A 15-year-old sexually intact female ring-tailed lemur (Lemur catta) was evaluated at the Blank Park Zoo by the Iowa State University Cardiology Service because of a heart murmur and radiographic cardiomegaly. The lemur was privately owned as a pet for the first 4 years after birth; thereafter, the lemur was housed in institutions accredited by the Association of Zoos and Aquariums. A heart murmur and radiographic cardiomegaly were first detected incidentally at 4 years of age. On subsequent examinations (all performed with general anesthesia), the murmur was noted intermittently, and progressive radiographic LA enlargement was documented. Evaluation by the cardiology service was pursued when the lemur was 15 years of age after a brief thoracic ultrasonographic examination showed severe LA dilation.
Anesthesia was induced and maintained with inhaled isoflurane to perform physical and echocardiographic examinations. Body weight was 3.56 kg (7.83 lb). Heart rate (140 beats/min), RR (44 breaths/min), and body temperature (37.7°C [99.8°F]) were within reference limits for this species. Findings of thoracic auscultation indicated a grade 3/6 diastolic murmur with its point of maximal intensity over the left apex, occasional premature beats, and normal bronchovesicular lung sounds. Transthoracic echocardiographica examination showed MS with severe LA dilation. The leaflets of the MV were severely thickened and domed during diastole. The anterior and posterior MV leaflets were tethered to the interventricular septum and left ventricular posterior wall, respectively, resulting in severely decreased excursion of the leaflets. Turbulent blood flow across the MV from the LA to the left ventricle was noted in diastole, along with mild mitral regurgitation in systole. The tricuspid valve was mildly thickened, suspected to be because of mild dysplasia or myxomatous degeneration; mild tricuspid regurgitation was present but was considered hemodynamically insignificant because of the lack of right atrial and ventricular dilation. Velocity of tricuspid regurgitation was 2.4 m/s, which corresponded to a normal transtricuspid pressure gradient of 23 mm Hg and therefore suggested no evidence of pulmonary arterial hypertension. A concurrently recorded single-lead ECG trace indicated a normal sinus rhythm with occasional ventricular premature complexes.
Thoracic radiography revealed cardiomegaly with severe LA enlargement and no evidence of pulmonary edema (Figure 1). Results of CBC and serum biochemical analysis were unremarkable, including BUN (20 mg/dL; reference interval, 9.0 to 47.5 mg/dL), creatinine (0.7 mg/dL; reference interval, 0.5 to 1.5 mg/dL), sodium (149 mEq/L; reference interval, 139 to 156 mEq/L), and potassium (3.9 mEq/L; reference interval, 3.3 to 5.3 mEq/L) concentrations. Treatment was initiated with an angiotensin-converting enzyme inhibitor (benazepril, 0.35 mg/kg [0.16 mg/lb], PO, q 24 h) and aspirin (11.4 mg/kg [5.2 mg/lb], PO, q 72 h). Zookeepers administered these medications by concealing them within pieces of fruit fed to the lemur.
Left lateral thoracic radiographs of a 15-year-old female ring-tailed lemur (Lemur catta) with a grade 3/6 diastolic murmur first auscultated at 4 years of age. A—Image obtained at the time of initial examination by the cardiology service when the lemur had no clinical signs of heart disease. B—Image obtained 13 months after the onset of CHF when the lemur was receiving aspirin, benazepril, furosemide, and pimobendan. Both radiographs show severe cardiomegaly characterized by severe LA enlargement (arrowheads). In panel B, an unstructured interstitial lung pattern is present in the caudodorsal lung field (asterisk), consistent with pulmonary edema.
Citation: Journal of the American Veterinary Medical Association 257, 8; 10.2460/javma.257.8.849
Three months later, the lemur developed a progressively worsening cough and decreased physical ability during behavioral training. Because CHF was suspected, furosemide (1.8 mg/kg [0.82 mg/lb], PO, q 12 h) and pimobendan (0.37 mg/kg [0.17 mg/lb], PO, q 12 h) were added to the treatment regimen. Because of the zookeepers’ work schedule, furosemide and pimobendan were administered at approximately 8:00 am and between 4:00 pm and 5:00 pm, depending on the season, rather than every 12 hours. The cough markedly decreased with administration of furosemide and pimobendan; therefore, the dosage of furosemide was reduced to 0.9 mg/kg (0.41 mg/lb), PO, every 12 hours. The lemur was maintained on the prescribed dosages of benazepril, aspirin, furosemide, and pimobendan for the next 10 months without overt clinical signs of CHF. However, the cough recurred and an increased respiratory effort was observed, which prompted progressive escalation of the dosage of furosemide over the subsequent 3 months to 4 mg/kg (1.8 mg/lb), PO, every 12 hours.
Thirteen months after the presumptive onset of CHF, the lemur was again anesthetized for examination. The left apical diastolic murmur was now grade 4/6, and occasional premature beats were again auscultated. Thoracic radiography revealed worsening cardiomegaly with severe LA enlargement and mild pulmonary edema, consistent with CHF (Figure 1). Mitral valve appearance and movement were unchanged from the previous echocardiographic examination; mild mitral regurgitation and severe LA dilation also persisted (Figure 2; Supplementary Videos S1 and S2, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.257.8.849). The hemodynamics associated with MS were further assessed with spectral Doppler echocardiography. Maximum velocity of early diastolic filling across the MV (mitral E wave velocity) was increased at 2.18 m/s (reference, 0.91 ± 0.15 m/s).1 The pressure half-time of the Doppler mitral inflow signal was also increased at 135 milliseconds (reference range, 10 to 52 milliseconds).2 These echocardiographic measurements indicated the presence of an inflow obstruction that caused an abnormal pressure gradient between the LA and left ventricle during diastole, consistent with severe MS.3
Transthoracic echocardiographic images of left apical 4-chamber views from the lemur in Figure 1 obtained 13 months after the initial echocardiographic examination. A—Two-dimensional color Doppler echocardiography reveals turbulent transmitral inflow during diastole consistent with MS. B—Continuous-wave spectral Doppler echocardiography shows high-velocity transmitral inflow in early diastole and prolonged deceleration (prolonged pressure half-time) and MR. Two premature ventricular complexes are evident on the ECG trace (asterisks; speed 25 mm/s). LV = Left ventricle. RA = Right atrium.
Citation: Journal of the American Veterinary Medical Association 257, 8; 10.2460/javma.257.8.849
The dosage of pimobendan was increased to 0.5 mg/kg (0.23 mg/lb), PO, every 12 hours, and 2.1 mg of spironolactone/kg (0.95 mg/lb), PO, every 24 hours, was prescribed. The daily administered amounts of furosemide (4.2 mg/kg [1.9 mg/lb], PO, q 12 h), aspirin (13.5 mg/kg [6.1 mg/lb], PO, q 72 h), and benazepril (0.42 mg/kg [0.19 mg/lb], PO, q 24 h) remained unchanged, but because of a decrease in the lemur's body weight, dosages on a milligramper-kilogram basis were mildly increased. The lemur's activity was restricted, but the lemur had free access to air-conditioned environments. Clinical signs of CHF, specifically tachypnea and exercise intolerance, appeared adequately controlled for the next 12 months on the basis of the zookeepers’ and zoo veterinarian's assessments.
Thirteen months later, when the lemur was 17 years of age and onset of CHF was 26 months earlier, persistent tachypnea was noted (100 breaths/min). Other behaviors, including eating, drinking, and social interactions with conspecifics, remained normal. Because of the observed tachypnea, 0.4 mg of torsemide/kg (0.18 mg/lb), PO, every 12 hours, was substituted for furosemide. No meaningful change in the RR was noted over the subsequent weeks; therefore, the dosage of torsemide was increased to 0.6 mg/kg (0.27 mg/lb), PO, every 12 hours, but the RR (80 breaths/min) only minimally lessened. The lemur's clinical condition was status quo for 7 months, until the RR began to progressively increase. The dosage of torsemide was again increased to 0.8 mg/kg (0.36 mg/lb), PO, every 12 hours, yet no improvement in the RR and character was observed. Because of perceived poor quality of life, the lemur, at 18 years of age and 33 months after the onset of CHF, was subsequently euthanized. Postmortem examination revealed severe thickening and tethering of the MV leaflets, circumferential stenosis of the MV orifice, and marked LA dilation (Figures 3 and 4). Histologic examination of the MV showed an expansion of fibrous connective tissue with areas of lightly basophilic matrix. Gross and microscopic examinations of the lungs revealed evidence of chronic pulmonary congestion and edema.
Photographs of the heart of the lemur in Figure 1 that was euthanized and a necropsy performed 33 months after the onset of CHF. A—Note the severe dilation of the LA (asterisk) and its auricular appendage (arrow). B—Dorsal view of the LA with one of its walls incised and retracted to show severely thickened and fused MV leaflets that created a circumferential stenotic orifice (arrow).
Citation: Journal of the American Veterinary Medical Association 257, 8; 10.2460/javma.257.8.849
Photograph and corresponding echocardiographic image of the heart of the lemur in Figure 1. A—The heart, collected at necropsy, is cut in longitudinal section to show the severely dilated LA and thickening of the MV (asterisk). B—Left apical 4-chamber view obtained during transthoracic 2-D echocardiographic examination mirroring the heart in panel A. RV = Right ventricle. See Figure 2 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 257, 8; 10.2460/javma.257.8.849
Discussion
To the authors’ knowledge, this report has the first description of the diagnosis and treatment of valvular heart disease in a prosimian. Mitral stenosis is most commonly recognized as a congenital heart disease in dogs and cats resulting from dysplasia of the MV apparatus, and valvular and supravalvular stenoses have been reported.2,4,5 Recent data suggest a prevalence of MV dysplasia of approximately 1 in 10,000 dogs and 1 in 18,000 cats, accounting for approximately 7.4% and 3.4% to 10.1% of congenital heart diseases in dogs and cats, respectively.6,7
In contrast, MS in people is often an acquired change caused by RHD as a sequela of acute rheumatic fever.8,9 Acute rheumatic fever is characterized by an exaggerated inflammatory response to group A streptococcal antigens and clinical manifestations of arthritis and carditis. Streptococcal pharyngitis often precedes the development of acute rheumatic fever, but up to 40% of affected people do not have a history of streptococcal infection.9–11 Rheumatic heart disease, one of the most commonly diagnosed structural heart diseases in the developing world,12 can affect the pericardium, myocardium, and endocardium, yet most commonly affects the heart valves (ie, valvulitis). Cross-reactivity between valvular tissue and streptococcal antigens has been previously demonstrated9 and is the expected pathogenesis of valvulitis in people. The morphology of the MV progressively changes because of inflammation and subsequent fibrosis, characterized by commissural fusion and thickening of the leaflet margins, with or without involvement of the chordae tendineae.8,10,12 The American Heart Association recently updated the Jones criteria that are used in conjunction with laboratory evidence of recent group A streptococcal pharyngitis to include echocardiography to support a diagnosis of RHD. Echocardiography is now recognized as a valuable tool for the diagnosis of RHD because of its ability to identify the predictable valvular changes of RHD.12
A congenital defect was considered the most likely cause of MS for the lemur of this report because it was 4 years old when the heart murmur was initially auscultated and its risk of developing infectious disease while raised in captivity was perceived to be low. However, because of the paucity of published data regarding an association between heart disease and streptococcal infections in prosimians as well as the lack of bacteriologic testing of the lemur, acquired valvular disease cannot be completely excluded as the cause of MS. Additionally, the findings of the histologic examination of the lemur's MV cannot be used to differentiate between congenital and infectious causes of valve disease.
In humans with acquired MS, intervention via percutaneous balloon mitral valvuloplasty is the treatment of choice.8 Congestive heart failure and atrial fibrillation, which are concurrent in up to 20%10 and 40%9 of patients, respectively, are managed medically prior to surgery. Valve replacement and repair surgeries are performed in situations where a percutaneous approach is contraindicated.8,9 Surgical and other interventional treatments for congenital MS have also been reported for dogs and cats. Reports13–16 of individual dogs describe successful balloon valvuloplasty, closed commissurotomy, or bioprosthetic valve replacement for congenital MS. In a study4 of 14 cats with congenital supravalvular MS, 2 cats underwent open-heart surgery for attempted resection of the atrial membrane but died perioperatively. Surgical treatment was not pursued for the lemur of this report because of its small size and anticipated difficult postoperative management.
Information regarding heart disease in prosimians and the medical management of prosimians with heart disease is sparse. A single report17 describes the diagnosis and medical treatment of CHF secondary to an iatrogenic arteriovenous fistula in a ring-tailed lemur. Echocardiography revealed mild dilation of all heart chambers and pleural and peritoneal effusions. Tachypnea resolved with administration of furosemide (0.5 mg/kg/d) prior to surgery; furosemide was successfully discontinued several months after fistula ligation, and heart chambers returned to normal size, as determined with echocardiography.
Long-term medical management of CHF because of primary heart disease has not been reported for prosimians. At 15 years of age, the lemur of this report received a diagnosis of CHF, which was managed with a combination of aspirin, benazepril, a diuretic (initially furosemide and later torsemide), pimobendan, and spironolactone. The lemur was medically managed for 33 months after the onset of CHF, demonstrating that the clinical signs associated with CHF were adequately controlled with standard treatment often prescribed to dogs and cats with CHF. Dosages of prescribed medications were extrapolated from those for dogs and cats. No overt adverse drug effects were reported, including no abnormalities in serum kidney biomarkers and electrolytes, despite the relatively high dosages of furosemide and torsemide. The reported18,19 lifespan for this species in the wild is 18 to 20 years, and the lemur of the present report lived as long as those that live in the wild, despite severe MS.
Aspirin was administered to prevent cardiogenic thromboembolism. Although the risk of thrombosis in prosimians is unknown, aspirin is commonly prescribed for thromboprophylaxis in other captive primates with heart disease.20,21 Aspirin was seemingly well tolerated by this lemur, and spontaneous bleeding was not evident. Clopidogrel, alone or in combination with aspirin, has been shown to be superior for the prevention of thromboembolism in high-risk human22 and feline23 patients. However, clopidogrel was not considered a practical option for this lemur. Because clopidogrel has a bitter taste and medications were concealed in fruit to ensure their administration, the lemur may have developed a food aversion if clopidogrel was similarly concealed.
The use of pimobendan has become the standard of care for dogs with CHF because of its beneficial effects of mitigating or resolving clinical signs and increasing survival times.24–26 Pimobendan is also indicated for delaying the progression to CHF in dogs with advanced subclinical degenerative mitral valve disease27 or dilated cardiomyopathy.28 Although controversial, pimobendan is also commonly administered to cats with CHF, and cats tolerate it well.29,30 Currently in the United States, pimobendan is not labeled for use in people with heart disease, at least in part because of the results of a clinical trial31 suggesting that pimobendan has proarrhythmic effects and is associated with an increased risk of death, compared with placebo; however, for that same trial, no short-term adverse effects were reported, and exercise ability improved. Multiple placebo-controlled clinical trials32–34 of pimobendan in Japanese people with CHF revealed that pimobendan administration is safe long term. One report35 describes pimobendan use for a De Brazza monkey with dilated cardiomyopathy, but the monkey died 14 days after pimobendan administration was started. To the authors’ knowledge, this is the first report documenting the use of pimobendan in a prosimian. Dosage was between 0.4 and 0.5 mg/kg, PO, every 12 hours, which was higher than the labeled dosage of 0.25 mg/kg (0.11 mg/lb), PO, every 12 hours, for dogs. However, the dosage for the lemur of the present report was determined by the available tablet sizes. The good long-term outcome for this lemur with the administration of pimobendan plus other standard medications for the management of CHF, without any observed adverse effects, including no development of a new arrhythmia or worsening of the preexisting arrhythmia, suggested that pimobendan may be useful for the management of CHF in this species.
The present report documented radiographic and echocardiographic findings of MS in a lemur that developed CHF. To our knowledge, this represented the first report of valvular heart disease in a prosimian and its medical management. Medical treatments adequately controlled clinical signs for 33 months. Whether RHD occurs in prosimians is unclear, but testing for group A streptococcal antigens could be considered in other prosimians with MS because of the high prevalence of RHD in people.
Acknowledgments
This study was not supported by any grant or other funding source. The authors declare that there were no conflicts of interest.
ABBREVIATIONS
| CHF | Congestive heart failure |
| LA | Left atrium |
| MS | Mitral stenosis |
| MV | Mitral valve |
| RHD | Rheumatic heart disease |
| RR | Respiratory rate |
Footnotes
Phillips CX50, Philips Healthcare, Andover, Mass.
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