Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a form of cardiomyopathy characterized by ventricular tachyarrhythmias and a fibrofatty infiltrate that is believed to preferentially affect the right ventricle. Mutations in the cardiac ryanodine receptor (RyR2) gene have been identified in some human families with a unique form of ARVC, ARVC2. Although the RyR2 has significant importance in excitation–contraction coupling across the ventricles, mutations in the gene encoding for it appear to have the greatest impact on the right ventricle in ARVC2. Using a canine model (boxer), the RyR2 protein and message RNA in the right ventricle, left ventricle and interventricular septum from normal dogs and dogs with ARVC were investigated by immunoblotting and real time PCR. The cardiac RyR2 message and protein expression were differentially expressed across the cardiac walls in the normal heart, with the lowest concentration expressed in the right ventricle (P < 0.05). The message and protein expression of the RyR2 were reduced in all chambers in the canine model of ARVC. We propose that the increased susceptibility of the right ventricle to ARVC may be associated with the lower baseline protein concentration of RyR2 in the normal right ventricle compared to the left ventricle and interventricular septum and that all three areas are equally affected in this canine model of ARVC. Using this naturally occurring model of canine ARVC, we may have provided new insights into the pathogenesis of this cardiomyopathy.
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Basso C, Fox PR, Meurs KM, Towbin JA, Spier AW, Calabrese F, Thiene G (2004) Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in Boxer dogs: new animal model of human disease. Circulation 109:1180–1185
Benkusky NA, Farrell EF, Valdivia HH (2004) Ryanodine receptor channelopathies. Biochem Biophys Res Commun. 322:1280–1285
Blough ER, Rennie ER, Zhang F, Reiser PJ (1996) Enhanced electrophoretic separation and resolution of myosin heavy chains in mammalian and avian skeletal muscles. Anal Biochem 233:31–35
Chelu MG, Danila CI, Gilman CP, Hamilton SL (2005) Regulation of ryanodine receptors by FK506 binding proteins. Trends Cardiovasc Med 14:227–234
Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossman KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36:1162–1164
Guyon R, Lorentzen TD, Hitte C, Kim L, Cadieu E, Parker HG, Quignon P, Lowe JK, Renier C, Gelfenbeyn B, Vignaux F, DeFrance HB, Gloux S, Mahairas GG, Andre C, Galibert F, Ostrander EA (2003) A1-Mb resolution radiation hybrid map of the canine genome. Proc Natl Acad Sci USA 100:5296–5301
Harpster N (1983) Boxer cardiomyopathy. In: Kirk RW (eds) Current veterinary therapy. WB Saunders Co, Philadelphia, pp 329–337
Harpster N (1991) Boxer cardiomyopathy. Vet Clin North Am Small Anim Pract 21:989–1004
Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K (2001) Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103:485–490
Lehnart SE, Wehrens XH, Laitinen PJ, Reiken SR, Deng SX, Cheng Z, Landry DW, Kontula K, Swan H, Marks AR (2004a) Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation 109:3208–3214
Lehnart SE, Wehrens XHT, Kushnir A, Marks AR (2004b) Cardiac ryanodine receptor function and regulation in heart disease. Ann N Y Acad Sci 1015:144–159
Marcus F, Towbin JA, Zareba W, Moss A, Calkins H, Brown M (2003) Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Circulation 107:2975–2978
Marks AR (2001) Ryanodine receptors/calcium release channels in heart failure and sudden cardiac death. J Mol Cell Cardiol 33:615–624
Meurs KM, Spier AW, Miller MW, Lehmkuhl L, Towbin JA (1999) Familial ventricular arrhythmias in boxers. J Vet Intern Med 13:437–439
Meurs KM, Spier AW, Wright NA, Hamlin RL (2001) Comparison of in-hospital versus 24-hour ambulatory electrocardiography for detection of ventricular premature complexes in mature Boxers. J Am Vet Med Assoc 218:222–224
Peters S, Peters H, Thierfelder L (1999) Heart failure in arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol 71:251–256
Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G,Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (2006) Mutations in desmoglein-2 gene are associated with Arrhythmogenic right ventricular cardiomyopathy. Circulation 113:1171–1179
Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2001) Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200
Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA (2002) Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of Arrhythmogenic right ventricular cardiomyopathy. J Hum Genet 71:1200–1206
Spier AW, Meurs KM (2004) Assessment of heart rate variability in boxers with arrhythmogenic right ventricular cardiomyopathy. J Am Vet Med Assoc 224:534–537
Spier AW, Meurs KM (2004) Use of signal-averaged electrocardiography in the evaluation of arrhythmogenic right ventricular cardiomyopathy in boxers. J Am Vet Med 255:1050–1055
Spier AW, Meurs KM, Muir WW, Lehmkuhl LB, Hamlin RL (2001) QT dispersion in the evaluation of familial ventricular arrhythmias in Boxer dogs. Am J Vet Res 62:1481–1485
Spier AW, Meurs KM, Lehmkuhl LB, Wright NA (2004) Evaluation of spontaneous variability in the frequency of ventricular premature complexes in boxer with arrhythmogenic right ventricular cardiomyopathy. J Am Vet Med 224:538–541
Terwilliger JD, Ott J (1994) Running the LINKAGE programs MLINK and ILINK. In: Handbook of human genetic linkage. The Johns Hopkins University Press, Baltimore, pp 22–32
Thiene G, Basso C (2001) Arrhythmogenic right ventricular cardiomyopathy: an update. Cardiovasc Pathol 10:109–117
Thiene G, Nava A, Corrado D, Rossi L, Pennelli N (1988) Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 318:129–133
Thomas WP, Gaber CE, Jacobs GJ (1993) Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. J Vet Intern Med 7:247–252
Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Ladaret G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A (2001) Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Gen 10:189–194
Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, Coromilas J, Landry DW, Marks AR (2004) Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304:292–296
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Funded by the American Boxer Charitable Foundation and the American Kennel Club Canine Health Foundation.
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Meurs, K.M., Lacombe, V.A., Dryburgh, K. et al. Differential expression of the cardiac ryanodine receptor in normal and arrhythmogenic right ventricular cardiomyopathy canine hearts. Hum Genet 120, 111–118 (2006). https://doi.org/10.1007/s00439-006-0193-2
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DOI: https://doi.org/10.1007/s00439-006-0193-2