Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats

Journal of Veterinary Cardiology (2015)

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Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats Donald P. Schrope, DVM Oradell Animal Hospital, 580 Winters Ave., Paramus, NJ 07652, USA Received 16 June 2014; received in revised form 16 February 2015; accepted 21 June 2015

KEYWORDS Feline; Canine; Cardiac; Congenital; Innocent murmur

Abstract Objective: Assess the prevalence of congenital heart disease (CHD) in a large population of mixed-breed dogs and cats. Animals: 76,301 mixed-breed dogs and 57,025 mixed-breed cats. Methods: Retrospective review of records and examinations based on specified diagnostic criteria. Results: Among mixed-breed dogs, the prevalence of CHD was 0.13% (51.4% female) and of innocent murmurs was 0.10% (53.0% male). Pulmonic stenosis was the most common defect followed by patent ductus arteriosus, aortic stenosis, and ventricular septal defect. Among mixed-breed cats, prevalence of CHD was 0.14% (55.2% male) and of innocent murmurs was 0.16% (54.4% male). When the 25 cats with dynamic left or right ventricular outflow obstruction were counted with cases of innocent murmurs, the overall prevalence was 0.2%. Ventricular septal defects were the most common feline CHD followed closely by aortic stenosis and hypertrophic obstructive cardiomyopathy. There was no overall sex predilection for CHD in mixed-breed cats or dogs, and no significant difference in CHD prevalence between cats or dogs. Among dogs, subvalvular aortic stenosis and mitral valve dysplasia had a male predisposition while patent ductus arteriosus had a female predisposition. Among cats, valvular pulmonic stenosis, subvalvular and valvular aortic stenosis, and ventricular septal defects had a male predisposition while pulmonary artery stenosis had a female predisposition. Conclusions: The prevalence of CHD in a mixed-breed dogs and cats is lower than for prior studies, perhaps due to the lack of purebreds in the study population or actual changes in disease prevalence. ª 2015 Elsevier B.V. All rights reserved.

E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jvc.2015.06.001 1760-2734/ª 2015 Elsevier B.V. All rights reserved.

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

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D.P. Schrope Abbreviations AS ASD AVSD DCM DCRV dLVOTO dRVOTO DORV HCM HOCM MVD PAS PDA PIS PPDH PS SAM SAS TA TOF TVD VSD

aortic stenosis atrial septal defect atrioventricular septal defect dilated cardiomyopathy double chamber right ventricle dynamic left ventricular outflow tract obstruction dynamic right ventricular outflow tract obstruction double outlet right ventricle hypertrophic cardiomyopathy hypertrophic obstructive cardiomyopathy mitral valve dysplasia pulmonary arterial stenosis patent ductus arteriosus primary infundibular stenosis pericardial-peritoneal diaphragmatic hernia pulmonic stenosis systolic anterior motion of the mitral valve subaortic stenosis truncus arteriosus tetralogy of Fallot tricuspid valve dysplasia ventricular septal defect

Introduction The prevalence of congenital heart disease (CHD) among cats and dogs has been well documented in the literature.1e9 However, obtaining an ideal or representative study population is challenging and has resulted in some limitations to available studies. Study samples obtained through a university or large referral hospital can be artificially skewed towards a higher prevalence of CHD due to referral. Study populations based on voluntary databases depend on participation and the data might not reflect the underlying population of interest. In both situations, the samples studied are often a mixture of purebred and mixed-breed animals. Purebred representation likely varies among studies and can contribute both to the reported prevalence of disease as well as the distribution of types of CHD. In the author’s opinion, the ideal population sample for evaluating the prevalence of CHD would be obtained through a large general practice, animal shelter, or both as these would likely be a better reflection of the general veterinary population as a whole. A population composed completely of mixed-breed animals might also reduce or eliminate skewing related to purebreds. Such data could then be used as a comparator to assess risk for a specific CHD within each specific breed. It is also possible,

based on a review of older studies of CHD, that the prevalence of specific cardiac malformations is changing. This would be another benefit in reassessing the prevalence of CHD. Lastly, innocent murmurs can make the auscultatory diagnosis of CHD challenging. Understanding the prevalence of innocent murmurs, including those generated by isolated dynamic right ventricular outflow tract obstruction (dRVOTO) and dynamic left ventricular outflow tract obstruction (dLVOTO), in a large population of dogs and cats would be helpful. The purpose of this study therefore was to assess the prevalence and types of CHD as well as the prevalence of innocent murmurs among a large population of mixed-breed dogs and cats seen through a large shelter. It was hypothesized that the prevalence among the mixed-breed population would be lower than that in previous studies that included purebred animals.

Animals, materials and methods Between the years of 1997 and 2003 the signalment of all dogs and cats examined in a large nokill shelter was reviewed. This period of time was used due to availability of records and because during that interval the author was the only

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

Prevalence of congenital heart disease cardiologist consulted by the shelter. This situation allowed for consistency in diagnoses. All animals were identified as purebred or mixed-breed at the time of entry into the shelter by the shelter staff (veterinarians and technical staff). All dogs and cats with evidence of cardiac disease based on examination by shelter veterinarians were subsequently evaluated by the author. In most cases, cardiac evaluation was sought following the identification of a heart murmur, gallop sound, arrhythmia, cardiomegaly on radiographs, or clinical signs consistent with heart disease. Only patients evaluated specifically for cardiac disease had an echocardiogram performed. The breed, age, and sex of each animal were reviewed and those identified as purebred were removed from the study population. Echocardiograms were performed on all patients with suspected cardiac disease, including those with a murmur whether the suspected etiology was functional (innocent) or pathological. Other diagnostic tests including radiographs and electrocardiograms were performed as indicated. All echocardiograms were reviewed retrospectively by the author to ensure consistency of the diagnosis. Patients were included in the study and classified with CHD if they fit one of the two criteria. First, if a cardiac defect that is known to be congenital in origin was identified [e.g. atrial septal defect (ASD), ventricular septal defect (VSD), or patent ductus arteriosus (PDA)] the patient was included. Second, in the case of diseases that could potentially be congenital in origin or acquired later in life (e.g. mitral valve disease, cardiomyopathy, or ventricular arrhythmia) the disorder had to be diagnosed no later than 10 weeks of age. Due to some inconsistencies among previous studies regarding the definition of various CHDs, specific criteria were used for disease classification in the present study. Anatomic locations of pulmonic stenosis (PS), aortic stenosis (AS), VSD, and ASD were recorded. Ventricular septal defects were classified as muscular, membranous, or outlet (subarterial) defects. An inflow VSD was classified as a partial atrioventricular septal defect (AVSD) as discussed below.10 Atrial septal defects were classified as secundum or sinus venosus defects. Patients with a primum atrial septal defect were classified as a partial AVSD as discussed below.10 Pulmonic and aortic stenoses were classified as subvalvular, valvular, or supravalvular. The classification of subvalvular or supravalvular was used if the stenosis was immediately above or below the valve but subjectively still associated with the valve apparatus. In contrast, a stenosis above the pulmonic valve apparatus within the

3 main pulmonary artery was classified as pulmonary artery stenosis (PAS).11 A discrete fixed stenosis below the pulmonic valve apparatus within the infundibulum was classified as primary infundibular stenosis (PIS).12 The term double chamber right ventricle (DCRV) was only used if the infundibulum was obstructed by hypertrophied muscle bundles as previously reported.12 Echocardiographic diagnosis of tetralogy of Fallot (ToF) was made if PS (valvular, subvalvular, or both) was identified along with a malalignment VSD resulting in (subjectively) at least 50% commitment of the aorta to the right ventricle. Echocardiographic diagnosis of double outlet right ventricle (DORV) was made if a malalignment VSD was present with complete commitment of the aorta to the right ventricle and a lack of fibrous continuity between the anterior mitral valve and the aortic valve. Presumptive diagnosis of truncus arteriosus (TA) was made if a malalignment VSD was present with enlargement and dextropositioning of the aorta as well as apparent complete agenesis of the right ventricular outflow tract as determined by twodimensional echocardiography. All cases of TA were confirmed at necropsy. As previously described, AVSDs were classified as partial or complete.10 An AVSD with both atrial and ventricular communications was classified as a complete AVSD. An AVSD with only atrial communication (primum ASD) was classified as a partial AVSD with atrial communication and an AVSD with only ventricular communication (inflow VSD) was classified as a partial AVSD with ventricular communication. This classification scheme is an older approach that is independent of atrioventricular valve morphology but might be more useful clinically in cats. Patients with PS or AS were graded as mild (peak systolic gradient <50 mmHg), moderate (50e80 mmHg), or severe (>80 mmHg) based on the maximal Doppler-echocardiographic gradient as calculated from the simplified Bernoulli equation. Patients with valvular PS were further classified as narrow or wide annulus based on a pulmonary valve annulus to aortic valve annulus ratio. An aortic-to-pulmonary artery ratio >1.2 was considered a narrow annulus.13 Effective orifice area was not routinely calculated for patients with PS or AS. In patients with PAS the stenosis severity was assessed using peak gradient as well as diastolic flow patterns as previously described.11 The diagnosis of subaortic stenosis (SAS) was only made if a discrete fibrous or fibromuscular shelf was subjectively identified on twodimensional echocardiography. Alternatively,

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

4 when a bulging of the basilar septum was present that appeared to be purely muscular in nature, a diagnosis of hypertrophic cardiomyopathy (HCM) or hypertrophic obstructive cardiomyopathy (HOCM) was made. Ventricular septal defects were graded as small, moderate, or large. The defect was considered small if it was difficult to confirm on twodimensional echocardiography or could only be identified with color flow Doppler imaging. The defect was consider moderate if it was clearly visible but <50% the diameter of the aortic annulus in systole (long axis) and large if
50% of this diameter.14 A PDA was diagnosed and confirmed using twodimensional and Doppler echocardiography. A reverse PDA was initially identified on echocardiography and saline contrast echocardiography, then confirmed at necropsy. A pericardial-peritoneal diaphragmatic hernia (PPDH) was diagnosed based on radiographs and echocardiography. Situs inversus was diagnosed based on ventraledorsal thoracic radiographs and confirmed with echocardiography. The prevalence of innocent murmurs was also estimated in the population. A murmur was considered functional or innocent when associated with a normal echocardiogram with Doppler study. Further diagnostics such as hematology and clinical chemistries were not always performed or recorded in those patients with innocent murmurs. In general, these patients were asymptomatic. Feline HCM was considered as congenital in origin if the disorder was present in a cat 10 weeks of age (see Discussion for details). Diagnostic criteria for HCM were left ventricular septal or freewall thickness
6.0 mm in diastole independent of weight and age in an otherwise-healthy and normovolemic cat. The term HCM was used in the absence of systolic anterior motion of the mitral valve (SAM). Patients with HCM and dLVOTO were classified as HOCM. Dynamic left ventricular outflow tract obstruction was defined by the presence of SAM on two-dimensional or M-mode echocardiography, an elevated peak left ventricular outflow tract velocity (>2.0 m/s), and evidence of dynamic obstruction on the spectral Doppler envelope. Patients with outflow obstruction due to an apparent fixed subvalvular muscular obstruction were also classified as HOCM and patients with a discrete subvalvular fibrous shelf were classified as SAS. If a patient could not be classified as one or the other, it was removed from the study database. Mitral or tricuspid valve dysplasia was diagnosed if the patient was 10 weeks of age and there was

D.P. Schrope valvular regurgitation subjectively graded as mild or greater along with evidence of dysplasia of the valve on two-dimensional imaging. The latter abnormalities could include thickening of the leaflets, shortened or thickened chordae tendineae, or insertion of the papillary muscles directly to the valve leaflets. Trace regurgitation was not diagnosed as valve dysplasia. If a patient had morphologic changes of the mitral valve but also had SAM, the case was defined as having isolated dLVOTO. This approach was taken due to the inability to easily differentiate mitral valve dysplasia (MVD) with secondary SAM and SAM with secondary thickening of the mitral valve. Although generally considered normal variation, the presence of isolated dLVOTO or isolated dRVOTO was reported in this study.15,16 Dynamic right ventricular outflow tract obstruction was diagnosed if the following criteria were fulfilled; Doppler peak velocity across the infundibular region of >1.5 m/s with spectral evidence of dynamic obstruction; two-dimensional evidence of systolic obliteration of the outflow tract; and color flow Doppler turbulence in the infundibular region with no evidence of a fixed obstructive lesion in the infundibulum. Isolated dLVOTO was defined as described above. In this study, an isolated ventricular arrhythmia was considered congenital if identified in a patient 10 weeks of age and if a ventricular premature complex was present at least once every 10 beats. Supraventricular tachycardia was considered congenital in a young patient (<1 year of age) if sustained runs of supraventricular tachycardia were identified that initiated or terminated abruptly. The percentages of male and female dogs and of male and female cats affected with a specific congenital heart defect were compared within species using a Chi-square analysis for the comparison of two independent samples. Yates’ correction for continuity was applied.a Owing to the small number affected with certain defects, statistical comparisons were only made when the number of affected animals numbered five or more for that malformation (see Tables 1 and 2). Statistical significance was set at p <0.05. Other categorical data was analyzed using a Chi-square (goodness of fit) test after expected values were generated.b Results were reported as p-values with a value <0.05 considered statistically significant.

MedCalc for Windows, version 13.12.0, Ostend, Belgium. Microsoft Excel for Mac 2011, Microsoft Corporation, Redmond, WA, USA. a

b

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

Prevalence of congenital heart disease

5

Table 1 Sex distribution of canine congenital heart disease. The frequency of each defect is shown with the male and female percentages. Chi-square analysis was performed on those diagnoses with sufficient numbers. The p-values are shown. Not assessed ¼ N/A. Pulmonic Stenosis, Valvular Aortic Stenosis, Subvalvular Atrial Septal Defect, Secundum Ventricular Septal Defect, Membranous Tetralogy of Fallot Patent Ductus Arteriosus Reverse Patent Ductus Arteriosus Dilated Cardiomyopathy Mitral Valve Dysplasia Tricuspid Valve Dysplasia Situs Inversus Dilated Coronary Sinus Ventricular arrhythmias Supraventricular arrhythmias

N ¼ 105

Male%

Female%

p-Value

33 16 2 15 1 18 1 2 8 2 2 1 2 2

45 69 50 53 100 17 0 100 63 50 50 100 100 0

55 31 50 47 0 83 100 0 37 50 50 0 0 100

0.0520 <0.0001 N/A 0.2488 N/A <0.0001 N/A N/A <0.0001 N/A N/A N/A N/A N/A

predisposition for CHD in dogs (p ¼ 0.597) or cats (p ¼ 0.120).

Results Results summarized below are presented by species and presented in Figures 1 and 2 and in Tables 1 and 2. There was no significant difference between the prevalence of CHD in cats and dogs (p ¼ 0.300). There was no overall sex

Canine cases The records from 80,186 dogs were reviewed of which 46.1% were male and 53.9% were female.

Table 2 Sex distribution of feline congenital heart disease. The frequency of each defect is shown with the male and female percentages. Chi-square analysis was performed on those diagnoses with sufficient numbers. The p-values are shown. Not assessed ¼ N/A. Pulmonic Stenosis, Valvular Infundibular Stenosis Pulmonary Artery Stenosis Aortic Stenosis  Subvalvular  Valvular  Supravalvular Atrial Septal Defect, Secundum Ventricular Septal Defect, Membranous Atrioventricular Septal Defect  Partial, atrial communication  Partial, ventricular communication Conotruncal Defect  Tetralogy of Fallot  Truncus Arteriosus  Double Outlet Right Ventricle Patent Ductus Arteriosus Dilated Cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic Obstructive Cardiomyopathy Mitral Valve Dysplasia Tricuspid Valve Dysplasia Pericardial-peritoneal Diaphragmatic Hernia Caudal vena caval aneurysm Ventricular arrhythmias

N ¼ 87

Male%

Female%

p-Value

7 4 5

71 50 40

29 50 60

<0.0001 N/A 0.0009

8 7 1 3 18

75 71 0 67 67

25 29 100 33 33

<0.0001 <0.0001 N/A N/A <0.0001

2 4

100 50

0 50

N/A N/A

3 2 1 4 1 1 4 3 4 3 1 1

67 0 0 25 100 100 50 100 0 0 0 100

33 100 100 75 0 0 50 0 100 100 100 0

N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

6

Figure 1 Distribution of canine congenital heart disease. Types of congenital heart disease with only one patient were grouped together under the category “other” and included single cases of tetralogy of Fallot, reverse patent ductus arteriosus, and dilated coronary sinus. PS, valve ¼ valvular pulmonic stenosis; AS, subvalv ¼ subvalvular aortic stenosis; Vent Arrhyth ¼ ventricular arrhythmia.

Among this population 76,301 were classified as mixed-breed (95.1%). Ninety-eight mixed-breed dogs were identified with CHD resulting in a calculated prevalence of 0.13%. Eight of the 97 dogs had multiple cardiac lesions with a total of 105 congenital heart defects identified. The distribution of the types of defects is presented in Figure 1. Of the dogs with CHD 48.6% were male and 51.4% were female. Sex distribution for each

Figure 2 Distribution of feline congenital heart disease. Types of congenital heart disease with only one patient were grouped together under the category “other” and included single cases of supravalvular aortic stenosis, dilated caudal vena cava, double outlet right ventricle, dilated cardiomyopathy, hypertrophic cardiomyopathy, and ventricular arrhythmias. PS, valve ¼ valvular pulmonic stenosis; AS, sub ¼ subvalvular aortic stenosis; AS, valve ¼ valvular aortic stenosis.

D.P. Schrope identified defect is recorded in Table 1. Of the dogs with multiple CHD lesions only the combination of SAS and valvular PS was seen more than once. This combination occurred in two dogs. All 33 dogs with PS had valvular stenosis. Twenty-four of these were diagnosed with a normal annulus (11 had mild, four had moderate, and nine had severe PS). Nine of the 33 had a narrow annulus (two had mild and seven had severe PS). All 16 dogs with AS had subvalvular obstructions (16 mild, three moderate, and six severe). Atrioventricular valve dysplasia was diagnosed in 10 dogs; 8 of which had MVD and 2 had tricuspid valve dysplasia (TVD). The average age of the dogs diagnosed with MVD was 9.8 weeks old. Of the canine patients with ASD all were diagnosed as secundum type, while all 15 cases of VSD were membranous in location (14 were classified as small and one as moderate). A PDA was diagnosed in 18 dogs and a reverse PDA in one. Only one dog had a conotruncal septal defect, which was classified as TOF. One dog was diagnosed with a markedly dilated coronary sinus consistent with a persistent left cranial vena cava; angiography or an echocardiographic contrast study was not performed to confirm the lesion (a VSD prompted cardiac evaluation in this case). Two mixed-breed dogs were identified with situs inversus, but normal abdominal organ orientation on abdominal radiographs. Both cases were initially recognized from thoracic radiographs and had radiographic and clinical evidence of pneumonia. Other than inverted orientation of the heart in the chest, the echocardiograms were normal. Five dogs were diagnosed with significant arrhythmias believed to be congenital in origin. Three had ventricular arrhythmias and two had supraventricular tachycardia. The average age of the dogs diagnosed with ventricular arrhythmias was 7 weeks old. Perinatal myocarditis could not be excluded as an underlying cause in these cases. The sex distribution was assessed in those lesions with sufficient numbers of cases. A male predisposition was found with canine AS (p < 0.0001) and MVD (p < 0.0001). A female predisposition was found with PDA (p < 0.0001). A female predisposition was suggested in dogs with PS but this did not reach statistical significance as defined (p ¼ 0.052).

Feline cases The data from 57,418 feline cases were reviewed of which 49.4% of the cats were male and 50.6%

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

Prevalence of congenital heart disease female. Among this population, 57,025 (99.3%) were classified as mixed-breed. Seventy-nine mixed-breed cats were identified with CHD yielding a prevalence of 0.14%. Eight of the 79 cases had multiple cardiac lesions with a total of 87 congenital heart defects identified. The distribution of the types of defects is presented in Figure 2. Of the cats with CHD, 55.2% were male and 44.8% were female. Sex distribution for each identified defect is recorded in Table 2. If cats diagnosed with HCM or HOCM were removed from the database, the prevalence of CHD remained the same at 0.14%. Of the cats with multiple CHD lesions only the combination of AS and a VSD (n ¼ 3) was seen more than once; two cats with valvular AS and one with SAS. All 7 cats identified with PS had valvular stenosis with three diagnosed with a normal annulus (one had mild and two had severe stenosis). Four of the seven cases had a narrow annulus (one had moderate stenosis and three had severe stenosis). Four cats were diagnosed with PIS (one had mild, two had moderate, and one had severe stenosis). Five cats were diagnosed with PAS (four had mild to moderate and one had severe stenosis). Sixteen cats were identified with AS. Seven had valvular stenosis (three had mild and four had moderate stenosis), one had supravalvular stenosis (severe stenosis) and eight had subvalvular stenosis. Among the eight, five were felt to have an accurate echocardiographic gradient based on alignment to flow; one had mild, one had moderate, and three had severe stenosis. Two had concurrent SAM at the time of assessment making severity assessment difficult. These two cases had distinctive subvalvular ridges that were not believed to represent a contact plaque (kissing lesion). The other three cases had a high intensity murmur, subjective two-dimensional evidence of moderate to severe narrowing of the subaortic area, and a peak outflow velocity of at least 4 m/s and were therefore assessed as at least moderate to severe SAS. Atrioventricular valve dysplasia was identified in seven cats; three had MVD and four had TVD. The average age of cats diagnosed with MVD was 7 weeks. Of the three cats with an ASD all were diagnosed as secundum in location. All 18 cats diagnosed with a VSD had a membranous lesion (twelve had small, four had moderate, and two had large diameter defects). Six cats were diagnosed with an AVSD. All had partial defects. No complete AVSDs were diagnosed. Of the six with partial AVSD, two had only atrial and four had only ventricular communications. A PDA was diagnosed in four cats while conotruncal septal defects were diagnosed in six

7 cases (three had TOF, two had TA, and 1 had DORV). A total of 6 cats were diagnosed with a likely congenital cardiomyopathy based on the young age at recognition (one had DCM, one had HCM, and four had HOCM). The one cat with HCM had severe biventricular hypertrophy and was diagnosed at 10 weeks of age. The average age of the cats diagnosed with HOCM was 9.5 weeks old and ranged from 8 to 10 weeks. Myocarditis could not be excluded as a cause of DCM in the one kitten. One cat was diagnosed with a congenital ventricular arrhythmia. A PPDH was diagnosed in 3 cats. One cat had a marked, focal aneurysmal dilation of the caudal vena cava, which was initially identified on radiographs. Echocardiographic and angiographic evaluation showed no evidence of obstruction. The sex distribution was assessed in those lesions with sufficient numbers of cases. A male predisposition was found with feline PS (p < 0.0001), valvular AS (p < 0.0001), and SAS (p < 0.0001) as well as VSD (p < 0.0001). A female predisposition was found with PAS (p < 0.0009).

Non-pathologic murmurs Seventy-four of the 76,301 mixed-breed dogs were identified with an innocent murmur giving a prevalence of 0.10%. Of the 74, 39 (52.7%) were male and 35 (47.3%) were female. Among the dogs with an innocent murmur that had the murmur intensity recorded none had an intensity of IV/VI or greater, 9% had a murmur intensity of III/VI, and the remaining 91% had a murmur intensity of IeII/VI. Ninety-two of the 57,025 mixed-breed cats were identified with an innocent murmur with a prevalence of 0.16%. Of the 92, 50 (54.4%) were male and 42 (45.6%) were female. Among the cats with an innocent murmur that had the intensity recorded none had an intensity of IV/VI or greater, 5% had a murmur intensity of III/VI, and the remaining 95% had a murmur intensity IeII/VI. Twenty-five cats had isolated dynamic outflow obstruction without evidence of concurrent cardiomyopathy or other CHD. Thirteen had dLVOTO (7 male and 6 female) and 12 had dRVOTO (7 male and 5 female) with two cats having both. Of the 13 with dLVOTO, five were subjectively assessed as having significant thickening of the mitral valve suggesting possible MVD. All of these cats appeared clinically normal but further diagnostics such as a blood pressure, thyroid level, or clinical laboratory tests were not consistently performed

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

8 at the shelter. If the cats with innocent murmurs were combined with those with isolated dLVOTO and dRVOTO, the prevalence of “non-pathologic murmurs” was 0.20%. In comparison, a single male dog was identified with isolated dLVOTO at 1.5 months of age and the obstruction resolved as the animal matured.

Discussion The study population used in the present analysis is unique in the literature of CHD population studies. It is minimally biased when compared to a hospital population that might be heavily biased by patients with medical concerns or referred for specific cardiac evaluation. Additionally, it also an extremely large sample lending strength to the conclusions made about the general population of non-purebred dogs and cats. Conversely, the dogs and cats included in this study are probably less well-defined than those observed at a typical veterinary hospital, meaning that the details of each animal (breed, sex, age, clinical presentation) may not always be as well characterized. It is also somewhat unrepresentative considering purebred dogs are excluded, but this feature should also provide useful comparative data for other investigations of specific breed predilections to CHD. In previous studies, the prevalence of CHD in dogs (purebred combined with mixed-breed) ranged from 0.5 to 1.0%.1e4,9 Most studies estimated prevalence at <0.6%. The prevalence in the current study of mixed-breed dogs (0.13%) is dramatically lower than most previous studies, suggesting either a decrease in the prevalence of CHD in dogs or the effects of bias when including purebred dogs and cases from mostly referral (and university) hospitals in the samples. The samples used in the previously-referenced studies included a very high prevalence (67.1%e87.5%) of purebred dogs supporting the latter assertion.1e3 This is also supported by one study finding a significantly greater prevalence of CHD in purebred (0.89%) vs. mixed-breed (0.26%) dogs.2 Studies of CHD in cats are less available, but estimates of prevalence have ranged from 0.02% to 0.10%.6,7 Prevalence in this study was higher at 0.14%. The higher prevalence in cats in the current study might suggest a true increase in prevalence of CHD, but it is also possible that with current imaging technologies our ability to identify CHD in very small animals has improved. It is also possible that earlier recognition of heart murmurs with opportunity for referral prior to

D.P. Schrope death has facilitated the diagnosis of CHD in this species. Furthermore, of the feline studies previously-referenced, none include cases of congenital cardiomyopathy, which might suggest the disease has been overlooked. The occurrence of congenital HCM (or HOCM), present at birth in cats is largely undocumented although it has been recognized in human infants.17,18 Accordingly, these very young cats were included as possible congenital cases, accepting that we have limited knowledge about congenital cardiomyopathy in kittens. In addition, the differentiation of HOCM and SAS can be difficult, even in mature cats and dogs, as there is considerable phenotypic crossover on echocardiography. As previously described, patients with a fibrous or fibromuscular basilar ridge were defined as SAS whereas cats with a muscular subvalvular ridge were defined as HOCM. Until we have genetic tests available to better distinguish these conditions some ambiguity will persist. Therefore very young cats with HOCM were included. It is possible that the criteria used to define HCM or HOCM as congenital might be considered a contributing factor to the higher prevalence of feline CHD, although due to the large number of animals studied the prevalence of CHD was unchanged by the inclusion of HCM and HOCM. It is of interest that when compared to older studies, the prevalence of CHD was lower in mixed-breed dogs but higher in mixed-breed cats. Purebred dogs seem much more common in the overall pet population compared to purebred cats; therefore, their exclusion would likely have a greater impact on the prevalence in dogs. In humans the prevalence of CHD also varies from study to study with reports ranging from 0.24% to 2.66%.19e23 Most human studies report a prevalence of around 0.8%. The higher prevalence of CHD in humans might relate to a more effective identification rate due to prenatal and neonatal diagnosis. Early recognition of life-threatening CHD in infants in developed countries is typical, but would be less likely in companion animals leading to perinatal death of a kitten or puppy prior to diagnosis. In addition, many human studies of CHD include common but often trivial defects such as nonstenotic, bicuspid aortic valve. Some of these conditions might not be readily apparent in the veterinary population. In all previous studies of CHD prevalence in dogs, the three most common types of CHD were PS, AS, and PDA,1e4,8,9,24 with PDA most common in the majority of surveys. In the current study of mixed-breed dogs, PS was found to be most common with PDA, AS, and VSD having similar but

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

Prevalence of congenital heart disease lower prevalence. These might represent differences in the population sample relative to other studies. In all but one of the previously-referenced studies, VSD was among the five most common CHD, which is similar to the current study. A persistent right aortic arch was commonly described in some of the manuscripts but not seen in the current population. Since the majority of the patient in this study were diagnosed via echocardiography it is possible that a persistent right aortic arch could have been missed if asymptomatic, although clinical signs would be expected. Some of the previous studies do identify a small number of dogs with MVD and TVD. This study may show a slightly higher prevalence of atrioventricular valve malformations. Unfortunately assessment of these lesions is most always subjective lending to differing diagnostic criteria and interpretations. The author attempted to employ relatively strict diagnostic criteria and may have underestimated the prevalence. Situs inversus is a rare CHD in the dog.24 To the author’s knowledge it has only been documented in a mixed-breed dog once previously.25 In both cases in this study the presence of concurrent pneumonia would support ciliary dyskinesis as the underlying etiology although other causes cannot be ruled out. In the majority of the previous studies evaluating the prevalence of CHD in cats, MVD and TVD were the most common defects identified followed by AS and VSD.4e6,9 In the current study the prevalence of MVD and TVD was high, but AS, VSD, and HOCM were slightly more common. Endocardial fibroelastosis was identified in cats in previous reports, but not in the present study, probably from exclusion of purebred cats,26,27 a decrease in disease prevalence, or difficulty in identification without post-mortem evaluation. In humans VSD, ASD, and PDA are the most commonly identified CHD with PS usually within the top four identified defects.19e23 It appears that humans could have more in common with dogs as far as distribution of CHD types. Sex distribution in dogs is generally equal when looking at all cases of CHD although a slight male predisposition has also been reported.24 Most previous studies identify a female predisposition for PDA,1e3,8,9 while multiple studies focusing on AS support a male predisposition.24,28 The sex distribution for PS is fairly balanced in most studies quoted, although a male predisposition has been uncommonly reported.28 Similar findings were seen in the current study. Sex distribution of CHD in cats is not as well described and somewhat more inconsistent. Some

9 studies suggested an increased prevalence in males with MVD, TVD, AS, or endocardial fibroelastosis.4,6 Another study suggested a lack of sex predilection in cats with CHD overall, but a possible female predisposition for endocardial fibroelastosis and TOF.7 In the current study, no overall sex predilection was evident. Similar to other studies a male predisposition was seen with AS but other predispositions could not be assessed due to small numbers of affected cats. Sex predisposition to CHD in humans is about equal for the sexes.20,21 A female predisposition for PDA, a male predisposition to TOF, AS, aortic coarctation, and TA, and a borderline male predisposition to VSD and PS are reported.23 Overall human sex distribution seems more similar to dogs. The prevalence of innocent murmurs among cats was 0.16% and among dogs was 0.10%. Overall this suggested that the number of young dogs and cats with an innocent murmur was similar to the number with actual CHD. Other studies similarly show a significant prevalence of innocent murmurs in the cat.29 Unfortunately, due to the retrospective nature of this study, murmur intensity was not consistently recorded in the shelter records. Moreover, auscultation was generally performed by experienced veterinarians, but not by cardiologists so the actual prevalence of murmurs and minor defects might have been affected. Last, the population itself may have influenced the prevalence, especially if purebred dogs demonstrate a higher prevalence of innocent murmurs compared to mixed-breed dogs. As one would expect, the murmurs auscultated by the author and associated with a normal echocardiogram were invariably of low intensity. The large number of dogs screened for CHD, the exclusion of purebred dogs, and the cardiac examinations conducted by a single, experienced cardiologist represent strengths of the current report. The major limitations are the retrospective nature of the study and auscultatory screenings performed by non-cardiologists. The classification of breeds was performed by various employees at the shelter and included non-veterinarians. This could lead to some inconsistency in the breed identification. It would have been ideal to perform genetic testing on each of the studied patients with CHD to confirm their breed characteristics. Those animals diagnosed with an innocent murmur would have optimally been screened for systemic diseases such as anemia. In addition, echocardiography, the gold standard for diagnosis in this study, was not used in screening all animals for CHD, and only those with some evidence of cardiac disease were evaluated fully. This may have

Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001

10 underestimated malformations that can be “clinically silent” if mild to moderate such as cor triatriatum, ASD, and tricuspid stenosis. Definitive diagnosis was based on a single echocardiogram, and especially in very young animals, it can be challenging to fully define a CHD and its severity. For example, a single evaluation could result in a missed diagnosis or misdiagnosis of mild or developing SAS. Last, ideally a necropsy would have been performed on each animal to confirm the diagnosis but this was not realistic in the setting of the study.

Conclusions The current study demonstrates that the prevalence of CHD in mixed-breed cats is higher than for mixed-breed dogs and the prevalence of canine CHD is lower when compared to previous studies that included purebred dogs. The most common forms of CHD in dogs were PS followed by PDA, AS, and VSD. In cats the most common form of CHD was a VSD, followed by subvalvular and valvular AS, HOCM, and PS. Overall, there was no sex predisposition for CHD in mixed-breed cats or dogs, although a predilection was suggested for some malformations; this requires further study. Innocent murmurs were nearly as common as those caused by CHD, although an innocent murmur intensity of greater than II/VI was rare. It is hoped that the detailed descriptions of the diagnostic criteria used in the report will be valuable when comparing these data to other populations including specific breeds.

Conflicts of interest The author declares no conflicts of interest relative to this work.

Acknowledgments The author would like to acknowledge Dr. John Bonagura for his guidance and helpful comments regarding data analysis.

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Please cite this article in press as: Schrope DP, Prevalence of congenital heart disease in 76,301 mixed-breed dogs and 57,025 mixed-breed cats, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.06.001