- Email: [email protected]
Update on the Great Ape Heart Project
82
Update on the Great Ape Heart Project HAYLEY WESTON MURPHY AND MARIETTA DINDO DANFORTH
Introduction
Great Ape Cardiovascular Disease
Cardiovascular disease (CVD) is a major cause of mortality in all four great ape taxa in managed care: western lowland gorillas (Gorilla gorilla gorilla), orangutans (Pongo pygmaeus, P. abelii, and P. hybrids), chimpanzees (Pan troglodytes), and bonobos (Pan paniscus). CVD has been seen in wild living great apes, but there is limited information available on CVD prevalence and severity.1–12 The Great Ape Heart Project (GAHP), based at Zoo Atlanta (Atlanta, Georgia), is an innovative and coordinated program to investigate ape CVD and establish uniform strategies for the diagnosis, treatment, and prevention of great ape CVD. A focus of the GAHP has been to develop guidelines and recommendations that support zoological professionals in diagnosing and treating CVD in great apes. This has been accomplished by professional capacity building, cardiac examination reviews, clinical support to attending veterinarians, and easy access to subject matter experts (SMEs) such as cardiologists, pathologists, and species experts. The GAHP is led by a Project Director and a dedicated full-time Database Manager, assisted by an Executive Committee made up of cardiologists, sonographers, pathologists, and Species Survival Plan (SSP) veterinary, pathology, and nutrition advisors for all four great ape taxa.
Types of great ape CVD reported include: myocardial fibrosis in the absence of coronary infarction, aortic dissections, atherosclerosis, arteriosclerosis, valvular degeneration, infectious myocarditis, and congestive heart failure.3 Affected apes are typically adult to older adult individuals, and CVD predominately affects males. The most common finding at necropsy in affected apes is myocardial replacement fibrosis, often termed interstitial myocardial fibrosis or fibrosing cardiomyopathy.10,13 Myocardial injuries, such as inflammation, ischemia, vasospasm, and hypertension, all may result in the formation of fibrosis of the myocardium. Regardless of the inciting process, myocardial fibrosis results in increased myocardial stiffness, loss of contractile ability, increase in arrhythmogenic potential, and eventual cardiac dysfunction or sudden cardiac death.
What We Do The GAHP functions like the hub of a wheel, facilitating communication and support among stakeholders and SMEs. This system aids zoos and stakeholders who are interested in CVD research, as well as great ape care and welfare. In essence, the GAHP creates connections to facilitate the highest level of cardiac care for these highly endangered apes (Fig. 82.1). A customized web-based database is used to trace ape relatedness and links clinical information to postmortem data, creating a foundation for CVD-based research and the establishment of taxon-specific echocardiographic reference parameters (Fig. 82.2). Facilitating access and clinical support between veterinarians, keepers, and dedicated SMEs has been the cornerstone to the success of the GAHP.
Clinical Signs Subtle signs of CVD in apes may include lethargy, anorexia, changes in weight, avoidance of antagonistic or aggressive interactions with conspecifics, and loss of social ranking. As CVD progresses, animals may exhibit sudden death, especially during or immediately following respiratory illness or times of increased stress or activity. Progressive signs of CVD such as weight gain, peripheral edema, and progressive respiratory compromise may occur, and sudden death has been attributed to aortic dissections, arrhythmias secondary to extensive myocardial fibrosis, thromboembolic events, or decompensated congestive heart failure with multisystemic failure.8,14
Cardiovascular Changes Expected cardiovascular systemic changes due to aging typically result in left ventricular (LV) wall thickening, increased myocyte size with decreased numbers, increased interstitial connective tissue, and loss of elasticity.10 Histologic examination of the heart in great apes with CVD exhibits these changes, but the changes have typically been advanced, with fibrosis frequently seen around small intrinsic coronary arterioles, often with hyalinization (arteriosclerosis) and larger 581
582 SE C T I O N 16 Great Apes
• Figure 82.1
By focusing on collaboration and information sharing, zoos and ape caregivers do not need to “reinvent the wheel” of establishing a network of subject matter experts, diagnostic approaches, and treatment methods in the care of their great apes.
areas of fibrosis extending through the cardiac chamber walls. Left ventricular hypertrophy (LVH) is a common finding and some apes will progress to have dilated and enlarged hearts in end-stage heart failure.3 In humans, the association between sudden cardiac death due to myocardial fibrosis and fatal arrhythmias may be similar to what is seen in chimpanzees with interstitial myocardial fibrosis, cardiac arrhythmias, and sudden cardiac death.13,15 The GAHP has developed clinical assessment categories, using ejection fraction (EF) and assessment of functional capacity of the heart to determine disease severity. The majority of affected apes have been broadly categorized as follows: apes with LVH and intact systolic function, apes with LVH and systolic dysfunction, and apes with a dilated cardiomyopathy phenotype. Aortic dissections are the second leading cause of cardiovascular-related deaths in gorillas and bonobos and typically result in acute collapse and death.10,14 Other significant findings (but not as frequently seen) have been aortic root dilation, left atrial enlargement, thromboembolism, right-sided enlargement, arrhythmogenic right ventricular dysplasia/cardiomyopathy, pulmonary hypertension, inflammatory heart disease, and pericardial effusions. Valvular regurgitation is not typically clinically significant. Etiologic factors contributing to ape CVD are yet unknown.
Blood Pressure and Hypertension In humans, elevated blood pressure (BP) is a major risk factor for the development of heart failure, and long-term
treatment of both systolic and diastolic hypertension has been shown to reduce the risk of heart failure.16 Echocardiographic evidence of concentric LVH and systemic changes in affected apes, similar to those seen in humans with hypertension, have strongly implicated hypertension as a factor in great ape CVD.10,17 Defining BP reference ranges for adult, healthy great apes has been logistically challenging. Historically, BP measurements were attained only from anesthetized great apes and the effects of various anesthetic agents on BP have not been systematically analyzed. Attaining a BP reading as soon as possible after anesthetic induction and before commencing inhalant anesthetics, if not using alpha-2 agonists, may give the most accurate BP in an anesthetized ape. By human standards, consistent systolic readings of greater than 140 mm Hg or diastolic readings ≥90 mm Hg fit the definition of hypertension.18 In chimpanzees, obesity has been shown to be a risk factor for the development of systolic hypertension in females, and increasing age is a risk factor for development of diastolic hypertension in both sexes.19 Attempts to define BP ranges in nonanesthetized great apes are underway. Generating individual “baselines” for BP by consistently attaining BP readings over time may help to provide an ancillary tool to monitor great apes for hypertension. This information can be used to detect changes in BP over time and during CVD treatment regimes. Until BP reference ranges can be developed, it would appear reasonable that animals with systolic BP consistently above 160 mm Hg be treated for hypertension.18,19
CHAPTER 82 Update on the Great Ape Heart Project
• Figure 82.2
583
Great Ape Heart Project exam submission process.
Diet Diet, lifestyle, body weight, metabolic syndrome (MS), and sodium intake have all been linked to hypertension and heart disease in humans.16 Great apes have a predominantly vegetarian, low fat, high fiber, and very low cholesterol diet in the wild (see Chapter 83).20 While some blood lipids, measured as HDL, LDL, and total cholesterol, change or increase with age in captive apes and may be well above the mean for the human population and for wild-living great apes, these levels do not appear to correlate to increased risk of ape CVD.8,20–24 Increased sodium intake in humans is
associated with increased systolic BP, cardiovascular events, and death in people with hypertension.25 In one study done in chimpanzees, salt was progressively added to the diet over 20 months and caused a significant rise in body weight, as well as systolic, mean, and diastolic BP that was reversed after cessation of additional salt. Dietary sodium requirements for great apes are poorly understood, and the above study concluded that in chimpanzees, feeding a balanced diet with no more than 30–40 mmol of sodium per day would be advised.26 The current recommended levels for nonhuman primates of 0.25%–0.65% dietary sodium is
584 SE C T I O N 16 Great Apes
potentially too high and, until more research can be done, it is prudent to monitor great ape dietary sodium intake closely.27
Metabolic Syndrome In humans, MS is a risk factor associated with cardiomyopathy and is defined as the presence of at least three of the following: obesity, increased serum triglycerides, reduced HDL, hypertension, increased fasting glucose, and increased serum insulin levels.21 More research into the role of MS in ape CVD is needed. In one study done on 16 geriatric female chimpanzees, 43.8% of the animals met the criteria for MS. Of these animals, 81.2% had some type of CVD.21
Cardiac Health Monitoring Echocardiography provides the most practical, clinically relevant, and accurate assessment of cardiac functionality, valve anatomy, chamber sizes, and ventricular mass and is a critical tool used for diagnosing CVD in great apes.28 Considerable expertise is needed in order to obtain a diagnostic echocardiogram. For this reason, the GAHP strongly recommends that institutions housing great apes establish relationships with local cardiologists and echocardiographers.
Performing Cardiac Examinations Echocardiographic assessments should be done on great apes during every anesthetized examination once the ape reaches adulthood. At a minimum, adult echocardiograms should be done every 2–3 years on animals with normal cardiac health. Once an animal is determined to be affected by CVD, a risk analysis should be used to aid in determining anesthesia and examination frequency (Table 82.1).
TABLE Great Ape Heart Project Recommendations 82.1 for Frequency of Blood Pressure and
Echocardiograms Standardization and accuracy of echocardiographic examinations done in great apes have been essential in detecting and monitoring great ape CVD, and the GAHP has developed standardized guidelines for great ape echocardiography. A great ape’s size, positioning, and conformation may all affect imaging. It is generally recommended to perform echocardiography on anesthetized apes placed in left lateral recumbency, with the left arm extended cranially (Fig. 82.3). Accurate and complete examinations require a skilled examiner and consist of a comprehensive, two-dimensional transthoracic echocardiogram with Doppler color flow study capabilities, and all GAHP recommended measurements stored as DICOM (Digital Imaging and Communications in Medicine).29,30 While it is possible to review measurements saved as movie and jpg files, DICOM standard capabilities are the gold standard, especially if participation in the GAHP is to be maximized. This capability allows for postprocessing measurements and assessment of images, ensuring data validity and remote storage capability.
Echocardiograms on Nonanesthetized Great Apes The GAHP has been able to utilize advances in animal training to encourage cardiovascular monitoring in great apes without the aid of anesthesia. The advantages of performing echocardiography and BP monitoring on nonanesthetized apes include less frequent anesthetic episodes, more frequent monitoring, and lack of anesthetic effects on the cardiovascular system. The disadvantages include training time and logistics, risk to the trainer and equipment, less thorough echocardiograms, and a missed opportunity to do a complete physical examination. Unfortunately, echocardiograms done on awake animals may take several sessions to obtain all the necessary measurements. Therefore, while not ideal, the GAHP recommends that measurements from training sessions obtained within a 30-day period be submitted as one examination.
Echocardiography Exam Based on Age and Health Status
Age/Health Status
Frequency of Exams
Neonate
Opportunistically if a neonate has to be removed from the dam for any reason, a neonatal exam should be done.
9 years
Baseline exam
10–20 years
Every 3–5 years
>20 years
Every 2–3 years
Animals with cardiac disease
Examination frequency should be determined on a case-by-case basis in order to monitor and manage treatment.
• Figure 82.3
An anesthetized gorilla (Gorilla gorilla) shown in left lateral recumbency.
CHAPTER 82 Update on the Great Ape Heart Project
Electrocardiogram Whenever possible, an electrocardiogram (ECG) should be recorded. Male chimpanzees have been shown to develop increasing frequencies of cardiac arrhythmias as they age, with up to 75% of geriatric males showing some kind of ectopy, most commonly characterized by ventricular premature complexes.15,30 To date most ECG information has been recorded from the great apes under general anesthesia. There have been several zoological and research institutions, however, that have successfully used implantable ECG loop recorders to monitor and detect for cardiac arrhythmias and heart rate variability in chimpanzees and gorillas, and this technology shows promise for use in animals at risk for or with cardiac dysrhythmias.31–33 Additional modalities for cardiac assessment include magnetic resonance imaging (MRI) and cardiac computed tomography (CT). Both of these modalities may provide additional information for cardiac evaluations such as detailed cardiac structural assessments, myocardial perfusion and viability information, and coronary artery assessment, and have been used extensively in human medicine.16 Unfortunately, the availability, cost, and logistics involved in utilizing these advanced modalities have often been prohibitive in the great apes.
Anesthesia Considerations Echocardiographic assessments performed while the animal is anesthetized offer the most diagnostic and accurate views of the heart, as well as providing opportunity for a complete physical examination and ancillary diagnostics. There is wide variation in anesthetic protocols used in great apes. The most commonly used protocols involve the use of either tiletamine hydrochloride (HCL) and zolazepam HCL (Telazol), ketamine HCL with or without additional sedatives, or ketamine HCL and medetomidine HCL combinations, all usually followed by inhalant anesthetic for maintenance of anesthesia.34 When choosing an anesthetic regime, in addition to drug safety, mode of delivery, efficacy, and reversibility, the effect of the drug on the cardiovascular system must be considered. There have been varying reports of the use of alpha-2 adrenergic agonists in great apes, with generally favorable reviews on safety and reversibility; however, in great apes with CVD, the cardiovascular effects of these agents deserve special consideration.35,36 Alpha-2 agonists result in an increase in systemic vascular resistance and this intense vasoconstriction results in increased cardiac afterload and a reflex bradycardia. Decreased stroke volume and heart rate result in decreased LV blood flow and decreased cardiac output. As the peripheral vasoconstriction wears off, the central effects, primarily decreased sympathetic output, may result in hypotension.37,38 Echocardiographic examinations of animals that received alpha-2 agonists are notable for the presence of an enlarged LV due to impaired LV outflow and slow heart rate. Increased LV pressure may
585
also result in appearance of an alpha-2 agonist-induced mitral valve regurgitation, left atrial enlargement, and systolic dysfunction, potentially leading to an animal with a functionally normal heart being classified as abnormal.39–41 When alpha-2 agonists are combined with inhalant anesthetics such as isoflurane, the combined decreases in mean arterial pressures due to vasodilation and decreased systemic vascular resistance may cause hypotension at a much lower inhalant concentration, exacerbating the cardiovascular effects of these drugs.38 Although there are not sufficient data to provide a clear contraindication on the use of alpha-2 agonists for anesthesia in great apes, the risk/benefit analysis of using these protocols needs to be considered. Due to these considerations, the GAHP considers echocardiograms done on apes anesthetized with alpha-2 agonists as nondiagnostic.
Biomarkers Blood work may be a valuable ancillary assessment tool for great apes when evaluating their cardiac status, as well as general health. Ideally, biomarkers for CVD should have a high sensitivity and specificity, have good predictive values, be low-cost, and be validated for use in great apes.
B-type Natriuretic Peptide B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from the cardiac ventricles, particularly the left ventricle, in response to ventricular volume expansion and increased pressures.42 BNP is a recommended biomarker in human cases of LV fibrogenic remodeling, a classic finding in great ape CVD, making this particular biomarker of significant interest.42 In chimpanzees, BNP was found to be elevated in cases of cardiomyopathy and valve disease, and a preliminary reference interval for BNP was suggested as 23–163 pg/mL in healthy animals with BNP levels greater than 163 pg/mL having a specificity of 90.5% for CVD.43
C-Reactive Protein C-reactive protein is a nonspecific indicator of inflammation and in humans has been associated with atherosclerosis and CVD. Studies performed in chimpanzees affected with CVD did not find that this was a useful or predictive biomarker.43
Troponins Cardiac troponin T (cTnT) and troponin I (cTnI) are cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin. The measurement of serum cTnI and cTnT is used to detect cardiac muscle damage, and increased cardiac troponin concentrations are standard biochemical markers used for the diagnosis of myocardial infarction in humans.44 Cardiac troponins may also be increased in nonischemic myocardial disease, LV dysfunction, and hypertrophic cardiomyopathy, and as such are also of interest in the great apes.44 In a study of
586 SE C T I O N 16 Great Apes
28 chimpanzees, cTnI levels were found to have a predictive value for CVD disease in cases of advanced/severe cardiac disease, but the levels were not predictive in cases of mild to moderate severity.43 The authors of this study concluded that any observed value of cTnI above the detection threshold of the assay used (0.20 ng/mL) should be treated as an indicator of potential CVD in chimpanzees, although a limitation of this study was that the cTnI assay used had an analytic sensitivity above the threshold for humans and veterinary species; therefore some chimpanzees with heart disease may not have been detected.43 Biomarkers to detect extracellular matrix remodeling and fibrogenesis resulting in myocardial fibrosis formation and turnover in great apes have shown promise and are currently under investigation.45
clinically relevant diagnostic and treatment criteria for future evaluations.
Treating Cardiovascular Disease in Great Apes
1. Seiler BM, Dick EJ, Jr, Guardado-Mendoza R, et al: Spontaneous heart disease in the adult chimpanzee (Pan troglodytes), J Med Primatol 38:51–58, 2009. 2. Lammey ML, Lee DR, Ely JJ, et al: Sudden cardiac death in 13 captive chimpanzees (Pan troglodytes), J Med Primatol 37(Suppl 1):39–43, 2008. 3. McManamon R, Lowenstine L: Cardiovascular disease in great apes. In Miller RE, Fowler ME, editors: Fowler’s zoo and wild animal medicine current therapy, ed 1, 2012, pp 408–415. 4. Meehan T, Lowenstine L: Causes of mortality in captive lowland gorillas: a survey of the SSP population. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1994, pp 190–192. 5. Lowenstine L, McManamon R, Bonar CJ, et al: Preliminary results of a survey of United States and Canadian orangutan mortalities in the North American SSP population from 1980 to March 2008. In Proceedings of the American Association of Zoo Veterinarians Conference, 2008. 6. Gamble KC: Pathologic review of the chimpanzee (Pan troglodytes): 1990–2003. In Proceedings of the American Association of Zoo Veterinarians/American Association of Wildlife Veterinarians Conference, 2004, pp 561–566. 7. Clyde VL, Roth L, Bell B, et al: Cardiac and gestational ultrasound parameters in nonanesthetized bonobos (Pan paniscus). In Proceedings of the American Association of Zoo Veterinarians Annual Meeting, 2002, pp 365–368. 8. Varki N, Anderson D, Herndon JG, et al: Heart disease is common in humans and chimpanzees, but is caused by different pathological processes, Evol Appl 2:101–112, 2009. 9. Junge RE, Mezei LE, Muhlbauer MC, et al: Cardiovascular evaluation of lowland gorillas, J Am Vet Med Assoc 212:413–415, 1998. 10. Lowenstine LJ, McManamon R, Terio KA: Comparative pathology of aging great apes, Vet Pathol 53:250–276, 2015. 11. Kambale ES, Ramer JC, Gilardi K, et al: Cardiovascular and hepatic disease in wild Eastern Lowland Gorillas (Gorilla beringei graueri). In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014, p 115. 12. Terio KA, Kinsel MJ, Raphael J, et al: Pathologic lesions in chimpanzees (Pan trogylodytes schweinfurthii) from Gombe National Park, Tanzania, 2004–2010, J Zoo Wildl Med 42:597–607, 2011. 13. Lammey ML, Baskin GB, Gigliotti AP, et al: Interstitial myocardial fibrosis in a captive chimpanzee (Pan troglodytes) population, Comp Med 58:389–394, 2008.
Standard pharmacologic therapies for cardiomyopathies including LV dysfunction in humans include betaadrenergic blockade, renin-angiotensin-aldosterone system antagonism, and diuretics as necessary for congestive heart failure.16 To date, most of the GAHP advisory experience in the great apes has been with beta-blockade and angiotensin-converting enzyme (ACE) inhibition, with other pharmacologic agents used on a more sporadic basis. It is worth emphasizing that no clinical studies have been performed on the efficacy, safety, or pharmacokinetics of any cardiovascular therapeutics in apes, so recommendations are based purely on experience with them in apes over the course of the GAHP studies, as well as hypothetical assumptions that apes would react in much the same way as humans do to these drugs. Attending veterinarians must use their best judgment when prescribing these drugs as “off-label” medications and should monitor animals very closely for any adverse side effects. Thromboembolism and cerebral infarcts have been documented in the great apes.21,46,47 In these cases, aspirin therapy has been recommended.21
Postmortem Cardiac Evaluations The pathology group of the GAHP has collected and reviewed available necropsy and histopathology reports from captive apes. All information collected is reviewed and entered into the GAHP database and is analyzed for antemortem clinical correlations, inter and intra-specific taxon trends, and disease classifications. Novel postmortem cardiac tissue collection and evaluation techniques for great ape necropsies have been developed, and these protocols have established a new “best practices” approach to ape heart evaluation that is more closely aligned with techniques used in human cardiac autopsies.48 These guidelines may be found at www.greatapeheartproject.org. Database inquiry coupled with simultaneous multipathologist review will allow the GAHP to establish more precise and
Acknowledgments The GAHP is supported by the Institute of Museum and Library Services (Grants LG-26-12-0526-12 and MG-30-15-0035-15) and Zoo Atlanta. We are grateful for the support and involvement of the Ape Taxon Advisory Group, the individual ape SSPs (veterinary, pathology, and nutrition advisors), the veterinary and medical cardiologists and sonographers who generously donate their time, and various staff at all participating institutions.
References
CHAPTER 82 Update on the Great Ape Heart Project
14. Kenny DE, Cambre RC, Alvarado TP, et al: Aortic dissection: an important cardiovascular disease in captive gorillas (Gorilla gorilla gorilla), J Zoo Wildl Med 25:561–568, 1994. 15. Doane CJ, Lee DR, Sleeper MM: Electrocardiogram abnormalities in captive chimpanzees (Pan troglodytes), Comp Med 56:512–518, 2006. 16. Yancy CW, Jessup M, Bozkurt B, et al: 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines, Circulation 128:1810–1852, 2013. 17. Grim CE, Highland MA, Beehler L, et al: Familial hypertension and stroke in bonobo chimpanzees (Pan paniscus). In Proceedings of the American Heart Association, Hypertension E127–E127, 2010. 18. Ely JJ, Zavaskis T, Lammey ML, et al: Blood pressure reference intervals for healthy adult chimpanzees (Pan troglodytes), J Med Primatol 40:171–180, 2011. 19. Ely JJ, Zavaskis T, Lammey ML: Hypertension increases with aging and obesity in chimpanzees (Pan troglodytes), Zoo Biol 32:79–87, 2013. 20. Popovich DG, Jenkins DJ, Kendall CW, et al: The western lowland gorilla diet has implications for the health of humans and other hominoids, J Nutr 127:2000–2005, 1997. 21. Nunamaker EA, Lee DR, Lammey ML: Chronic diseases in captive geriatric female chimpanzees (Pan troglodytes), Comp Med 62:131–136, 2012. 22. Seng CF, Meng GY, Abdullah R: A comparative study of blood lipids and stress levels between captive and semi-captive orangutans (Pongo pygmaeus) under tropical conditions. In Proceedings of the American Association of Zoo Veterinarians/American Association of Wildlife Veterinarians/American Zoo Association/ Nutrition Advisory Group Joint Conference, 2007. 23. Schmidt DA, Ellersieck MR, Cranfield MR, et al: Cholesterol values in free-ranging gorillas (Gorilla gorilla gorilla and Gorilla beringei) and Bornean orangutans (Pongo pygmaeus), J Zoo Wildl Med 37:292–300, 2006. 24. Baitchman EJ, Calle PP, Clippinger TL, et al: Preliminary evaluation of blood lipid profiles in captive western lowland gorillas (Gorilla gorilla gorilla), J Zoo Wildl Med 37:126–129, 2006. 25. Mente A, O’Donnell M, Rangarajan S, et al: Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies, Lancet 388:465–475, 2016. 26. Denton D, Weisinger R, Mundy NI, et al: The effect of increased salt intake on blood pressure of chimpanzees, Nat Med 1:1009–1016, 1995. 27. Council NR, Studies DEL, Resources BAN, et al: Nutrient requirements of nonhuman primates, Revised ed 2, 2003, National Academies Press. 28. Lang RM, Badano LP, Mor-Avi V, et al: Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, J Am Soc Echocardiogr 28:1–39, 2015. 29. Shave R, Oxborough D, Somauroo J, et al: Echocardiographic assessment of cardiac structure and function in great apes: a practical guide, Int Zoo Yearb 48:218–233, 2014. 30. Sleeper MM, Drobatz K, Lee DR, et al: Echocardiographic parameters of clinically normal adult captive chimpanzees (Pan troglodytes), J Am Vet Med Assoc 244:956–960, 2014. 31. Lammey ML, Jackson R, Ely JJ, et al: Use of an implantable loop recorder in the investigation of arrhythmias in adult captive chimpanzees (Pan troglodytes), Comp Med 61:71–75, 2011.
587
32. Magden ER, Sleeper MM, Buchl SJ, et al: Use of an implantable loop recorder in a chimpanzee (Pan troglodytes) to monitor cardiac arrhythmias and assess the effects of acupuncture and laser therapy, Comp Med 66:52–58, 2016. 33. Duncan AE, Kutinsky I, Murray S, et al: Use of implantable loop recorders to monitor for cardiac disease in captive gorillas (Gorilla gorilla gorilla), Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014. 34. West G, Heard D, Caulkett N: Zoo animal and wildlife immobilization and anesthesia, ed 2, 2014, pp 573–584. 35. Adami C, Wenker C, Hoby S, et al: Evaluation of effectiveness, safety and reliability of intramuscular medetomidine-ketamine for captive great apes, Vet Rec 171:196, 2012. 36. Horne WA, Norton TM, Loomis MR: Cardiopulmonary effects of medetomidine-ketamine-isoflurane anesthesia in the gorilla (Gorilla gorilla) and chimpanzee (Pan troglodytes). In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1997, pp 140–142. 37. Talke P, Lobo E, Brown R: Systemically administered α2-agonist-induced peripheral vasoconstriction in humans, Anesthesiology 99:65–70, 2003. 38. Naples LM, Langan JN, Kearns KS: Comparison of the anesthetic effects of oral transmucosal versus injectable medetomidine in combination with tiletamine-zolazepam for immobilization of chimpanzees (Pan troglodytes), J Zoo Wildl Med 41:50–62, 2010. 39. Pypendop BH, Verstegen JP: Hemodynamic effects of medetomidine in the dog: a dose titration study, Vet Surg 27:612–622, 1998. 40. Napier JE, Kutinsky IB, Armstrong DL, et al: Evaluating echocardiogram and indirect blood pressure results in male western lowland gorillas (Gorilla gorilla gorilla) during three phases of an anesthetic protocol, J Zoo Wildl Med 44:875–881, 2013. 41. Lopez del Rio PR, Sanchez C, Stembridge M, et al: Comparison of indirect blood pressure values in chimpanzees (Pan troglodytes) anesthetized with two anesthetic protocols: tiletamine-zolazepam and titetamine-zolazepam-medetomidine. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014. 42. Raizada A, Bhandari S, Khan MA, et al: Brain type natriuretic peptide (BNP) - A marker of new millennium in diagnosis of congestive heart failure, Indian J Clin Biochem 22:4–9, 2007. 43. Ely JJ, Zavaskis T, Lammey ML, et al: Association of braintype natriuretic protein and cardiac troponin I with incipient cardiovascular disease in chimpanzees (Pan troglodytes), Comp Med 61:163–169, 2011. 44. Sharma S, Jackson PG, Makan J: Cardiac troponins, J Clin Pathol 57:1025–1026, 2004. 45. Ely JJ, Bishop MA, Lammey ML, et al: Use of biomarkers of collagen types I and III fibrosis metabolism to detect cardiovascular and renal disease in chimpanzees (Pan troglodytes), Comp Med 60:154–158, 2010. 46. Weisenberg E, Snook S, Letcher J: Sudden death in an obese orangutan with hypertensive heart disease and a history of stroke (abstract). Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1991. 47. Trupkiewicz JG, McNamara TS, Weidenham KM, et al: Cerebral infarction associated with coarctation of the aorta in a lowland gorilla (Gorilla gorilla gorilla), J Zoo Wildl Med 26:123–131, 1995. 48. Terio KA, McManamon R, Ellis AE, et al: Best practices for the cardiac necropsy: tips for clinicians (and pathologists) performing ape necropsies. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014, pp 88–90.
Update on the Great Ape Heart Project HAYLEY WESTON MURPHY AND MARIETTA DINDO DANFORTH
Introduction
Great Ape Cardiovascular Disease
Cardiovascular disease (CVD) is a major cause of mortality in all four great ape taxa in managed care: western lowland gorillas (Gorilla gorilla gorilla), orangutans (Pongo pygmaeus, P. abelii, and P. hybrids), chimpanzees (Pan troglodytes), and bonobos (Pan paniscus). CVD has been seen in wild living great apes, but there is limited information available on CVD prevalence and severity.1–12 The Great Ape Heart Project (GAHP), based at Zoo Atlanta (Atlanta, Georgia), is an innovative and coordinated program to investigate ape CVD and establish uniform strategies for the diagnosis, treatment, and prevention of great ape CVD. A focus of the GAHP has been to develop guidelines and recommendations that support zoological professionals in diagnosing and treating CVD in great apes. This has been accomplished by professional capacity building, cardiac examination reviews, clinical support to attending veterinarians, and easy access to subject matter experts (SMEs) such as cardiologists, pathologists, and species experts. The GAHP is led by a Project Director and a dedicated full-time Database Manager, assisted by an Executive Committee made up of cardiologists, sonographers, pathologists, and Species Survival Plan (SSP) veterinary, pathology, and nutrition advisors for all four great ape taxa.
Types of great ape CVD reported include: myocardial fibrosis in the absence of coronary infarction, aortic dissections, atherosclerosis, arteriosclerosis, valvular degeneration, infectious myocarditis, and congestive heart failure.3 Affected apes are typically adult to older adult individuals, and CVD predominately affects males. The most common finding at necropsy in affected apes is myocardial replacement fibrosis, often termed interstitial myocardial fibrosis or fibrosing cardiomyopathy.10,13 Myocardial injuries, such as inflammation, ischemia, vasospasm, and hypertension, all may result in the formation of fibrosis of the myocardium. Regardless of the inciting process, myocardial fibrosis results in increased myocardial stiffness, loss of contractile ability, increase in arrhythmogenic potential, and eventual cardiac dysfunction or sudden cardiac death.
What We Do The GAHP functions like the hub of a wheel, facilitating communication and support among stakeholders and SMEs. This system aids zoos and stakeholders who are interested in CVD research, as well as great ape care and welfare. In essence, the GAHP creates connections to facilitate the highest level of cardiac care for these highly endangered apes (Fig. 82.1). A customized web-based database is used to trace ape relatedness and links clinical information to postmortem data, creating a foundation for CVD-based research and the establishment of taxon-specific echocardiographic reference parameters (Fig. 82.2). Facilitating access and clinical support between veterinarians, keepers, and dedicated SMEs has been the cornerstone to the success of the GAHP.
Clinical Signs Subtle signs of CVD in apes may include lethargy, anorexia, changes in weight, avoidance of antagonistic or aggressive interactions with conspecifics, and loss of social ranking. As CVD progresses, animals may exhibit sudden death, especially during or immediately following respiratory illness or times of increased stress or activity. Progressive signs of CVD such as weight gain, peripheral edema, and progressive respiratory compromise may occur, and sudden death has been attributed to aortic dissections, arrhythmias secondary to extensive myocardial fibrosis, thromboembolic events, or decompensated congestive heart failure with multisystemic failure.8,14
Cardiovascular Changes Expected cardiovascular systemic changes due to aging typically result in left ventricular (LV) wall thickening, increased myocyte size with decreased numbers, increased interstitial connective tissue, and loss of elasticity.10 Histologic examination of the heart in great apes with CVD exhibits these changes, but the changes have typically been advanced, with fibrosis frequently seen around small intrinsic coronary arterioles, often with hyalinization (arteriosclerosis) and larger 581
582 SE C T I O N 16 Great Apes
• Figure 82.1
By focusing on collaboration and information sharing, zoos and ape caregivers do not need to “reinvent the wheel” of establishing a network of subject matter experts, diagnostic approaches, and treatment methods in the care of their great apes.
areas of fibrosis extending through the cardiac chamber walls. Left ventricular hypertrophy (LVH) is a common finding and some apes will progress to have dilated and enlarged hearts in end-stage heart failure.3 In humans, the association between sudden cardiac death due to myocardial fibrosis and fatal arrhythmias may be similar to what is seen in chimpanzees with interstitial myocardial fibrosis, cardiac arrhythmias, and sudden cardiac death.13,15 The GAHP has developed clinical assessment categories, using ejection fraction (EF) and assessment of functional capacity of the heart to determine disease severity. The majority of affected apes have been broadly categorized as follows: apes with LVH and intact systolic function, apes with LVH and systolic dysfunction, and apes with a dilated cardiomyopathy phenotype. Aortic dissections are the second leading cause of cardiovascular-related deaths in gorillas and bonobos and typically result in acute collapse and death.10,14 Other significant findings (but not as frequently seen) have been aortic root dilation, left atrial enlargement, thromboembolism, right-sided enlargement, arrhythmogenic right ventricular dysplasia/cardiomyopathy, pulmonary hypertension, inflammatory heart disease, and pericardial effusions. Valvular regurgitation is not typically clinically significant. Etiologic factors contributing to ape CVD are yet unknown.
Blood Pressure and Hypertension In humans, elevated blood pressure (BP) is a major risk factor for the development of heart failure, and long-term
treatment of both systolic and diastolic hypertension has been shown to reduce the risk of heart failure.16 Echocardiographic evidence of concentric LVH and systemic changes in affected apes, similar to those seen in humans with hypertension, have strongly implicated hypertension as a factor in great ape CVD.10,17 Defining BP reference ranges for adult, healthy great apes has been logistically challenging. Historically, BP measurements were attained only from anesthetized great apes and the effects of various anesthetic agents on BP have not been systematically analyzed. Attaining a BP reading as soon as possible after anesthetic induction and before commencing inhalant anesthetics, if not using alpha-2 agonists, may give the most accurate BP in an anesthetized ape. By human standards, consistent systolic readings of greater than 140 mm Hg or diastolic readings ≥90 mm Hg fit the definition of hypertension.18 In chimpanzees, obesity has been shown to be a risk factor for the development of systolic hypertension in females, and increasing age is a risk factor for development of diastolic hypertension in both sexes.19 Attempts to define BP ranges in nonanesthetized great apes are underway. Generating individual “baselines” for BP by consistently attaining BP readings over time may help to provide an ancillary tool to monitor great apes for hypertension. This information can be used to detect changes in BP over time and during CVD treatment regimes. Until BP reference ranges can be developed, it would appear reasonable that animals with systolic BP consistently above 160 mm Hg be treated for hypertension.18,19
CHAPTER 82 Update on the Great Ape Heart Project
• Figure 82.2
583
Great Ape Heart Project exam submission process.
Diet Diet, lifestyle, body weight, metabolic syndrome (MS), and sodium intake have all been linked to hypertension and heart disease in humans.16 Great apes have a predominantly vegetarian, low fat, high fiber, and very low cholesterol diet in the wild (see Chapter 83).20 While some blood lipids, measured as HDL, LDL, and total cholesterol, change or increase with age in captive apes and may be well above the mean for the human population and for wild-living great apes, these levels do not appear to correlate to increased risk of ape CVD.8,20–24 Increased sodium intake in humans is
associated with increased systolic BP, cardiovascular events, and death in people with hypertension.25 In one study done in chimpanzees, salt was progressively added to the diet over 20 months and caused a significant rise in body weight, as well as systolic, mean, and diastolic BP that was reversed after cessation of additional salt. Dietary sodium requirements for great apes are poorly understood, and the above study concluded that in chimpanzees, feeding a balanced diet with no more than 30–40 mmol of sodium per day would be advised.26 The current recommended levels for nonhuman primates of 0.25%–0.65% dietary sodium is
584 SE C T I O N 16 Great Apes
potentially too high and, until more research can be done, it is prudent to monitor great ape dietary sodium intake closely.27
Metabolic Syndrome In humans, MS is a risk factor associated with cardiomyopathy and is defined as the presence of at least three of the following: obesity, increased serum triglycerides, reduced HDL, hypertension, increased fasting glucose, and increased serum insulin levels.21 More research into the role of MS in ape CVD is needed. In one study done on 16 geriatric female chimpanzees, 43.8% of the animals met the criteria for MS. Of these animals, 81.2% had some type of CVD.21
Cardiac Health Monitoring Echocardiography provides the most practical, clinically relevant, and accurate assessment of cardiac functionality, valve anatomy, chamber sizes, and ventricular mass and is a critical tool used for diagnosing CVD in great apes.28 Considerable expertise is needed in order to obtain a diagnostic echocardiogram. For this reason, the GAHP strongly recommends that institutions housing great apes establish relationships with local cardiologists and echocardiographers.
Performing Cardiac Examinations Echocardiographic assessments should be done on great apes during every anesthetized examination once the ape reaches adulthood. At a minimum, adult echocardiograms should be done every 2–3 years on animals with normal cardiac health. Once an animal is determined to be affected by CVD, a risk analysis should be used to aid in determining anesthesia and examination frequency (Table 82.1).
TABLE Great Ape Heart Project Recommendations 82.1 for Frequency of Blood Pressure and
Echocardiograms Standardization and accuracy of echocardiographic examinations done in great apes have been essential in detecting and monitoring great ape CVD, and the GAHP has developed standardized guidelines for great ape echocardiography. A great ape’s size, positioning, and conformation may all affect imaging. It is generally recommended to perform echocardiography on anesthetized apes placed in left lateral recumbency, with the left arm extended cranially (Fig. 82.3). Accurate and complete examinations require a skilled examiner and consist of a comprehensive, two-dimensional transthoracic echocardiogram with Doppler color flow study capabilities, and all GAHP recommended measurements stored as DICOM (Digital Imaging and Communications in Medicine).29,30 While it is possible to review measurements saved as movie and jpg files, DICOM standard capabilities are the gold standard, especially if participation in the GAHP is to be maximized. This capability allows for postprocessing measurements and assessment of images, ensuring data validity and remote storage capability.
Echocardiograms on Nonanesthetized Great Apes The GAHP has been able to utilize advances in animal training to encourage cardiovascular monitoring in great apes without the aid of anesthesia. The advantages of performing echocardiography and BP monitoring on nonanesthetized apes include less frequent anesthetic episodes, more frequent monitoring, and lack of anesthetic effects on the cardiovascular system. The disadvantages include training time and logistics, risk to the trainer and equipment, less thorough echocardiograms, and a missed opportunity to do a complete physical examination. Unfortunately, echocardiograms done on awake animals may take several sessions to obtain all the necessary measurements. Therefore, while not ideal, the GAHP recommends that measurements from training sessions obtained within a 30-day period be submitted as one examination.
Echocardiography Exam Based on Age and Health Status
Age/Health Status
Frequency of Exams
Neonate
Opportunistically if a neonate has to be removed from the dam for any reason, a neonatal exam should be done.
9 years
Baseline exam
10–20 years
Every 3–5 years
>20 years
Every 2–3 years
Animals with cardiac disease
Examination frequency should be determined on a case-by-case basis in order to monitor and manage treatment.
• Figure 82.3
An anesthetized gorilla (Gorilla gorilla) shown in left lateral recumbency.
CHAPTER 82 Update on the Great Ape Heart Project
Electrocardiogram Whenever possible, an electrocardiogram (ECG) should be recorded. Male chimpanzees have been shown to develop increasing frequencies of cardiac arrhythmias as they age, with up to 75% of geriatric males showing some kind of ectopy, most commonly characterized by ventricular premature complexes.15,30 To date most ECG information has been recorded from the great apes under general anesthesia. There have been several zoological and research institutions, however, that have successfully used implantable ECG loop recorders to monitor and detect for cardiac arrhythmias and heart rate variability in chimpanzees and gorillas, and this technology shows promise for use in animals at risk for or with cardiac dysrhythmias.31–33 Additional modalities for cardiac assessment include magnetic resonance imaging (MRI) and cardiac computed tomography (CT). Both of these modalities may provide additional information for cardiac evaluations such as detailed cardiac structural assessments, myocardial perfusion and viability information, and coronary artery assessment, and have been used extensively in human medicine.16 Unfortunately, the availability, cost, and logistics involved in utilizing these advanced modalities have often been prohibitive in the great apes.
Anesthesia Considerations Echocardiographic assessments performed while the animal is anesthetized offer the most diagnostic and accurate views of the heart, as well as providing opportunity for a complete physical examination and ancillary diagnostics. There is wide variation in anesthetic protocols used in great apes. The most commonly used protocols involve the use of either tiletamine hydrochloride (HCL) and zolazepam HCL (Telazol), ketamine HCL with or without additional sedatives, or ketamine HCL and medetomidine HCL combinations, all usually followed by inhalant anesthetic for maintenance of anesthesia.34 When choosing an anesthetic regime, in addition to drug safety, mode of delivery, efficacy, and reversibility, the effect of the drug on the cardiovascular system must be considered. There have been varying reports of the use of alpha-2 adrenergic agonists in great apes, with generally favorable reviews on safety and reversibility; however, in great apes with CVD, the cardiovascular effects of these agents deserve special consideration.35,36 Alpha-2 agonists result in an increase in systemic vascular resistance and this intense vasoconstriction results in increased cardiac afterload and a reflex bradycardia. Decreased stroke volume and heart rate result in decreased LV blood flow and decreased cardiac output. As the peripheral vasoconstriction wears off, the central effects, primarily decreased sympathetic output, may result in hypotension.37,38 Echocardiographic examinations of animals that received alpha-2 agonists are notable for the presence of an enlarged LV due to impaired LV outflow and slow heart rate. Increased LV pressure may
585
also result in appearance of an alpha-2 agonist-induced mitral valve regurgitation, left atrial enlargement, and systolic dysfunction, potentially leading to an animal with a functionally normal heart being classified as abnormal.39–41 When alpha-2 agonists are combined with inhalant anesthetics such as isoflurane, the combined decreases in mean arterial pressures due to vasodilation and decreased systemic vascular resistance may cause hypotension at a much lower inhalant concentration, exacerbating the cardiovascular effects of these drugs.38 Although there are not sufficient data to provide a clear contraindication on the use of alpha-2 agonists for anesthesia in great apes, the risk/benefit analysis of using these protocols needs to be considered. Due to these considerations, the GAHP considers echocardiograms done on apes anesthetized with alpha-2 agonists as nondiagnostic.
Biomarkers Blood work may be a valuable ancillary assessment tool for great apes when evaluating their cardiac status, as well as general health. Ideally, biomarkers for CVD should have a high sensitivity and specificity, have good predictive values, be low-cost, and be validated for use in great apes.
B-type Natriuretic Peptide B-type natriuretic peptide (BNP) is a cardiac neurohormone secreted from the cardiac ventricles, particularly the left ventricle, in response to ventricular volume expansion and increased pressures.42 BNP is a recommended biomarker in human cases of LV fibrogenic remodeling, a classic finding in great ape CVD, making this particular biomarker of significant interest.42 In chimpanzees, BNP was found to be elevated in cases of cardiomyopathy and valve disease, and a preliminary reference interval for BNP was suggested as 23–163 pg/mL in healthy animals with BNP levels greater than 163 pg/mL having a specificity of 90.5% for CVD.43
C-Reactive Protein C-reactive protein is a nonspecific indicator of inflammation and in humans has been associated with atherosclerosis and CVD. Studies performed in chimpanzees affected with CVD did not find that this was a useful or predictive biomarker.43
Troponins Cardiac troponin T (cTnT) and troponin I (cTnI) are cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin. The measurement of serum cTnI and cTnT is used to detect cardiac muscle damage, and increased cardiac troponin concentrations are standard biochemical markers used for the diagnosis of myocardial infarction in humans.44 Cardiac troponins may also be increased in nonischemic myocardial disease, LV dysfunction, and hypertrophic cardiomyopathy, and as such are also of interest in the great apes.44 In a study of
586 SE C T I O N 16 Great Apes
28 chimpanzees, cTnI levels were found to have a predictive value for CVD disease in cases of advanced/severe cardiac disease, but the levels were not predictive in cases of mild to moderate severity.43 The authors of this study concluded that any observed value of cTnI above the detection threshold of the assay used (0.20 ng/mL) should be treated as an indicator of potential CVD in chimpanzees, although a limitation of this study was that the cTnI assay used had an analytic sensitivity above the threshold for humans and veterinary species; therefore some chimpanzees with heart disease may not have been detected.43 Biomarkers to detect extracellular matrix remodeling and fibrogenesis resulting in myocardial fibrosis formation and turnover in great apes have shown promise and are currently under investigation.45
clinically relevant diagnostic and treatment criteria for future evaluations.
Treating Cardiovascular Disease in Great Apes
1. Seiler BM, Dick EJ, Jr, Guardado-Mendoza R, et al: Spontaneous heart disease in the adult chimpanzee (Pan troglodytes), J Med Primatol 38:51–58, 2009. 2. Lammey ML, Lee DR, Ely JJ, et al: Sudden cardiac death in 13 captive chimpanzees (Pan troglodytes), J Med Primatol 37(Suppl 1):39–43, 2008. 3. McManamon R, Lowenstine L: Cardiovascular disease in great apes. In Miller RE, Fowler ME, editors: Fowler’s zoo and wild animal medicine current therapy, ed 1, 2012, pp 408–415. 4. Meehan T, Lowenstine L: Causes of mortality in captive lowland gorillas: a survey of the SSP population. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1994, pp 190–192. 5. Lowenstine L, McManamon R, Bonar CJ, et al: Preliminary results of a survey of United States and Canadian orangutan mortalities in the North American SSP population from 1980 to March 2008. In Proceedings of the American Association of Zoo Veterinarians Conference, 2008. 6. Gamble KC: Pathologic review of the chimpanzee (Pan troglodytes): 1990–2003. In Proceedings of the American Association of Zoo Veterinarians/American Association of Wildlife Veterinarians Conference, 2004, pp 561–566. 7. Clyde VL, Roth L, Bell B, et al: Cardiac and gestational ultrasound parameters in nonanesthetized bonobos (Pan paniscus). In Proceedings of the American Association of Zoo Veterinarians Annual Meeting, 2002, pp 365–368. 8. Varki N, Anderson D, Herndon JG, et al: Heart disease is common in humans and chimpanzees, but is caused by different pathological processes, Evol Appl 2:101–112, 2009. 9. Junge RE, Mezei LE, Muhlbauer MC, et al: Cardiovascular evaluation of lowland gorillas, J Am Vet Med Assoc 212:413–415, 1998. 10. Lowenstine LJ, McManamon R, Terio KA: Comparative pathology of aging great apes, Vet Pathol 53:250–276, 2015. 11. Kambale ES, Ramer JC, Gilardi K, et al: Cardiovascular and hepatic disease in wild Eastern Lowland Gorillas (Gorilla beringei graueri). In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014, p 115. 12. Terio KA, Kinsel MJ, Raphael J, et al: Pathologic lesions in chimpanzees (Pan trogylodytes schweinfurthii) from Gombe National Park, Tanzania, 2004–2010, J Zoo Wildl Med 42:597–607, 2011. 13. Lammey ML, Baskin GB, Gigliotti AP, et al: Interstitial myocardial fibrosis in a captive chimpanzee (Pan troglodytes) population, Comp Med 58:389–394, 2008.
Standard pharmacologic therapies for cardiomyopathies including LV dysfunction in humans include betaadrenergic blockade, renin-angiotensin-aldosterone system antagonism, and diuretics as necessary for congestive heart failure.16 To date, most of the GAHP advisory experience in the great apes has been with beta-blockade and angiotensin-converting enzyme (ACE) inhibition, with other pharmacologic agents used on a more sporadic basis. It is worth emphasizing that no clinical studies have been performed on the efficacy, safety, or pharmacokinetics of any cardiovascular therapeutics in apes, so recommendations are based purely on experience with them in apes over the course of the GAHP studies, as well as hypothetical assumptions that apes would react in much the same way as humans do to these drugs. Attending veterinarians must use their best judgment when prescribing these drugs as “off-label” medications and should monitor animals very closely for any adverse side effects. Thromboembolism and cerebral infarcts have been documented in the great apes.21,46,47 In these cases, aspirin therapy has been recommended.21
Postmortem Cardiac Evaluations The pathology group of the GAHP has collected and reviewed available necropsy and histopathology reports from captive apes. All information collected is reviewed and entered into the GAHP database and is analyzed for antemortem clinical correlations, inter and intra-specific taxon trends, and disease classifications. Novel postmortem cardiac tissue collection and evaluation techniques for great ape necropsies have been developed, and these protocols have established a new “best practices” approach to ape heart evaluation that is more closely aligned with techniques used in human cardiac autopsies.48 These guidelines may be found at www.greatapeheartproject.org. Database inquiry coupled with simultaneous multipathologist review will allow the GAHP to establish more precise and
Acknowledgments The GAHP is supported by the Institute of Museum and Library Services (Grants LG-26-12-0526-12 and MG-30-15-0035-15) and Zoo Atlanta. We are grateful for the support and involvement of the Ape Taxon Advisory Group, the individual ape SSPs (veterinary, pathology, and nutrition advisors), the veterinary and medical cardiologists and sonographers who generously donate their time, and various staff at all participating institutions.
References
CHAPTER 82 Update on the Great Ape Heart Project
14. Kenny DE, Cambre RC, Alvarado TP, et al: Aortic dissection: an important cardiovascular disease in captive gorillas (Gorilla gorilla gorilla), J Zoo Wildl Med 25:561–568, 1994. 15. Doane CJ, Lee DR, Sleeper MM: Electrocardiogram abnormalities in captive chimpanzees (Pan troglodytes), Comp Med 56:512–518, 2006. 16. Yancy CW, Jessup M, Bozkurt B, et al: 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines, Circulation 128:1810–1852, 2013. 17. Grim CE, Highland MA, Beehler L, et al: Familial hypertension and stroke in bonobo chimpanzees (Pan paniscus). In Proceedings of the American Heart Association, Hypertension E127–E127, 2010. 18. Ely JJ, Zavaskis T, Lammey ML, et al: Blood pressure reference intervals for healthy adult chimpanzees (Pan troglodytes), J Med Primatol 40:171–180, 2011. 19. Ely JJ, Zavaskis T, Lammey ML: Hypertension increases with aging and obesity in chimpanzees (Pan troglodytes), Zoo Biol 32:79–87, 2013. 20. Popovich DG, Jenkins DJ, Kendall CW, et al: The western lowland gorilla diet has implications for the health of humans and other hominoids, J Nutr 127:2000–2005, 1997. 21. Nunamaker EA, Lee DR, Lammey ML: Chronic diseases in captive geriatric female chimpanzees (Pan troglodytes), Comp Med 62:131–136, 2012. 22. Seng CF, Meng GY, Abdullah R: A comparative study of blood lipids and stress levels between captive and semi-captive orangutans (Pongo pygmaeus) under tropical conditions. In Proceedings of the American Association of Zoo Veterinarians/American Association of Wildlife Veterinarians/American Zoo Association/ Nutrition Advisory Group Joint Conference, 2007. 23. Schmidt DA, Ellersieck MR, Cranfield MR, et al: Cholesterol values in free-ranging gorillas (Gorilla gorilla gorilla and Gorilla beringei) and Bornean orangutans (Pongo pygmaeus), J Zoo Wildl Med 37:292–300, 2006. 24. Baitchman EJ, Calle PP, Clippinger TL, et al: Preliminary evaluation of blood lipid profiles in captive western lowland gorillas (Gorilla gorilla gorilla), J Zoo Wildl Med 37:126–129, 2006. 25. Mente A, O’Donnell M, Rangarajan S, et al: Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: a pooled analysis of data from four studies, Lancet 388:465–475, 2016. 26. Denton D, Weisinger R, Mundy NI, et al: The effect of increased salt intake on blood pressure of chimpanzees, Nat Med 1:1009–1016, 1995. 27. Council NR, Studies DEL, Resources BAN, et al: Nutrient requirements of nonhuman primates, Revised ed 2, 2003, National Academies Press. 28. Lang RM, Badano LP, Mor-Avi V, et al: Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, J Am Soc Echocardiogr 28:1–39, 2015. 29. Shave R, Oxborough D, Somauroo J, et al: Echocardiographic assessment of cardiac structure and function in great apes: a practical guide, Int Zoo Yearb 48:218–233, 2014. 30. Sleeper MM, Drobatz K, Lee DR, et al: Echocardiographic parameters of clinically normal adult captive chimpanzees (Pan troglodytes), J Am Vet Med Assoc 244:956–960, 2014. 31. Lammey ML, Jackson R, Ely JJ, et al: Use of an implantable loop recorder in the investigation of arrhythmias in adult captive chimpanzees (Pan troglodytes), Comp Med 61:71–75, 2011.
587
32. Magden ER, Sleeper MM, Buchl SJ, et al: Use of an implantable loop recorder in a chimpanzee (Pan troglodytes) to monitor cardiac arrhythmias and assess the effects of acupuncture and laser therapy, Comp Med 66:52–58, 2016. 33. Duncan AE, Kutinsky I, Murray S, et al: Use of implantable loop recorders to monitor for cardiac disease in captive gorillas (Gorilla gorilla gorilla), Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014. 34. West G, Heard D, Caulkett N: Zoo animal and wildlife immobilization and anesthesia, ed 2, 2014, pp 573–584. 35. Adami C, Wenker C, Hoby S, et al: Evaluation of effectiveness, safety and reliability of intramuscular medetomidine-ketamine for captive great apes, Vet Rec 171:196, 2012. 36. Horne WA, Norton TM, Loomis MR: Cardiopulmonary effects of medetomidine-ketamine-isoflurane anesthesia in the gorilla (Gorilla gorilla) and chimpanzee (Pan troglodytes). In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1997, pp 140–142. 37. Talke P, Lobo E, Brown R: Systemically administered α2-agonist-induced peripheral vasoconstriction in humans, Anesthesiology 99:65–70, 2003. 38. Naples LM, Langan JN, Kearns KS: Comparison of the anesthetic effects of oral transmucosal versus injectable medetomidine in combination with tiletamine-zolazepam for immobilization of chimpanzees (Pan troglodytes), J Zoo Wildl Med 41:50–62, 2010. 39. Pypendop BH, Verstegen JP: Hemodynamic effects of medetomidine in the dog: a dose titration study, Vet Surg 27:612–622, 1998. 40. Napier JE, Kutinsky IB, Armstrong DL, et al: Evaluating echocardiogram and indirect blood pressure results in male western lowland gorillas (Gorilla gorilla gorilla) during three phases of an anesthetic protocol, J Zoo Wildl Med 44:875–881, 2013. 41. Lopez del Rio PR, Sanchez C, Stembridge M, et al: Comparison of indirect blood pressure values in chimpanzees (Pan troglodytes) anesthetized with two anesthetic protocols: tiletamine-zolazepam and titetamine-zolazepam-medetomidine. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014. 42. Raizada A, Bhandari S, Khan MA, et al: Brain type natriuretic peptide (BNP) - A marker of new millennium in diagnosis of congestive heart failure, Indian J Clin Biochem 22:4–9, 2007. 43. Ely JJ, Zavaskis T, Lammey ML, et al: Association of braintype natriuretic protein and cardiac troponin I with incipient cardiovascular disease in chimpanzees (Pan troglodytes), Comp Med 61:163–169, 2011. 44. Sharma S, Jackson PG, Makan J: Cardiac troponins, J Clin Pathol 57:1025–1026, 2004. 45. Ely JJ, Bishop MA, Lammey ML, et al: Use of biomarkers of collagen types I and III fibrosis metabolism to detect cardiovascular and renal disease in chimpanzees (Pan troglodytes), Comp Med 60:154–158, 2010. 46. Weisenberg E, Snook S, Letcher J: Sudden death in an obese orangutan with hypertensive heart disease and a history of stroke (abstract). Proceedings of the American Association of Zoo Veterinarians Annual Conference, 1991. 47. Trupkiewicz JG, McNamara TS, Weidenham KM, et al: Cerebral infarction associated with coarctation of the aorta in a lowland gorilla (Gorilla gorilla gorilla), J Zoo Wildl Med 26:123–131, 1995. 48. Terio KA, McManamon R, Ellis AE, et al: Best practices for the cardiac necropsy: tips for clinicians (and pathologists) performing ape necropsies. In Proceedings of the American Association of Zoo Veterinarians Annual Conference, 2014, pp 88–90.