Hypothyroidism and Myocardial Failure in Two Great Danes
Two Great Danes were evaluated for signs of congestive heart failure. Dilated cardiomyopathy was diagnosed in each dog. Both dogs were diagnosed concurrently with primary hypothyroidism. Following appropriate supplementation with levothyroxine, both dogs showed significant improvement in myocardial contractility, as demonstrated by increased fractional shortening and reductions in left atrial size, and left ventricular end-systolic and diastolic diameters. These observations suggest that hypothyroidism may lead to myocardial failure in Great Danes that is partially or fully reversible following thyroid hormone replacement therapy, and that hypothyroidism should be considered in all Great Danes presenting with systolic failure.
Case Reports
Case No. 1
A 2-year-old, 76.6-kg, intact male Great Dane was referred to the Kansas State University Veterinary Medical Teaching Hospital (KSU-VMTH) for evaluation of lethargy of 4 weeks’ duration, tachypnea of 1 week’s duration, and a recently detected arrhythmia. Upon physical examination, the dog appeared quiet with an elevated respiratory rate of 60 breaths per minute and an elevated heart rate of 160 beats per minute (bpm). The dog’s skin appeared generally thickened, particularly over the face, suggestive of myxedema. Auscultation of the heart revealed an irregular rhythm with pulse deficits.
Initial diagnostic evaluation included a complete blood count (CBC), serum biochemistry profile, serum total thyroxine (TT4) concentration,electrocardiogram (EKG), thoracic radiographs, echocardiogram, and an occult heartworm test. Results of the CBC revealed eosinophilia (3,100/μL; reference range, 0 to 750/μL), basophilia (320/μL; reference range, 0 to 100/μL), and monocytosis (1,100/μL; reference range, 100 to 800/μL). Serum biochemical abnormalities included mild hyperkalemia (6.0 mmol/L; reference range, 3.8 to 5.5 mmol/L) with a normal sodium level (143 mmol/L; reference range, 141 to 156 mmol/L), moderate hypercholesterolemia (690 mg/dL; reference range, 124 to 335 mg/dL), and an elevated alkaline phosphatase (ALP, 288 U/L; reference range, 12 to 122 U/L). The TT4 concentration was undetectable (<5.1 nmol/L; reference range, 10.0 to 45.5 nmol/L), indicating hypothyroidism or euthyroid sick syndrome. A complete thyroid function panela was performed, and results included a low TT4 (6 nmol/L; reference range, 15 to 50 nmol/L), low total triiodothyronine (TT3) (0.3 nmol/L; reference range, 1.0 to 2.5 nmol/L), low free T4 (FT4; by equilibrium dialysis) (2 pmol/L; reference range, 12 to 33 pmol/L), low free T3 (FT3) (2.3 pmol/L; reference range, 2.8 to 6.5 pmol/L), and an elevated thyroglobulin autoantibody (379%; reference range, <200%), suggestive of primary autoimmune thyroiditis. Thyroid stimulating hormone (TSH) results were within reference ranges (19 mU/L; reference range, 0 to 30 mU/L). Results of the heartworm test were negative. Thoracic radiography revealed cardiomegaly with significant left atrial (LA) enlargement, enlarged pulmonary veins, and a diffusely increased bronchointerstitial pattern that was most severe in the hilar region, consistent with pulmonary edema. A routine EKG confirmed atrial fibrillation with a ventricular rate between 160 and 180 bpm. An echocardiogram was performed and showed a decreased fractional shortening (FS) of 8% (reference range, 33% to 46%1), an increased left ventricular internal systolicdiameter (LVIDs) of 60.0 mm (reference range, 36 to 43 mm1), and a left ventricular internal diastolic diameter (LVIDd) of 65.5 mm (reference range, 57 to 65 mm1). These findings were consistent with dilated cardiomyopathy (DCM). The LA diameter measured 60.8 mm (reference range, 32 to 38 mm1) in two-dimensional (2D) imaging.
The dog was treated with digoxinb (0.20 mg/m2 per os [PO] q 12 hours), sustained-release diltiazemc (6 mg/kg body weight, PO, q 24 hours), furosemided (1.5 mg/kg body weight, PO, q 12 hours), lisinoprile (0.5 mg/kg body weight, PO, q 24 hours), and levothyroxinef (0.02 mg/kg body weight, PO, q 12 hours). The dose of digoxin was chosen based on body surface area and lean body weight to avoid problems with toxicity based on body weight alone due to the presence of myxedema. The digoxin trough serum concentration was measured 7 days later by the referring veterinarian and was found to be within the recommended therapeutic range (1.7 ng/mL; reference range, 0.8 to 2.0 ng/mL). Relevant serum biochemistry abnormalities at that time included an elevated blood urea nitrogen (BUN, 39 mg/dL; reference range, 8 to 22 mg/dL) and a hypercholesterolemia of 453 mg/dL (reference range, 0 to 199 mg/dL). The dog was no longer tachypneic, and the furosemide was discontinued. Repeat thoracic radiographs were not performed at this time.
A CBC, serum biochemical profile, serum TT4 and digoxin concentrations, routine EKG, and an echocardiogram were performed 4 weeks after the initial evaluation. The owner reported that the dog was doing well at that time. Upon physical examination, pulse and respiratory rates had declined to 60 bpm and 30 breaths per minute, respectively. An arrhythmia was detected on auscultation, and occasional pulse deficits were noted. The dog had lost 10.8 kg and no longer appeared myxedematous. His overall body condition was assessed as normal. Results of the CBC and serum biochemistry profile showed no significant abnormalities. The eosinophilia, basophilia, and mild hyperkalemia noted on the previous blood work were no longer present and were not investigated further. Serum cholesterol was now within reference range (185 mg/dL). Serum TT4 concentration (6 hours after pill administration) was slightly above the reference range (47.0 nmol/L). Serum digoxin levels were within the recommended therapeutic range (1.4 ng/mL). The EKG revealed ventricular premature contractions (i.e., ventricular bigeminy) with a ventricular rate of 60 bpm and atrial fibrillation. Results of the echocardiogram showed an improved FS of 27%, a LVIDs of 44.9 mm, a LVIDd of 61.6 mm, and a LA diameter measuring 54.8 mm. No additional therapy was initiated at this time.
The dog was evaluated 30 days later, at which time the EKG identified atrial fibrillation with a ventricular rate of 70 bpm; no ventricular premature contractions were noted. Significant echocardiographic findings included a further improved FS of 37%, a LVIDs of 37.4 mm, a LVIDd of 58.9 mm, and a LA diameter of 49.2 mm. Due to the marked improvement in myocardial contractility and the suspected association with correction of hypothyroidism, digoxin and lisinopril were discontinued.
Subsequent echocardiographic examination 6 weeks later revealed a FS of 36%, a LVIDs of 39.2 mm, a LVIDd of 61.5 mm, and a LA diameter that measured 55.8 mm. Slight increases in LVIDs, LVIDd, and LA diameter were attributed to an increase in preload following cessation of lisinopril therapy. Electrocardiographic evidence of atrial fibrillation was still evident with a ventricular rate of 84 bpm. Since then, no additional diagnostic imaging has been performed; but the dog remains clinically normal over 3 years (i.e., 38 months) since initial presentation. Current medications include levothyroxine (0.02 mg/kg body weight, PO, q 12 hours) and diltiazem (6 mg/kg body weight, PO, q 24 hours).
Case No. 2
A 4-year-old, 67.5-kg, neutered male Great Dane was referred to KSU-VMTH for evaluation of a 1-week history of coughing, lethargy, inappetence, and diarrhea. A CBC and serum biochemical analyses performed by the referring veterinarian 2 days earlier had yielded only a mild, normocytic, normochromic anemia (hematocrit [HCT], 34%; reference range, 37% to 55%) with no other significant abnormalities. Upon physical examination, the dog was lethargic with an elevated respiratory rate of 90 breaths per minute. Auscultation of the heart revealed an irregular rhythm with pulse deficits. Thoracic radiographs revealed severe cardiomegaly, pulmonary venous enlargement, and an increased interstitial pattern in the hilar region of the heart, consistent with pulmonary edema. Results of an EKG confirmed atrial fibrillation with a ventricular rate of 160 bpm. Findings on the echocardiogram included a decreased FS of 10%, an increased LVIDd of 66.4 mm (reference range, 57 to 65 mm1), an increased LVIDs of 60.0 mm (reference range, 36 to 43 mm1), and a LA diameter of 69.5 mm (reference range, 32 to 38 mm1) in 2D imaging. Dilated cardiomyopathy was diagnosed, and treatment was initiated with furosemide (1.5 mg/kg body weight, PO, q 12 hours), lisinopril (0.5 mg/kg body weight, PO, q 24 hours), sustained-release diltiazem (4 mg/kg body weight, PO, q 24 hours), and digoxin (0.005 mg/kg body weight, PO, q 12 hours).
Two weeks later, the dog remained lethargic and lacking in appetite, although he was subjectively brighter than at initial examination. The pulse rate had decreased to 65 bpm, and the respiratory rate was normal. Digoxin toxicity was suspected and confirmed by measuring serum digoxin concentration (4.0 ng/mL). This was likely due to the failure to adjust the initial dosage based on lean body weight and body surface area, as was done in case no. 1. A routine EKG confirmed the presence of atrial fibrillation. Echocardiographic findings included a FS of 18%, LVIDs of 50.5 mm, LVIDd of 61.4 mm, and a LA diameter of 52.0 mm. The digoxin dosage was decreased by 50% (0.0025 mg/kg body weight, PO, q 12 hours), and the furosemide was discontinued. Repeat thoracic radiographs were not performed at this time.
Three months later, the dog had gained 14.4 kg, remained lethargic, and had an occasional cough. Diagnostic evaluation at that time included a CBC, serum biochemical profile, serum TT4 and digoxin concentrations, EKG, and thoracic radiographs. Abnormalities identified on CBC and serum biochemical analyses included a mild normocytic, normochromic anemia (HCT, 35%), hypercholesterolemia (690 mg/dL), and a mildly increased ALP (150 U/L). Serum digoxin levels were slightly below therapeutic range (0.7 ng/mL). Serum TT4 concentration was undetectable (<5.1 nmol/L), indicating hypothyroidism or euthyroid sick syndrome. Results of a complete thyroid function panela identified a low TT4 (1 nmol/L), low TT3 (0.4 nmol/L), low FT4 (0 pmol/L by equilibrium dialysis), elevated thyroglobulin autoantibody (303%), and a high normal TSH concentration (30 mU/L), suggesting autoimmune thyroiditis. The results of an EKG revealed the presence of atrial fibrillation with a ventricular rate of 64 bpm. Thoracic radiographs revealed no evidence of pulmonary edema or pulmonary venous enlargement. Therapy with levothyroxine (0.02 mg/kg body weight, PO, q 12 hours) was initiated. Following 2 weeks of therapy, thyroxine levels 6 hours after pill administration were taken by the referring veterinarian and found to be elevated (level not reported); the dosage was decreased by 25% (0.015 mg/kg body weight, PO, q 12 hours).
The dog was reevaluated at KSU-VMTH 4 weeks after initiating therapy with levothyroxine. The owner reported that the dog was more active and his appetite had improved. The dog had lost 12.2 kg since thyroxine supplementation had been initiated. Serum thyroxine concentration was measured and found to be elevated (106 nmol/L). Electrocardiographic evidence of atrial fibrillation was still evident with a ventricular rate of 80 bpm. Echocardiographic evaluation revealed a significantly improved FS of 28%. Other findings included a LVIDs of 46.1 mm, LVIDd of 63.6 mm, and a LA diameter measuring 51.6 mm. Due to the marked improvement in myocardial contractility and suspected association with concurrent levothyroxine administration, digoxin and lisinopril were discontinued. The dosage of levothyroxine was decreased to 0.01 mg/kg body weight, PO, q 12 hours.
The dog did not return to KSU-VMTH until 5 months later. At that time, the owner reported the dog was slightly less active but appeared otherwise healthy. Serum TT4 was measured and found to be in the low end of the reference range (15.4 nmol/L). Echocardiographic evaluation identified a decrease in FS to 17%, an increase in LVIDs of 52.7 mm, and a LVIDd of 63.6 mm. The LA diameter remained similar to the previous study at 50.4 mm. Continued evidence of atrial fibrillation was evident on EKG examination with a ventricular rate of 160 bpm. The decline in myocardial contractility was attributed to a decrease in the dosage of levothyroxine (0.005 mg/kg body weight, PO, q 12 hours) that had inadvertently occurred since the previous visit. The dosage of thyroid supplementation was subsequently increased to 0.01 mg/kg body weight, PO, q 12 hours. The diltiazem therapy had also been inadvertently stopped and was reinstituted at the same dosage as previously (4 mg/kg body weight, PO, q 24 hours).
Echocardiographic reevaluation 4 weeks later documented only mild improvement in FS (21%), LVIDs (47.3 mm), and LVIDd (60.0 mm), despite a return to euthyroidism (TT4, 42.0 nmol/L). The LA diameter measured 59.0 mm. The ventricular rate had increased to 180 bpm, and the dosage of diltiazem was increased to twice daily (4 mg/kg body weight, PO, q 12 hours).
At both 32 weeks and approximately 18 months from original presentation, the LVIDs and LVIDd had increased slightly compared with previous studies to 53.0 mm and 65.5 mm, respectively, with no improvement noted in the FS (19%) and LA diameter (53.3 mm). The ventricular rate remained approximately 120 bpm. The TT4 remained within reference range (36.4 nmol/L).
At the most recent reevaluation (24 months after presentation), the FS had improved to 24% with a LVIDd of 58.0 mm and a LVIDs of 44.0 mm. The LA diameter measured 55.0 mm on 2D imaging. Atrial fibrillation remained present with a ventricular rate of 92 bpm. Thoracic radiographs were taken and reported to be within normal limits. Current medications consist of sustained release diltiazem (6 mg/kg body weight, PO, q 12 hours) and levothyroxine (0.01 mg/kg body weight, PO, q 12 hours); the dog continues to do well clinically.
Discussion
The association between hypothyroidism and canine DCM has been a subject of some controversy. The myocardium is known to be especially sensitive to the effects of thyroid hormone.2 Decreased concentrations of circulating thyroid hormone are associated with many clinically recognizable effects; among them, decreased heart rate, decreased inotropic state of the myocardium, and increased ventricular size and mass.2 Abnormal echocardiographic findings in dogs with hypothyroidism are well documented.23 These include decreases in FS, increased LVIDd, decreased velocity of circumferential fiber shortening, and increased preejection period, indicating impaired left ventricular function.23 Electrocardiographic abnormalities such as decreased amplitude of P waves and R waves have also been documented in dogs with spontaneous hypothyroidism.3 Further, all of these changes have been shown to be reversible.3 It has been assumed that heart failure associated with primary hypothyroidism represents an exacerbation of intrinsic cardiac disease by the superimposed hemodynamic effects of low circulating levels of thyroid hormone.4 To date, however, no causative relationship between hypothyroidism and canine DCM has been identified.
Observations on the two dogs presented in this report strongly suggest that the etiology of their myocardial failure was primary hypothyroidism, although, since no direct cause and effect relationship was clearly defined, the possibility exists that these conditions were distinct and coincidental. Both dogs were considered profoundly hypothyroid with clinicopathological findings consistent with primary autoimmune thyroiditis. The levels of TSH in both cases were not elevated; this finding is supported by two recent studies documenting that 24% and 63% of dogs, respectively, with naturally occurring hypothyroidism had TSH levels within the reference range.56 Tidholm, et al., looked at thyroid hormone concentrations in dogs with DCM and found that TT4 and TSH did not differ significantly between normal dogs, dogs with asymptomatic DCM, and dogs with clinical signs of DCM; however, FT4 was significantly lower in dogs with clinical signs of DCM as compared to the other two groups.7 Both dogs in this report had low TT4 and FT4, supportive of the diagnosis of hypothyroidism.
Therapy with levothyroxine in both dogs resulted in a dramatic and significant improvement in the left ventricular FS, LVIDd, LVIDs, and LA diameter, all of which persisted after discontinuation of digoxin and angiotensin-converting enzyme (ACE) inhibitor therapy. In case no. 1, myocardial contractility returned to normal following levothyroxine supplementation, resulting in a complete recovery. The atrial fibrillation remained, but it is well-managed using diltiazem therapy. In case no. 2, the response to thyroid replacement therapy was initially similar, with a marked improvement in cardiac function. However, following a decrease in levothyroxine therapy, cardiac function declined. Since then, continued improvements have been noted with appropriate thyroid supplementation, though not as dramatic as in case no. 1. The reason for this is unclear. It is possible that in this dog, the more prolonged period of hypothyroidism may have resulted in permanent ultrastructural changes in the myocardium that were not fully reversible with additional therapy. It has been suggested that in dogs with hypothyroidism, infiltration of the myocardium with mucopolysaccharides, coronary arterial atherosclerosis, or both, may result in prolonged impairment of cardiac function.3 Alternatively, primary myocardial disease exacerbated by hypothyroidism may be present in this patient. The authors believe the persistence of atrial fibrillation in both cases may represent irreversible ultrastructural damage that occurred from severe atrial distention secondary to myocardial failure.
It has been suggested by some that the increased metabolic rate associated with a return to the euthyroid state can potentially increase myocardial workload and contribute to worsening of heart failure.89 Current recommendations for dogs with primary hypothyroidism and DCM include treatment with a low dose of levothyroxine (i.e., 25% of the normal supplementation) followed by a gradual increase in order to avoid adverse effects of a sudden, rapid change in metabolic demands.10 Recommendations for humans with underlying ischemic heart disease are similar to those for dogs.11 The authors are unaware of any published data to support this recommendation for dogs. Young humans with cardiovascular changes secondary to hypothyroidism, such as decreased contractility, decreased ventricular filling, bradycardia, increased ventricular ectopy, and increased afterload, are initiated on standard replacement dosages of levothyroxine at the outset.11 Since the authors suspected the systolic dysfunction in these dogs was secondary to primary hypothyroidism, it was elected to follow these recommendations for young humans and initiate full replacement doses of levothyroxine. Neither dog of this report showed exacerbation of CHF after initiation of full replacement therapy. Case no. 1 developed ventricular bigeminy, which may have been the result of myocardial ischemia secondary to rapidly establishing a euthyroid state.
Increases in left ventricular FS in hypothyroid dogs with DCM following levothyroxine replacement therapy have been documented previously;3 however, these increases have been quite small. In that study, the median FS measured before and after appropriate thyroid supplementation showed an increase of only 4%.3 Further, none of the dogs presented with signs of CHF. In the same study, clinical signs of hypothyroidism were present for an extended period (median, 9 months); however, dogs were treated for a mean period of only 64±12 days.3
Most dogs with evidence of CHF from DCM die from the disease within a year; 50% of these die within the first 3 months.12 In a recent study,13 where six Great Danes were investigated specifically, all dogs had died within 12 to 18 months from the onset of clinical signs of DCM. At the time of this writing, the two dogs of this report had survived 38 (case no. 1) and 25 (case no. 2) months; both dogs were clinically asymptomatic for their disease. All cardiac medications, with the exception of diltiazem, have been discontinued.
The etiology of idiopathic DCM is not known. Only in a few instances have metabolic etiologies responsive to specific therapy been identified; among them are taurine deficiency in cats14 and carnitine deficiency in a small number of dogs15 and humans.16 To the authors’ knowledge, there are few reports in the human literature where DCM is believed to have been caused by hypothyroidism. One study documented alterations in myocardial gene expression, specifically changes in α- and β-myosin heavy-chain (MHC) mRNA levels, that were fully reversible following thyroxin therapy.17 In the myocardium, thyroid hormones regulate gene expression of myosin and actin heavy-chain isoforms.18 Thyroid hormone has been shown to regulate the expression of ventricular myosin isoenzymes by causing an accumulation of α-MHC mRNA and inhibiting expression of β-MHC mRNA.19 The relative proportions of the isoforms seem to be directly related to the speed of contraction.19 Ladenson, et al. used endomyocardial biopsies to document alterations in gene expression in the dilated myopathic heart that were correctable following thyroid hormone replacement.17 Whether similar mechanisms could be involved in the pathogenesis of the heart failure in these dogs is unknown. To the authors’ knowledge, myocardial contractile protein concentrations in dogs with DCM have not yet been investigated.
The fact that both dogs in this study were Great Danes may suggest an underlying breed association, or it may simply reflect the high prevalence of hypothyroidism and DCM within this breed. The Great Dane is reportedly the second most common breed of dog with DCM, and a recent report strongly suggests DCM is familial in this breed.2021 Hypothyroidism is commonly diagnosed in Great Danes and other large breeds, including Doberman pinchers.10 However, a report of 152 Doberman pinchers did not identify an increased prevalence of hypothyroidism in those with congestive heart failure, DCM, or both, compared with dogs ill from noncardiac disease.22 That study did not investigate whether levothyroxine supplementation in those dogs with DCM and hypothyroidism resulted in any clinical improvement in their cardiac disease.
Conclusion
The observations for case nos. 1 and 2 described in this report, suggest that hypothyroidism can lead to systolic failure that may be partially or fully reversible following appropriate thyroid supplementation. This type of systolic dysfunction mimics that observed in cases of idiopathic DCM and should be considered as a differential diagnosis in any dog presenting with signs of DCM. Thyroid function should be evaluated in all dogs with evidence of impaired left ventricular function, especially those with recent evidence of weight gain. Based on the authors’ observations, the treatment of two hypothyroid dogs with standard replacement dosages of levothyroxine did not appear to exacerbate CHF. Concurrent treatment with diuretics, ACE inhibitors, and digoxin may have negated any potential adverse effects caused by increased metabolic demands associated with levothyroxine therapy. Alternatively, prior recommendations to begin treating hypothyroid dogs with CHF at a level of 25% of the replacement dosage may be overly conservative, but studies are currently lacking. Pending further investigation, initiation of replacement dosages of levothyroxine in these patients should be followed by frequent reevaluation using EKG, radiography, and echocardiography until the dog is stable.
Animal Health Diagnostic Laboratory, Endocrine Diagnostic Section; Michigan State University, Lansing, MI
Lanoxin; GlaxoSmithKline, Research Triangle Park, NC
Dilacor XR; Rhone Poulenc-Rorer Pharmaceuticals, Inc., Swiftwater, PA
Lasix; Intervet Inc., Millsboro, DE
Zestril; AstraZeneca Pharmaceuticals LP, Wilmington, DE
Soloxine; Daniels Pharmaceuticals, St. Petersburg, FL
