Relationship between syringomyelia and myxomatous mitral valve disease in Cavalier King Charles spaniels

Abstract

Background

Syringomyelia (SM) and myxomatous mitral valve disease (MMVD) are highly prevalent in Cavalier King Charles spaniels (CKCS). Cardiac status in CKCS with and without SM is currently unknown.

Objectives

To investigate the association between SM and MMVD severity in CKCS and CKCS with SM with and without clinical signs of SM.

Animals

Fifty‐five CKCS: 40 with SM (22 symptomatic and 18 asymptomatic) and 15 without SM.

Methods

A combined retrospective and prospective study. MRI and echocardiography were used to diagnose SM and MMVD, respectively. The association between SM and MMVD severity (left ventricle internal diameter in diastole normalized to bodyweight [LVIDDN] and left atrium to aortic ratio [LA/Ao]) were tested using multivariable linear regression analysis adjusting for sex and age.

Results

Overall, no significant difference in LVIDDN and LA/Ao was found between CKCS with or without SM. However, CKCS with symptomatic SM had significantly smaller LVIDDN (1.45 [1.30‐1.50]) (median [IQR]) and LA/Ao (1.20 [1.10‐1.28]) compared to CKCS with asymptomatic SM (1.60 [1.50‐1.90] and 1.40 [1.20‐1.75]) as well as CKCS without SM (0.24 [0.03‐0.45] and 0.30 [0.05‐0.56]) (all P values <.03).

Conclusions and Clinical Importance

An association between MMVD and SM was not confirmed in this cohort of CKCS, indicating that MMVD and SM do not co‐segregate. However, CKCS with symptomatic SM had smaller left ventricle and atrial size compared to CKCS with asymptomatic SM and CKCS without SM.

Abbreviations

CKCS

Cavalier King Charles spaniels

LA/Ao

left atrium to aortic ratio

LVIDD

end‐ diastolic diameter of the left ventricle

LVIDDN

left ventricle internal diameter in diastole normalized to bodyweight

MMVD

myxomatous mitral valve disease

MRI

magnetic resonance imaging

SM

syringomyelia

1. INTRODUCTION

Cavalier King Charles spaniels (CKCS) are predisposed to heritable diseases, including syringomyelia (SM) ¹ , ² , ³ , ⁴ and myxomatous mitral valve disease (MMVD). ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ Both SM and MMVD are highly prevalent in the breed, and the diseases progress in some dogs into disabling conditions. ¹ , ² , ³ , ⁴ , ⁹ , ¹¹ , ¹²

Syringomyelia is a neurological disorder characterized by the accumulation of fluid‐filled cavities (syrinxes) in the spinal cord parenchyma. ¹³ , ¹⁴ , ¹⁵ Lesions more frequently affect the cervical region, although syrinxes can form in any part of the spinal cord. ¹³ Syringomyelia is typically seen in conjunction with Chiari‐like malformation. ¹³ , ¹⁴ , ¹⁵ Dogs with SM can express clinical signs or be clinically silent. ² , ¹⁶ Syrinx width and asymmetry have been coupled to the severity of clinical signs. Dogs with a wide and asymmetric syrinx are more likely to develop clinical signs than dogs with a smaller and symmetrical syrinx. ² , ¹⁷ , ¹⁸

Syringomyelia has a polygenic mode of inheritance with variable penetrance. In CKCS, genetics have a high impact on clinical disease expression (estimated heritability of 0.81), ² and 2 possible candidate loci (CFA22 and CFA26), associated with Chiari‐like malformation and SM, have been identified. ¹⁹

Myxomatous mitral valve disease is the most common heart disease in dogs and accounts for up to 37% of the total deaths among CKCS younger than 10 years. ⁸ It is a progressive disorder characterized by mitral valve degeneration leading to prolapse and regurgitation. ²⁰ In severe cases, progressive valvular regurgitation causes left ventricular remodeling and eventually congestive heart failure. ¹¹ , ¹² , ²⁰

Based on the high prevalence of MMVD in certain breeds, a genetic background has long been suspected ²⁰ and a strong genetic background with polygenic inheritance is likely ⁵ , ⁶ , ²¹ , ²² with a high heritability (0.67) for MMVD in CKCS. ⁷

Over the years, national breeding schemes have been established to reduce the occurrence of MMVD in CKCS, reducing the prevalence of early onset heart murmur in CKCS. ²³ At the same time, however, no such breeding restrictions have been established to remove CKCS with early‐onset SM from the breeding program, thereby reducing the incidence of SM.

The concern that longstanding MMVD‐breeding restrictions could potentially influence the prevalence of SM, motivated the present study. Therefore, this study aimed to investigate MMVD in CKCS with and without SM. The secondary aim of this study was to investigate the severity of MMVD in SM affected CKCS with and without clinical signs of SM.

2. MATERIALS AND METHODS

The study was conducted at the Department of Veterinary Clinical Sciences and Department of Veterinary and Animal Sciences, University of Copenhagen from spring 2014 to spring 2015. Approved by the Ethical Committee, University of Copenhagen [File number 2014‐5] and by the Danish Animal Experiments Inspectorate [license no. 2006/561‐1145, 2012‐15‐2934‐00700, and 2016‐15‐0201‐01074].

The study cohort consisted of 55 CKCS, 40 CKCS with SM and 15 CKCS without SM that had Magnetic Resonance Imaging (MRI) at the University Hospital for Companion Animals, Department of Veterinary Clinical Sciences in 2007‐2015.

Dogs in the study cohort were enrolled by fulfilling the following criteria:

1. All dogs had an MRI of the neurocranium and cervical spinal cord or the cervical spinal cord at the University Hospital for Companion Animals diagnostic imaging facility between 2007 and 2015. MRI scans included as a minimum standardized T1‐ and T2‐weighted sagittal and transverse sequences. MRI was performed using a 0.2 Tesla Esaote Vet‐scan, and a standard protocol for investigating SM in CKCS was used. ⁴ , ²⁴

2. Either dogs had previously participated in cardiac investigations (auscultation and echocardiographic examination) at the Department of Veterinary and Animal Sciences or the Department of Veterinary Clinical Sciences, or owners were willing to let their dog participate in cardiac investigations at the Department of Veterinary and Animal Sciences at the time of the study. In both cases, the dogs had to be ≥4 years at the time of cardiac investigations.

3. CKCS with SM were defined by having a syrinx (a T1 weighted hypointense fluid‐filled cavity in the spinal cord parenchyma) on MRI with a diameter ≥2 mm. ²⁴ , ²⁵ , ²⁶

4. CKCS without SM were defined by having no syrinx at MRI and being ≥5 years old during the MRI investigations.

5. All dog owners were willing to participate in a questionnaire interview in 2014‐2015 regarding signs of SM.

Thirty‐five of 55 CKCS were included based on MR imaging records from MRI scans performed from 2007 to 2014 (28 CKCS with SM and 7 CKCS without SM) (Figure 1). Of these 35 CKCS, 11 dogs already had an echocardiography performed in 2006‐2013, and the remaining 24 dogs had a cardiac examination performed between April and July 2014. In order to increase the number of CKCS without SM in the study, 20 CKCS without clinical signs of SM were invited for MR imaging and echocardiography between April and July 2015 (Figure 1). These 20 CKCS were recruited through the Danish Cavalier King Charles breed club by inviting dogs more than 5 years old that showed no clinical signs of SM (apparently healthy CKCS) for study participation. Out of these 20 dogs, 8 were MRI confirmed as SM negative and 12 had SM without clinical signs and were included in the study.

FIGURE 1.

Study inclusion flowchart. CKCS, Cavalier King Charles spaniels; MRI, magnetic resonance imaging; SM, syringomyelia.

Of the 55 CKCS included in this study, 13 CKCS with SM and 9 CKCS without SM participated in other unrelated research studies (CKCS with SM: n = 1, ²³ n = 2, ²⁷ n = 1, ² , ²⁸ n = 3, ¹⁸ n = 5, ² and n = 1 ² , ²⁹ , ³⁰ , ³¹ ; CKCS without SM: n = 8 ²⁴ and n = 1 ³² ).

2.1. Investigations performed in the study

2.1.1. MRI investigations re‐evaluating MRI scans

All MRI scans were re‐evaluated by an ECVDI 3rd year resident in 2015 to confirm the presence or absence of SM in the CKCS. The investigator was blinded to the dog's identity and previous MRI diagnosis. The maximum syrinx width, symmetry or right or left asymmetry were recorded. All syrinx measurements were assessed on T1‐weighted images to avoid a potential overestimation of syrinx size caused by edema and presyrinx formation visible in the T2‐weighted sequence. ³³

2.1.2. Cardiac investigations (auscultation and echocardiographic examination)

Cardiac investigations included an owner interview using a questionnaire addressing clinical signs of cardiac disease, history, clinical examination, and standardized transthoracic echocardiography with continuous ECG monitoring as previously described. ³⁴ Two experienced echocardiographers performed all echocardiographic examinations with commercially available ultrasound units and transducers (Vivid3 [2006‐2008], Vividi or Vivid7 [2008‐2014] echocardiographs with 5 MHz transducers and VividE9 echocardiograph with a 5Sc transducer [2014‐2017]; GE Healthcare A/S).

All echocardiographic examinations were masked and retrospectively re‐evaluated offline in commercial software (EchoPac Software Version 202) by an experienced observer.

Echocardiographic variables were reported as a mean of 3‐5 cardiac cycles. From the right parasternal short axis view, the left atrial‐to‐aortic root ratio (LA/Ao) was measured at the level of the aortic root at the first frame after the closure of the aortic valve. ³⁵ , ³⁶ In addition, the end‐diastolic diameter of the left ventricle (LVIDD) was measured in M‐mode at chordae tendineae level (identified in a 2D image before placement of the M‐mode cursor) ³⁷ and normalized to bodyweight (LVIDDN). ³⁸ The presence and severity of mitral regurgitation were evaluated from the left apical 4‐chamber view using color Doppler based on the regurgitant jet area relative to the left atrial area. ³⁹ The gain was set just below the color sparkling artifact in the myocardium and the Nyquist limit was between −0.62 and −0.98 m/s.

Based on American College of Veterinary Internal Medicine (ACVIM) consensus statement guidelines, the severity of MMVD was staged as follows: Group A, CKCS with no auscultatory heart murmur and normal echocardiogram (no or minimal MR [MR < 20%]); group B1, CKCS with an auscultatory heart murmur or MR ≥20% and echocardiographic evidence of MMVD but no cardiac enlargement (LA/Ao < 1.6 and LVIDDN < 1.7) ¹¹ , ⁴⁰ ; group B2, CKCS with heart murmur ≥3 of 6 and current or previous echocardiographic evidence of cardiac enlargement (LA/Ao ≥ 1.6 and LVIDDN ≥ 1.7 ¹¹ , ⁴⁰ ), but without current or previous clinical signs of CHF; group C, CKCS with CHF. ¹¹ , ⁴⁰ Congestive heart failure was defined as a history of MMVD, clinical signs of CHF (eg, cough, dyspnea, tachypnea, nocturnal restlessness, and exercise intolerance), echocardiographic changes compatible with CHF caused by MMVD and response to diuretic treatment.

2.1.3. Questionnaire investigation addressing signs of SM

A structured interview was conducted (spring 2014 to spring 2015) with all 55 owners using a standardized questionnaire. ² The questionnaire was designed to detect if clinical signs of SM were present or absent. Thus, the questionnaire served to evaluate if dogs with an MRI‐confirmed syrinx (diagnosing the dog with SM) were clinically affected or clinically non‐affected and to secure that those dogs with no syrinx on MRI (CKCS without SM) did not display any clinical signs of SM. The SM questionnaire consisted of 14 dichotomous questions (yes or no) and 5 questions with a grading of the clinical signs (never (0), occasionally (1), often (2) or always (3)) (cf. Table S1). The questionnaires were blindly evaluated.

2.2. Statistical analysis

All statistical analyses were performed with software (RStudio, Version 1.4.1717), and statistical significance was set at P < .05.

Descriptive MRI data, including the syrinx diameter, distribution of the syrinx (symmetric or asymmetric) and syrinx to spinal cord ratio, were presented as medians with interquartile ranges or as numbers within groups (CKCS with and without SM, as well as CKCS with SM with and without clinical signs).

Likewise, were descriptive echocardiographic data, including; the percent mitral regurgitation, left ventricle internal diameter in diastole (LVIDD), LVIDD normalized to bodyweight (LVIDDN), left atrium to aortic ratio (LA/Ao) and MMVD stage, presented as medians with interquartile ranges or as numbers within groups (CKCS with and without SM, as well as CKCS with SM with and without clinical signs).

Nonparametric Mann‐Whitney U test was used to test differences in continuous descriptive MRI and echocardiographic characteristics and Fisher's exact test was used to test differences in the distribution of descriptive categorical variables between groups.

Using multivariable linear regression, differences in MMVD severity between dogs with and without SM were tested, adjusting for the influence of sex and age. The dependent variable MMVD severity was assessed as LVIDD, LVIDDN and LA/Ao, respectively, in 3 multivariable linear regression models. All 3 models included the 3 explanatory variables: sex, age and SM status (a nominal variable with 2 categories: CKCS with SM versus CKCS without SM). Furthermore, the differences in MMVD severity (LVIDD, LVIDDN and LA/Ao, respectively) between dogs with SM with and without clinical signs were tested in 3 similar multivariable linear regression analyses, including the 3 explanatory variables: sex, age, and SM clinical signs (a nominal variable with 3 categories: CKCS without SM, CKCS with SM and clinical signs and CKCS with SM without clinical signs). Residuals were tested for normality and homogeneity using QQ and residual plots.

Dogs related at the parent level were defined as close relatives, and the multivariable linear regression analyses were repeated using a generalized estimation equation with robust standard errors, considering that some dogs were close relatives (20 dogs had a total of 10 relations at the parental level), to check that the conclusions of the multivariable regression analysis hold true even when accounting for the relatedness among these dogs.

3. RESULTS

Of the 40 dogs with MRI confirmed SM, 22 dogs showed clinical signs compatible with SM, whereas 18 dogs expressed no clinical signs. Summary statistics for the 55 CKCS included (40 CKCS with SM and 15 CKCS without SM) are presented in Table 1. There was no statistically significant difference in sex distribution, weight, age or furosemide treatment at the time of echocardiography among dogs with and without SM or among dogs with SM with and without clinical signs. Dogs with symptomatic SM had a wider syrinx, and a larger syrinx‐to‐spinal‐cord ratio and the spinal distribution was more often asymmetric than dogs with asymptomatic SM (Table 1).

TABLE 1.

Summary statistics for the 55 Cavalier King Charles Spaniels included.

	Dogs without SM (n = 15)	Dogs with SM (n = 40)	P	SM without clinical signs (n = 18)	SM with clinical signs (n = 22)	P
Sex (F/M)	7/8	28/12	.13	13/5	15/7	1.00
Weight (kg)	9.45 (7.90‐10.00)	9.18 (8.58‐9.69)	.86	9.33 (8.68‐9.59)	8.98 (8.30‐9.91)	.54
AgeMRI (years)	7.10 (5.74‐7.89)	5.77 (4.50‐6.83)		6.82 (5.50‐8.30)	4.94 (3.31‐6.13)
AgeEcho (years)	7.42 (6.52‐8.35)	6.62 (5.43‐8.62)	.29	7.13 (5.62‐8.54)	6.28 (5.14‐8.45)	.39
TimeMRI to Echo (years)	0.00 (0.00‐0.38)	0.40 (0.00‐2.37)		0.00 (0.00‐0.12)	1.91 (0.48‐3.89)
T1 width (mm)		4.90 (3.28‐6.20)		3.60 (2.85‐4.90)	6.00 (4.33‐7.00)	.005
T1:Spinalcord		0.60 (0.43‐0.69)		0.48 (0.35‐0.61)	0.66 (0.56‐0.72)	.006
Asymmetry (No/Yes)		28/12		17/1	11/11	.004
MR jet (<20%/20%‐50%/>50%)	1/8/6	12/21/7	.09	4/8/6	8/13/1	.08
LVIDD (mm)	29.20 (27.30‐39.20)	28.20 (27.00‐30.65)	.39	30.70 (28.00‐36.65)	27.20 (25.85‐28.80)	<.001
LVIDDN (cm/kg0.294)	1.60 (1.45‐2.00)	1.50 (1.40‐1.60)	.30	1.60 (1.50‐1.80)	1.45 (1.30‐1.50)	.001
LA:Ao	1.35 (1.20‐1.88) n = 13	1.20 (1.10‐1.40)	.15	1.40 (1.20‐1.58)	1.20 (1.10‐1.28)	.005
MMVD stage a (A/B1/B2/C)	1/9/4/1	12/23/3/2	.10	4/10/2/2	8/13/1/0	.35
Furosemide b (Yes/No)	0/15	9/31	.05	2/16	7/15	.15

Note: The descriptive echocardiography data presented are unadjusted for sex and age.

Abbreviations: Echo, echocardiography; F, female; LA:Ao, left atrial‐to‐aortic root ratio; LVIDD, end‐diastolic diameter of the left ventricle; LVIDDN, end‐diastolic diameter of the left ventricle normalized to bodyweight; M, male; MMVD, myxomatous mitral valve disease; MR, mitral regurgitation; MRI, magnetic resonance imaging; SM, syringomyelia.

^a The American College of Veterinary Internal Medicine myxomatous mitral valve disease staging system with a modified group A—including dogs with a MR <20%. Continuous variables are presented as medians with interquartile ranges and categorical data are presented as numbers. Nonparametric Mann‐Whitney U test was used to test differences in continuous descriptive characteristics and Fisher's exact test used to test differences in distribution of descriptive categorical variables between groups.

^b Receiving diuretics at the time of echocardiography because of SM or MMVD.

In total, 32 of the 55 CKCS were diagnosed with ACVIM MMVD stage B1, 7 with stage B2 and 3 dogs with stage C. Summary statistics from the cardiac examinations in CKCS with and without SM, as well as CKCS with SM with and without clinical signs, are presented in Table 1 and depicted in Figure 2. The summary statistics were not sex or age‐adjusted.

FIGURE 2.

Echocardiographic findings in the 55 Cavalier King Charles spaniels included. End‐diastolic diameter of the left ventricle (A), end‐diastolic diameter of the left ventricle normalized to bodyweight (B), and left atrial‐to‐aortic root ratio (C) for Cavalier King Charles spaniels without SM and Cavalier King Charles spaniels with SM with and without clinical signs. The visualized echocardiographic data are unadjusted for sex and age, whereas the P‐values given are from the multivariable regression analyses adjusting for sex and age. CKCS, Cavalier King Charles spaniels; LA:Ao, Left atrial‐to‐aortic root ratio; LVIDD, End‐diastolic diameter of the left ventricle; LVIDDN, End‐diastolic diameter of the left ventricle normalized to bodyweight; SM, Syringomyelia.

The multivariable linear regression analysis adjusting for sex and age showed no significant difference in LVIDD (P = .32), LVIDDN (P = .29) or LA/Ao (P = .15) between CKCS with SM and CKCS without SM.

The multivariable linear regression analysis comparing SM‐affected dogs with and without clinical signs (SM status in the multivariable linear regression analysis: CKCS without SM and SM‐affected dogs with and without clinical signs, n = 55) showed that LVIDD was 6.12 mm (95% CI: 2.19‐10.05 mm, P = .003), LVIDDN 0.29 (95% CI: 0.10‐0.49, P = .003), and LA/Ao 0.28 (95% CI: 0.05‐0.51, P = .02) smaller in CKCS with SM with clinical signs compared to CKCS without clinical signs. In addition, the multivariable linear regression analysis showed that LVIDD was 4.82 mm (95% CI: 0.59‐9.05 mm, P = .03), LVIDDN 0.24 (95% CI: 0.03‐0.45, P = .02), and LA/Ao 0.30 (95% CI: 0.05‐0.56, P = .02) significantly smaller in CKCS with symptomatic SM compared to CKCS without SM. The complete results of the multivariable linear regression analyses are included in Table 2.

TABLE 2.

Results from the linear regression models describing the association between the heart size measurements and SM status, adjusted for age and sex.

Regression models
Heart measurement = Age + Sex + SM status(CKCS without SM/CKCS with SM) a
	Intercept	Age	Sex(Male)	SM status(CKCS with SM)
LVIDD (mm)	27.26 P < .001	0.63 P = .19	0.71 P = .71	−2.09 P = .32
LVIDDN (cm/kg0.294)	1.41 P < .001	0.04 P = .13	0.00 P = .99	−0.11 P = .29
LA/Ao	1.09 P < .001	0.06 P = .03	0.00 P = .10	−0.18 P = .15

Regression models
Heart measurement = Age + Sex + SM clinical signs(CKCS with SM with clinical signs/CKCS with SM without clinical signs/CKCS without SM) b
	Intercept	Age	Sex(Male)	SM clinical signs(CKCS with SM without clinical signs)
LVIDD (mm)	22.74 P < .001	0.57 P = .20	0.89 P = .62	6.12 P = .003
LVIDDN (cm/kg0.294)	1.19 P < .001	0.03 P = .13	0.01 P = .93	0.29 P = .003
LA/Ao	0.80 P < .001	0.06 P = .03	0.01 P = .94	0.28 P = .02

Note: Estimates for SM status_{CKCS without SM}: LVIDD 4.82 (P = .03), LVIDDN 0.24 (P = .02), and LA/Ao 0.30 (P = .02).

Abbreviations: CKCS, Cavalier King Charles Spaniels; LA:Ao, left atrial‐to‐aortic root ratio; LVIDD, end‐diastolic diameter of the left ventricle; LVIDDN, end‐diastolic diameter of the left ventricle normalized to bodyweight; SM, syringomyelia.

^a With Sex_Female and SM status_{CKCS without SM} being the reference categories, respectively.

^b With Sex_Female and SM status_{CKCS with SM with clinical signs} being the reference categories, respectively.

The multivariable linear regression analyses using robust standard errors did not change these significant findings.

4. DISCUSSION

This study found no association between MMVD severity and the occurrence of SM (symptomatic and asymptomatic pooled together). Although both diseases are highly prevalent and heritable in CKCS, this finding indicates that it is unlikely that they are co‐segregating in the population. However, left ventricular and left atrial remodeling measurements (LVIDD, LVIDDN, and LA/Ao) were all significantly smaller in CKCS with symptomatic SM compared to CKCS with asymptomatic SM and CKCS without SM, indicating less cardiac enlargement due to MMVD among the CKCS with symptomatic SM, and thus a potential more complex relationship between MMVD and symptomatic SM might exist.

Seven dogs with symptomatic SM, 2 dogs with asymptomatic SM and none of the dogs without SM received daily treatment with furosemide at the time of echocardiography, and this might have influenced the LVIDD and LA/Ao measurements and the finding of decreased cardiac dimensions in the dogs with symptomatic SM. 2.5 mg/kg IV furosemide dose followed by 4‐hour water deprivation can decrease the left end diastolic volume in healthy dogs. ⁴¹ None of the dogs in the present study had, restricted water intake before echocardiography, and when repeating the statistical analyses adjusting for furosemide treatment, the reported differences between groups did not change (data not shown).

It could be argued that CKCS with clinical signs of SM developing concurrent MMVD are at higher risk of euthanasia early in life, and this could have affected our results due to selection bias (dogs with concurrent MMVD not being included in the symptomatic SM group). None of the CKCS with SM that were euthanized before the age of 4 had a known heart murmur due to MMVD, and consequently we find the risk of selection bias low.

Due to the inclusion criteria and study design, the CKCS with symptomatic SM participating in the study were younger at the time of MRI scan than the CKCS with asymptomatic SM and the CKCS without SM, and consequently the timespan between the MRI and echocardiography was longer for this group. Since the diagnosis of symptomatic SM will not change status over time, we do however not believe that this time difference influenced our results. Also, a previous study has shown that CKCS with asymptomatic SM at the age of 6 are unlikely to change status later in life. ² Furthermore, as all CKCS included had a recent echocardiographic examination after the age of 4 years, there was no significant age difference between the groups at the time of echocardiography, and all multivariable analyses were adjusted for the age at the time of echocardiography.

Well established MMVD‐breeding restrictions issued by the Danish Kennel Club, assessing mitral regurgitation murmurs and mitral valve prolapse severities as early markers of mitral valve disease, have proven to effectively reduce the prevalence of early‐onset MMVD in CKCS excluding only approximately 5% from breeding. ²³ Although a low percentage, it cannot be excluded that it influences the breeding material in a population with a small effective population size. Independently of the MMVD breeding program, SM breeding guidelines have also been established in CKCS, grading dogs according to MRI status and age. ⁴² These breeding guidelines are based on information showing that healthy offspring are more common if both parents are without SM—whereas mating a SM free with a SM‐affected parent increases the risk of SM affected offspring significantly. ⁴³

The link between the syrinx geometry and the expression of clinical signs reported in Table 1 in the present study, is of particular interest as the heritability of symptomatic SM is high, ² and the CFA22 locus has been associated with syrinx width and clinical signs in CKCS. ¹⁹ Given this, it might be worth integrating the syrinx size and geometry into the current SM breeding recommendations.

This study had some limitations of which the relatively small and selected study cohort, defined by having available MRI scans as well as echocardiographic evaluations, is the most obvious. A larger sample size of CKCS without SM (confirmed by MRI) would have strengthened the study by increasing the statistical power, thereby minimizing the risk of type II error. A post hoc power calculation was performed based on the 3 multivariable regression analyses comparing the heart size measurements (LVIDD, LVIDN, and LA/Ao, respectively) in CKCS with and without SM, assuming that population parameters were as estimated in these regression analyses (see Table 2 for parameter estimates). With the current sample size of 55 dogs, the powers of detecting a real effect of having a syrinx, as given by the point estimates, were 16%, 18%, and 31% for LVIDD, LVIDDN, and LA/Ao, respectively. We stress, however, that this does not mean that there is an effect of syrinx, as our analyses give no evidence of such an effect. It is merely a speculative calculation suggesting that if there is, in fact, an effect as given by the point estimate, the 55 subjects give low power to detect such an effect.

Nine out of the 55 CKCS (7 symptomatic SM and 2 with asymptomatic SM that were older than 9 years old) had passed away at the time of the questionnaire investigation. We can therefore not exclude recollection bias with respect to clinical signs for these dogs.

Finally, as our results represents a study cohort including CKCS studied between 2007 and 2015, there might be some uncertainty whether breeding practices and genetic selection could have changed and affected the CKCS population since then.

In the interest of promoting the health in the CKCS breed, it is of importance to carefully manage the breeding practice and reduce the prevalence of both MMVD and SM.

5. CONCLUSIONS

This study investigates the co‐occurrence of SM and MMVD. We found no overall association between SM (symptomatic and asymptomatic pooled together) and the severity of MMVD in CKCS, but CKCS with symptomatic SM exhibited smaller left ventricular and left atrial dimensions compared to those with asymptomatic SM and CKCS without SM, suggesting that a complex relationship might exist. However, this study was limited by a relatively small and selected study sample.

CONFLICT OF INTEREST DECLARATION

Authors declare no conflict of interest.

OFF‐LABEL ANTIMICROBIAL DECLARATION

Authors declare no off‐label use of antimicrobials.

INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) OR OTHER APPROVAL DECLARATION

Approved by the Ethical Committee, University of Copenhagen (file number 2014‐5) and by the Danish Animal Experiments Inspectorate (license numbers 2006/561‐1145, 2012‐15‐2934‐00700, and 2016‐15‐0201‐01074).

HUMAN ETHICS APPROVAL DECLARATION

Authors declare human ethics approval was not needed for this study.

Supporting information

Appendix S1: Questionnaire.

Bach MBT, Stougaard CL, Thøfner MS, et al. Relationship between syringomyelia and myxomatous mitral valve disease in Cavalier King Charles spaniels. J Vet Intern Med. 2024;38(2):904‐912. doi: 10.1111/jvim.17018