Histologic Characterization of Canine Dilated Cardiomyopathy

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2005 42: 1Vet PatholA. Tidholm and L. Jnsson

Histologic Characterization of Canine Dilated Cardiomyopathy

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Vet Pathol 42:18 (2005)

REVIEW ARTICLE

Histologic Characterization of Canine Dilated CardiomyopathyA. TIDHOLM AND L. JONSSON

Albano Animal Hospital of Stockholm, Rinkbyvagen 23, Dander yd, 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 anddiastolic dysfunction, is one of the most common heart diseases in dogs. The clinical diagnosis is based onfindings on echocardiographic and Doppler examinations, with the active exclusion of other acquired or con-genital heart diseases. However, the echocardiographic criteria for the diagnosis of DCM are not wholly specificfor the disease, and histologic examination may be necessary forfinal diagnosis. Review of reports on histologicfindings in dogs with clinically diagnosed DCM reveals two histologically distinct forms of DCM: 1) cardio-

myopathy of Boxers and Doberman Pinschers, corresponding to the fatty infiltrationdegenerative type and2) the form seen in many giant, large-, and medium-sized breeds, including some Boxers and DobermanPinschers, classified as the attenuated wavy fiber type of DCM. The histologic changes of the attenuatedwavy fiber type of DCM may precede clinical and echocardiographic signs of heart disease, thus indicating anearly stage of DCM.

Key words: dilated, cardiomyopathy, canine, histology

The classification of cardiomyopathies introduced

by the World Health Organization is based on patho-

physiology or, where possible, on etiologic or patho-

genetic factors. Dilated cardiomyopathy (DCM) is

characterized by chamber dilatation and predominantlysystolic and, to a lesser degree, diastolic dysfunction.66

DCM was first 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 Box-

ers35 and of Doberman Pinschers,14,15,30,36 correspond-

ing to the fatty infiltrationdegenerative 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 classified as the

attenuated wavy fiber type of DCM.1,21,69,77,82,83,88,96

Presumably, specific histologic myocardial changes re-

flect specific disease processes. Aiming for a histologic

confirmation and classification 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 deficiencies, metabolic disorders, immuno-

logic abnormalities, infectious diseases, and drug-,

toxin-, and tachycardia-induced myocardial hypoki-

nesis.

DCM is considered to be hereditary in approxi-

mately 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 specific fam-

ilies of dogs.76 An autosomal dominant mode of trans-

mission 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 investi-

gated in the development of DCM, and the dystrophin

gene has been identified as being responsible for X-

linked DCM.89 Canine X-linked muscular dystrophy

may cause severe cardiac involvement,91 and deletion

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2 Vet Pathol 42:1, 2005Tidholm and Jonsson

of the entire dystrophin gene has been demonstratedin German Shorthaired Pointers with skeletal myopa-

thy and DCM.70 Mutations in the actin gene have beenassociated with DCM in humans.63 However, molecu-

lar analysis of the cardiac actin gene in 16 DobermanPinschers with DCM did not reveal any abnormali-

ties.55

Nutritional abnormalities causing myocardial hy-pokinesis, i.e., carnitine or taurine deficiencies (or

both), have been described in humans,65 dogs,3841,43

and cats.64 Metabolic disorders associated with DCM

include hypothyroidism, diabetes mellitus, and pheo-chromocytoma.4,76,98

Immunologic processes have been suspected to be

involved in the pathogenesis of DCM because auto-antibodies have been detected against several cardiac

structures, such as the -adrenergic receptor,47 the mi-tochondria,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 specificfor DCM because they are also detected in myocar-ditis, hypertrophic cardiomyopathy, and hypertensiveheart disease.5 Inflammatory response to infectious

agents, such as viruses,2,12,17,58 bacteria,46,79 and proto-zoa,6,7 has been proposed to be involved in the path-

ogenesis of myocarditis and DCM.Cardiotoxicity may be caused by doxorubicin and

other antineoplastic agents, ethanol, cobalt, lead, cat-echolamines, histamine, methylxanthines, and vitaminD.93 Studies on naturally occurring tachycardia as well

as experimentally induced tachycardia report devel-opment of chamber dilatation and CHF.3,34,60,97

Clinical Findings

Overt DCM, i.e., dogs with DCM exhibiting signsof CHF or arrhythmias, is preceded by a preclinicalstage of various lengths. Clinical signs in dogs with

DCM include dyspnea, cough, depression, exercise in-tolerance, inappetence, syncope, weight loss, abdomi-

nal distention, and polydipsia. The clinical examina-tion commonly reveal tachypnea, dyspnea, tachycar-

dia, arrhythmia, a low-intensity systolic murmur insome dogs, weak femoral arterial pulses, ascites, andweight loss.76,85 Most dogs with DCM show abnor-

malities on electrocardiogram recordings, such as atrial

fibrillation or ventricular arrhythmias. Radiographic

findings in dogs with DCM include cardiomegaly withprominence of the left atrium, pulmonary venous con-

gestion, and interstitial or alveolar pulmonary edema.These changes are diagnostic of left-sided or biventric-

ular CHF and not specific for DCM. The diagnosis ofDCM is usually based on echocardiographic findingsof myocardial hypokinesia and chamber dilatation,

with the active exclusion of other significant congen-ital and acquired heart disease. The sensitivity of stan-

dard clinical and echocardiographic criteria was foundto be 93% in one study, when final diagnosis is based

on postmortem findings.82 Differential diagnoses in-cluded arteriosclerosis, myocardial infarcts, endocar-

diosis, and myocarditis.

Survival and Prognosis

Survival times in dogs with DCM vary from daysto several years. Attempts to correlate different clinical

and echocardiographic parameters with prognosis havebeen made. In one study of 189 dogs with DCM, only

3 of 27 tested variables were shown to influence sur-vival, i.e., young age at onset of clinical disease, dys-

pnea, and ascites.86 Another study of 37 dogs identified

pleural effusion and pulmonary edema as independentprognostic indicators for dogs with DCM.57 Neither of

these studies found breed or parameters of systolicfunction to be significant 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 variationin survival times may partly depend on different func-tional classes of CHF in different studies. Medicaltreatment, especially the use of angiotensin-converting

enzyme inhibitors and -blocking agents, varied con-siderably between different studies, which also may be

a source of variation in survival times. However, theexceptionally low survival rate at 1 year of Doberman

Pinschers (3%) may indicate that the fatty infiltrationdegenerative type of DCM carries a worse prognosiscompared with the attenuated wavy fiber type of

DCM.

Gross Pathology and HistopathologyGross pathology examination of the heart of dogs

with DCM generally reveals marked dilatation of allfour chambers or predominantly the left chambers. Inone study, dilatation of all four chambers was found

in 85% of dogs with DCM.85 Myocardial eccentric hy-pertrophy, rather than true dilatation, is evident by in-

creased heart weight to body weight ratio, togetherwith a decreased ratio of the left ventricular thickness

to chamber diameter.76,85 The term hypertrophy impliesa pathologic process where the weight of the organ isincreased because of an increase in cell size rather than

in cell number. In myocardial eccentric hypertrophy,the sarcomeres are increased in numbers in series rath-

er than parallel, as in concentric hypertrophy. Myo-cardial eccentric hypertrophy is commonly caused by

volume overload.44

In the literature, there appear to be two histologi-cally distinct forms of canine DCM: the attenuated

wavy fiber type seen in many giant, large-, and me-dium-sized dogs, and the fatty infiltrationdegenera-

tive type of DCM seen in mainly Boxers and Dober-man Pinschers (Table 1). Some other studies report



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Vet Pathol 42:1, 2005 3Canine Dilated Cardiomyopathy

Table 1. Classification of canine DCM in different studies in chronological order, based on the reported histopathologiccharacteristics.

Author BreedNumber of Dogs

in Study Mean Age of Dogs

Attenuated wavy fiber type

Tilley and Liu88 Large and giant breeds 12 5 years

Sandusky et al.69 Large and giant breeds 11 Tidholm et al.82 23 large and medium-sized breeds 64 5 yearsDambach et al.21 Portugese Water Dogs 12 13 weeksTidholm et al.83 Newfoundlands 7 2.5 yearsA. Tidholm (unpublished) Newfoundlands five other breeds 33 5.4 yearsAlroy et al.1 Portugese Water Dogs 2 9 weeksVollmar et al.96 Doberman Pinschers 3 3 weeksSleeper et al.77 Portugese Water Dogs 10 17 weeks

Total number of dogs 154

Fatty infiltrationdegenerative type

Calvert et al.14 Doberman Pinchers 6 6.7 yearsHazlett et al.36 Doberman Pinschers 14 4.7 yearsHarpster35 Boxers 64 8.2 years

Calvert et al.15

Doberman Pinschers 12 Everett et al.30 Doberman Pinschers 32 Males: 7.2 years

Females: 9.4 years

Total number of dogs 128

information not available.

Fig. 1. Left ventricular myocardium of a dog with attenuated wavyfiber type of DCM. The myofibers are thinner thannormal and have a wavy appearance. Massons trichrome. Bar 20 m.

Fig. 2. Left ventricular myocardium of a dog with fatty infiltrationdegenerative type of DCM. Vacuolar degenerationof myofibers (small arrows), atrophic myofibers, lipid deposits (large arrows), and cords of collagen (blue staining) are

evident. Massons trichrome. Bar 20 m.

nonspecific findings, such as necrosis, infarcts, fibro-sis, vacuolization of myocytes, and hyperplasia of ar-

teries.33,51,78,94

The attenuated wavy fiber 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 attenua-tion, of myofibers without a wavy appearance has been

reported in several additional studies in human patientswith DCM.25,32,37,61,62,67,90 Myofiber atrophy is a com-mon response to processes that prevent normal con-tractile activity and to various pathologic stimuli.19 At-rophy of cardiac myocytes has been shown to occurafter prolonged mechanical support using left ventric-

ular assist device systems42 and after heterotopic iso-transplantation.68 Wavy myocardial fibers, especially



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when associated with focal edema, are characteristicsigns of acute myocardial ischemia in humans26 and in

dogs,26,27 but have also been described in human pa-tients with DCM.52,59

The myocardial lesions associated with the attenu-ated wavy fiber type of DCM consist of myocardial

cells 6 m in diameter (normal myofi

ber diameterranges from 10 to 20 m92) with a wavy appearance,comprising at least half of the thickness of the myo-

cardial specimens from the upper and lower portionsof the left ventricular wall. The myocytes are separated

by a clear space generally free from cellular infiltrates,suggestive of edematous fluid. In many cases, there is

also a diffuse infiltration of subendocardial fibrosis(Fig. 1). It is suggested that myocardial specimensshould be taken from the proximal (11.5 cm distal to

the base of the atrioventricular valves), distal (11.5cm proximal to the apex), and middle (midway be-

tween the proximal and the distal specimens) portions

of the lateral wall of the left ventricle, lateral wall ofthe right ventricle, and interventricular septum, andfrom the papillary muscles of the left ventricle. Threeslides from each of the 10 specimens should be eval-

uated for the presence of attenuated wavy fibers.82,83

Unfortunately, myocardial biopsy specimens col-

lected in vivo from the right ventricle may not be suf-ficient for identifying dogs with attenuated wavy fibers

because the abnormal myofibers were most abundantin the lateral wall of the left ventricle.83 Detection ofattenuated wavy fibers in the myocardium of dogs has

been shown to have a high sensitivity (98%) for DCM.The specificity of this finding was found to be 100%

because attenuated wavy fibers were not found in 147necropsied dogs with other heart diseases, such as

chronic valvular disease, congenital heart disease,myocardial infarcts, myocarditis or endocarditis, al-though the majority of these hearts were dilated.82

In a subsequent study, attenuated wavy fibers weredetected in Newfoundlands from a kennel with a

known predisposition to DCM, but without clinical orechocardiographic evidence of heart disease.83 These

findings suggest that development of attenuated wavyfibers is not a response to chamber dilatation andstretching of the myocytes, as has been proposed.71 To

the contrary, attenuated wavy fibers may represent anearly pathologic change in the myocardium of dogs

with DCM.

The fatty infiltrationdegenerative type of DCM

It was first described as boxer cardiomyopathy in64 Boxers by Harpster35 in 1983 (Fig. 2). The myo-

cardial lesions associated with the fatty infiltrationdegenerative type of DCM include myocytolysis, myo-

fiber degeneration, vacuolization, and myocyte atrophywith extensive fibrosis and fatty infiltration replacing

myofibers (Fig. 2). Similar myocardial lesions were

first described by Calvert et al. in 198214 and later by

the same and by other authors in a total of 64 Dob-erman Pinschers with clinically diagnosed DCM.15,30,36

In one of the reports by Everett et al. the myocardiallesions have been described extensively, characterized

by myofi

ber degeneration and atrophy, and replace-ment of myocardium by dense bundles of collagen andclusters of adipocytes.30 The lesions have been com-

pared to arrhythmogenic right ventricular cardiomy-opathy (ARVC) in dogs31,53,75 and in humans.8,81 How-

ever, the myocardial changes in ARVC are usuallyconfined to the right ventricle and profound to the ex-

tent that they are evident already on gross pathologyexamination. Myocyte transdifferentiation of myocytesto adipocytes was suggested as a possible mechanism

for ARVC in a recent report.20

Discussion

The attenuated wavy fiber type of DCM seems tobe the most prevalent form of DCM because manymore breeds are afflicted with this disease comparedwith the fatty infiltrationdegenerative type of DCM.

However, there are to date relatively few authors (Ta-ble 1) who have reported on this histopathologic find-

ing. There may be many reasons for this lack of re-porting. In the hitherto largest study of dogs with the

attenuated wavy fiber form of DCM, as many as 27slides from nine different locations in the ventricleswere evaluated for presence of attenuated wavy fibers.

Although, in many dogs, attenuated wavy fibers werefound in the majority of the specimens, the abnormal

fibers were most abundant in the lateral wall of the leftventricle.83 By examining only a limited number of

myocardial specimens, presence of attenuated wavy fi-bers may indeed be missed.

The technical process for preparation of the slides

from the specimens may influence the morphology.The technique used for dehydration of the specimens

may vary. The slicing technique may produce artificialwaviness of the myofibers. 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 dis-ruption of collagen tethers aligning the cardiomyocytes

that occurs in the remodeling process involved in di-latation. The artifact may reflect the loss of volume

distention after death and fragmentation of collagentethers that maintain alignment (J. Turk, personal com-

munication). However, this supposed artifact onlyseems to occur in hearts where dilatation is due to

DCM and not in hearts where dilatation is due tochronic valvular disease or congenital heart disease.82

Also, attenuated wavy fibers have been found in myo-

cardium of dogs where no dilatation is present.83 Wavymyocardial fibers (not attenuated) have also been de-



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scribed in human patients and in dogs with acute myo-cardial ischemia.26,27

Fibro-fatty replacement of myocardial tissue isthought to be a consequence of myocyte loss due to

different causes, such as myocarditis or other noxiousstimuli. Fatty infiltration of the myocardium is report-

ed to be a majorfi

nding in ethanol-induced cardio-myopathy.22 A number of antineoplastic agents, suchas doxorubicin and cyclophosphamide, may cause ex-

tensive myocyte vacuolization.93

The characteristic histologic findings presumably re-

flect specific disease processes, rather than being theend result of many different pathologic processes. As

the very structure of the myocytes is distorted in theattenuated wavy fiber type of DCM, the cause may bea defect in the cytoskeletal proteins. It has been sug-

gested that DCM in human patients should be termedcytoskeletalopathy due to mutations found in dys-

trophin, actin, and desmin.11 The cytoskeletal proteins

transmits the contractile force to adjacent sarcomeresand myocytes. Such an impairment will prevent nor-mal contractility and, thus may cause myocyte atrophy.

In conclusion, there appears to be at least two his-

tologically distinct forms of idiopathic canine DCM,presumably reflecting different disease processes. His-

tologic classification of canine DCM is therefore es-sential for scientific studies of the disease.

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Histologic Characterization of Canine Dilated Cardiomyopathy