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Departmental Papers (Vet) School of Veterinary Medicine

1-1999

Familial Dilated Cardiomyopathy of Young

Portuguese Water Dogs
Donna M. Dambach

Anne Lannon

Meg M. Sleeper

James W. Buchanan
University of Pennsylvania, [email protected]

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Recommended Citation
Dambach, D. M., Lannon, A., Sleeper, M. M., & Buchanan, J. W. (1999). Familial Dilated Cardiomyopathy of Young Portuguese Water
Dogs. Journal of Veterinary Internal Medicine, 13 (1), 65-71. http://dx.doi.org/10.1111/j.1939-1676.1999.tb02167.x

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For more information, please contact [email protected].
Familial Dilated Cardiomyopathy of Young Portuguese Water Dogs
Abstract
A novel dilated cardiomyopathy (DCM) in 12 related Portuguese Water Dogs was identified by retrospective
analysis of postmortem and biopsy case records. Male and female puppies born to clinically healthy parents
typically died at 13 (± 7.3) weeks of age (range, 2–32 weeks) because of congestive heart failure. Puppies died
suddenly without previous signs or with mild depression followed by clinical signs of congestive heart failure
1–5 days before death. There was no sex predilection. The hearts were enlarged and rounded, with marked left
ventricular and atrial dilation. No other significant structural cardiac defects were noted. The histologic
changes in the myocardium were diffuse and characterized by myofibers of irregular sizes separated by an
edematous interstitium. The myofibers had multifocal swollen, cleared segments often involving perinuclear
areas that contained granular, phosphotungstic-acid-hematoxylin-positive material consistent with
mitochondria. There was loss of the cross-striation pattern, and intercalated discs were difficult to identify.
There was no evidence of concurrent myocardial fibrosis; rare chronic inflammatory infiltrates were noted in
one dog. Noncardiac skeletal muscles were not affected. The underlying cause is unknown. From the pedigree
analysis, an autosomal recessive pattern of inheritance is suspected. Based on the histologic findings, this
DCM is most likely due to an underlying molecular (biochemical or structural) defect. The early onset and
rapid progression of the disease makes this a clinically distinctive form of canine DCM.

Keywords
Dog, Idiopathic dilated cardiomyopathy

Disciplines
Animal Diseases | Cardiology | Cardiovascular Diseases | Congenital, Hereditary, and Neonatal Diseases and
Abnormalities | Veterinary Infectious Diseases

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J Vet Intern Med 1999;13:65–71

Familial Dilated Cardiomyopathy of Young Portuguese Water Dogs

Donna M. Dambach, Anne Lannon, Meg M. Sleeper, and James Buchanan

A novel dilated cardiomyopathy (DCM) in 12 related Portuguese Water Dogs was identified by retrospective analysis of postmortem
and biopsy case records. Male and female puppies born to clinically healthy parents typically died at 13 (6 7.3) weeks of age
(range, 2–32 weeks) because of congestive heart failure. Puppies died suddenly without previous signs or with mild depression
followed by clinical signs of congestive heart failure 1–5 days before death. There was no sex predilection. The hearts were
enlarged and rounded, with marked left ventricular and atrial dilation. No other significant structural cardiac defects were noted.
The histologic changes in the myocardium were diffuse and characterized by myofibers of irregular sizes separated by an edematous
interstitium. The myofibers had multifocal swollen, cleared segments often involving perinuclear areas that contained granular,
phosphotungstic-acid-hematoxylin–positive material consistent with mitochondria. There was loss of the cross-striation pattern, and
intercalated discs were difficult to identify. There was no evidence of concurrent myocardial fibrosis; rare chronic inflammatory
infiltrates were noted in one dog. Noncardiac skeletal muscles were not affected. The underlying cause is unknown. From the
pedigree analysis, an autosomal recessive pattern of inheritance is suspected. Based on the histologic findings, this DCM is most
likely due to an underlying molecular (biochemical or structural) defect. The early onset and rapid progression of the disease makes
this a clinically distinctive form of canine DCM.
Key words: Dog; Idiopathic dilated cardiomyopathy.

D ilated cardiomyopathy (DCM) is the most commonly

reported form of canine cardiomyopathy.1,2 DCM is
most often associated with large and giant breed dogs and
Pennsylvania, for the period 1987–1996. Postmortem examinations
were performed on 5 pups, and heart weight and heart : body weight
ratio were recorded in 3 pups. Heart weight was determined after re-
moval of the pericardium and great vessels and after all heart chambers
the Doberman Pinscher, Boxer, and English and American
were opened and blood clots were removed. Body weight and condi-
Cocker Spaniel breeds.3–7 In all breeds, the age range of
tion were recorded at postmortem to allow calculation of heart : body
affected dogs is wide (6 months to 15 years), although the weight ratios. Tissues and information from the remaining 7 cases of
typical age range of clinical presentation is 4–8 years.1 For DCM were obtained through submissions to the Surgical Pathology
the Boxer, Doberman Pinscher, and Great Dane breeds, less Service. Hearts from clinically normal age- and breed-matched pups
than 1% of cases are made up of dogs younger than 1 year were also examined histologically. All tissues were fixed in 10% neu-
of age.8 There is a 2 : 1 male predilection reported in the tral buffered formalin, routinely processed, embedded in paraffin, and
affected breeds.8 Survival is poor after onset of signs rang- sectioned at 3–5 mm for light microscopy. Tissue sections were stained
ing from 6 weeks to 2 years, and death is due to congestive with hematoxylin and eosin, Masson’s trichrome for collagen, alcian
heart failure or fatal arrhythmias. The predisposition of spe- blue (pH 2.7) for mucopolysaccharides, phosphotungstic acid–hema-
toxylin for mitochondria, and periodic acid–Schiff for glycogen. For-
cific breeds for DCM suggests a heritable basis for the dis-
malin-fixed, frozen tissue from 1 pup (10) was stained with oil red O
ease, but the exact underlying molecular or biochemical
for lipid. When whole hearts were submitted for evaluation, the fol-
mechanism(s) for canine DCM in all cases is unknown. lowing were examined histologically: sections through the entire left
Many of the structural and biochemical changes noted may and right free walls (atria, atrioventricular valves, and ventricles) and
be secondary manifestations of the failing heart. This is the sections through the entire interventricular septum, including right
first report of DCM in the Portuguese Water Dog breed. atrioventricular valve and aortic valve.
This disease appears to be familial, but it has features that Clinical and historical data were obtained either by examination of
distinguish it from other canine dilated cardiomyopathies. the clinical records from affected pups at the Veterinary Hospital, Uni-
versity of Pennsylvania, or from the referring veterinarians. Two pups
Materials and Methods (4, 10) were clinically evaluated with radiographs, EKG, and echo-
cardiography prior to death. Results of serum clinicopathologic anal-
The 12 cases of DCM in Portuguese Water Dogs (POWD) were ysis and CBCs were available for 1 pup (10). Urinary metabolic
identified by review of the records of the Necropsy and Surgical Pa- screening was performed on pup 10 using spot tests and 1-dimensional
thology Services of the School of Veterinary Medicine, University of paper chromatography to analyze the types of amino acids, organic
acids, and carbohydrates in urine.9 Pedigree analysis was performed
From the Departments of Pathobiology (Dambach) and Clinical using 4–6-generation predigree information from affected pups pro-
Studies (Medical Genetics [Lannon] and Cardiology [Sleeper, Bu- vided by owners and breeders.
chanan]), School of Veterinary Medicine, University of Pennsylvania,
Philadelphia, PA. Dr. Dambach is currently affiliated with the De- Results
partment of Experimental Pathology, Bristol-Myers-Squibb, Princeton,
NJ; e-mail: [email protected]. Dr. Lannon is cur-
Clinical Findings
rently affiliated with Guide Dogs for the Blind, San Rasal, CA. Pre- The clinical courses of the 12 pups were similar. The
viously presented in poster form at the 1996 Meeting of the American affected pups were 13 6 7.3 (SD) weeks of age (range, 2–
College of Veterinary Pathologists, Seattle, WA.
32 weeks) at the time of death. The longest clinical course
Reprint requests: Donna M. Dambach, VMD, Laboratory of Pa-
was 5 days and was characterized by depression and de-
thology, School of Veterinary Medicine, University of Pennsylvania,
3800 Spruce Street, Philadelphia, PA 19104. creased appetite, collapse, and death. The remainder of the
Accepted February 27, 1998. pups presented with either an acute onset of respiratory
Copyright q 1999 by the American College of Veterinary Internal distress leading to death within hours or sudden unexpected
Medicine collapse and death (Table 1). There was no evidence of
0891-6640/99/1301-0010/$3.00/0 protracted disease, even in the 32-week-old male. Because
66 Dambach et al

Table 1. Characteristics of Portuguese Water Dog pups with dilated cardiomyopathy.

Age Heart Weight (g)
Pup No. (weeks) Gender (% body weight) Clinical History
1a
12 Female Several days depression, anorexia; sudden collapse, death
2a 12 Female 24-hour respiratory distress, death; cardiomegaly, pulmonary edema
3 32 Male 174 (1.06%) Acute onset respiratory distress; enlarged heart, pulmonary edema
4 14 Female 73 (1.3%) Few hours of weakness, then respiratory distress, cyanosis, death; pup
from previous litter from same parents died with similar signs
5 2 Male Respiratory distress; failure to thrive
6 7 Male Sudden, unexpected death
7b 9 Male Not available
8b 11 Female 44 Respiratory distress; severe interstitial pattern
9 8 Female 32 Lethargic, decreased appetite on day of death; died suddenly while
playing; breeder reported another littermate died
10c 14 Female 67 (1.09%) Quiet pup; echocardiography showed dilated heart; all other clinical
data normal; euthanized
11c 13 Male 73 Sudden onset respiratory distress; exercise intolerance; died 4 hours later
12c 17 Female 83 Sudden onset respiratory distress; died 30 minutes later

Pups with same superscript are littermates.

of the unexpected onset of the clinical signs and the rapid apex. The cardiac rhythm was regular; however, weak puls-
decline, 10 of 12 pups lacked clinicopathologic data. Two es and pale mucous membranes were detected. Crackles
pups (4, 10) were evaluated and followed clinically from were auscultatable over all lung fields, and the pup was
the onset of clinical signs to death. Pup 4 was presented markedly dyspneic. Radiographs revealed left-sided cardio-
because of respiratory distress. Physical examination re- megaly and a hilar alveolar pattern consistent with pul-
vealed a grade III/VI soft systolic murmur at the left cardiac monary edema. The vertebra : heart ratio measurement was
11.9 (normal 5 8.6–10.6).10 Echocardiography revealed a
severely dilated left ventricle with a shortening fraction of
10% (normal 5 27–48%)11 (Fig 1). The pup was treated
with furosemide (2 mg/kg IV q8h), nitroglycerine (0.6mL
sc q6h), digoxin (0.04 mg PO q12h), and increased inspired
oxygen tension via an oxygen cage. The pup underwent
cardiac arrest later that day, and resuscitation attempts were
not successful.
Pup 10 was presented because a littermate (pup 11) died
suddenly, and cardiomyopathy was diagnosed at postmor-
tem. Physical examination of pup 10 at the time of presen-
tation revealed a slightly muffled 1st heart sound; however,
no murmur was detected. Normal bronchovesicular lung
sounds were auscultated over all lung fields. Radiographs
revealed a heart size at the upper limit of normal, with a
vertebra : heart ratio of 10.7. The right cranial pumonary
arteries and veins were enlarged. All variables on an EKG
examination were within normal limits (PR 5 80 ms; QRS
5 40 ms; QT 5 200 ms; RII 5 1.7 mV; mean electrical
axis 5 normal), although a sinus tachycardia was present
(heart rate [HR] 5 180beats/minute). An echocardiogram
revealed cardiomegaly, with a left ventricular end diastolic
diameter of 3.7 cm and a left ventricular systolic diameter
of 3.4 cm (respective normal values from an age-, breed-,
and size-matched control animal: 2.3 and 1.5 cm). The
Fig 1. M-mode echocardiographs from affected pup 10 (A, C) and shortening fraction was 10%. E-point septal separation was
a normal age-, breed-, and weight-matched pup (B, D). The affected 1.1 cm (normal, 0.3 cm), and the aortic ejection time was
pup had increased left ventricular end-diastolic diameter (1) (3.7 cm) 0.135 seconds (normal, 0.185 seconds) (Sleeper, unpub-
and increased end-systolic diameter (2) (3.4 cm), yielding a shortening
lished data). Mild mitral regurgitation was detected with
fraction of 10%. Respective values in the normal pup (B) were 2.3
cm, 1.5 cm, and a shortening fraction of 35%. An echocardiogram of
Doppler investigation.
the affected pup (C) showed mitral valve (MV) motion and increased The following day, the pup remained tachycardic, and a
E-point septal separation (EPSS) of 1.1 cm. EPSS in the normal pup faint, intermittent diastolic gallop was occasionally auscul-
(D) was 0.5 cm. S 5 interventricular septum, FW 5 left ventricular tatable. By that evening, the pup was slightly weak and had
free wall. a decreased appetite. Bronchovesicular sounds were in-
 Portuguese Water Dog Cardiomyopathy 67

Fig 2. Pedigree analysis of 8 pups affected with dilated cardiomy-

opathy (DCM). The arrow indicates the propositus (pup 10). Pedigree
analysis reveals common ancestry of the 8 POWD affected with DCM.
Both genders are affected and were produced by phenotypically nor-
mal parents. In another family of POWD sharing no common ancestor
Fig 3. Transverse section of heart from pup 10 with dilated cardio-
with the propositus within 6 generations, there are 4 affected dogs (1
myopathy. The heart is globoid due to diffuse chamber dilation, which
male, 3 females). These results are highly suggestive of an autosomal
is most pronounced for the left ventricle and atrium. S 5 septum; LV
recessive mode of inheritance.
5 left ventricular free wall. Bar 5 1 cm.

creased; however, no distinct crackles were auscultatable.

Mild end expiratory effort was noted. The 2nd day after were produced by phenotypically normal parents. Both
presentation as a clinically normal pup, the dog was weaker males (n 5 5) and females (n 5 7) were affected. Based
and anorectic. Auscultation revealed a grade V/VI pansys- upon these findings, the pedigree is most consistent with an
tolic murmur with the point of maximal intensity at the left autosomal recessive mode of inheritance, but a polygenic
apex. A prominent gallop rhythm was also noted, and puls- mode of inheritance cannot be ruled out without further test
es were of a short duration and weak. Crackles became breedings. Although there are several anecdotal reports of
auscultatable bilaterally in the thorax several hours later, pups dying with clinical signs similar to those reported
and a bolus of 1 mg/kg furosemide was administered IV. here, the true incidence of this disease in the POWD breed
Over the following 2 hours, crackles became more promi- cannot be determined at this time.
nent, as did tachypnea and dyspnea. During this period, the
pup vomited and remained severely depressed. An EKG Postmortem Results
exam demonstrated sinus tachycardia (HR5190 beats/mi- Entire hearts of 9 pups were available for examination,
nute) but was otherwise unremarkable. Another bolus of IV but only sections of heart were submitted for the remaining
furosemide was administered; however, the pup remained 3 pups. Of the 9 hearts examined, all had similar changes
in respiratory distress and was euthanized and submitted (Fig 3). The hearts were enlarged and globoid with round-
for postmortem. A CBC and serum and urinary biochemical ing of the apex. The left auricle was markedly dilated, often
analyses on pup 10 did not reveal any abnormalties. Ra- larger than the right auricle. The left ventricle was dilated
diographic abnormalities for pups 4, 10, and 11 included and easily compressible from the epicardial surface. On cut
pulmonary interstitial patterns characteristic of edema in all section, the left ventricular lumen was expanded with flat-
3 pups and cardiomegaly in 2. tening of papillary muscles. The left ventricular free wall
The treatment for 7 pups consisted of emergency sup- thickness was noticeably reduced (measurements of thick-
portive care to stabilize the cardiovascular system, includ- ness were not routinely made). The endocardium of the left
ing 1 or more of the following: cardiopulmonary resusci- ventricle was diffusely opaque, corresponding histological-
tation (n 5 3); digoxin (n 5 1), furosemide (n 5 3), nitro- ly to endocardial fibrosis. The right ventricle and atrium
glycerine (n 5 1), oxygen (n 5 3), corticosteroids (n 5 1), were also dilated, but these changes were not as pronounced
fluids (n 5 1), epinephrine (n 5 2), and aminophylline (n at that seen in the left hemiportion of the heart. A patent
5 1). foramen ovale (1 3 0.4 cm) was noted in case pup 2. No
other structural abnormalities were found in the remaining
Pedigree Analysis 8 hearts.
Pedigree analysis revealed common ancestry of 8 of the Lung changes were noted grossly at postmortem in 5
POWD affected with DCM (Fig 2). One female was the pups; lungs were wet and rubbery, congested, and slightly
dam of 4 affected pups, the granddam of 2 affected pups, firm. Lungs from 11 pups were examined histologically.
the great-granddam of 1 pup, and a half-sister to the re- Interstitial edema and alveolar histiocytosis were noted in
maining affected pup. Another family of POWD sharing no all pups, and in 7 pups there was minimal to mild acute
common ancestor to pup 10 within 6 generations did in- interstitial pneumonia with infiltrates of neutrophils and the
clude the 4 additional affected pups. All 12 affected pups presence of alveolar fibrin and necrosis of individual cells
68 Dambach et al

Fig 4. Histologic section of myocardium from pup affected with di-

lated cardiomyopathy. The interstitial space between the myofibers is
prominent. The myofibers are generally thinner than normal and dis-
organized; their size varies markedly. The swollen, cleared areas of
the sarcoplasm are obvious at this magnification (arrows). Hematox-
ylin and eosin. Bar 5 61 mm.

in the septa. Erythrophagocytosis was noted in only 1 pup

(9); however, red blood cells were noted in alveoli in all
11 pups examined. The changes are consistent with those
found in congestive heart failure and secondary hypoxia.
The mild acute interstitial inflammation may have also been
the result of mild aspiration during the bouts of dyspnea.
Other changes noted at postmortem or from tissues sub-
mitted were consistent with those resulting from heart fail- Fig 5. Histologic appearance of myocardium from POWD affected
ure. Hepatic congestion was found histologically in the 6 with DCM (a) and from a clinically normal pup (b). The myocardi-
pups where liver was available for evaluation. Hepatomeg- ocytes from the affected dog (a) are expanded segmentally by cleared
aly was reported in 6 pups; hepatic capsular fibrin was also areas of the sarcoplasm, which are typically prominent in perinuclear
reported in 1 pup. These gross findings are consistent with regions (arrowhead) but extend to affect large areas of the fibers, lead-
passive hepatic congestion of cardiac origin. Peritoneal cav- ing to loss of regular cross-striations (arrows). There is greater nuclear
ity ascites was reported in 2 pups, and pleural effusion size/shape variability in the affected heart when compared with tissue
from a breed/age-matched control dog (b). Hematoyxlin and eosin.
(transudate) was reported in 1 pup.
Bars 5 57 mm.

Histologic Examination
Heart tissue from 5 normal breed-matched dogs (4 pups stained dark blue with phosphotungstic acid–hematoxylin,
6–18 weeks of age and one 4-year-old adult dog) were com- which is consistent with mitochondria. However, the
pared with that of affected pups. The changes in the myo- cleared areas of the myofiber sarcoplasm did not stain with
cardium from affected pups were most obvious upon ex- special stains for mucopolysaccharides, lipid, or glycogen,
amination of longitudinal sections of myofibers. The myo- which suggests that the swelling was due to accumulation
fibers were accentuated by an interstitium expanded by of intracellular fluid (hydropic change).
clear space that did not stain with special stains for mu- There was no histologic evidence of myocardial fibrosis
copolysaccharides, lipid, or glycogen and was therefore in any pup when tissues were examined with a trichrome
consistent with edema. The myofibers often appeared irreg- stain. Myofiber nuclei had marked size variability, with kar-
ular in thickness and wavy to bent; many myofibers ap- yomegaly and occasional indented nuclei. The nuclei also
peared to taper or branch. These changes created a disor- were slightly more hyperchromatic when compared with
ganized appearance of the myofibers in some areas when the nuclei from normal myocardium. These nuclear changes
examined at low magnification (Fig 4). There was a gen- are consistent with those described in cases of myocardial
eralized loss of the normal pattern of cross-striations in af- hypertrophy.12 On cross-section, the changes in the myofi-
fected myofibers, and intercalated discs were not seen. The bers were more difficult to appreciate when compared with
irregularity in myofiber thickness was due predominately to normal myocardium; the most prominent changes included
swelling and clearing of the sarcoplasm, which resulted in nuclear hyperchromasia and myofibers of irregular shape
an overall decrease in staining intensity when compared and size that often appeared more angular.
with normal myocardium (Fig 5). The zones of clearing in Myocardial inflammation was absent in all except pup 2,
the myofibers were multifocal and segmental and typically in which rare mixed inflammatory cells (neutrophils, lym-
included prominent perinuclear staining with pinpoint eo- phocytes, and macrophages) were noted associated with the
sinophilic granular material (Fig 5). This granular material endocardium and perivascularly. Rare Anitchkow cells
 Portuguese Water Dog Cardiomyopathy 69

were noted in the interstitium of case pup 12. Myofiber satory and related to deranged energy metabolism (mito-
degeneration and necrosis were also absent in all pups ex- chondrial changes, lipid and glycogen accumulation) and
amined. Coronary arterial and venous vasculatures were hypertrophy (Z-band thickening).15
histologically normal. Skeletal muscle obtained from the The causes of DCM can be divided into 2 major cate-
extremities was also histologically normal. gories: primary (idiopathic) and secondary. Secondary
DCM is the result of cardiac dysfunction due to extracar-
Discussion diac factors that affect cardiac function. These factors are
usually systemic in origin and include infectious agents,
DCM is characterized by generalized dilation of both toxins, and inflammatory or neoplastic conditions that result
atria and ventricles of the heart.2 Clinical manifestations of in destruction of the myocardium and acquired or inherited
DCM result from decreased pump function leading to re- metabolic diseases that affect myofiber function.1 Primary
duced cardiac output. A narrow pulse pressure may be de- or idiopathic DCM principally or exclusively affects the
tected on physical examination, and ventricular gallops typ- myocardium, and the etiology is unknown. The clinical de-
ically develop once cardiac decompensation occurs. Body termination of idiopathic DCM is based upon the absence
cavity and pulmonary fluid accumulation and hepatomegaly of underlying systemic, coronary, valvular, structural (con-
result from a compensatory increase in preload and the de- genital), hypertensive, or pericardial disease. Suspected
creased forward movement of the blood through the heart causes of idiopathic DCM include inherited (genetic) de-
to the arterial system. The most striking clinical signs are fects, infectious agents (enteroviral), immunologic disease,
related to hypoxia and hypoperfusion, with weakness, ex- and endstage disease of unknown origin (toxic, infectious,
ercise intolerance, syncope, coughing, respiratory distress, inflammatory).12,18,19 The latter proposed etiologies are
and tachypnea frequently observed. The development of based upon the finding of inflammatory infiltrates in the
these clinical signs typically occurs late in the course of myocardium. The only definitive virus-induced DCM de-
disease and is ominous.13 Murmurs due to consequent val- scribed in the dog is parvoviral myocarditis. Pups affected
vular insufficiency occur if dilation is severe enough to en- with parvoviral myocarditis are between 2 and 16 weeks
large the valve annulus. Arrhythmias are a common finding, of age with no apparent familial, breed, or sex predilec-
as are radiographic and echocardiographic evidence of heart tion.20 Histologically, the changes in the myocardium cor-
enlargement. Echocardiographic findings consistent with respond to a lymphocytic, end-stage myocarditis with myo-
cardiac enlargement include increased end-diastolic and fiber loss and replacement by extensive fibrosis. In early
end-systolic ventricular volumes and increased atrial di- stages of disease, viral inclusions are noted in myofibers,
ameter; changes are more frequently detected on the left often without concurrent inflammation. Subacute changes
side. The shortening fraction is typically lowered, with a include myofiber necrosis and mild inflammatory infiltrates.
decreased left ventricular free wall thickness. An additional Immune-mediated myocarditis leading to endstage DCM
common feature is a reduced left ventricular ejection time. has also been suggested as a possible etiological subset of
Death is due to congestive heart failure or fatal arrhythmias. human DCM,18,19 but an immune-mediated cause of canine
The histologic changes noted in cases of DCM are not DCM has not been proved. A subset of human DCM ap-
pathognomonic for DCM nor are they indicative of a spe- pears to have a genetic basis. Inherited DCM can be further
cific cause. In the dog, as in humans, the histologic changes subdivided into disorders of substrate and energy metabo-
differ among individuals, but several changes are common- lism, storage diseases, and disorders of mechanisms yet to
ly found in all DCM cases, including 1 or more of the be determined that are classified as heritable because of
following: myofiber degeneration (vacuoles or fracturing) evidence of familial relatedness.19,21,22 In other forms of hu-
and necrosis, interstitial fibrosis in areas of myofiber loss, man cardiomyopathy, such as hypertrophic cardiomyopa-
mononuclear (lymphoplasmacytic and histiocytic) inflam- thy, genetic defects have been related to contractility pro-
mation, infiltration of adipocytes, and myofiber atrophy. teins (cardiac beta-myosin heavy chain), cytoskeletal pro-
Myofiber hypertrophy is also a common compensatory oc- teins, and proteins involved in either signal transduction or
currence because the affected hearts have increased metabolism.19 Similar defects have not been found to date
weights. Variable myofiber size with thin and wavy fibers for DCM in dogs.
has also been reported.14 Other etiologies that have been considered for DCM in
Ultrastructural changes are also inconsistent among cases humans and animals revolve around defects in energy me-
of canine DCM and include myofibrillysis (disorientation tabolism or decreased levels of compounds that protect
and loss of myofibrils), increased intermyofibrillar space, against oxidative damage. These problems include deficien-
sarcoplasmic reticulum dilation, interstitial edema, thick- cies in magnesium, thiamine, selenium, vitamin E, and tau-
ening of Z-bands, mitochondria of irregular shape and size, rine.23–25 Deficiencies of these compounds have not been
and increases in the numbers of mitochondria, glycogen thoroughly explored in the dog.26 Catecholamine excess has
granules, lysosomes, lipofuscin granules, and lipid vacu- also been suggested in human DCM because DCM has
oles.14–17 Additional mitochondrial changes include swollen been identified in patients with actively secreting pheochro-
and disrupted cristae, myelin figure formation, and spheri- mocytomas and in animals given catecholamines.27 The ex-
cal intramitochondrial inclusions. In general, the ultrastruc- act mechanism of catecholamine-induced cardiomyopathy
tural changes are also nonspecific and have been noted in is unknown.
a variety of chronic cardiac diseases. Some changes indi- In dogs, idiopathic DCM is generally suspected to be
cate an increase in cell breakdown products, ie, lipofuscin heritable based upon the various breed predilections, but
and myelin figures. Other changes are most likely compen- heterogeneous underlying biochemical/metabolic defects
70 Dambach et al

are suspected. Substantive evidence supporting the possible changes in the myofibers and interstitium were diffusely
underlying causes or mechanisms is quite limited. De- distributed in the myocardium of affected POWD but were
creased myocardial L-carnitine concentrations have been most pronounced in the left ventricular and septal myocar-
noted in related Boxer dogs with DCM and in some Do- dium. The cause of the expanded interstitium was edema,
berman Pinschers with DCM.28,29 However, L-carnitine con- and the myofiber swelling and loss of cross-striations was
centrations are also lowered with advanced cardiac disease attributable to cytoplasmic fluid accumulation (hydropic
of any cause, and therefore a lower concentration is not a change) and an apparent increase in the numbers of mito-
definitive indicator of underlying cause.23 Supplementation chondria as confirmed by use of special stains to detect the
may serve to enhance remaining cardiac function. deposition of lipid, glycogen, or mucopolysaccharides,
Decreased cardiac myosin levels have been noted in clin- which may have expanded the interstitium and sarcoplasm.
ically normal Doberman Pinschers and Doberman Pin- Hydropic change is a nonspecific indicator of membrane
schers affected with DCM when compared with cardiac dysfunction caused by a defect in energy production or
myosin levels in other dog breeds.30 Lower myosin levels structural membrane failure. Although myofibers were thin-
may predispose the heart to failure due to diminished pro- ner than normal, the increased heart weights and the nuclear
tective effects against cellular hypoxia. The myoglobin con- hyperchromasia and size variability are consistent with
centration noted in clinically normal Doberman Pinschers myofiber hypertrophy. Myofiber splitting/branching and
was similar to cardiac myoglobin concentrations in dogs disarray, noted in other forms of cardiomyopathy, were also
with heart failure experimentally induced by rapid ventric- noted in the myocardium of the affected POWD. There was
ular pacing.30 These findings indicate that changes in myo- no evidence of active myofiber necrosis in the 12 pups ex-
globin concentration may be important in the progression amined. Thus, myocardial decompensation probably is
of heart failure and that it may be an important component acute and rapidly fatal, precluding cellular degeneration that
of the DCM of Doberman Pinschers. However, the fact that would be noted histologically.
experimentally induced heart failure resulted in a lowering There was no evidence for myocardial storage disease as
of myoglobin may also suggest that the lowered myoglobin a cause for POWD DCM. Eleven of the POWD pups lacked
found in the clinically normal Doberman Pinschers may any evidence of cardiac inflammation; however, a single
simply be yet another indicator of underlying cardiac dys- pup did have rare perivascular and endocardial inflamma-
function due to some other etiology. In the same study, tion. The significance of the inflammation noted in the sin-
mitochondrial ATPase activity was 45% lower in both clin- gle pup is unknown. The general lack of inflammation sug-
ically affected and normal Doberman Pinschers when com- gests that the underlying cause is most likely not infectious
pared with normal dogs. A similar decrease was also noted or immune mediated. However, because this is a prelimi-
in experimental models of heart failure, suggesting again nary description of a new DCM, the possibility of under-
that this finding is most likely a result rather than a cause lying infectious or immune-mediated causes should still be
of heart failure.30 considered. There was no indication that this DCM was the
McCutcheon et al31 examined myocardial metabolite and result of primary vascular disease; all coronary vasculature
enzyme levels for the major metabolic pathways for energy examined histologically and at postmortem was normal.
production and calcium transfer in Doberman Pinschers Skeletal muscle obtained from the extremities of affected
with DCM. They found significant decreases of metabolites pups was histologically normal, indicating that a primary
and enzymes associated with mitochondrial ATP produc- DCM is present in the POWD breed. There was also no
tion. The greatest decreases were found for the mitochon- clinical evidence of noncardiac skeletal muscle involve-
drial respiratory chain enzymes and myoglobin. The au- ment. The finding of Anitchkow cells in the interstitium of
thors conceded that their findings do not indicate whether 1 pup is nonspecific. Anitchkow cells are mesenchymal
the decreased mitochondrial energy production is a primary cells located in the myocardial interstitium and are sus-
or secondary defect. Comparison with experimentally in- pected to be activated myofibroblasts, considered indicative
duced models of heart failure will help resolve this ques- of myocardial damage.33
tion. Lower concentrations of enyzmes and myoglobin in The clinical course of the POWD DCM was distinctive.
DCM of Doberman Pinschers may not be unique to that The age of onset noted in the POWD (13 6 7.3 weeks) is
form of DCM but may be secondary compensatory changes the youngest for any form of canine DCM, and the pro-
of the failing heart. gression of disease (sudden death to 5 days) is significantly
The clinical and postmortem findings in the 12 affected more rapid than has been reported in other dogs with DCM
POWD described in this report are consistent with the find- (0.5–24 months). All pups either died suddenly without pre-
ings reported for other canine DCM. The heart : body vious clinical signs or had vague clinical signs related to
weight ratios available for 3 of the pups were all above 1%, left ventricular failure for 1–5 days prior to death, and treat-
which is greater than that reported for normal dogs ment did not affect outcome in these pups. Pups evaluated
(0.084%).32 The lack of apparent underlying systemic or prior to death had signs referrable to left ventricular failure
structural causes for DCM in these dogs places this form and radiographic, electrocardiographic, and echocardio-
of DCM in the category of primary or idiopathic DCM, graphic indices consistent with a diagnosis of DCM. Serum
and the apparent autosomal recessive pattern of inheritance biochemical and urine analyses and CBCs were within nor-
is consistent with a familial disease. mal ranges for the pups examined, and urinary metabolic
The histologic features noted in the myocardium are sub- screening for inborn errors of metabolism did not indicate
tle and lack changes associated with chronicity, ie, fibrosis inherited metabolic diseases such as mucopolysacchridosis
or inflammation found in other forms of canine DCM. The and several amino acidurias (data not shown). Unfortunate-
 Portuguese Water Dog Cardiomyopathy 71

ly, no additional biochemical evaluations for serum con- 11. Boon J, Wingfield WE, Miller C. Echocardiographic indices in the
stituents more specific for cardiac disease, eg, creatine normal dog. Vet Radiol 1983;24:214–221.
phosphokinase or plasma carnitine, were performed on 12. Gilbert EM, Bristow MR. Idiopathic dilated cardiomyopathy. In:
Schlant RC, Alexander RW, eds. The Heart Arteries and Veins, 8th ed.
these pups.
New York, NY: McGraw-Hill; 1994:1609–1619.
The true prevalence of DCM in the POWD breed cannot
13. Wynne J, Braunwald E. The cardiomyopathies and myocarditities:
be determined at this time. The POWD are a relatively new Toxin, chemical, and physical damage to the heart. In: Braunwald E, ed.
breed in the United States, and they comprise a small pop- Heart Disease: A Textbook of Cardiovascular Medicine, Vol 4. Philadel-
ulation. All of the current US dogs came from foundation phia, PA: WB Saunders; 1992:1394–1450.
stock originating in Portugal, hence the gene pool is small. 14. Sandusky GE, Capen CC, Kerr KM. Histological and ultrastructural
Several breeders in the USA and Portugal have anecdotally evaluation of cardiac lesions in idiopathic cardiomyopathy in dogs. Can J
reported sudden death in young pups, but the causes of Comp Med 1984;48:81–86.
these deaths have not been investigated. 15. Bishop L. Ultrastructural investigations of cardiomyopathy in the
This study was limited by the lack of available fresh dog. J Comp Pathol 1986;96:685–698.
16. Bishop SP, Cole CR. Ultrastructural changes in the canine myo-
tissues and active cases for more complete analysis. Future
cardium with right ventricular hypertrophy and congestive heart failure.
investigations should be designed to expand information
Lab Invest 1969;20:219–229.
concerning biochemical, molecular, and histologic/ultra- 17. Van Vleet JF, Ferrans VJ, Weirich WE. Pathologic alterations in
structural changes and to confirm the mode of inheritance. congestive cardiomyopathy of dogs. Am J Vet Res 1981;42:416.
POWD DCM also may serve as a useful canine model for 18. Abelman WH. Classification and natural history of primary myo-
DCM. cardial disease. Prog Cardiovasc Dis 1984;27:73–94.
This newly described familial DCM of the Portuguese 19. Mestroni L, Krajinovic M, Severini GM, et al. Familial dilated
Water Dog breed appears to have an autosomal recessive cardiomyopathy. Br Heart J 1994;72(Suppl):S35-S41.
mode of inheritance. It is distinguished clinically from other 20. Meunier PC, Cooper BJ, Appel MJG, Slauson DO. Experimental
forms of canine DCM by the young age at onset (13 6 7.3 viral myocarditis: Parvoviral infection in neonatal pups. Vet Pathol 1984;
21:509–515.
weeks) and the rapid clinical course (days). The preliminary
21. Kelly DP, Strauss AW. Inherited cardiomyopathies. N Engl J Med
histologic findings suggest that this DCM is not the result
1994;330:913–919.
of an infectious or immune-mediated etiology, but it is most 22. Servidei S, Bertini E, DiMauro S. Hereditary metabolic cardio-
likely caused by an underlying molecular (biochemical/ myopathies. Adv Pediatr 1994;41:1–32.
structural) defect. 23. Gretz EW. Cardiomyopathic Syrian hamster: A possible model for
human disease. In: Homburger F, ed. Progress in Experimental Tumor
Acknowledgments Research: Pathology of the Syrian Hamster. New York, NY: S Karger;
1972:16:242–260.
We acknowledge the Portuguese Water Dog breeders for 24. Gross ER. Naturally occurring models of cardiovascular disease.
their assistance in supplying pedigree information and Ja- In: Gross ER, ed. Developments in Cardiovascular Research: Animal
mie Hayden for his technical help. Models in Cardiovascular Research, 2nd ed. Boston, MA: Kluwer Aca-
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