Echocardiographic Reference Intervals with Allometric Scaling of 823 Clinically Healthy Rhesus Macaques (Macaca Mulatta)

Abstract

Background: Echocardiography is commonly used for assessing cardiac structure and function in various species including non-human primates. A few previous studies reported normal echocardiographic reference intervals of clinically healthy rhesus macaques under sedation. However, these studies were under-powered, and the techniques were not standardized. In addition, body weight, age, and sex matched reference intervals should be established as echocardiographic measurements are commonly influenced by these variables. The purpose of this study was to establish reference intervals for complete echocardiographic parameters based on a large cohort of clinically healthy rhesus macaques with wide ranges of weight and age distributions using allometric scaling. Results: A total of 823 rhesus macaques (ages 6 months to 31 years old; body weights 1.4 to 22.6 kg) were enrolled. Of these rhesus macaques, 421 were males and 402 were females. They were assessed with a complete echocardiographic examination including structural and functional evaluation under sedation with ketamine hydrochloride. The reference intervals of the key echocardiographic parameters were indexed to weight, age, and sex by calculating the coefficients of the allometric equation Y = aMb. On correlation matrix, body weight, age, sex, and heart rate were significantly correlated with various echocardiographic parameters and some of the parameters were strongly correlated with body weight and age. Multiple regression analysis was also performed to predict various echocardiographic parameters from heart rate, body weight, age and sex. Heart rate and body weight statistically significantly predicted various echocardiographic parameters. Valve regurgitation including tricuspid, aortic, pulmonic, and mitral regurgitations without other cardiac structural and functional abnormalities are common in clinically healthy rhesus macaques under ketamine sedation. Conclusions: In this study, the reference intervals of echocardiographic parameters were established by performing complete echocardiographic examinations on a large number of clinical healthy rhesus macaques. In addition, allometric scaling was performed based on their weight, and further indexed to age and sex. These allometrically scaled reference intervals can be used to accurately evaluate echocardiographic data in rhesus macaques and diagnose structural and functional evidence of cardiac disease.

Echocardiographic evaluation of cardiac function in cynomolgus monkeys over a wide age range

“…Electrophysiological assessments have suggested that cardiac functions are similar between humans and cynomolgus monkeys [2]. Only a few reports have described echocardiographic reference values for cynomolgus monkeys [18,29,32,36], and standardized echocardiographic reference values are incomplete, because those studies used small colonies and monkeys with a limited age range. However, echocardiography offers a graphic, real-time means of intravital imaging and has more potential for diagnosis than electrocardiography.…”

“…Nonhuman primates are optimal experimental animals because of their similarity to humans in terms of anatomy and physiology. In addition, their cardiovascular system resembles that of humans and their body size is appropriate for examinations; thus, experimental monkeys are necessary to develop cardiovascular medicines for humans [1,29,36]. In addition, general aging and growth patterns of monkeys, including cynomolgus monkeys (Macaca fascicularis) resemble those of humans, while the rate of aging in these monkeys is 3 times that in humans [26,37].…”

“…Although echocardiographic parameters in nonhuman primates have been investigated [18,29,32,34,36], these studies investigated small cohorts with limited age ranges and primate species other than cynomolgus monkeys. The pathophysiological background of CVD can be spontaneous, autoimmune, heritable and age-related.…”

“…Echocardiographic reference values do not appear to have been reported previously for elderly monkeys. We therefore analyzed echocardiographic data for a wide range of ages in monkeys, because agerelated CVDs are reportedly increased specifically in the elderly stage [33,36].…”

Echocardiographic reference intervals with allometric scaling of 823 clinically healthy rhesus macaques (Macaca mulatta)

“…A few previous studies reported normal echocardiographic reference ranges of clinically healthy rhesus macaques under sedation [ 1 , 2 ]. In addition, the authors of the present study reported echocardiographic reference intervals in geriatric rhesus macaques older than 18 years [ 3 ]. These studies reported that the reference intervals of various echocardiographic parameters in geriatric rhesus macaques are different from those in younger adult rhesus macaques.…”