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A. Tidholm and L. Jnsson Vet Pathol 2005 42: 1 DOI: 10.1354/vp.42-1-1 The online version of this article can be found at: http://vet.sagepub.com/content/42/1/1

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Vet Pathol 42:18 (2005)

REVIEW ARTICLE Histologic Characterization of Canine Dilated Cardiomyopathy

A. TIDHOLM
AND NSSON L. JO

Albano Animal Hospital of Stockholm, Rinkbyva gen 23, Danderyd, Sweden (AT); and Department of Pathology, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden (LJ) Abstract. Dilated cardiomyopathy (DCM), characterized by chamber dilatation and myocardial systolic and diastolic dysfunction, is one of the most common heart diseases in dogs. The clinical diagnosis is based on ndings on echocardiographic and Doppler examinations, with the active exclusion of other acquired or congenital heart diseases. However, the echocardiographic criteria for the diagnosis of DCM are not wholly specic for the disease, and histologic examination may be necessary for nal diagnosis. Review of reports on histologic ndings in dogs with clinically diagnosed DCM reveals two histologically distinct forms of DCM: 1) cardiomyopathy of Boxers and Doberman Pinschers, corresponding to the fatty inltrationdegenerative type and 2) the form seen in many giant, large-, and medium-sized breeds, including some Boxers and Doberman Pinschers, classied as the attenuated wavy ber type of DCM. The histologic changes of the attenuated wavy ber type of DCM may precede clinical and echocardiographic signs of heart disease, thus indicating an early stage of DCM. Key words: dilated, cardiomyopathy, canine, histology

The classication of cardiomyopathies introduced by the World Health Organization is based on pathophysiology or, where possible, on etiologic or pathogenetic factors. Dilated cardiomyopathy (DCM) is characterized by chamber dilatation and predominantly systolic and, to a lesser degree, diastolic dysfunction.66 DCM was rst reported in dogs in 1970, as congestive heart failure (CHF) in conjunction with dilatation of the cardiac chambers and absence of other clinically important cardiovascular disease by Ettinger, Bolton and Lord.28 DCM has been recognized in many breeds85 but seems to be more prevalent in certain breeds such as English Cocker Spaniels,78 Doberman Pinschers,14 Boxers,35 Newfoundlands,23,84 and Irish Wolfhounds.95 Gross pathology examination of dogs with DCM generally shows dilatation of all four cardiac chambers or predominant dilatation of the left cardiac chambers. There appears to be at least two histologically distinct forms of canine DCM: 1) the cardiomyopathy of Boxers35 and of Doberman Pinschers,14,15,30,36 corresponding to the fatty inltrationdegenerative type of DCM and 2) the form detected in many giant, large-, and medium-sized breeds (including some Boxers and Doberman Pinschers), which can be classied as the attenuated wavy ber type of DCM.1,21,69,77,82,83,88,96 Presumably, specic histologic myocardial changes re1

ect specic disease processes. Aiming for a histologic conrmation and classication of clinical cases of DCM is essential for increasing our knowledge of the disease. Etiology and Pathogenesis The etiology is generally not established in the individual case of DCM in dogs. However, several causes have been proposed, including genetic factors, nutritional deciencies, metabolic disorders, immunologic abnormalities, infectious diseases, and drug-, toxin-, and tachycardia-induced myocardial hypokinesis. DCM is considered to be hereditary in approximately 2035% of human patients.56,74 Canine DCM has been suspected to be an inherited disease because of its prevalence in certain breeds and in specic families of dogs.76 An autosomal dominant mode of transmission has been reported in the Irish Wolfhound,18 Newfoundlands,24 and Doberman Pinschers.54 In the juvenile Portugese Water Dog, an autosomal recessive transmission has been documented.1,21,77 The role of cytoskeletal proteins has been investigated in the development of DCM, and the dystrophin gene has been identied as being responsible for Xlinked DCM.89 Canine X-linked muscular dystrophy may cause severe cardiac involvement,91 and deletion

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Tidholm and Jo nsson

Vet Pathol 42:1, 2005

of the entire dystrophin gene has been demonstrated in German Shorthaired Pointers with skeletal myopathy and DCM.70 Mutations in the actin gene have been associated with DCM in humans.63 However, molecular analysis of the cardiac actin gene in 16 Doberman Pinschers with DCM did not reveal any abnormalities.55 Nutritional abnormalities causing myocardial hypokinesis, i.e., carnitine or taurine deciencies (or both), have been described in humans,65 dogs,3841,43 and cats.64 Metabolic disorders associated with DCM include hypothyroidism, diabetes mellitus, and pheochromocytoma.4,76,98 Immunologic processes have been suspected to be involved in the pathogenesis of DCM because autoantibodies have been detected against several cardiac structures, such as the -adrenergic receptor,47 the mitochondria,45,72,73 and the myosin heavy chains,13 both in humans and in experimental animals. However, many of these antibodies do not seem to be specic for DCM because they are also detected in myocarditis, hypertrophic cardiomyopathy, and hypertensive heart disease.5 Inammatory response to infectious agents, such as viruses,2,12,17,58 bacteria,46,79 and protozoa,6,7 has been proposed to be involved in the pathogenesis of myocarditis and DCM. Cardiotoxicity may be caused by doxorubicin and other antineoplastic agents, ethanol, cobalt, lead, catecholamines, histamine, methylxanthines, and vitamin D.93 Studies on naturally occurring tachycardia as well as experimentally induced tachycardia report development of chamber dilatation and CHF.3,34,60,97 Clinical Findings Overt DCM, i.e., dogs with DCM exhibiting signs of CHF or arrhythmias, is preceded by a preclinical stage of various lengths. Clinical signs in dogs with DCM include dyspnea, cough, depression, exercise intolerance, inappetence, syncope, weight loss, abdominal distention, and polydipsia. The clinical examination commonly reveal tachypnea, dyspnea, tachycardia, arrhythmia, a low-intensity systolic murmur in some dogs, weak femoral arterial pulses, ascites, and weight loss.76,85 Most dogs with DCM show abnormalities on electrocardiogram recordings, such as atrial brillation or ventricular arrhythmias. Radiographic ndings in dogs with DCM include cardiomegaly with prominence of the left atrium, pulmonary venous congestion, and interstitial or alveolar pulmonary edema. These changes are diagnostic of left-sided or biventricular CHF and not specic for DCM. The diagnosis of DCM is usually based on echocardiographic ndings of myocardial hypokinesia and chamber dilatation, with the active exclusion of other signicant congenital and acquired heart disease. The sensitivity of stan-

dard clinical and echocardiographic criteria was found to be 93% in one study, when nal diagnosis is based on postmortem ndings.82 Differential diagnoses included arteriosclerosis, myocardial infarcts, endocardiosis, and myocarditis. Survival and Prognosis Survival times in dogs with DCM vary from days to several years. Attempts to correlate different clinical and echocardiographic parameters with prognosis have been made. In one study of 189 dogs with DCM, only 3 of 27 tested variables were shown to inuence survival, i.e., young age at onset of clinical disease, dyspnea, and ascites.86 Another study of 37 dogs identied pleural effusion and pulmonary edema as independent prognostic indicators for dogs with DCM.57 Neither of these studies found breed or parameters of systolic function to be signicant prognostic factors in DCM. Survival rate at 1 year varied between 3 and 54% in different studies.9,10,16,29,50,57,80,86,87,95 The wide variation in survival times may partly depend on different functional classes of CHF in different studies. Medical treatment, especially the use of angiotensin-converting enzyme inhibitors and -blocking agents, varied considerably between different studies, which also may be a source of variation in survival times. However, the exceptionally low survival rate at 1 year of Doberman Pinschers (3%) may indicate that the fatty inltration degenerative type of DCM carries a worse prognosis compared with the attenuated wavy ber type of DCM. Gross Pathology and Histopathology Gross pathology examination of the heart of dogs with DCM generally reveals marked dilatation of all four chambers or predominantly the left chambers. In one study, dilatation of all four chambers was found in 85% of dogs with DCM.85 Myocardial eccentric hypertrophy, rather than true dilatation, is evident by increased heart weight to body weight ratio, together with a decreased ratio of the left ventricular thickness to chamber diameter.76,85 The term hypertrophy implies a pathologic process where the weight of the organ is increased because of an increase in cell size rather than in cell number. In myocardial eccentric hypertrophy, the sarcomeres are increased in numbers in series rather than parallel, as in concentric hypertrophy. Myocardial eccentric hypertrophy is commonly caused by volume overload.44 In the literature, there appear to be two histologically distinct forms of canine DCM: the attenuated wavy ber type seen in many giant, large-, and medium-sized dogs, and the fatty inltrationdegenerative type of DCM seen in mainly Boxers and Doberman Pinschers (Table 1). Some other studies report

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Table 1. Classication of canine DCM in different studies in chronological order, based on the reported histopathologic characteristics.
Author Breed Number of Dogs in Study Mean Age of Dogs

Attenuated wavy ber type Tilley and Liu88 Sandusky et al.69 Tidholm et al.82 Dambach et al.21 Tidholm et al.83 A. Tidholm (unpublished) Alroy et al.1 Vollmar et al.96 Sleeper et al.77 Total number of dogs

Large and giant breeds Large and giant breeds 23 large and medium-sized breeds Portugese Water Dogs Newfoundlands Newfoundlands ve other breeds Portugese Water Dogs Doberman Pinschers Portugese Water Dogs

12 11 64 12 7 33 2 3 10 154 6 14 64 12 32 128

5 years 5 years 13 weeks 2.5 years 5.4 years 9 weeks 3 weeks 17 weeks

Fatty inltrationdegenerative type Calvert et al.14 Doberman Pinchers Doberman Pinschers Hazlett et al.36 Boxers Harpster35 Doberman Pinschers Calvert et al.15 Doberman Pinschers Everett et al.30 Total number of dogs
information not available.

6.7 years 4.7 years 8.2 years Males: 7.2 years Females: 9.4 years

nonspecic ndings, such as necrosis, infarcts, brosis, vacuolization of myocytes, and hyperplasia of arteries.33,51,78,94
The attenuated wavy ber type of DCM

It has been described in dogs,1,48,69,77,82,83,88,96 cats,49 and human patients (Fig. 1).22,71 Atrophy, or attenuation, of myobers without a wavy appearance has been

reported in several additional studies in human patients with DCM.25,32,37,61,62,67,90 Myober atrophy is a common response to processes that prevent normal contractile activity and to various pathologic stimuli.19 Atrophy of cardiac myocytes has been shown to occur after prolonged mechanical support using left ventricular assist device systems42 and after heterotopic isotransplantation.68 Wavy myocardial bers, especially

Fig. 1. Left ventricular myocardium of a dog with attenuated wavy ber type of DCM. The myobers are thinner than normal and have a wavy appearance. Massons trichrome. Bar 20 m. Fig. 2. Left ventricular myocardium of a dog with fatty inltrationdegenerative type of DCM. Vacuolar degeneration of myobers (small arrows), atrophic myobers, lipid deposits (large arrows), and cords of collagen (blue staining) are evident. Massons trichrome. Bar 20 m.

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when associated with focal edema, are characteristic signs of acute myocardial ischemia in humans26 and in dogs,26,27 but have also been described in human patients with DCM.52,59 The myocardial lesions associated with the attenuated wavy ber type of DCM consist of myocardial cells 6 m in diameter (normal myober diameter ranges from 10 to 20 m92) with a wavy appearance, comprising at least half of the thickness of the myocardial specimens from the upper and lower portions of the left ventricular wall. The myocytes are separated by a clear space generally free from cellular inltrates, suggestive of edematous uid. In many cases, there is also a diffuse inltration of subendocardial brosis (Fig. 1). It is suggested that myocardial specimens should be taken from the proximal (11.5 cm distal to the base of the atrioventricular valves), distal (11.5 cm proximal to the apex), and middle (midway between the proximal and the distal specimens) portions of the lateral wall of the left ventricle, lateral wall of the right ventricle, and interventricular septum, and from the papillary muscles of the left ventricle. Three slides from each of the 10 specimens should be evaluated for the presence of attenuated wavy bers.82,83 Unfortunately, myocardial biopsy specimens collected in vivo from the right ventricle may not be sufcient for identifying dogs with attenuated wavy bers because the abnormal myobers were most abundant in the lateral wall of the left ventricle.83 Detection of attenuated wavy bers in the myocardium of dogs has been shown to have a high sensitivity (98%) for DCM. The specicity of this nding was found to be 100% because attenuated wavy bers were not found in 147 necropsied dogs with other heart diseases, such as chronic valvular disease, congenital heart disease, myocardial infarcts, myocarditis or endocarditis, although the majority of these hearts were dilated.82 In a subsequent study, attenuated wavy bers were detected in Newfoundlands from a kennel with a known predisposition to DCM, but without clinical or echocardiographic evidence of heart disease.83 These ndings suggest that development of attenuated wavy bers is not a response to chamber dilatation and stretching of the myocytes, as has been proposed.71 To the contrary, attenuated wavy bers may represent an early pathologic change in the myocardium of dogs with DCM.
The fatty inltrationdegenerative type of DCM

myobers (Fig. 2). Similar myocardial lesions were rst described by Calvert et al. in 198214 and later by the same and by other authors in a total of 64 Doberman Pinschers with clinically diagnosed DCM.15,30,36 In one of the reports by Everett et al. the myocardial lesions have been described extensively, characterized by myober degeneration and atrophy, and replacement of myocardium by dense bundles of collagen and clusters of adipocytes.30 The lesions have been compared to arrhythmogenic right ventricular cardiomyopathy (ARVC) in dogs31,53,75 and in humans.8,81 However, the myocardial changes in ARVC are usually conned to the right ventricle and profound to the extent that they are evident already on gross pathology examination. Myocyte transdifferentiation of myocytes to adipocytes was suggested as a possible mechanism for ARVC in a recent report.20 Discussion The attenuated wavy ber type of DCM seems to be the most prevalent form of DCM because many more breeds are aficted with this disease compared with the fatty inltrationdegenerative type of DCM. However, there are to date relatively few authors (Table 1) who have reported on this histopathologic nding. There may be many reasons for this lack of reporting. In the hitherto largest study of dogs with the attenuated wavy ber form of DCM, as many as 27 slides from nine different locations in the ventricles were evaluated for presence of attenuated wavy bers. Although, in many dogs, attenuated wavy bers were found in the majority of the specimens, the abnormal bers were most abundant in the lateral wall of the left ventricle.83 By examining only a limited number of myocardial specimens, presence of attenuated wavy bers may indeed be missed. The technical process for preparation of the slides from the specimens may inuence the morphology. The technique used for dehydration of the specimens may vary. The slicing technique may produce articial waviness of the myobers. There may be a question of whether the waviness may be an artifact in vitro, not present in vivo. The cause for this may be a disruption of collagen tethers aligning the cardiomyocytes that occurs in the remodeling process involved in dilatation. The artifact may reect the loss of volume distention after death and fragmentation of collagen tethers that maintain alignment (J. Turk, personal communication). However, this supposed artifact only seems to occur in hearts where dilatation is due to DCM and not in hearts where dilatation is due to chronic valvular disease or congenital heart disease.82 Also, attenuated wavy bers have been found in myocardium of dogs where no dilatation is present.83 Wavy myocardial bers (not attenuated) have also been de-

It was rst described as boxer cardiomyopathy in 64 Boxers by Harpster35 in 1983 (Fig. 2). The myocardial lesions associated with the fatty inltration degenerative type of DCM include myocytolysis, myober degeneration, vacuolization, and myocyte atrophy with extensive brosis and fatty inltration replacing

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Canine Dilated Cardiomyopathy

scribed in human patients and in dogs with acute myocardial ischemia.26,27 Fibro-fatty replacement of myocardial tissue is thought to be a consequence of myocyte loss due to different causes, such as myocarditis or other noxious stimuli. Fatty inltration of the myocardium is reported to be a major nding in ethanol-induced cardiomyopathy.22 A number of antineoplastic agents, such as doxorubicin and cyclophosphamide, may cause extensive myocyte vacuolization.93 The characteristic histologic ndings presumably reect specic disease processes, rather than being the end result of many different pathologic processes. As the very structure of the myocytes is distorted in the attenuated wavy ber type of DCM, the cause may be a defect in the cytoskeletal proteins. It has been suggested that DCM in human patients should be termed cytoskeletalopathy due to mutations found in dystrophin, actin, and desmin.11 The cytoskeletal proteins transmits the contractile force to adjacent sarcomeres and myocytes. Such an impairment will prevent normal contractility and, thus may cause myocyte atrophy. In conclusion, there appears to be at least two histologically distinct forms of idiopathic canine DCM, presumably reecting different disease processes. Histologic classication of canine DCM is therefore essential for scientic studies of the disease. References
1 Alroy J, Rush JE, Freeman L, Amarendhra Kumar MS, Karuri A, Chase K, Sarkar S: Inherited infantile dilated cardiomyopathy in dogs: genetic, clinical, biochemical, and morphologic ndings. Am J of Med Genet 95:57 66, 2000 2 Archard LC, Bowles NE, Olsen EGJ, Richardson PJ: Detection of persistent coxsackie B virus RNA in dilated cardiomyopathy and myocarditis. Eur Heart J 8:437 440, 1987 3 Armstrong PW, Stopps TP, Ford SE: Rapid ventricular pacing in the dog: pathophysiological studies of heart failure. Circulation 74:1075, 1986 4 Atkins CE: The role of noncardiac disease in the development and precipitation of heart failure. Vet Clin North Am Small Anim Pract 21:10351080, 1991 5 Autore C, Fiorito S, Pelliccia A, Caselli G, Fragola PV, Picelli A, Maccari AM, Pocobelli D, Cannata D, Sangiorgi M: Antimitochondrial autoantibodies in myocardial hypertrophy: comparison between hypertrophic cardiomyopathy, hypertensive heart disease, and athletes heart. Am Heart J 116:496500, 1988 6 Barr SC: American trypanosomiasis in dogs. Compend Contin Ed 13:745752, 1991 7 Barr SC, Simpson RM, Schmidt SP, Bunge MM, Authement JM, Lozano F: Chronic dilatative myocarditis caused by Trypanosoma cruzi in two dogs. J Am Vet Med Assoc 195:12371239, 1989 8 Basso C, Thiene G, Corrado D, Angelini A, Nava A,

10 11

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13

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16

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Valente M: Arrhythmogenic right ventricular cardiomyopathy (dysplasia, dystrophy or myocarditis?). Circulation 94:983994, 1996 Borgarelli M, Tarducci A, Bussadori C, Santilli RA, Priano L: Echocardiographic and echoDoppler prognostic indicators in dogs with dilated cardiomyopathy. Eur Soc Vet Intern Med Annu Congr 7:2528, 1997 Borgarelli M, Tarducci A, Tidholm A, Ha ggstro m A: Canine idiopathic dilated cardiomyopathy. Part II: pathophysiology and therapy. Vet J 162:182185, 2001 Bowles NE, Bowles KR, Towbin JA: The nal common pathway hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. Herz 25:168175, 2000 Bowles NE, Rose ML, Taylor P, Banner NR, MorganCapner P, Cunningham L, Archard LC, Yacoub MH: End-stage dilated cardiomyopathy: persistence of enterovirus RNA in myocardium at cardiac transplantation and lack of immune response. Circulation 80:11281136, 1989 Caforio ALP, Grazzini M, Mann JM, Keeling PJ: Identication of alpha-and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation 85:17341742, 1992 Calvert CA, Chapman WL, Toal RL: Congestive cardiomyopathy in Doberman Pinscher dogs. J Am Vet Med Assoc 181:598602, 1982 Calvert CA, Hall G, Jacobs G, Pickus C: Clinical and pathologic ndings in Doberman pinschers with occult cardiomyopathy that died suddenly or developed congestive heart failure: 54 cases (19841991). J Am Vet Med Assoc 210:505511, 1997 Calvert CA, Pickus CW, Jacobs GJ, Brown J: Signalment, survival and prognostic factors in Doberman Pinschers with end-stage cardiomyopathy. J Vet Intern Med 11:323326, 1997 Cambridge G, Mac Arthur CGC, Waterson AP, Goodwin JF, Oakley CM,: Antibodies to Coxsackie B viruses in congestive cardiomyopathy. Br Heart J 41:692696, 1979 Cobb MA, Brownlie SE, Pidduck HG, Batt RM: Evidence for genetic involvement in dilated cardiomyopathy in the Irish Wolfhound. Annu Congr BSAVA 215, 1996 Cullen MJ, Mastalgia FL: Pathological reactions in skeletal muscle. In: Skeletal Muscle Pathology, ed. Mastalgia FL, and Walton J, pp. 88139. Churchill Livingstone, Edinburgh, UK, 1982 dAmati G, di Gioia CR, Giordano C, Gallo P: Myocyte transdifferentiation. A possible pathogenetic mechanism for arrhythmogenic right ventricular cardiomyopathy. Arch Pathol Lab Med 124:287290, 2000 Dambach DM, Lannon A, Sleeper MM, Buchanan J: Familial dilated cardiomyopathy of young Portuguese water dogs. J Vet Intern Med 13:6571, 1999 Davies MJ: The cardiomyopathies: a review of terminology, pathology and pathogenesis. Histopathology 8: 363393, 1984 Dukes McEwan J: Dilated Cardiomyopathy in Newfoundlands. The Veterinary Cardiovascular Society Meeting. 24 1998 [Abstract]

Downloaded from vet.sagepub.com by guest on February 2, 2013

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24 Dukes-McEwan J: Echocardiographic/Doppler Criteria of Normality, the Findings in Cardiac Disease and the Genetics of Familial Dilated Cardiomyopathy in Newfoundland Dogs. University of Edinburgh, Edinburgh, UK, 318, 1999 25 Edwards WD: Cardiomyopathies. Human Pathol 18: 625628, 1987 26 Eichbaum F: Wavy myocardial bers in spontaneous and experimental adrenergic cardiopathies. Cardiology 60: 358365, 1975 27 Eliot RS, Clayton FC, Todd P, Todd G: Inuence of environmental stress on the pathogenesis of sudden cardiac death. Fed Proc 36:17191724, 1977 28 Ettinger S, Bolton G, Lord P: Idiopathic cardiomyopathy in the dog. J Am Vet Assoc 156:1225, 1970 29 Ettinger SJ, Benitz AM, Ericsson GF, Cifelli S, Jernigan AD, Longhofer SL, Trimboli W, Hanson PD: Effects of enalapril maleate on survival of dogs with naturally occurring acquired heart failure. J Am Vet Med Assoc 213: 15731577, 1998 30 Everett RM, McGann J, Wimberly HC, Althoff J: Dilated cardiomyopathy of Doberman pinschers: retrospective histomorphologic evaluation of heart from 32 cases. Vet Pathol 36:221227, 1999 31 Ferna ndez del Palacio MJ, Bernal LJ, Bayo n A, Bernabe A, Montes de Oca R, Seva J: Arrhythmogenic right ventricular dysplasia/cardiomyopathy in a Siberian husky. J Small Anim Pract 42:137141, 2001 32 Fujimoto S, Mizuno R, Nakagawa Y, Kimura A, Yamaji K, Yutani C, Dohi K, Nakano H: Ultrasonic tissue characterization in patients with dilated cardiomyopathy: comparison with ndings from right ventricular endomyocardial biopsy. Int J Card Imaging 15:391396, 1999 33 Gooding JP, Robinson WF, Wyburn RS, Cullen LK: A cardiomyopathy in the English Cocker Spaniel: a clinicopathological investigation. J Small Anim Pract 23:133 149, 1982 34 Grogan M, Smith HC, Gersh BJ, Wood D: Left ventricular dysfunction due to atrial brillation in patients initially believed to have dilated cardiomyopathy. Am J Cardiol 69:15701573, 1992 35 Harpster NK: Boxer cardiomyopathy. In: Current Veterinary Therapy VIII, ed. Kirk RW, pp. 329337. WB Saunders, Philadelphia, PA, 1983. 36 Hazlett MJ, Maxie MG, Allen DG, Wilcock BP: A retrospective study of heart disease in Doberman pinscher dogs. Can Vet J 24:205210, 1983 37 Izumi T, Hattori A, Higuma N, Tamura K: Cardiac myobril disorientation and Z band abnormalities in idiopathic cardiomyopathy. An electron microscope study. Arch Histol Jpn 41:293308, 1978 38 Keene BW: Canine cardiomyopathy. In: Current Veterinary Therapy X. Small Animal Practice, ed. Kirk RW, pp. 240251. WB Saunders, Philadelphia, PA, 1989 39 Keene BW, Kittleson MD, Rush JE: Frequency of myocardial carnitine deciency associated with spontaneous dilated cardiomyopathy. Proc Annu Vet Med Forum 6: 757, 1988 40 Keene BW, Panciera DL, Regitz V: Carnitine-linked de-

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42

43

44 45

46 47 48 49 50

51 52

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56

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fects of myocardial metabolism in canine dilated cardiomyopathy. Proc Am Coll Vet Intern Med 118, 1986 Keene BW, Panciera DP, Atkins CE, Regitz V, Schmidt MJ, Shug AL: Myocardial L-carnitine deciency in a family of dogs with dilated cardiomyopathy. J Am Vet Med Assoc 198:647650, 1991 Kinoshita M, Takano H, Taenaka Y, Mori H, Takaichi S, Noda H, Tatsumi E, Yagura A, Seekii H, Akutsu T: Cardiac disuse atrophy during LVAD pumping. ASAIO Trans 34:208212, 1988 Kittelson MD, Keene B, Pion PD, Loyer CG: Results of the multicenter spaniel trial (MUST): taurine- and carnitine-responsive dilated cardiomyopathy in American cocker spaniels with decreased plasma taurine concentration. J Vet Intern Med 11:204211, 1997 Kittleson M: Left ventricular functionpart I. Compend Contin Ed Pract Vet 16:287305, 1994 Klein R, Maisch B, Kochsiek K, Berg PA: Demonstration of organ specic antibodies against heart mitochondria (anti-M7) in sera from patients with some forms of heart diseases. Clin Exp Immunol 58:283292, 1984 Levy SA, Duray PH: Complete heart block in a dog seropositive for Borrelia burgdorferi. Similarity to human Lyme Carditis. J Vet Intern Med 2:138144, 1988 Limas CJ: Autoimmunity in dilated cardiomyopathy and major histocompatibility complex. Int J Cardiol 54:113 116, 1996 Liu S-K, Hsu FS, Lee RCT: An Atlas of Cardiovascular Pathology. Wonder Enterprise Co., Taiwan, 1989 Liu S-K, Tashijan RJ, Patniak AK: Congestive heart failure in the cat. J Am Vet Med Assoc 156:13191330, 1970 Martin M, Celona B, King J, Strehlau G: A retrospective review of the clinical presentation and survival of 202 cases of canine dilated cardiomyopathy. Eur Soc Vet Intern Med Congr 11:99100, 2001 McCarthy G: Idiopathic congestive cardiomyopathy of large breeds of dogs: observations on eleven cases. Irish Vet J 38:155158, 1984 McCarthy PM, Nakatani S, Vargo R, Kottke-Marchant K, Harasaki H, James KB, Savage RM, Thomas JD: Structural and left ventricular histologic changes after implantable LVAD insertion. Ann Thorac Surg 59:609 613, 1995 McIntosh Bright J, McEntee M: Isolated right ventricular cardiomyopathy in a dog. J Am Vet Med Assoc 207:64 66, 1995 Meurs KM: Insight into the hereditability of canine cardiomyopathy. Vet Clin North Am Small Anim Pract 28: 14491457, 1998 Meurs KM, Magnon AL, Spier AW, Miller MW, Lehmkuhl LB, Towbin JA: Evaluation of the cardiac actin gene in Doberman pinschers with dilated cardiomyopathy. J Vet Intern Med 13:247, 1999 [Abstract] Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, Burnett, JC, Rodeheffer RJ, Chesebro JH, Tazelaar HD: The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Eng J Med 9:7782, 1992 Monnet E, Orton C, Salman M, Boon J: Idiopathic di-

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lated cardiomyopathy in dogs: survival and prognostic indicators. J Vet Intern Med 9:1217, 1995 Muir P, Tilzey AJ, English TAH, Nicholson F, Signy M, Banatvala JE: Chronic relapsing pericarditis and dilated cardiomyopathy: serological evidence of persistent enterovirus infection. Lancet 1989:804806 Nakatani S, McCarthy PM, Kottke-Marchant K, Harasaki H, James KB, Savage RM, Thomas JD: Left ventricular echocardiographic and histologic changes: impact of chronic unloading by an implantable ventricular assist device. J Am Coll Cardiol 27:894901, 1996 OBrien PJ, Ianuzzo CD, Moe GW, Stopps TP, Armstrong PW: Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies. Can J Physiol Pharmacol 68:3438, 1990 Olsen EGJ: Pathology of primary cardiomyopathies. Postgrad Med J 48:732737, 1972 Olsen EGJ: The pathogenesis of dilated cardiomyopathy. Postgrad Med J 68:S7S10, 1992 Olson TM, Michels VV, Thibodeau SN, Tai Y, Keating MT: Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 280:750752, 1998 Pion PD, Kittleson MD, Rogers QR, Morris JG: Myocardial failure in cats associated with low plasma taurine: a reversible cardiomyopathy. Science 237:764768, 1987 Regitz V, Shug AL, Fleck E: Defective myocardial carnitine metabolism in congestive heart failure secondary to coronary, hypertensive, and valvular heart diseases. Am J Cardiol 65:755759, 1990 Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, OConnell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P: Report of the 1995 World Health Organisation/International Society and Federation of Cardiology Task Force on the denition and classication of cardiomyopathies. Circulation 93:637640, 1996 Roberts WC, Ferrans VJ, Buja LM: Pathologic aspects of idiopathic cardiomyopathies. Comp Pathol Heart 13: 349367, 1974 Rossi MA: Chronic hemodynamic unloading regulates the morphologic development of newborn mouse hearts transplanted into the ear of isogenic adult mice. Am J Pathol 141:183191, 1992 Sandusky GE, Capen CC, Kerr KM: Histological and ultrastructural evaluation of cardiac lesions in idiopathic cardiomyopathy in dogs. Can J Comp Med 48:8186, 1984 Schatzberg SJ, Olby NJ, Breen M, Anderson LVB, Langford CF, Dickens HF, Wilton SD, Zeiss CJ, Binns MM, Kornegay JN, Morris GE, Sharp NJH: Molecular analysis of a spontaneous dystrophin knockout dog. Neuromuscul Disord 9:289295, 1999 Scheinin S, Capek P, Radovancevic B, Duncan M, McAllister H, Frazier O: The effect of prolonged left ventricular support on myocardial histopathology in patients with end-stage cardiomyopathy. ASAIO J 38:M271 M274, 1992 Schultheiss HP, Bolte HD: Immunological analysis of auto-antibodies against the adenine nucleotide translo-

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cator in dilated cardiomyopathy. J Mol Cell Cardiol 17: 603617, 1985 Schulze K, Becker BF, Schauer R, Schultheiss HP: Antibodies to ADP-ATP carrieran autoantigen in myocarditis and dilated cardiomyopathy-impair cardiac function. Circulation 81:959969, 1990 Seidman JG, Seiman C: The genetic basis for cardiomyopathy: from mutation to mechanistic paradigms. Cell 104:557567, 2001 Simpson KW, Bonagura JD, Eaton KA: Right ventricular cardiomyopathy in a dog. J Vet Intern Med 8:306309, 1994 Sisson D, OGrady MR, Calvert CA: Myocardial diseases of dogs. In: Textbook of Canine and Feline Cardiology: Principles and Clinical Practice, ed. Fox PR, Sisson D, and Moise NS, pp. 581619. WB Saunders, Philadelphia, PA 1999 Sleeper MM, Henthorn PS, Vijayasarathy C, Dambach DM, Bowers T, Tijskens P, Armstrong CF, Lankford EB: Dilated cardiomyopathy in juvenile Portugese water dogs. J Vet Intern Med 16:5262, 2002. Staaden RV: Cardiomyopathy of English Cocker Spaniels. J Am Vet Assoc 178:12891292, 1981 Stanek G, Klein J, Bittner R, Glogar D: Isolation of Borrelia burgdorferi from myocardium of a patient with longstanding cardiomyopathy. N Engl J Med 322:249 252, 1990 The Bench (Benazepril in canine heart disease) study group: The effect of benazepril on survival times and clinical signs of dogs with congestive heart failure: results of a multicenter, prospective, randomized, doubleblinded, placebo-controlled long-term clinical trial. J Vet Cardiol 1:717, 1999 Thiene G, Nava A, Corrado D: Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 318:129133, 1988 Tidholm A, Ha ggstro m J, Jo nsson L: Prevalence of attenuated wavy bers in the myocardium of dogs with dilated cardiomyopathy. J Am Vet Med Assoc 212: 17321734, 1998 Tidholm A, Ha ggstro m J, Jo nsson L: Detection of attenuated wavy bers in the myocardium of Newfoundlands without clinical or echocardiographic evidence of heart disease. Am J Vet Res 61:238241, 2000 Tidholm A, Jo nsson L: Dilated cardiomyopathy in the New Foundland: a study of 37 cases (19831994). J Am Anim Hosp Assoc 32:465470, 1996 Tidholm A, Jo nsson L: A retrospective study of canine dilated cardiomyopathy (189 cases). J Am Anim Hosp Assoc 33:544550, 1997 Tidholm A, Svensson H, Sylve n C: Survival and prognostic factors in 189 dogs with dilated cardiomyopathy. J Am Anim Hosp Assoc 33:364368, 1997 Tidholm A, Svensson H, Sylve n C: Effects on survival of combination treatment with propranolol and thyroid hormone treatment or placebo in conjunction with digoxin and furosemide in euthoroid dogs with myocardial hypokinesia and congestive heart failure. Eur Soc Vet Intern Med Congr 11:159, 2001 Tilley LP, Liu S-K: Cardiomyopathy in the dog. Recent Adv Stud Cardiac Struct Metab 10:641653, 1975

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89 Towbin JA, Hejtmancik JF, Brink P, Gelb B, Zhu XM, Chamberlain JS, McCabe ERB, Swift M: X-linked cardiomyopathy: molecular genetic evidence of linkage to the Duchenne muscular dystrophy dilated gene at the Xp21 locus. Circulation 87:18541865, 1993 90 Urie PM, Billingham ME: Ultrastructural features of familial cardiomyopathy. Am J Cardiol 62:325327, 1988 91 Valentine BA, Cummings JF, Cooper BJ: Development of Duchenne-type cardiomyopathy: morphologic studies in a canine model. Am J Pathol 135:671678, 1989 92 Van Fleet J, Ferrans V: Pathology of the Cardiovascular System. Thomsons Special Veterinary Pathology, 2nd ed., pp. 175208. Mosby, St. Louis, MO, 1995 93 Van Fleet JF, Ferrans VJ: Myocardial diseases of animals. Am J Pathol 124:98178, 1986 94 Van Fleet JF, Ferrans VJ, Weirich WE: Pathological al-

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terations in congestive cardiomyopathy of dogs. Am J Vet Res 42:416424, 1981 Vollmar A: The prevalence of cardiomyopathy in the Irish Wolfhound: a clinical study of 500 dogs. J Am Anim Hosp Assoc 36:125131, 2000 Vollmar AC, Fox PR, Meurs KM, Liu S-K : Dilated cardiomyopathy in juvenile Doberman pinscher dogs. J Vet Cardiol 5(1):2327, 2005 Wright KN, Mehdirad AA, Giacobbe P, et al: Radiofrequency catheter ablation of atrioventricular accessory pathways in 3 dogs with subsequent resolution of tachycardia-induced cardiomyopathy. J Vet Intern Med 13: 361371, 1999 Wynne J, Braunwald E: The cardiomyopathies and myocarditides. In: Heart Disease: A Textbook of Cardiovascular Medicine, ed. Braunwald E, 5th ed., p. 1404. WB Saunders, Philadelphia, PA, 1997

Request reprints from Dr. A. Tidholm, Albano Animal Hospital of Stockholm, Rinkbyva gen 23, S-182 36 Danderyd (Sweden). E-mail: annatidholm@hotmail.com.

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