Nutritional dilated cardiomyopathy in a 5 year-old mixed-breed dog Tyler M. Kelleher Eva M. Oxford, DVM, PhD Joseph J. Wakshlag, MS, DVM, PhD Senior Seminar Paper Cornell University College of Veterinary Medicine April 23, 2014 Key Words: DCM, cardiomyopathy, taurine, deficiency, canine, nutrition SUMMARY Though rare in its occurrence, taurine deficiency is a potential cause for dilated cardiomyopathy in the dog. This paper describes a case of a taurine-deficient dilated cardiomyopathy in a mixed-breed dog, referred to Cornell University Hospital for Animals’ Cardiology Service in October of 2013. A brief overview of the veterinary profession’s current understanding of how taurine deficiency plays a role in the development of dilated cardiomyopathy in dogs will also be discussed. INTRODUCION The first disease related with taurine deficiency observed in veterinary medicine was retinal degeneration in cats as reported by Hayes et al1 in 1975. Taurine-deficient dilated cardiomyopathy in the cat can be completely reversed with medical treatment and taurine supplementation as demonstrated in 1987 by Pion et al.2 This disease was initially assumed to be an inexistent disease process in the dog mainly due to the markedly higher activity levels of cysteine sulfinic acid decarboxylase (the rate-limiting enzyme in the pathway used to endogenously synthesize taurine from cysteine and methionine) in dogs compared to cats.3-4 However, a study published in 1991 by Moise et al5 demonstrated that a taurine-deficient dilated cardiomyopathy is present and capable of being reversed in foxes with appropriate treatment and taurine supplementation. Therefore, the question arose as whether taurine deficiency and subsequent dilated cardiomyopathy could in occur in the dog. Within the next few years, case reports6-7 and a cooperative study between Animal Medical Center (New York, NY) and the University of California at Davis8 demonstrated a number of dogs who were diagnosed with dilated cardiomyopathy while having simultaneously low plasma taurine levels. Though quite rare in dogs, this condition has been reported in many breeds, including but not limited to 1 American Cocker Spaniels7-10, Golden Retrievers8-9,11, Newfoundlands9,12-13, Labrador Retrievers4,8-9, Dalmatians4, English Bulldogs4, Portuguese Water Dogs14, and Irish Wolfhounds15. The following sections include the description a case of taurine-deficient dilated cardiomyopathy in a mixed-breed dog that was referred to the Cornell University Hospital for Animals’ Cardiology Service in October of 2013 as well as a summary of the veterinary profession’s current knowledge of how taurine deficiency plays a role in the development of dilated cardiomyopathy in dogs. SIGNALMENT AND HISTORY A 5 year-old spayed female mixed-breed dog (weight = 20 kg) presented to the Cornell University Hospital for Animals’ Cardiology Service on October 30, 2013 for a recent onset of coughing. The patient was presented to her primary care veterinarian two days previously, and after being evaluated, she was diagnosed with congestive heart failure of unknown etiology. The patient was treated with Lasix (furosemide) and was subsequently sent home on a course of Lasix (37.5 mg [1.9 mg/kg] PO TID) with referral to the Cardiology Service at Cornell for further evaluation. The other notable component to her presenting history is that she had been fed a home-cooked vegan diet consisting of brown rice and lentils for several years. PHYSICAL EXAMINATION On presentation to the Cardiology Service, the patient was bright, alert, and responsive, but nervous, with a body condition score of 3/9 (5 being ideal). On physical examination the following abnormalities were noted: tachycardia (164 beats/minute), tachypnea (36 breaths/minute), mild to moderately increased respiratory effort, gallop rhythm over the left heart base, grade III/VI systolic murmur with point of maximal intensity over left 5th intercostal space, an abnormal posture while standing with both elbows abducted, mild to moderate generalized 2 muscle atrophy, and mild abdominal distention with a questionable fluid wave on abdominal palpation. All other findings on a general physical examination were within normal limits. These abnormalities can be consolidated into a prioritized problem list: (1) left apical systolic heart murmur, (2) tachypnea and increased respiratory effort, (3) generalized muscle atrophy, and (4) malnutrition. Of these problems, the patient was only displaying clinical signs for two of the problems on the list, and her tachypnea and increased respiratory effort were most likely secondary to her cardiac disease. Differentials for a heart murmur on the left side of the thorax in a dog include myxomatous mitral valve disease, dilated cardiomyopathy (primary idiopathic, nutritional, tachycardiomyopathy), subaortic stenosis, and patent ductus arteriosus. Using the nature and the location of the murmur (left systolic apical murmur with point of maximal intensity over the left 5th intercostal space), subaortic stenosis and patent ductus arteriosus could be ruled prior to any diagnostics. DIAGNOSTICS To establish a complete database of information to evaluate the patient, a complete blood count (CBC), chemistry panel, two-view thoracic radiographs (dorsal-ventral and right lateral), and a full echocardiogram was agreed upon with the owner as an initial diagnostic plan. The submitted CBC and chemistry panel revealed a mature neutrophilia (18.3 thou/ul; normal = 2.7 – 9.4) with a left shift (0.2 thou/ul; normal = 0 – 0.1 thou/ul), panhypoproteinemia (4.4 g/dL; normal = 5.3 – 7.0 g/dL) with albumin = 2.7 g/dL (normal = 3.1 – 4.2 g/dL) and globulins = 1.7 g/dL (normal = 1.9 – 3.6 g/dL), hypokalemia (3.5 mEq/L; normal = 3.8 – 5.4 mEq/L), and hypochloremia (98 mEq/L; normal = 105 – 116 mEq/L). The neutrophilia and hyperglycemia were likely secondary to the stress of being hospitalized. The electrolyte changes, hypochloremia and hypokalemia, could have been due furosemide inhibiting the Na+/K+/2 Cl- pump in the 3 ascending loop of Henle, and/or volume retention secondary to activation of the reninangiotensin-aldosterone system seen in congestive heart failure patients. The panhypoproteinemia could have been explained by either chronic malnutrition and/or volume retention as previously mentioned. Two-view thoracic radiographs revealed moderate to severe generalized cardiomegaly, mild to moderate pleural fluid, mild pulmonary edema, and questionable peritoneal fluid. An echocardiogram revealed evidence of bi-ventricular and bi-atrial enlargement, severe systolic dysfunction (fractional shortening = 12%), enlargement of the pulmonary veins, severe mitral regurgitation, and moderate tricuspid regurgitation. No irregularity, thickening, prolapse, or systolic anterior motion was observed in the mitral valve leaflets, ruling out myxomatous mitral valve disease as the cause for the murmur. DIAGNOSIS With the patient’s history of eating a home-cooked vegan diet for a prolonged period of time coupled with physical, radiographic, and echocardiographic indications of right and left sided congestive heart failure secondary to a dilated cardiomyopathy, the presumptive diagnosis of a nutritional dilated cardiomyopathy was made. Additionally, the owner previously had two other dogs diagnosed with dilated cardiomyopathy that had been fed the same home cooked diet of brown rice and lentils. One of the dogs, a 3.5 year-old castrated male Irish Wolfhound, presented to the Cornell University Hospital for Animal’s Emergency Service on October 22, 2013, one week prior to the patient being described in this paper, and was ultimately euthanized due to being in end-stage dilated cardiomyopathy (severely decreased systolic function) with severe decompensation characterized by pulmonary edema, pleural fluid, and peritoneal fluid. 4 However, despite convincing historical and clinical evidence in favor a diagnosis of nutritional dilated cardiomyopathy, other causes (e.g. primary idiopathic) for the cardiac changes observed in the patient could not be completely ruled out at the time. The patient was continued on furosemide (37.5 mg [1.9 mg/kg] PO TID) while also being started on spironolactone (25 mg [1.25 mg/kg] PO BID), enalapril (10 mg [0.5 mg/kg] PO BID), and pimobendan (5 mg [0.25 mg/kg] PO BID). After a consultation with the Nutrition Service, a dietary change was made to Hill’s Prescription Diet j/d for its adequate protein levels while also possessing a high omega-3 fatty acid content to mitigate the inflammatory effects of chronic heart failure. Oral supplementation with taurine (500 mg [25 mg/kg] PO TID) and carnitine (2000 mg [100 mg/kg] PO TID) was also initiated for their pro-myocardial effects. TAURINE Taurine, a sulfur-containing amino acid, is a free amino acid not used in the synthesis of proteins unlike the other sulfur amino acids, cysteine and methionine.4 Outside of its use in the conjugation of bile acids and detoxification of xenobiotics through conjugation and excretion in bile, the functions of taurine within the mammalian body are not clearly understood but are numerous, including playing a role in antioxidation, retinal photoreceptor activity, development of the nervous system, stabilization of neural membranes, reduction in platelet aggregation, and reproduction.4 Its proposed functions within the myocardium include modulating tissue calcium concentrations and availability (the best supported function by existing literature) as well as inactivation of free radicals, changing cellular osmolality, myocardial osmoregulation, Nmethylation of cell membrane phospholipids, a direct effect on contractile proteins, and interactions with the renin-angiotensin-aldosterone system.4 However, the true importance of taurine to proper myocardial function has yet to be fully elucidated. 5 TAURINE-DEFICIENT DILATED CARDIOMYOPATHY After many anecdotal reports and a few published case reports of taurine-deficient dilated cardiomyopathy in dogs, a collaborative study between Animal Medical Center (New York, NY) and the University of California at Davis evaluated the plasma taurine levels in 75 dogs diagnosed with dilated cardiomyopathy and found 17% of those dogs had low plasma taurine concentrations.8 Overrepresented among these dogs with low plasma taurine concentrations and dilated cardiomyopathy were breeds not typically associated with primary idiopathic dilated cardiomyopathy, namely Golden Retrievers and American Cocker Spaniels.8 Inspired by the results from of the AMC-UC Davis study as well as other anecdotal reports and the personal experience of one of the principal investigators at UC Davis (successfully treating two American Cocker Spaniels diagnosed with dilated cardiomyopathy with medical management plus taurine and carnitine supplementation), the Multi-center Spaniel Trial (MUST) study was initiated.10 The study evaluated the response of American Cocker Spaniels diagnosed dilated cardiomyopathy to taurine and carnitine supplementation. The study included 11 American Cocker Spaniels, all diagnosed via echocardiogram with dilated cardiomyopathy and simultaneously found to have low plasma taurine concentrations, after which the group supplemented with taurine and carnitine displayed significant echocardiographic improvement within 2 to 4 months after starting supplementation while the group receiving the placebo did not.10 All dogs receiving the placebo during the initial 4 month period were subsequently supplemented with taurine and carnitine, after which they also showed significant echocardiographic improvement within 2 to 4 months after beginning supplementation.10 Although the degree of echocardiographic improvement seen in these American Cocker Spaniels was not as dramatic as observed in cats2 and foxes5, in which echocardiographic measurements return to within normal limits, these dogs 6 were ultimately able to be weaned off of all traditional cardiac medications (diuretics, ACE inhibitors, etc.) and were only continued on taurine and carnitine supplementation.10 Similar responses to medical therapy and taurine supplementation have been reported in other dogs diagnosed with dilated cardiomyopathy including an American Cocker Spaniel7, a Beagle4, a family of Golden Retrievers11, and three Newfoundlands13. All of these dogs were diagnosed with dilated cardiomyopathy via an echocardiogram and showed echocardiographic improvement between 2 to 6 months after starting to receive taurine supplementation. All but one of these dogs were also weaned off of all traditional cardiac medications while continuing taurine +/- carnitine supplementation, and the author of that study was unclear whether weaning off of cardiac medications was even considered.7 In dogs which develop taurine-deficient dilated cardiomyopathy, there are two factors at play: (1) a genetic predisposition to developing the condition, and (2) the individual’s diet. In one study evaluating and comparing the levels of taurine synthesis and excretion between a group of Beagles and a group of Newfoundlands, the Newfoundlands were found to have a lower rate of endogenous taurine synthesis (per kilogram of metabolic body weight) and a higher rate of biliary taurine excretion (per kilogram of metabolic body weight).13 A similar difference in endogenous taurine synthesis between a group of Beagles and a group of large, mixed-breed dogs was also reported in a study evaluating the relationship between maintenance energy requirement and endogenous taurine synthesis rate.16 These two factors of a lower endogenous taurine synthesis rate and higher biliary taurine excretion rate combine to create a higher dietary taurine requirement (per kilogram of metabolic body weight) in large breed dogs. While this genetic predisposition determines the relative risk an individual dog has of developing the condition, the dog’s diet is the ultimate decider as to whether the dog will become 7 taurine deficient and develop a dilated cardiomyopathy. While reports of taurine-deficient dilated cardiomyopathy in dogs have certainly been associated with the feeding of incomplete, unbalanced, home-cooked diets by owners (e.g. 2 dogs fed a tofu-based diet, or 3 Golden Retrievers fed a vegetarian diet),9 several studies have also demonstrated a relationship between the feeding of certain commercially-available diets containing lamb and rice (with rice bran or whole grain brown rice as significant ingredients) and taurine deficiency.9,17-19 There are two major proposed mechanisms for why this association exists. The first proposed mechanism is the reported observation that ileal digestibility of amino acids is contingent upon the ingredients in the diet and the temperature used to process the diet.4 The second, but related, mechanism lies in the thinking that low quality protein present in these diets is not properly digested, makes its way to the colon, and stimulates bacterial growth where some of these bacteria produce cholytaurine hyrdrolase.4 This enzyme cleaves taurine off of taurocholic acid and other bile acids normally reabsorbed via enterohepatic circulation, resulting in increased fecal loss of taurine.4 However, despite the obvious correlation between taurine deficiency and these lamb and rice commercial diets, no good data exists in the current literature to thoroughly support either of these two proposed mechanisms. A second dietary factor, which specifically puts large breed dogs at risk of developing taurine deficiency and dilated cardiomyopathy, was reported in the previously mentioned study evaluating the relationship between maintenance energy requirement and endogenous taurine synthesis rate.16 In the study, the analysis showed that although the large, mixed-breed dogs were eating enough of the provided diet to maintain their current body condition, they were eating a significantly smaller amount of the diet (per kilogram of metabolic body weight) to do so when compared to the group of Beagles.16 By eating significantly less food (per kilogram of metabolic 8 body weight), these dogs were ultimately limiting their sulfur amino acid intake, putting them at higher risk of becoming taurine deficient.16 This effect only becomes exacerbated once dilated cardiomyopathy develops and they begin to display inappetance or anorexia secondary to their disease process.20 RECOMMENDATIONS When presented with a canine patient possessing physical, radiographic, and echocardiographic indications of congestive heart failure and dilated cardiomyopathy coupled with a dietary history that puts the individual at risk for developing a taurine deficiency, begin medical treatment and dietary supplementation immediately. The medications used to address the clinical signs in the short-term are the same ones used for any other congestive heart failure patient: (1) furosemide (loop diuretic) with or without spironolactone (potassium-sparing distal tubule and collecting duct diuretic) to decrease preload, (2) enalapril (an ACE inhibitor) which mediates effects that both decrease preload and afterload, and (3) pimobendan (a positive ionotrope) to increase cardiac contractility, which increases stroke volume, ultimately increasing cardiac output. In addition to medical management and switching the dog to a complete, balanced commercial diet, taurine +/- carnitine supplementation is the other essential component to the treatment plan for these patients. The recommended doses for supplementation are as follows: taurine (500-1000 mg PO BID to TID for small dogs, 1-2 g BID to TID for large dogs) and carnitine (100 mg/kg PO TID).4 Taurine supplements are relatively inexpensive and affordable, so a vast majority of pet owners will agree to begin taurine supplementation.4 Carnitine supplements on the other hand are quite expensive, making the cost a definite deterrent for some pet owners, especially the owners of large-breed dogs.4 9 Continued follow-up examinations are highly encouraged to monitor the clinical progression of the patient and assess their response to the treatment plan agreed upon with the owner. Although resolution of clinical signs (e.g. coughing, lethargy, inappetance, etc.) can be observed within a matter of days to weeks after starting medical treatment, echocardiographic improvement is usually observed between 2 to 4 months, and definitely by 6 months, after beginning taurine +/- carnitine supplementation.10-11,13 As in all disease processes, some patients will not respond to therapeutic intervention. Monitoring for clinical signs and assessing their echocardiographic measurements is essential for deciding when it could be potentially safe to stop administering traditional cardiac medications (diuretics, ACE inhibitors, positive ionotropes) while continuing their taurine +/-carnitine supplementation. No guidelines have been established in the literature as to when it is safe to try discontinuing cardiac medications, and therefore it is up to the discernment of the clinician on a case by case basis, by utilizing all the clinical information available from the initial evaluation and the follow-up examinations. Taurine-deficient dilated cardiomyopathy carries a much better prognosis than primary idiopathic (i.e. genetic) dilated cardiomyopathy, which is extremely important with regards to client communication. Dogs that present in congestive heart failure with severe systolic dysfunction for which malnutrition is the cause for their dilated cardiomyopathy can have a significantly longer survival times (28.3 months +/- 19.3 months among the 11 dogs in the MUST study) if they respond to medical treatment and dietary supplementation,10 while dogs with a primary idiopathic cause for their dilated cardiomyopathy that present with similar clinical findings have much shorter survival times (9.65 weeks among a study including 66 Doberman Pinschers).21 10 REFERENCES 1) Hayes, KC, RE Carey, SY Schmidt. “Retinal degeneration associated with taurine deficiency in the cat”. Science. 1975. 188:4191:949-951. 2) Pion, PD, MD Kittleson, QR Rogers, JG Morris. “Myocardial failure in cats associated with low plasma taurine: a reversible cardiomyopathy”. Science. 1987. 237:4816:764768. 3) Freeman, LM, JE Rush. “Nutrition and cardiomyopathy: lessons from spontaneous animal models”. 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