Taurine-Deficient Dilated Cardiomyopathy in a Family of Golden Retrievers
A reversible taurine-deficient dilated cardiomyopathy occurred in five related golden retrievers. An apical systolic heart murmur was the most common physical abnormality. According to fractional shortening and end-systolic diameter on echocardiography, significant improvements (P<0.005) were recorded within 3 to 6 months of starting taurine supplementation. The dogs regained substantial systolic function, and four were weaned off all cardiac medications except taurine. This response to therapy was unusual, because canine dilated cardiomyopathy is generally progressive and fatal.
Introduction
Taurine is a sulfur-containing amino acid that is not incorporated into proteins but remains free in plasma and tissues. It is found in the highest concentrations in the heart, muscles, central nervous system, and platelets.1 Taurine is the most abundant free amino acid in the mammalian heart, and it plays important roles in cardiac contractility and osmoregulation.2,3 When the intracellular content of taurine is dramatically reduced, the heart develops contractile defects.4 The mechanisms by which taurine increases cardiac inotropy are unclear, but available evidence suggests that taurine potentiates calcium uptake by the sarcoplasmic reticulum, increases the sensitivity of the myofilaments to calcium, and affects the long-lasting (L-type), voltage-dependent calcium channels.1,5–8 Taurine is also a natural antagonist of angiotensin II.4,9–12
Low plasma taurine concentration was first recognized by Hayes et al. in cats with retinal degeneration that were fed a taurine-deficient diet.13 In the late 1980s, Pion et al. reported a reversible taurine-deficient dilated cardiomyopathy (DCM) in cats.14–16 A similar DCM in a population of foxes was documented by Moise et al. in 1989.17 This latter study raised the possibility of a significant association between low taurine concentrations and DCM in canine species.
Dilated cardiomyopathy is the most common acquired cardiac disease of large-breed dogs.18 It is characterized by left ventricular dilatation and systolic dysfunction. Dilated cardiomyopathy associated with a low taurine concentration has been reported in the American cocker spaniel, Dalmatian, boxer, Newfoundland, Portuguese water dog, English setter, Alaskan malamute, and Scottish terrier.16,19–22 An autosomal recessive transmission has been documented in a family of Portuguese water dogs with juvenile taurine-deficient DCM.19,23 In humans, between 20% and 25% of idiopathic DCM cases are familial.24
A taurine-deficient DCM has also been identified in the golden retriever, but little information on the clinical features of this disease has been published.25 The purposes of this study are to describe the clinical features and outcome of a taurine-deficient DCM observed in a family of golden retrievers, and to determine the mode of inheritance of the disease.
Materials and Methods
Case Selection
Medical records of golden retrievers examined at the Hôpital Vétérinaire Rive-Sud (Quebec, Canada) between 1999 and 2001, in which taurine-deficient DCM had been diagnosed, were reviewed. Clinical and historical data were obtained by examination of the clinical records or from communication with the owners. All dogs were evaluated by physical examination, thoracic radiography, electrocardiography, plasma taurine concentration, and echocardiography. Primary echocardiographic diagnostic criteria for DCM were end-systolic diameter (ESD) >3.5 cm (reference range 1.8 to 3.5 cm) and end-diastolic diameter (EDD) >5.1 cm (reference range 3.7 to 5.1 cm), fractional shortening (FS) ≤20%, and mitral valve E-point to septal separation (EPSS) >7 mm.26 Clinical evidence of congestive heart failure was defined as the presence of pulmonary edema or pleural effusion on thoracic radiography and/or ascites on physical examination.
Taurine Analysis
Blood samples were collected by jugular venipuncture after a 6- to 12-hour fast. Samples were carefully transferred from preheparinized 3-mL syringes to heparinized tubes to avoid any cell damage. Plasma was immediately retrieved and frozen to −17°C. Taurine concentration was determined in all samples by amino acid analysisa after deproteinization with an equal volume of aqueous sulfosalicylic acid (60 g/L). All taurine assays were performed by the Amino Acid Laboratory at the University of California, Davis. A plasma taurine concentration <40 nmol/mL was considered supportive of a taurine-deficient state. The diet fed to every animal was recorded for the 4 months prior to sampling, and the amount and frequency of feeding were determined to ensure that the diet was not responsible for insufficient taurine intake.
Treatment and Follow-Up
All dogs were reevaluated at the Hôpital Vétérinaire Rive-Sud or Veterinary Teaching Hospital of the University of Montreal by the same clinician (Bélanger) at 3, 6, 12, and 24 months after the onset of taurine supplementation (500 mg per os [PO] q 12 hours).20 Physical examinations, thoracic radiographs, and echocardiographs were evaluated. Changes in ESD and FS before and after supplementation were recorded, as well as the duration of cardiovascular medications.
Pedigree Analysis
Pedigrees of dogs with taurine-deficient DCM were obtained from the owners. Pedigrees were assembled and examined for evidence of any specific mode of inheritance of the disease.27 Dominant, recessive, autosomal, and X-linked monogenic modes of inheritance were considered. A dominant mode of inheritance was considered if the disease occurred in successive generations and at least one parent of an affected offspring showed the disease.27 A recessive mode of inheritance was considered if the disease tended to occur in one generation and then skipped one or two generations until suspected carrier descendants were mated again, allowing the gene to occur in the homozygous state.27 If most affected offspring were males, X-linked inheritance was considered likely.27 Polygenic inheritance was defined as no predictable mendelian transmission associated with the disease, which appeared to be erratic in occurrence.27
Statistical Analysis
Descriptive statistics (mean ± standard deviation) were calculated for age, echocardiographic parameters, and plasma taurine concentration. The echocardiographic responses to therapy were evaluated using analysis of variance on repeated measures. If significance was reached, Bonferroni multiple comparison procedure was then used to pinpoint which time was different. The statistical analysis was performed by a statistical software program.b Probability values <0.05 were considered significant.
Results
Clinical Data
Seven golden retrievers were found to have taurine-deficient DCM during the review period, but two were excluded from the study because of incomplete records and follow-up information [see Table]. Age at the time of diagnosis ranged from 6 to 9 years. Gender included two sexually intact males, one castrated male, and two spayed females. Both females were presented with heart failure. Reasons for presentation included anorexia (n=2), lethargy (n=3), coughing (n=3), exercise intolerance (n=3), dyspnea (n=2), ascites (n=1), asymptomatic cardiac arrhythmia (n=1), or asymptomatic heart murmur heard incidentally by the referring veterinarian (n=2). The most common physical abnormality was an apical systolic heart murmur (n=5).
Cardiac arrhythmias occurred in two dogs and included atrial premature beats (n=1) and rare ventricular premature contractions (n=1). Radiographic abnormalities included pulmonary edema (n=2), generalized cardiac enlargement (n=5), left atrial enlargement (n=5), and pleural effusion (n=1). Baseline FS and ESD ranged from 9% to 20% and 30.0 mm to 66.7 mm, respectively.
Baseline plasma taurine concentrations in the five affected dogs ranged from 2 to 20 nmol/mL [see Table]. Whole blood and plasma taurine concentrations were also determined in 24 related dogs. In these dogs, whole blood and plasma taurine concentrations were normal and ranged from 244 to 668 nmol/mL and 69 to 166 nmol/mL, respectively. The diets consisted of commercial dog food in all subjects. The primary ingredients included lamb and rice (n=2), lamb meal and rice (n=1), chicken meal and corn (n=1), and chicken and corn (n=1) [see Appendix].
Dogs that were presented with heart failure were initially stabilized with cardiovascular medications and reevaluated frequently in the first month. All dogs received a combination of cardiovascular medications to treat DCM and/or heart failure. These medications included furosemide (n=2, case nos. 3, 4), an angiotensin-converting enzyme (ACE) inhibitor (n=2, case nos. 3, 4), and digoxin (n=5). All dogs responded positively to therapy. There was a significant improvement of the FS (P<0.001) recorded as early as 3 months after taurine supplementation. All four investigations (at 3, 6, 12, and 24 months) revealed values that were increased compared to baseline data in the five dogs [Figure 1, Table]. After 3 months of taurine supplementation, FS values improved by an average of 50.9% compared to baseline values. Significant improvement (P<0.002) was also observed in ESD measurements [see Table]. Values recorded at 6, 12, and 24 months after taurine supplementation were decreased compared to baseline. Although the echocardiographic parameters continued to improve, there were no statistical differences between the posttherapy FS values at 3, 6, 12, and 24 months or between the ESD values at 6, 12, and 24 months.
All dogs that presented without signs of heart failure regained normal systolic function within the first 2 years of therapy, as their echocardiographic parameters corresponded to the lowest normal range reported for the breed.26 Diuretics were discontinued in two dogs originally in heart failure at 3 months after the initiation of taurine supplementation. In these two dogs, ACE inhibitors were also discontinued at 6 and 8 months. All dogs survived >3 years, and the only death recorded was of noncardiac origin (i.e., renal failure). Four of five dogs are still alive at the time of this writing and remain on treatment with taurine supplementation (n=4) and digoxin (n=1).
Pedigree Analysis
Pedigrees of the five affected dogs were studied, and all dogs were linked to a single family. Pedigree analysis revealed common ancestry with a male that died suddenly from an unknown cause. Pedigrees of 24 other golden retrievers with normal plasma taurine concentrations (>50 nmol/L) were also linked to this family. A simplified pedigree chart was drawn, taking into account the single common ancestor and using the pedigrees of the five affected dogs, eight related dogs with normal taurine concentrations, and 21 other related dogs without any history of cardiac disease [Figure 2]. Because many related dogs were unavailable for taurine measurement, evaluation of the mode of inheritance was complicated. A dominant pattern of inheritance was excluded, because at least one parent of case nos. 1, 2, and 4 should have been affected. The X-linked transmission was also ruled out, because both genders were equally affected. The pedigree analysis was most consistent with an autosomal recessive mode of inheritance.
Discussion
Dilated cardiomyopathy is a common disease in large-breed dogs.18 There is wide variability in the clinical features (e.g., age at onset, sex predisposition, presence or type of arrhythmia, prognosis) in the different breeds affected.27 These breed variations may depend on the different etiologies of DCM, such as toxic, inflammatory, metabolic, infectious, immunological, ischemic, nutritional, and familial.27 Because of these differences, an investigation of DCM is necessary in each breed to describe the clinical features, family history, response to therapy, and prognosis.
In 1995, Kramer et al. found that 17% of dogs with DCM had low plasma taurine concentrations, and 31% of these taurine-deficient dogs were golden retrievers.25 Results of the study reported here suggest that taurine-deficient DCM in golden retrievers is characterized by adult onset of systolic dysfunction associated with ventricular and atrial dilatation that may lead to left-sided or biventricular heart failure. The mean age at presentation was 7.4 years, which was comparable to the age at onset of idiopathic DCM in many large-breed dogs (mean 6.6 years).24 The population of dogs in the present study was too small to draw any conclusions on sex predisposition.
The clinical signs observed in these taurine-deficient dogs were similar to those associated with idiopathic DCM. Cardiac arrhythmias were not an important feature in the taurine-deficient golden retrievers. One dog was presented with paroxysmal premature atrial beats, which converted to normal sinus rhythm after 12 months of therapy. This finding corroborated the observations of Chazov et al. that taurine supplementation could reverse some electrocardiographic abnormalities such as S-T segment changes, T-wave inversions, and extra systoles in animals with chemically induced arrhythmias.28 Only rare premature ventricular contractions were observed in the dogs of this study throughout the follow-up period; however, continuous ambulatory Holter monitoring was not performed in any of the dogs.
Retinal lesions are common in cats with taurine deficiency.13 Fundic examinations were only performed in two dogs in this study and were unremarkable. The typical lesions of retinal degeneration associated with feline taurine deficiency have not been reported in dogs with taurine-deficient DCM. Recently, Backus et al. performed ophthalmological examinations in taurine-deficient Newfoundlands and found no typical fundic abnormalities.29
A special prognostic feature of the DCM in these dogs was its reversibility, which appeared to be improved by early detection and therapy. In these dogs, the most dramatic myocardial recoveries and returns to normal systolic function were observed in dogs that were presented with less ventricular dilatation and without heart failure. Although the dogs that were presented with heart failure did recover and survived >3 years, their ESD, EDD, EPSS, and FS values did not return to normal throughout the follow-up period. These findings suggest that the progression of the disease to overt heart failure might render the myocardium resistant to taurine therapy, perhaps because failing cardiac myocytes lose their ability to take up taurine (an active process regulated by two calcium-sensitive enzymes, protein kinase C and calmodulin) or because taurine deficiency potentiates angiotensin II-induced apopto-sis.9–12,30 Chronic and severe taurine-deficient DCM cases may lose any cellular reserve capacity after significant apoptosis has occurred.30 Improvement in FS was recorded 3 months after taurine supplementation in the five affected golden retrievers of this study. In addition, an average improvement of 77.5% over baseline values occurred after 2 years of therapy.
The golden retrievers of this study all survived >3 years, and this finding strongly contrasted with the reported mean survival time of 120 days in dogs with idiopathic DCM and congestive heart failure.31 Two other studies reported 17.5% and 37.5% probability rates of survival 1 year after diagnosis of DCM. The median survival times in these two studies were 27 and 65 days, respectively.32,33
Dilated cardiomyopathy has been shown to be inherited in some breeds, including the Portuguese water dog, Doberman pinscher, boxer, and Great Dane.19,23,34–37 An autosomal recessive mode of inheritance has been described in juvenile Portuguese water dogs with taurine-deficient DCM.19 In cats, a heritable susceptibility to DCM was described by Lawler et al. in a genetic evaluation of a large cattery.37 Familial or heritable limitations in taurine absorption, metabolism, and excretion might explain the genetic variation in the development of DCM. Evaluation of the pedigrees from the affected golden retrievers in this study suggested a familial tendency. An autosomal recessive mode of inheritance was suspected, although polygenic transmission could not be ruled out. Additional data including measurement of taurine concentrations and echocardiography in offspring or other closely related dogs are needed to definitively identify the mode of transmission of taurine deficiency in golden retrievers.
The etiology of taurine-deficient DCM in dogs remains unknown. Taurine represents approximately 60% of the free amino acid pool of the heart in small animals.6 Insufficient synthesis, impaired absorption, inadequate dietary supply, increased metabolic need, alteration in the enterohepatic circulation of taurine-conjugated bile acids, inability to use glycine instead of taurine in conjugated bile acids, and enhanced urinary excretion of taurine or its precursors (i.e., cysteine and methionine) are all possible causes of taurine deficiency in dogs.16,38 Probable mechanisms for development of DCM in taurine deficiency involve calcium regulation, free radical inactivation, disturbances in osmoregulation, and potentiation of angiotensin II-induced apoptosis.9,12
The contribution of diet merits further investigation, since three of five dogs in this study were eating commercial diets that included lamb or lamb meal and rice as the primary ingredients. Historically, dietary causes of taurine-deficient DCM in dogs have been ignored, because taurine is not recognized as an essential amino acid in dogs.6 However, recent studies by Delaney et al. have prompted new insights into the possible relation between taurine deficiency in dogs and diets containing whole-grain rice, rice bran or barley, and lamb meal.38 It has been reported that dietary bran rice decreases plasma and whole-blood taurine concentrations in cats by accelerating the excretion of bile acids.39 The role of lamb meal in taurine deficiency remains obscure, but lamb meal may limit the bioavailability of sulfur amino acids.40 Recently, low blood taurine concentrations have been identified in a cohort of Newfoundland dogs fed lamb meal and rice.29 In an extensive genetic study performed by Alroy et al. on Portuguese water dogs, two litters were obtained following a breeding of presumptive carriers of DCM. Two (29%) of seven puppies in the first litter developed DCM while they were fed a commercial growth formula that included ground corn and poultry byproduct meal as primary ingredients.19 The second litter was fed a lamb meal and rice puppy diet, and eight (89%) of nine puppies developed signs of taurine-deficient DCM.19 The role of diet was not investigated in that study, but it could be hypothesized that the heritable predisposition to taurine-deficient DCM in juvenile Portuguese water dogs was precipitated by feeding a lamb meal and rice diet. Torres et al. showed that feeding lamb meal and rice to young beagles for 8 months significantly decreased their plasma taurine concentrations during the first month, but no change occurred thereafter, and the depletion was insufficient to cause DCM in these dogs.41 On the other hand, a decreased urinary taurine excretion was observed despite a lack of change in plasma taurine concentrations, indicating a certain physiological adaptation to conserve taurine in the face of depletion.41
The main limitation of the study reported here was its retrospective nature and the availability of echocardiographic data. Other echocardiographic measurements would have been useful to examine the systolic dysfunction and to follow the response to therapy. It has been reported that concurrent whole-blood taurine and plasma taurine deficiencies correlate better with myocardial taurine deficiency in dogs than either whole-blood taurine or plasma taurine concentration alone.42 Nonetheless, all subjects included in this study had very low plasma taurine concentrations, which implied a clinically significant taurine deficiency.38
Conclusion
Taurine-deficient DCM was found in five adult golden retrievers. The dogs regained substantial systolic function following taurine supplementation, and all but one were weaned off other cardiac medications. Genetic and nutritional etiologies were suspected in this taurine-deficient DCM, but further studies are needed in the golden retriever to substantiate these preliminary findings.
Beckman model 6300 automated amino acid analyzers; Beckman Coulter, Inc., Fullerton, CA 92834-3100
Number Cruncher Statistical System 2001; NCSS, Kaysville, UT 84037
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410284
Citation: Journal of the American Animal Hospital Association 41, 5; 10.5326/0410284
Fractional shortening values for five golden retrievers with taurine-deficient cardiomyopathy, recorded at presentation and during a 24-month follow-up period. Note that case nos. 2 and 5 had similar values at Time 0 and 3 months, hence the overlap.
Simplified pedigree of the family of golden retrievers with dogs diagnosed with taurine-deficient cardiomyopathy. Circles denote females; squares denote males. Solid black symbols represent affected dogs and their case number. The arrow indicates the suspected single progenitor of taurine-deficient dilated cardiomyopathy in this family. White symbols denote clinically normal dogs. A white symbol with a black dot in the middle denotes dogs that would be carriers with an autosomal recessive mode of inheritance. Case nos. 15, 18, 21, 22, and 26 through 29 were clinically normal and had plasma taurine concentrations >50 nmol/mL.
