Primary Infundibular Stenosis and Pedigree Analysis in Three Golden Retriever Littermates
Three eight-week-old golden retriever puppy littermates were evaluated because of left basilar systolic murmurs and were diagnosed with primary infundibular stenosis. Pedigree analysis in this line was also performed to identify a mode of inheritance. All dogs were asymptomatic at the time of diagnosis; two of the three had congenital lesions in addition to primary infundibular stenosis. Two additional affected dogs were identified in the line, and pedigree analysis suggested an autosomal recessive mode of inheritance. Another, unrelated golden retriever was also identified with isolated infundibular stenosis in the record database. Primary infundibular stenosis should be considered in the differential diagnoses for golden retriever dogs with a left basilar systolic murmur, and is often associated with complex congenital cardiac disease. Primary infundibular stenosis may worsen in severity with time, and in this line of dogs an autosomal recessive pattern of inheritance is likely.
Introduction
Primary infundibular stenosis has been described in dogs, though it is a rare congenital defect. However, to the authors knowledge it has never been described in littermates, and a potential mode of inheritance has never been described. This case report highlights the disease in three littermates, and determines a suggested mode of inheritance after a pedigree analysis was performed.
Case Report
Three 8 wk old golden retriever littermates (two males, one female) weighing between 4.3 kg and 4.7 kg were referred to the Matthew J. Ryan Veterinary Hospital, University of Pennsylvania, PA, for previously ausculted heart murmurs. The puppies were otherwise in good health and had begun their vaccination series. Case 1 presented with a grade V/VI left basilar ejection quality murmur, normal jugular venous pulsations, and strong synchronous femoral arterial pulses bilaterally. Six-lead electrocardiography was consistent with a sinus tachycardia (heart rate was 180 beats/min), with a mean electrical axis of +100° (reference range, +40–+100°). Thoracic radiographs revealed marked right ventricular enlargement and moderate right atrial enlargement. Echocardiography revealed a fibromuscular ring in the right ventricular infundibulum, with moderate concentric hypertrophy proximal to the obstruction and normal myocardial thickness distal to the ring (Figures 1A, B). Continuous wave Doppler assessment revealed a velocity of 5.51 m/sec (calculated pressure gradient was 122 mm Hg) through the obstruction. Additional congenital lesions included a small perimembranous ventricular septal defect (with bidirectional shunting) and a thick, irregular tricuspid valve with moderate regurgitation noted with color Doppler. Moderate right atrial enlargement was also present.
Citation: Journal of the American Animal Hospital Association 48, 1; 10.5326/JAAHA-MS-5654
Case 2 presented with a grade IV/VI ejection quality, left and right basilar murmur. Jugular venous and femoral arterial pulse quality and intensity were within normal limits, and a moderate sternal deformity (pectus excavatum) was noted on physical examination. A six-lead electrocardiogram was performed and was within normal limits. Thoracic radiography confirmed the pectus excavatum and identified a leftward displacement of the cardiac silhouette and mild right ventricular enlargement. Two-dimensional echocardiography revealed a similar fibromuscular obstruction within the right ventricular infundibulum, with mild right ventricular hypertrophy proximally. Continuous wave Doppler revealed a velocity of 2.9 m/sec across the obstruction (33 mm Hg). A small left to right shunting perimembranous ventricular septal defect was also identified in this patient (Figure 2).
Citation: Journal of the American Animal Hospital Association 48, 1; 10.5326/JAAHA-MS-5654
The female littermate (case 3) presented with a grade V/VI ejection quality murmur at the left heart base and an otherwise normal physical examination. An electrocardiogram showed a sinus tachycardia (heart rate 170 beats/min) and a right axis deviation (mean electrical axis +110°). A mild pectus excavatum and mild right ventricular enlargement were demonstrated by thoracic radiography. Echocardiographically, moderate right ventricular concentric hypertrophy was noted proximal to a similar appearing right ventricular infundibular stenotic lesion (a calculated velocity of 3.5 m/sec and pressure gradient of 48 mm Hg was determined across the obstruction). No other congenital lesions were identified in this patient.
Several months later, at 8 mo of age, case 2 represented prior to anesthesia for castration. At this time, similar physical examination and electrocardiographic findings were noted; however, an echocardiogram showed more severe right ventricular concentric hypertrophy proximal to the obstruction and an increased flow velocity and pressure gradient across the obstruction (4.6 m/sec and 85 mm Hg, respectively). The previously identified small ventricular septal defect was not evident. A subaortic fibrous ring and mild aortic ouflow tract obstruction (velocity of 2.8 m/sec, pressure gradient of 31 mm Hg) was diagnosed.
Discussion
Primary infundibular stenosis can be divided into two anatomic subtypes. The first is caused by the presence of a fibromuscular obstruction within the right ventricular outflow tract and is termed infundibular pulmonic stenosis in humans.1–3 The second subtype, termed double chambered right ventricle is characterized by anomalous muscle bundles obstructing the right ventricular outflow tract and has been described as a separate condition from true infundibular pulmonic stenosis.1,4,6 The stenotic lesion, regardless of the subtype, functionally divides the right ventricle into inlet (high pressure) and outlet (low pressure) chambers, leading to hypertrophy of the chamber proximal to the obstruction.1,4
Primary infundibular stenosis is considered a rare congenital anomaly in veterinary medicine (as in human medicine), accounting for 0.5–2.0% of all congenital cardiac lesions in people.1–5,7–9 Infundibular pulmonic stenosis and double chambered right ventricle can be isolated lesions, but are often associated with concurrent congenital conditions, most commonly membranous ventricular septal defects (VSD).1,3,5,10,11 In fact, it has been postulated that the condition may be associated with a VSD early in life, and that older patients with isolated infundibular stenosis may have previously had a VSD that has spontaneously closed as noted in one of the cases presented here.1,12
Diagnosis is typically achieved through the use of two-dimensional echocardiography; however, transesophageal echocardiography may improve imaging quality of the infundibular region to better identify the regional anatomy and improve Doppler-derived systolic pressure gradients.1,5,7,11 Other potential diagnostic aids include cardiac catheterization, angiography, and magnetic resonance imaging, which may confirm the diagnosis and lessen the chance of misdiagnosis in difficult cases or those where poor echocardiographic image quality is of concern.1,5,7,13
Treatment in humans usually involves cardiopulmonary bypass and surgical resection of the anomalous muscle bundle or fibromuscular obstructive tissue with satisfactory results.10,14 Similar treatment has been reported in a small number of canine patients.4 Other described options in veterinary patients include balloon dilation (usually with unsatisfactory results) and surgical dilation without the need for cardiopulmonary bypass or inflow occlusion using a pediatric valve dilator.1,4,8 However, solid clinical evidence regarding the optimal treatment in animals is limited.
Although no breed predilection for infundibular stenosis has been confirmed, it has been suggested that Golden retrievers, Siberian huskies, and boxers seem to be over-represented.1,4 To the authors’ knowledge, this is the first time primary infundibular stenosis has been recognized in family of related Golden retrievers. Extended family studies revealed that two additional affected puppies had been previously diagnosed with primary infundibular stenosis echocardiographically at the Matthew J. Ryan Veterinary Hospital (Figure 3). One of those puppies was an offspring of the same mother as the puppies described here (dog 201) from a breeding with the great-grand sire (dog 40) of the reported puppies. That dog (40) was also the sire of the second puppy from a breeding to a different bitch (34), which was distantly related to the mother of the puppies reported here (dam 201) as dogs 78 and 79 are siblings. Pedigree analysis revealed that the parents of the puppies reported in this study share common ancestors of which the closest is the grandmother (dog 43), leading to inbreeding coefficients of 0.03 and 0.05 for each parent (25 and 201) and 0.08 for the puppies of this litter. The information provided by this pedigree suggests an autosomal recessive mode of inheritance of primary infundibular pulmonic stenosis in the Golden retriever. An additional unrelated Golden retriever was also identified echocardiographically with primary infundibular pulmonic stenosis at the Matthew J. Ryan Veterinary Hospital; however, the authors could not find a common ancestor to the family reported in this study and were therefore unable to include it in the pedigree analysis. Nonetheless, these findings are consistent with previous suggestions that this breed is predisposed to this anomaly and that the lesion is not isolated to this particular pedigree. It is possible that other affected puppies in this line were missed because not all had echocardiograms performed; however, all puppies with murmurs were evaluated by a cardiologist with routine screening echocardiograms.
Citation: Journal of the American Animal Hospital Association 48, 1; 10.5326/JAAHA-MS-5654
As mentioned previously, primary infundibular pulmonic stenosis is often associated with additional congenital abnormalities, consistent with the diagnosis of a complex congenital heart disease in two of the three littermates in this report. It is also noteworthy that Golden retrievers have a breed predilection and high relative risk for subaortic stenosis.15 Considering the location of the murmur and breed, primary infundibular stenosis may be easily confused for subaortic stenosis on the basis of physical examination and signalment, although echocardiographic analysis can easily differentiate the two and even identify patients with both conditions. In addition, there was an absence of significant right axis deviation on electrocardiography in the puppies described in this case report that would be expected to differentiate the two conditions. This report also underlies the importance of serially screening patients with primary infundibular stenosis because additional inherited abnormalities may develop and this disease may mature or worsen with age, which occurs with other congenital cardiac disease such as subaortic stenosis.16
Conclusion
Although primary infundibular stenosis is rare, it should be considered as a differential diagnosis in puppies with ejection quality murmurs, especially Golden retrievers. Based on a pedigree analysis, there appears to be an autosomal recessive inheritance pattern in Golden retrievers. In addition, careful screening of these patients for additional defects is warranted as they are often associated with complex congenital cardiac disease. Further studies are needed to help better predict the natural history of the disease and therapeutic options in dogs affected with the condition.
Two-dimensional echocardiogram from the right short axis view at the heart base from case 1. Notice the fibromuscular obstruction (arrow) in the right ventricular infundibulum and the concentric hypertrophy proximal to the obstruction (arrowhead). (B) Two-dimensional echocardiogram of the same patient from the right parasternal short axis projection at the heart base with color Doppler (arrow). Notice the turbulence beginning at the level of the infundibular obstruction. AO, aorta; LA, left atrium.
Two-dimensional echocardiogram from the right-sided short axis view at the heart base from case 2 taken during early diastole. Notice the small, left to right shunting ventricular septal defect (arrow) and the infundibular obstruction (arrowhead). LV, left ventricle; RV, right ventricle.
Extended pedigree of the three probands (arrows). The coefficients of inbreeding are provided below the dogs for which they were calculated. Dogs 78 and 79 are siblings. Circles represent females, squares represent males, diamonds indicate siblings of unknown sex, and filled symbols represent dogs affected with primary infundibular pulmonic stenosis.
Contributor Notes
J. Arndt's present affiliation is Advanced Critical Care of Los Angeles, Culver City, CA.
P. Werner's present affiliation is Children's Hospital of Philadelphia, Philadelphia, PA.
