRefGoogle Scholar
  82. 82.
    Choisy SC, Arberry LA, Hancox JC, James AF. Increased susceptibility to atrial tachyarrhythmia in spontaneously hypertensive rat hearts. Hypertension. 2007;49:498–505.PubMedCrossRefGoogle Scholar
  83. 83.
    Wei SK, Ruknudin AM, Shou M, et al. Muscarinic modulation of the sodium-calcium exchanger in heart failure. Circulation. 2007;115:1225–1233.PubMedGoogle Scholar
  84. 84.
    Shiroshita-Takeshita A, Sakabe M, Haugan K, Hennan JK, Nattel S. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation. 2007;115:310–318.PubMedCrossRefGoogle Scholar
  85. 85.
    Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in two canine models of atrial fibrillation. Circ Res. 2007;100:425–433.PubMedCrossRefGoogle Scholar
  86. 86.
    Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm. 2007;4:S61–S64.PubMedCrossRefGoogle Scholar
  87. 87.
    Zhou J, Scherlag BJ, Edwards J, Jackman WM, Lazzara R, Po SS. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. J Cardiovasc Electrophysiol. 2007;18:83–90.PubMedCrossRefGoogle Scholar
  88. 88.
    Pan CH, Lin JL, Lai LP, Chen CL, Stephen Huang SK, Lin CS. Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation. FEBS Lett. 2007;581:526–534.PubMedCrossRefGoogle Scholar
  89. 89.
    Shiroshita-Takeshita A, Brundel BJ, Burstein B, et al. Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure. Cardiovasc Res. 2007;74:75–84.PubMedCrossRefGoogle Scholar
  90. 90.
    Seger DL. A critical reconsideration of the clinical effects and treatment recommendations for sodium channel blocking drug cardiotoxicity. Toxicol Rev. 2006;25:283–296.PubMedCrossRefGoogle Scholar
  91. 91.
    Tabo M, Kimura K, Ito S. Monophasic action potential in anaesthetized guinea pigs as a biomarker for prediction of liability for drug-induced delayed ventricular repolarization. J Pharmacol Toxicol Methods. 2007;55:254–261.PubMedCrossRefGoogle Scholar
  92. 92.
    London B, Jeron A, Zhou J, et al. 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 USA. 1998;95:2926–2931.PubMedCrossRefGoogle Scholar
  93. 93.
    Xiao J, Luo X, Lin H, et al. MicroRNA miR-133 represses HERG K + channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem. 2007;282:12363–12367.PubMedCrossRefGoogle Scholar
  94. 94.
    Zhou YF, Yang XJ, Li HX. Hyperpolarization-activated cyclic nucleotide-gated channel gene: The most possible therapeutic applications in the field of cardiac biological pacemakers. Med Hypotheses. 2007;69:541–544.PubMedCrossRefGoogle Scholar
  95. 95.
    Blaschke RJ, Hahurij ND, Kuijper S, et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation. 2007;115:1830–1838.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • David R. Gross
    • 1
  1. 1.Department of Veterinary BiosciencesUniversity of Illinois, Urbana Champaign College of Veterinary MedicineUrbanaUSA

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