Korean Journal of
Veterinary Service

Morphological studies of patent ductus arteriosus (PDA) have important implications for both diagnosis and treatment (Krichenko et al, 1989; McNamara and Sehgal, 2007). These analyses are critical for assessing the progression and risk level of PDA, guiding the selection of suitable treatment methods, and offering predictive insights into treatment outcomes (Krichenko et al, 1989). Furthermore, morphological research provides anatomical information necessary for surgical intervention and transcatheter occlusion (McNamara et al, 2007).

Studies of PDA in monkeys are rare, and no cases of solitary PDA in Japanese macaques have been reported thus far. PDA is a rare condition in monkeys and has been documented in only a few species, including rhesus macaques (Freigang and Knobil, 1967; Peterson et al, 1997), stump-tailed macaques (Jerome, 1987), cynomolgus macaques (Jerome, 1987), and African green monkeys (Jerome, 1987). A study of rhesus macaques identified only 1 case of PDA among 4,390 individuals, indicating a low incidence of PDA in this species (Peterson et al, 1997).

Here, we present the first report of solitary PDA in a monkey (Japanese macaque [Macaca fuscata]). Based on the morphological characteristics of the PDA, we attempted to estimate the hemodynamic status and cardiac function of the Japanese macaque.

This case study involved a 9-year-old male Japanese macaque that had resided in a zoo in Busan, Korea for exhibition purposes from 2015 to 2021. The macaque weighed 11 kg. The macaque was accommodated in an outdoor enclosure, thoughtfully equipped with vertical and horizontal structures to promote natural behaviors and welfare. A hot spring facility was also installed, reflecting their natural preferences. The diet included standard animal feed supplemented with various seasonal fruits and vegetables to meet their nutritional needs. Considering their social behavior, the macaque lived with a group of 15 others, providing essential social interactions.

The macaque became weak and fatigued despite regular food intake. Peripheral edema initially developed in the extremities before extending to the abdomen and rest of the body, constraining the animal’s mobility. The animal experienced significant weight loss, making the dorsal spinous processes along the spine easily palpable. At necropsy, chronic liver failure and cirrhosis were identified as the primary etiology. No lesions were observed in other organs such as the kidneys, spleen, lungs, and intestines, except the liver.

To investigate the branching pattern of the aortic arch in the Japanese macaque using a silicone cast, the cadaver was donated and transported to the Veterinary Anatomy Laboratory at Jeonbuk National University. Briefly, silicone (Cat. #LC909S, Wacker Chemicals, Ulsan, South Korea) was retrogradely injected into the abdominal aorta, cranial to the branching site of the celiac artery. During this process, we unexpectedly discovered a PDA connecting the descending aorta and pulmonary artery (PA) as the silicone entered the PA via the PDA.

Upon examination of the silicone cast, we identified an hourglass-shaped PDA linking the descending aorta and PA (Fig. 1). The PDA exhibited a central constriction and two ampullae: one connected to the aorta and the other to the PA. We measured the length and diameter of the blood vessels on the silicone cast with digital vernier calipers (Cat. #500-181-30, Mitutoyo, Kawasaki, Japan) to investigate the morphological characteristics of the PDA (Table 1).

Table 1 . Main morphometric parameters derived from vascular casting of the patent ductus arteriosus (PDA) and heart in the Japanese macaque.

Parameters		Values
Blood vessels parameters (mm)	Minimal diameter of PDA	6.7
	Total length of PDA	19.8
	Diameter of aorta	15.9
	Diameter of pulmonary artery	17.8
Cardiac parameters (mm)	Left ventricular marginal wall thickness	9.5
	Intraventricular septum thickness	6.1
	Internal luminal diameter of the left ventricle	15.1
	Right ventricular wall thickness	5.3
	Left atrial diameter	20.9
Diagnostic parameters	E:I ratio (left ventricular hypertrophy)	2.03
	PA:Ao ratio (pulmonary artery enlargement)	1.12
	LA:Ao ratio (left atrial hypertrophy)	1.31
	LVWT:RVWT ratio (right ventricular hypertrophy)	1.79

PDA, patent ductus arteriosus; E:I ratio, the ratio of the left ventricular external diameter to the internal luminal diameter; PA:Ao ratio, pulmonary artery diameter to aorta diameter ratio; LA:Ao ratio, left atrium to aortic root ratio; LVWT:RVWT ratio, the ratio of the left ventricular marginal wall thickness to the right ventricular wall thickness..

Figure 1. Vascular casting of the patent ductus arteriosus (PDA) in the Japanese macaque. (A) Ventrodorsal view. (B) Oblique dorsoventral view. The PDA displays an hourglass shape, with the pulmonary ampulla colored blue and the aortic ampulla colored red. Bidirectional arrows indicate (a) minimum diameter of the PDA, (b) total length of the PDA, (c) length of the aortic ampulla, and (d) length of the pulmonary ampulla. (C) Photograph of the aorta, pulmonary artery, and PDA, showing the vessels after removal of the vascular casting. (D) Photograph acquired with the same view as shown in Fig. 1C. Ao, aorta; AV, aortic valve; PA, pulmonary artery; PDA, patent ductus arteriosus; PV, pulmonary valve. (Scale bar: 10 mm).

We measured the morphological features of the PDA using the silicone cast. The minimum diameter of the PDA was 6.7 mm, with the pulmonary end measuring 16.4 mm and the aortic end measuring 15.0 mm. The length of the pulmonary ampulla from the pulmonary end to the constriction of the PDA was 8.1 mm. The length of the aortic ampulla from the aortic end to the constriction was 11.8 mm. The full length of the PDA from the pulmonary to aortic end was 19.8 mm.

To estimate how the PDA had influenced cardiac function and hemodynamic status (Reader et al, 2016; Kammerlander et al, 2017; Rishniw et al, 2019), we measured several morphological parameters of the heart and vessels, including the vessel diameters and heart wall thicknesses. The diameter of the aorta was 15.9 mm, and the diameter of the PA was 17.8 mm. The diameters of the right and left PA were 12.4 mm and 12.5 mm, respectively, below the bifurcation. The diameter of the aorta was measured immediately dorsal to the aortic valve (Rishniw et al, 2019), and the diameter of the PA was measured at the level of the bifurcation from the PA into the right and left PA (Kammerlander et al, 2017).

Dissection of the heart revealed that the marginal wall thickness of the left ventricle (LV) was 9.5 mm, the intraventricular septum thickness was 6.1 mm, and the internal luminal diameter of the LV was 15.1 mm. The external diameter of the LV was 30.7 mm (calculated by measurement of the above values) (Reader et al, 2016). The marginal wall thickness of the right ventricle (RV) was 5.3 mm. These measurements were obtained at the mid-ventricular level of the heart between the cardiac base and apex (Reader et al, 2016). The diameter of the left atrium (LA) on the transverse section immediately dorsal to the aortic valve (Rishniw et al, 2019) was 20.9 mm. We found no other congenital heart defects (Fig. 2).

Figure 2. Photograph of a longitudinal section of the heart of the Japanese macaque. Bidirectional arrows represent the measuring sites, indicating (a) right ventricular wall thickness, (b) intraventricular septum thickness, (c) internal luminal diameter of the left ventricle, and (d) marginal wall thickness of the left ventricle at the mid-ventricular level between the cardiac base and apex. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Scale bar: 10 mm).

Based on the obtained measurements, we calculated the values that reflected cardiovascular changes associated with the PDA status (Reader et al, 2016; Robinson and Robinson, 2016; Kammerlander et al, 2017; Rishniw et al, 2019). Generally, a large-diameter PDA leads to hemodynamic and cardiac functional changes due to the blood shunt from the aorta to the PA, including PA hypertension, LV hypertrophy, and LA enlargement (McNamara and Sehgal, 2007). In severe case, the PDA can lead to a reversal shunt from the PA to the aorta, which can result in RV hypertrophy. The ratio of the PA diameter to the aortic diameter (PA:Ao ratio) was 1.12, indicating PA hypertension (Kammerlander et al, 2017). The ratio of the external diameter to the internal luminal diameter of the LV (E:I ratio, equivalent to the O:I ratio) was 2.03 (Reader et al, 2016), not indicating LV hypertrophy. The LA to aortic root ratio (LA:Ao ratio) was 1.31, not indicating LA enlargement (Rishniw et al, 2019). The ratio of the LV marginal wall thickness to RV wall thickness (LVWT:RVWT ratio) was 1.79, indicating RV hypertrophy (Robinson and Robinson, 2016). In summary, the macaque exhibits PA hypertension and RV hypertrophy, while there are no pathological changes in the LV and LA.

Reports of PDA in monkeys are scarce, and only a few cases have been reported in various species. One study of PDA in monkeys revealed a low incidence, with only 1 case of PDA among 4,390 rhesus monkeys (Peterson et al, 1997). PDA in monkeys exists as a solitary condition or as a non-solitary condition combined with other congenital cardiovascular defects. Cases of solitary PDA have been reported only in rhesus monkeys (Freigang and Knobil, 1967) and stump-tailed monkeys (Jerome, 1987). Cases of non-solitary PDA have been observed in cynomolgus monkeys (Jerome, 1987), rhesus monkeys (Jerome, 1987), African green monkeys (Jerome, 1987), and Japanese macaques (Koie et al, 2007). Cases of PDA with arterial septal defects have been reported in cynomolgus and rhesus monkeys (Jerome, 1987), PDA with ventricular septal defects in cynomolgus and African green monkeys (Jerome, 1987), and PDA with tetralogy of Fallot in one Japanese macaque (Koie et al, 2007). In the present case, a solitary PDA without other congenital cardiovascular defects was identified in a Japanese macaque.

Krichenko et al (1989) established a classification system for PDA morphology based on angiography in humans. They identified five types of PDA (types A to E), each representing a different shape: conical, window, tubular, saccular, and elongated. In dogs, four types of PDA (types I, IIA, IIB, and III) have been identified, according to the degree and shape of ductal tapering of the aortic ampulla of the PDA (Miller et al, 2006). The PDA in our macaque exhibited an hourglass shape, inconsistent with existing morphologic classifications. With further accumulation of morphological data, PDA classification in various species of animals might become possible.

The ductal diameter is a key diagnostic factor in cases of PDA because it influences the volume of blood flow through the shunt (McNamara and Sehgal, 2007). In humans, a PDA diameter of ≥3.0 mm is considered large, and may lead to severe clinical symptoms such as pulmonary hypertension, systemic hypoperfusion, and intracranial hemorrhage (McNamara and Sehgal, 2007). In dogs, the experimental creation of an aortopulmonary shunt with a diameter of ≥5 mm was found to cause pulmonary hypertension and congestive heart failure (Robinson and Robinson, 2016). Large but untreated PDA can progress to right-to-left shunts, resulting in hypoxemia and cyanosis with a poor prognosis (Broaddus and Tilson, 2010). Considering these factors, the PDA diameter of 6.7 mm in this macaque likely contributed to the severe symptoms. The ductal size was considered large even after adjustment for the arterial flexibility associated with silicone injection pressure.

The combination of morphological findings with hemodynamic data may help to clarify the characteristics of PDA. Although cardiac function and hemodynamic data cannot be obtained from cadaver studies, we can estimate these parameters using morphological data from previous cadaveric and echocardiographic reports (Reader et al, 2016; Kammerlander et al, 2017; Rishniw et al, 2019). Due to the limited information on the normal measurements of the heart in Japanese macaques, we referred to the reference values from various animal species. Additionally, to offset differences due to species size, we used ratio-based reference values.

Kammerlander et al (2017) suggested using the PA:Ao ratio as an indicator of PA hypertension. They stated that a PA:Ao ratio of ≥1 generally implies PA hypertension. In a necropsy study of rhesus macaques, Reader et al (2016) proposed using an E:I ratio of >3.0 as a diagnostic marker for LV hypertrophy in the cadaver heart. The LA:Ao ratio serves as a diagnostic criterion for LA enlargement; it reflects the extent of volume overload and degree of pulmonary overflow (Rishniw et al, 2019). A ratio of >1.5 indicates moderate left heart volume loading, and a ratio of >2.0 indicates severe left heart volume loading. Generally, LV wall are normally 2∼4 times thicker than the RV wall in animals and the LVWT:RVWT ratio of <2.0 can indicate RV hypertrophy (Robinson and Robinson, 2016). The Japanese macaque in the present study displayed a PA:Ao ratio of 1.12, E:I ratio of 2.03, LA:Ao ratio of 1.31 and LVWT:RVWT ratio of 1.79. These findings suggest that the macaque had PA hypertension and RV hypertrophy without LV hypertrophy or LA enlargement.

We suspect that the limited mobility and sedentary lifestyle of monkeys in zoos may lead to undiagnosed cases of PDA. Monkeys in zoos are kept in isolation from other animal species and are raised without engagement in activities such as survival tasks or competition. In the environment with plentiful food available, individual competition among the monkeys was unnecessary. Additionally, since they were the only group housed in the enclosure, group competition was also not a factor. This lifestyle might prevent the development of PDA-induced hemodynamic changes, thus delaying the detection of PDA.

In summary, we conducted a morphological analysis to evaluate the condition of a Japanese macaque with PDA. The monkey had a large PDA diameter, the RV hypertrophy and a high risk of PA hypertension. However, these factors did not lead to observable pathologic changes in the LV or LA. To our knowledge, this report represents the first documented case of an isolated PDA in a Japanese macaque without other associated congenital cardiovascular anomalies.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT), Government of the Republic of Korea (Grant No. NRF-2019R1I1A3A01064272). We extend our sincere gratitude to the veterinarian who provided valuable information about the subject.

No potential conflict of interest relevant to this article was reported.