Relationship Between Circulating and Dietary Taurine Concentrations in Dogs with Dilated Cardiomyopathy

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1 Relationship Between Circulating and Dietary Taurine Concentrations in Dogs with Dilated Cardiomyopathy Lisa M. Freeman, DVM, PhD a John E. Rush, DVM, MS a Donald J. Brown, DVM, PhD a Philip Roudebush, DVM b a Tufts University School of Veterinary Medicine 200 Westboro Road North Grafton, MA b Hill s Science and Technology Center PO Box 1658 Topeka, KS ABSTRACT A retrospective study was conducted to determine dietary taurine concentrations in dogs with dilated cardiomyopathy (DCM) and to compare the clinical outcome of taurine-deficient and non taurine-deficient dogs. Taurine concentrations were low in blood samples from 20 of 37 dogs with DCM. Median dietary taurine concentration was not significantly different between taurine-deficient and nondeficient dogs. There was no correlation between dietary and circulating taurine concentrations. The outcome of taurine-deficient dogs supplemented with taurine was not different from the outcome of nondeficient dogs. The role of taurine and its relationship to dietary intake in canine DCM remain unclear. INTRODUCTION Taurine is an amino acid that is essential for normal cardiac, immune, retinal, platelet, and reproductive functions. 1 The function of taurine in calcium homeostasis as well as its high concentrations in the myocardium underscore its importance in cardiac function. The role of taurine deficiency in feline dilated cardiomyopathy (DCM) has been well described. 2 5 Because of the increased taurine supplementation of commercial cat foods in the late 1980s, there has been a dramatic decline in the incidence of feline DCM. The few cases of feline DCM still seen are predominantly either taurine independent or are the result of cats being fed unconventional diets. Unlike the situation in cats, taurine is not an essential amino acid in dogs. 1 The association between taurine and feline DCM, however, has prompted investigators to examine the role of taurine in canine DCM. Previous studies have shown that dogs with DCM that are of breeds that commonly develop this condition did not have low taurine concentrations, and taurine supplementation had no benefit on their cardiac 370

2 L. M. Freeman, J. E. Rush, D. J. Brown, and P. Roudebush function. 5 Although taurine deficiency is not present in most dogs with DCM, low taurine concentrations have been found in certain breeds of dogs with the disease. 3 This has been best established in the American cocker spaniel. 3,4 In a recent study, 11 cocker spaniels showed improvement in clinical parameters and echocardiographic measurements when supplemented with taurine and carnitine. 4 Whether the response would be similar with single therapy is unknown. Dogs of several other breeds not usually affected by DCM also have been found to have low taurine concentrations in association with DCM, but the relationship between canine DCM and taurine is still unknown. Currently, measurements of plasma and wholeblood taurine concentrations are recommended for cocker spaniels or other breeds with DCM that are not usually affected with this condition. 4,5 Supplementation with taurine (500 mg) and carnitine (1 g), given orally two or three times daily, also has been recommended for dogs with documented taurine deficiency until additional research is done. 4,5 The cause for low taurine concentrations in some dogs with DCM is unclear. Increased losses through the gastrointestinal or renal systems could account for low taurine concentrations, as could reduced taurine biosynthesis. Although dogs are thought to be able to synthesize adequate amounts of taurine, low or unavailable dietary concentrations might also decrease circulating concentrations. In addition, low taurine concentrations could be a secondary effect of the underlying disease. Myocardial carnitine concentrations, for example, are known to decrease in dogs that are experimentally induced to develop congestive heart failure (CHF) through rapid pacing. 6 Since dietary taurine has never been a concern for dogs because of their apparent lack of need for dietary intake of this amino acid, the relationship between dietary and circulating concentrations has not been examined. The purpose of the current study was to determine dietary taurine concentrations in dogs with DCM and to determine the clinical outcome of taurine-deficient dogs supplemented with taurine. MATERIALS AND METHODS Test Subjects All dogs having a diagnosis of DCM and having blood samples submitted to Tufts Veterinary Diagnostic Laboratory, North Grafton, MA between 1997 and 1999 were enrolled in this retrospective study. The medical record for each dog was reviewed using a standardized data sheet for information on signalment, physical examination, echocardiographic measurements, medical treatment, and outcome. For dogs that were not patients of Tufts University, information was collected by contacting the referring veterinarian. Although the exact cutoff for a definition of taurine deficiency is controversial, for the purposes of this study, dogs were classified as taurine deficient if the plasma taurine level was less than 45 nmol/ml or the whole-blood taurine level was less than 250 nmol/ml. 4,5 Evaluations Each dog s usual diet was determined from the medical record or by calling the owners. Dietary taurine concentration was determined from information provided by the manufacturer. The dogs responses to therapy were assessed by survival time, change in cardiac dimensions (e.g., left atrium, left ventricular internal diameter [LVID], interventricular septum, left ventricular free wall [LVFW], and right ventricle), fractional shortening on echocardiography, the ability to reduce the number of medications, furosemide dosage, and the severity of heart failure as measured by the modified New York Heart Association (MNYHA) classification (Table 1)

3 TABLE 1. Modified New York Heart Association Functional Classification 7 Class I II III IV Definition No limitation of physical activity. Ordinary physical activity does not cause undue fatigue or dyspnea. Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue or dyspnea. Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue or dyspnea. Unable to carry on any physical activity without symptoms. Symptoms are present even at rest. If any physical activity is undertaken, symptoms are increased. Statistical Analysis Categorical data were compared by chisquare analysis, while independent t-tests were used to compare continuous data. Paired t-tests were used to compare echocardiographic measurements before and after taurine supplementation within the taurine-deficient and the non taurine-deficient groups. RESULTS Blood samples from 37 dogs were submitted for taurine analysis. Twenty-three dogs were male and 14 were female. The mean age was years. Twenty of the 37 dogs had taurine deficiency based on either plasma or whole-blood analysis and 17 dogs were considered to have adequate taurine levels. Fifteen of the 20 deficient dogs had low levels of taurine in both plasma and whole blood; however, one dog had low plasma levels only (whole blood was not tested); two dogs had low whole-blood levels only (plasma was not tested); and two dogs had low whole-blood levels with normal plasma levels. Taurine levels were not impacted by sex or age of the dog (P >.05). Eleven males and nine females were taurine deficient compared with 12 males and five females that were not deficient. Taurine-deficient dogs were 8.3 ± 3.1 years of age versus 8.6 ± 2.9 years for the nondeficient dogs. The most common breed for which blood was submitted for taurine analysis was the cocker spaniel (Table 2). Of the ten dogs of this breed with blood submitted for analysis, seven were taurine deficient. Other commonly represented breeds were golden retriever and Labrador retriever. TABLE 2. Breed Distribution of Dogs Having Taurine Concentrations Determined in Whole-Blood Samples Taurine - Breed All Dogs deficient Dogs Cocker spaniel 10 7 Golden retriever 5 4 Labrador retriever 5 3 Dalmatian 3 0 St. Bernard 2 2 Rottweiler 2 1 Mixed breed 2 1 American bulldog 1 1 Collie 1 1 Mastiff 1 0 Border collie 1 0 Bulldog 1 0 Doberman 1 0 Springer spaniel 1 0 Irish setter 1 0 Total

4 L. M. Freeman, J. E. Rush, D. J. Brown, and P. Roudebush Breed distribution between the taurine-deficient and nondeficient groups was not significantly different (P =.18). Median plasma concentration of taurine was 4.0 nmol/ml for the 18 taurine-deficient dogs and nmol/ml for the 15 nondeficient dogs (P <.001) (Table 3). Median taurine concentration in wholeblood samples was nmol/ml from 19 taurine-deficient dogs and nmol/ml for 17 nondeficient dogs (P <.001) (Table 3). Taurine content of the dogs usual diets was also determined based on manufacturers data. Dietary information was available for 34 dogs and dietary taurine could be determined for 28 of 37 dogs. In the deficient group, seven of the diets were lamb and rice based and seven had increased concentrations of fiber (three diets had both of these properties). In the nondeficient group, three of the diets were lamb and rice based and one diet had increased concentrations of fiber (P =.07 versus the taurine-deficient group). Median dietary taurine (drymatter basis) was 300 ppm for the 18 taurine-deficient dogs and 285 ppm for the ten nondeficient dogs (Table 3). The difference was not significantly different (P =.58). There was no correlation between dietary taurine and circulating plasma (r =.26; P =.20) or wholeblood (r =.32; P =.11) taurine concentrations. At the initial presentation, mean body weight, heart rate, and furosemide dosage were similar for the taurine-deficient and nondeficient dogs (Table 4). Dogs with taurine deficiency were more likely (P =.01) to be in CHF (8 of 20 dogs) than were nondeficient dogs (9 of 17 dogs), and taurine-deficient dogs had a higher (P =.003) MNYHA classification ( versus ) on presentation (Table 4). Echocardiographic measurements at initial presentation were not significantly different between dogs with low and normal taurine concentrations (Table 4). Of the 20 dogs with taurine deficiency, two died in the hospital and one was lost to followup. Of the 17 that left the hospital and for which information was available, nine received taurine supplementation, six received taurine plus carnitine, and two received neither. All were treated with standard cardiac medications appropriate for their stage of disease and clinical signs. Medications (both in number of medications and in dosage) were not different between the two groups. Other medications administered included angiotensin-converting enzyme inhibitors (17 taurine-deficient and 16 nondeficient), digoxin (ten taurine-deficient and nine nondeficient), β-blockers (three taurine-deficient and four nondeficient), diltiazem (two nondeficient), spironolactone (one in each group), and spironolactone/hydrochloro- TABLE 3. Taurine Levels in Whole Blood, Plasma, and Diets for Taurine-deficient and Nondeficient Dogs Group Source Number of Dogs Median Range Taurine-deficient Plasma nmol/ml nmol/ml Dogs Whole blood nmol/ml nmol/ml Diet (dry-matter basis) ppm ppm Nondeficient Plasma nmol/ml nmol/ml Whole blood nmol/ml nmol/ml Diet (dry-matter basis) ppm ppm 373

5 TABLE 4. Baseline Clinical and Echocardiographic Parameters for All Taurine-deficient and Nondeficient Dogs Taurine-deficient Nondeficient Dogs Parameter Dogs (n=20) (n=17) Weight (kg) Heart rate (beats/min) MNYHA class* Furosemide dosage (mg/kg/day) Left ventricular internal diameter (diastole) (cm) Left ventricular internal diameter (systole) (cm) Aorta (cm) Left atrium (cm) Fractional shortening (%) *MNYHA = Modified New York Heart Association (refer to Table 1 for class definitions). Significantly greater than non taurine-deficient dogs (P <.05). thiazide (three nondeficient). There was a trend (P =.06) for more dogs in the taurine-deficient group to also receive furosemide (n = 16) compared with the nondeficient group (n = 11). The median dosage of supplements for the 15 dogs receiving taurine or carnitine was 42.5 mg taurine/kg/day (range = 18.8 to mg/kg/day) and mg L-carnitine/kg/day (range = to mg/kg/day). Nine of the 17 nondeficient dogs received taurine supplementation on a short-term basis (i.e., until taurine concentrations were available), three received taurine supplementation long-term, and five received no taurine. Of the 15 taurine-deficient dogs treated with taurine or carnitine and the 17 nondeficient dogs, ten in each group were given at least one follow-up evaluation; four dogs had multiple evaluations. Median time from initial presentation to the first follow-up evaluation was 117 days (range = 28 to 357 days). At the first follow-up evaluation, there was no difference in the number of medications that had been discontinued (five in the taurine-deficient and two in the nondeficient group) (Table 5). In addition, there was no difference between groups (P =.10) in the change in furosemide dosage ( mg/kg/day in the taurinedeficient group versus mg/kg/day in the nondeficient group). The MNYHA classification was significantly reduced (P =.007) in the taurine-deficient group ( ) compared with that for the nondeficient group ( ), but this difference was no longer significant (P >.05) after correcting for the greater severity in the taurine-deficient group at baseline. All ten dogs in the taurine-deficient group and seven of ten dogs in the nondeficient group had echocardiograms at the first reevaluation. Dogs in the taurine-deficient group had a significantly greater decrease (P =.04) in LVID in systole and a significantly greater increase (P =.04) in LVFW thickness in diastole compared with the nondeficient group (Table 5). There were no other echocardiographic differences between groups at the first reevaluation. At their final evaluation, dogs in the taurinedeficient group had a significantly greater decrease in LVID in systole (P =.03) and a sig- 374

6 L. M. Freeman, J. E. Rush, D. J. Brown, and P. Roudebush TABLE 5. Clinical and Echocardiographic Parameters for Taurine-deficient and Nondeficient Dogs Taurine-deficient Dogs* Nondeficient Dogs* Number Initial Visit Follow-up Final Number Initial Visit Follow-up Final Parameter of Dogs Evaluation Evaluation Evaluation of Dogs Evaluation Evaluation Evaluation Weight (kg) MNYHA class Furosemide dosage (mg/kg/day) Right ventricle (cm) Left ventricular internal diameter (diastole) (cm) Left ventricular internal diameter (systole) (cm) Interventricular septum (diastole) (cm) Interventricular septum (systole) (cm) Left ventricular free wall (diastole) (cm) Left ventricular free wall (systole) (cm) Aorta (cm) Left atrium (cm) Fractional shortening (%) *Includes only dogs for which a follow-up evaluation was available. MNYHA = Modified New York Heart Association; refer to Table 1 for class descriptions. Significantly different from non taurine-deficient dogs using independent t-tests (P <.05). Significantly different from baseline values using paired t-tests (P <.05). 375

7 nificantly greater increase in LVFW in diastole (P =.03) than in the nondeficient group (Table 5). Both groups had significant within-group decreases in LVID in diastole and in systole. The taurine-deficient group also had a significant within-group increase in LVFW in systole (P =.006) and fractional shortening (P =.002) and a significant within-group decrease in left atrial diameter (P =.03). Six dogs in the taurine-deficient group were able to discontinue medications compared with three in the nondeficient group (P =.29). The outcome for the dogs with taurine deficiency that were supplemented with taurine or carnitine and the nondeficient dogs was also compared. Nine of the 15 taurine-deficient dogs were still alive at the time data were gathered for this study, and eight of 17 nondeficient dogs were alive (P =.46). Six taurine-deficient dogs and seven nondeficient dogs had died by this time; two nondeficient dogs were lost to follow-up. The median survival for the taurine-deficient dogs that were supplemented with taurine was 340 days (range = 13 to 864 days) compared with 236 days (range = 21 to 609 days) for the nondeficient dogs (P =.27). DISCUSSION The fact that 20 taurine-deficient dogs with DCM were identified over a 3-year period suggests that this is a relatively common problem. What is less clear, however, is the role of taurine deficiency in canine DCM. A previous study by Kittleson and coworkers 4 showed a significant improvement in cardiac enlargement and fractional shortening after taurine and carnitine supplementation in cocker spaniels with DCM and low taurine concentrations. The current study, however, did not show a significant difference in outcome between taurine-deficient dogs supplemented with taurine (in addition to standard medical therapy) and non taurine-deficient dogs that were treated only with standard medical therapy. One possibility is that most dogs with DCM that are treated medically have clinical and echocardiographic improvements, as evidenced by a significantly smaller left ventricle. In a previous study, no differences in left ventricular size or fractional shortening were found after placebo administration in taurinedeficient cocker spaniels with DCM. 4 Beneficial effects of correcting taurine deficiency may be more pronounced in the cocker spaniel, especially the American variety of this breed. The group of cocker spaniels in this present study was too small to analyze this breed, but the previous study showed clinical improvements in cocker spaniels treated with taurine and carnitine. Since this was not a prospective study, there was no control group of taurine-deficient dogs treated with a placebo. In a previous study, cardiovascular function was improved to a greater degree in taurine-deficient cockers treated with taurine plus carnitine than for similar dogs treated with a placebo. 4 It is also possible that the potential benefits of taurine supplementation take longer than the time period the dogs in the current study were followed. In the previous study, taurine and carnitine supplementation was provided for 4 months. 4 The current study followed dogs for a median of 150 days (range = 28 to 635 days), so the duration of taurine supplementation may have been insufficient for some dogs. One of the outcome measures for clinical improvement in the current study was the ability to discontinue cardiovascular medications. In the previous study, all taurine-deficient cocker spaniels given taurine plus carnitine supplementation were successfully weaned off cardiovascular medications. 4 In the current study, there was no significant difference between groups for this factor. However, because this was a retrospective study, there were no criteria for when medications would be discontinued, 376

8 L. M. Freeman, J. E. Rush, D. J. Brown, and P. Roudebush and this determination was made by each individual clinician. Finally, dogs in the current study did not receive a standard regimen of taurine plus carnitine supplementation. The study conducted by Kittleson and coworkers 4 used a taurine dosage of approximately 125 mg/kg/ day, so it is possible that a higher dose or the concurrent use of taurine and carnitine is needed to realize the full benefits. Another reason for the improvement after taurine supplementation in the previous study is that taurine may have pharmacologic effects that are separate from its role in correcting a taurine deficiency. While correcting a taurine deficiency may be beneficial, taurine has been shown to be beneficial in animal models with experimentally induced heart failure. 8 Taurine also has been used in people as a nutritional pharmacological agent for its positive inotropic effect. In a clinical trial, human patients with CHF were given taurine or a placebo for one year. 9 Patients receiving taurine had a greater clinical improvement than the placebo group. Although further research is required, taurine supplementation may have modest benefits in cardiac patients even without taurine deficiency. Taurine concentrations in the diets of dogs included in this study varied widely (100 to 1300 ppm on a dry-matter basis). The recommended minimum taurine concentration in cat foods is 1000 ppm for extruded foods and 2000 ppm in canned foods (both on a dry-matter basis). Only one diet for one dog in this study (a dry dog food with a taurine content of 1300 ppm) would have met the feline minimum allowance. Although dogs are thought to synthesize adequate taurine endogenously and to not require dietary taurine, there may be some breeds or some individuals that do require dietary taurine to maintain normal blood concentrations. One limitation of the current study is that all dietary taurine concentrations were derived from manufacturers information, which can vary substantially from the actual taurine content on analysis. Dietary taurine analyses to determine taurine content and exact measurement of dietary intake would be useful for future studies. In addition, a complete diet history was not available for each dog, so the duration of time the dogs had been eating a particular diet was not known in all cases. It is not clear why some dogs eating a particular diet develop low blood taurine concentrations and others do not. This may be related to genetic factors that cause some breeds or individuals to have higher taurine requirements. The differences also may be related to diet ingredients. Of the taurine-deficient dogs in the current study, four ate a lamb-and-rice based diet, four ate a high-fiber diet, and three ate a high-fiber, lamb-and-rice based diet. Lamband-rice based diets have anecdotally been implicated in canine taurine deficiency. 10 Torres and coworkers 10 fed commercial diets based on either a lamb meal or poultry by-product meal to healthy beagles. Although plasma and whole-blood taurine concentrations were not different when dogs were eating the two different diets, plasma methionine was significantly higher in dogs eating the lamb-meal diet. 10 In addition, urinary taurine excretion was significantly lower in dogs eating the lamb- meal diet, suggesting a higher renal resorption. 10 These results suggest that there may be differences in taurine bioavailability in certain ingredients. Additional research into dietary bioavailability is needed and it still remains to be determined why certain dogs are more susceptible to taurine deficiency when eating low-taurine or taurine-precursor diets. There are a number of limitations in the current study. The population was skewed in that only dogs for which there was a suspicion of taurine deficiency were included, since these were the dogs for which blood was submitted for analysis. If blood had been submitted for all 377

9 dogs with DCM or even for all atypical breeds with DCM, the results might have been much different. It would be useful for future studies to measure taurine concentrations in all atypical breeds with DCM. A confounding factor is that two dogs in the non taurine-deficient group received long-term taurine supplementation. If taurine has effects other than correction of a taurine deficiency (i.e., positive inotropic, antioxidant, or other beneficial cardiovascular effects), this could have provided a better outcome for the nondeficient group. However, when the statistical analysis was repeated excluding these two dogs, there was no change in the findings. Another consideration is that no dogs had reevaluation of taurine concentrations. Although the dosage used has been shown to increase taurine concentrations to within the reference range, dogs may have had variable responses to supplementation in terms of cardiac function. 4 Furthermore, follow-up evaluation was not completed for all dogs (67% in the taurine-deficient group and 59% in the nondeficient group). Finally, not all dogs (67% in the taurine-deficient group and 41% in the nondeficient group) had a second echocardiogram, and long-term information was not available on all dogs. The results of this study, however, support further study of the role of taurine and its relationship to dietary intake in canine DCM. ACKNOWLEDGMENTS The authors wish to acknowledge the excellent technical assistance of Barbara Brewer, CVT, Tufts University, North Grafton, MA. REFERENCES 1. Kirk CA, Debraekeleer J, Armstrong PJ: Normal cats. In: Hand MS, Thatcher CD, Remillard RL, et al, eds. Small Animal Clinical Nutrition. 4 th ed. Marceline, Missouri: Walsworth Pub Co; 2000: Pion PD, Kittleson MD, Rogers QR, Morris JG: Myocardial failure in cats associated with low plasma taurine: A reversible cardiomyopathy. Science 237: , Kramer GA, Kittleson MD, Fox PR, et al: Plasma taurine concentrations in normal dogs and in dogs with heart disease. J Vet Intern Med 9: , Kittleson MD, Keene B, Pion PD, et al: 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: , Pion PD, Sanderson SL, Kittleson MD: The effectiveness of taurine and levocarnitine in dogs with heart disease. Vet Clin North Am Small Anim Pract 28: , Pierpont MEM, Foker JE, Pierpont GL: Myocardial carnitine metabolism in congestive heart failure induced by incessant tachycardia. Basic Res Cardiol 88: , Keene BW, Bush JE: Therapy of heart failure. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 4th ed. Philadelphia: WB Saunders Co; 1995: Elizarova EP, Orlova TR, Medvedeva NV: Effects on heart membranes after taurine treatment in rabbits with congestive heart failure. Arzneim Forsch/Drug Res 43: , Azuma J, and the Heart Failure Research with Taurine Group: Long-term effect of taurine in congestive heart failure: Preliminary report. In: Huxtable R, Michalk DV, eds. Taurine in Health and Disease. New York: Plenum Press; 1994: Torres CL, Fascetti AJ, Rogers QR: Taurine and sulfur amino acid status in dogs fed dry commercial poultry by-product meal or lamb meal diets. J Vet Intern Med 14:364,