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Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease
Journal of Veterinary Cardiology (2015)
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Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease S. Wesselowski, DVM, MS*, M. Borgarelli, DMV, PhD , G. Menciotti, DVM , J. Abbott, DVM Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA 24061, USA Received 5 July 2014; received in revised form 8 January 2015; accepted 16 January 2015
KEYWORDS Canine; Anterior leaflet; Annulus; Reference intervals
Abstract Objectives: To further characterize the echocardiographic anatomy of the canine mitral valve apparatus in normal dogs and in dogs affected by myxomatous mitral valve disease (MMVD). Animals: Twenty-two normal dogs and 60 dogs with MMVD were prospectively studied. Methods: The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured in the control group and the affected group, as were the diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs). The dogs with MMVD were staged based on American College of Veterinary Internal Medicine (ACVIM) guidelines and separated into groups B1 and B2/C. All measurements were indexed to body weight based on empirically defined allometric relationships. Results: There was a statistically significant relationship between all log10 transformed mitral valve dimensions and body weight. The AMVL, AMVW, AMVA, MVAd and MVAs were all significantly greater in the B2/C group compared to the B1 and control groups. The AMVW was also significantly greater in the B1 group compared to the control group. Interobserver % coefficient of variation (% CV) was <10% for AMVL, AMVA, MVAd and MVAs, but was 29.6% for AMVW. Intraobserver % CV was <10.4% for all measurements. Conclusions: Measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on allometric relationships.
* Corresponding author. E-mail address: [email protected] (S. Wesselowski). http://dx.doi.org/10.1016/j.jvc.2015.01.003 1760-2734/ª 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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S. Wesselowski et al. Preliminary reference intervals have been proposed over a range of body sizes. Relative to normal dogs, AMVL, AMVW, AMVA, MVAd and MVAs are greater in patients with advanced MMVD. ª 2015 Elsevier B.V. All rights reserved.
Abbreviations ACVIM American College of Veterinary Internal Medicine AMVA anterior mitral valve leaflet area AMVL anterior mitral valve leaflet length AMVW anterior mitral valve leaflet width MMVD myxomatous mitral valve disease MVAd mitral valve annulus diameter in diastole MVAs mitral valve annulus diameter in systole RC repeatability coefficients % CV % coefficient of variation
Introduction The most common acquired cardiac disease in canine patients is myxomatous mitral valve disease (MMVD).1,2 Gross pathology of affected mitral valve leaflets exhibits a wide spectrum of lesion severity; some dogs develop only mild nodular thickening of the leaflets, while others are found to have lengthening or rupture of the chordae tendineae with elongated and severely thickened leaflets.3,4 Dilation of the mitral valve annulus also develops in association with long-standing mitral regurgitation due to MMVD.5 Histopathology of affected leaflets shows an accumulation of proteoglycans and glycosaminoglycans in combination with connective tissue derangements.4e8 Standardized echocardiographic criteria distinguish between normal and abnormal mitral valve morphology in humans, but despite the high prevalence of MMVD in dogs, similar criteria for use in canine echocardiography have not been established.9e11 The lack of objective or quantitative echocardiographic criteria has hampered systematic investigation of the relationships between structural mitral valve abnormalities and clinical assessments of disease severity. Additionally, the prognostic relevance of abnormal mitral valve anatomy associated with MMVD in dogs has not been fully evaluated. In humans, mitral valve leaflets measuring 5 mm or greater in width during diastole are known to be a predictor of
complications associated with MMVD.12 The prognostic relevance of systolic thickness of the anterior mitral valve leaflet has been investigated in dachshunds, but this variable was not predictive of increases in left atrial and left ventricular enddiastolic diameters over a 3-year period.13 Further study of prognostic indicators related to mitral valve anatomy in dogs is needed. The image plane utilized most commonly for evaluation of the mitral valve in people, especially with regard to diagnosis of mitral valve prolapse, is the parasternal long axis view. This view corresponds most closely to the veterinary image plane known as the right parasternal long-axis left ventricular outflow view, which allows visualization of the aorta in addition to the left atrium, left ventricle and mitral valve leaflets.14 The right parasternal long-axis 4-chamber view, though not a standard image plane in human cardiology, is also considered a standard echocardiographic view for assessment of the canine mitral valve.7,14,15 Both views provide visualization of the mitral valve apparatus; however, the optimal image plane for assessment of the mitral valve in dogs has not been critically assessed. The goals of this study were: 1) to evaluate the relationships between mitral valve measurements and body size; 2) to propose preliminary reference intervals for echocardiographic measurements of the anterior mitral valve leaflet and the mitral valve annulus in normal dogs; 3) to determine which echocardiographic view provides more repeatable measurements of the mitral valve apparatus in dogs, and 4) to compare these echocardiographic measurements among groups of dogs defined by clinical stage of MMVD.
Animals, materials and methods The control group was made up of healthy dogs owned by faculty, staff and students of the Virginia Maryland Regional College of Veterinary Medicine as well as dogs presenting for pre-breeding cardiac screening to both the Virginia Maryland Regional College of Veterinary Medicine and the Kansas State University Veterinary Teaching Hospital.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs These dogs were evaluated with approval of the Virginia Tech Institutional Animal Care and Use Committee and were deemed cardiologically normal based on physical examination, complete echocardiographic evaluation and Dopplera blood pressure measurement. An ultrasound unitb equipped with 1.5e10 MHz phased array transducers was used to obtain standard M-mode, 2D, and Doppler blood flow measurements with contemporaneous electrocardiographic monitoring. Harmonic transducer settings were utilized for all studies. The frame rate of acquired images varied according to the transducer that was utilized and the machine settings that were required for patients of different size. Doppler blood pressure measurements were performed compliant with previously published recommendations.16 Criteria for exclusion included auscultation of a mid-systolic click or left apical systolic murmur, echocardiographic evidence of mitral valve prolapse or mitral regurgitation assessed as greater than trivial in severity, or evidence of cardiovascular or systemic disease expected to affect cardiovascular function. The study group comprised client-owned dogs that were presented to the Virginia Maryland Regional College of Veterinary Medicine Veterinary Teaching Hospital or the Kansas State University Veterinary Teaching Hospital for evaluation of MMVD. All dogs had complete echocardiographic evaluation and measurement of Doppler blood pressure. Thoracic radiographs were obtained only if clinically indicated. The diagnosis of MMVD was based on the echocardiographic identification of mitral valve thickening and/or prolapse, typically in combination with the presence of mitral regurgitation. In 3 cases, mitral valve prolapse was identified in 2 or more image planes in the absence of mitral regurgitation. Dogs were classified according to previously published American College of Veterinary Internal Medicine (ACVIM) staging guidelines.17 The distinction between Stage B1 and Stage B2 was based on radiographic and/or echocardiographic findings. Patients for which the vertebral heart scale exceeded 10.5, the echocardiographic left atrial volume indexed to body weight was greater than 1.1 ml/kg18 or the left ventricular end-diastolic dimension exceeded the upper limit of a published reference interval19 were classified as Stage B2. Dogs classified as Stage B1 made up one group while Stage B2 and Stage C
a b
811-B, Parks Medical Electronics, Inc, Aloha, OR. Vivid 7; GE-Medical, Milwaukee, WI.
3 dogs were grouped together (B2/C) to represent patients with advanced disease and cardiac remodeling. Both the control population and the study population were previously utilized for a separate echocardiographic study.18 Measurements of the mitral valve were obtained in the 4-chamber, right parasternal long-axis view and in the right parasternal long-axis left ventricular outflow view. The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured during diastole, when the leaflet was fully extended (Fig. 1A). The length of the leaflet was measured as a straight line from the hinge point of the mitral valve annulus to the tip of the leaflet when the leaflet was best visualized as a fully extended line during early or late diastole. The width was determined by measuring the widest part of the extended leaflet. Finally, the area of the leaflet was obtained using planimetry to trace its border. The mitral valve annulus was measured at both end-diastole (MVAd) and end-systole (MVAs) by measuring the distance from mitral valve hinge point to hinge point (Fig. 1B and C), with frame-by-frame advancement utilized to accurately identify each hinge point location. The first frame after mitral valve closure and the last frame prior to mitral valve opening defined end-diastole and end-systole, respectively. All measurements were repeated on 3 consecutive cardiac cycles and averaged. Average values were used in the statistical analysis. One operator (SW) obtained measurements on all dogs and these data were subject to the principal analyses. Measurements of the same stored images were repeated in a randomly selected subset of 6 control dogs by SW one week after the initial measurements. A second operator (MB) also obtained measurements from the stored images of those 6 dogs. These data were used to assess intraobserver and inter-observer repeatability. Because remodeling (Stage B2 and C) was obvious to the operator from the 2D echocardiographic image plane, blinding of the operator was not attempted.
Statistical analysis A relationship between mitral valve dimensions and body size was assumed. Therefore, exploratory analyses were used to identify the most appropriate measure of body size with which to index echocardiographic variables. More specifically, simple linear regression was used to evaluate relationships between echocardiographic variables and body-weights of the control group. This procedure was repeated with calculated body surface area serving as the explanatory variable. To
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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S. Wesselowski et al.
Figure 1 2-Dimensional right parasternal long-axis 4-chamber view demonstrating the measurement of A: anterior mitral valve leaflet length, width, and area, B: mitral valve annulus diameter in diastole, and C: mitral valve annulus diameter in systole.
explore the possibility of an allometric relationship between mitral valve dimensions and body size, log10 transformed echocardiographic dimensions were regressed against the log10 of body weight. For each variable, goodness of fit, defined by the coefficient of determination (R-squared), was greatest for the linear relationship between log10 transformed echocardiographic data and log10 of body weight. The parameters of the regression equation were used to define the terms of the allometric equation: y ¼ axb where y is the response variable, a is the proportionality constant, x is body-weight and b is the scaling exponent. For inter-group comparisons, echocardiographic variables were indexed to body weight raised to the scaling exponent defined by the aforementioned allometric relationship. Intraobserver and interobserver repeatability of variables obtained from the 4-chamber right parasternal long-axis view and from the right parasternal long-axis left ventricular outflow view were assessed through calculation of the % coefficient of variation (% CV). These values are presented in Table 1. Relative to those obtained from the right parasternal long-axis left ventricular outflow view, values of % CV were consistently lower for variables obtained from the 4-chamber right parasternal long-axis view. Additionally, right parasternal left ventricular outflow view images from five patients within the study group were of insufficient quality to obtain all measured variables. Therefore, further analyses were performed only on data obtained from the 4-chamber right parasternal long-axis image plane. Intraobserver and interobserver repeatability of variables obtained from the 4-chamber right
parasternal long-axis image plane were further characterized through calculation of repeatability coefficients (RC).20,21 Specifically, a mixed linear model that included the fixed effects of observer and time as well as the random effect of dog was developed. Variance components were derived from this model and used to calculate the RC. In some cases, measurement variability attributed to the operator was negligible and generated RC of zero. These data are presented in Table 1. Predicted values and 95% prediction intervals were derived from the allometric relationship between echocardiographic variables and bodysize and from these data, reference intervals for
Table 1 Percent coefficient of variation (% CV) and repeatability coefficients (RC) (linear dimensionsmm/area-mm2) of mitral valve measurements.
AMVL AMVW AMVA MVAd MVAs
CV(%) RC CV(%) RC CV(%) RC CV(%) RC CV(%) RC
Intraobserver
Interobserver
RP4
RPLVOT
RP4
RPLVOT
3.12 1.33 7.67 0.35 10.33 0.00 1.65 0.00 0.73 0.37
6.25
5.16 0.00 29.62 1.28 9.99 2.49 5.40 3.72 3.16 1.87
14.47
12.49 13.08 2.50 1.46
41.62 18.94 8.35 13.72
RP4, right parasternal 4-chamber view; RPLVOT, right parasternal left ventricular outflow tract view; Bold values: % CV; Italic values: RC; AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs ranges of body-weights were developed. Comparisons between study groups were by one-way analysis of variance for normally distributed data, and by a Kruskall-Wallis analysis of variance for data that were not normally distributed. When these tests disclosed a statistically significant difference between groups, post-hoc evaluation consisted of the Tukey’s HSD test or Steel-Dwass test as appropriate, based on distribution of data. Normally distributed data are presented as mean (SD) while non-normally distributed are presented as median (range). A p value of <0.05 was considered significant. Distributions of data and residual plots were graphically evaluated to ensure that the assumptions implicit in the use of statistical methods were met.
Results Twenty-two cardiologically normal dogs of 12 different breeds were enrolled in the control group. Ten dogs were of mixed breed origin, 2 were beagles, and the remaining 10 breeds were represented by 1 dog each. The mean age of the control group was 4.6 years (2.0 years) and median weight was 14.25 kg (4e37.1 kg). Sixty client-owned dogs with MMVD were enrolled in the study group. Twenty-seven breeds were represented, with the most common breeds being Cavalier King Charles spaniel (n ¼ 9), Toy Poodle (n ¼ 5), Pomeranian (n ¼ 4), Shih Tzu (n ¼ 3), Yorkshire terrier (n ¼ 3), and Labrador retriever (n ¼ 3). The median weight of the study group was 9.4 kg (2.5e51.5 kg) and the mean age was 10.5 years (2.7 years). Within the study group there were 13 dogs classified as ACVIM stage B1 and 47 classified as stage B2/C. The mean age of the dogs in group B1 was 8.3 years (2.5 years) and the mean age of the dogs in and in group B2/C was 11.1 years (2.5 years), both of which were significantly older than the mean age of dogs in the control group (p < 0.0001 and p < 0.001, respectively). Group B2/C dogs were also significantly older than those in group B1 (p ¼ 0.0011). The median body weight of dogs in group B1 was 17.4 kg (2.5e41.1 kg) and the median body weight of dogs in group B2/C was 7.7 kg (3.5e51.5 kg). There was no significant difference in body weight between the control group and group B1 (p ¼ 0.67), whereas body weight of group B2/C was significantly less than the weights of both the control group (p ¼ 0.027) and group B1 (p ¼ 0.028). There was a statistically significant relationship between all log transformed mitral valve
5 dimensions and body weight. Coefficients of determination (R-squared) for AMVL, AMVW, AMVA, MVAd and MVAs were 0.87, 0.93, 0.93, 0.93, and 0.88, respectively. The scaling exponents derived from these allometric relationships were close to the theoretical expectations of 0.33 for linear dimensions and 0.67 for areas; they were, respectively: 0.37, 0.41, 0.78, 0.37 and 0.4 for AMVL, AMVW, AMVA, MVAd and MVAs. Figure 2 relates measurements of AMVL, AMVW, AMVA, MVAd and MVAs from the control group to body-weight in scatterplot form. Table 2 shows predicted values for each mitral valve measurement for a range of body sizes. Comparisons of mitral valve measurements, indexed according to the empirically defined allometric relationship, are summarized in Table 3. The AMVL was significantly longer in the B2/C group compared to both the control group (p ¼ 0.0086) and the B1 group (p ¼ 0.0013). A significant difference between AMVL from the control group and dogs in stage B1 was not detected (p ¼ 0.56). The AMVW was significantly greater in the B2/C group compared to the control group (p < 0.001) and the B1 group (p < 0.001). Additionally, AMVW from the B1 group was significantly greater than AMVW from the control group (p ¼ 0.0296). The AMVA was significantly larger in the B2/C group than the control group (p < 0.001) and the B1 group (p < 0.001). There was no significant difference between the control group and the B1 group (p ¼ 0.5959) with respect to AMVA. MVAd was significantly greater in the B2/ C group than in the control group (p < 0.001) or the B1 group (p < 0.001), however there was no significant difference between the control group and the B1 group (p ¼ 0.7333). Finally, the dimension of the MVAs was also significantly greater in the B2/C group than the control group (p < 0.001) or the B1 group (p < 0.001). No significant difference in MVAs was found between the control group and the B1 group (p ¼ 0.9721).
Discussion The results of this study demonstrate an allometric relationship between mitral valve dimensions and body size. The scaling exponents derived for AMVL, AMVW, MVAd and MVAs were all close to the theoretical exponent of 1/3 expected for measurements related to body length, while the exponent derived for AMVA was close to the theoretical exponent of 2/3 for measurements related to body surface area. These findings are consistent with
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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S. Wesselowski et al. data presented in previously published studies of allometric scaling.19,22e25 We have proposed reference intervals across a range of body sizes that provide the basis of standardized criteria that define the quantitative echocardiographic characteristics of the normal canine mitral valve. Previously published data on the echocardiographic anatomy of the normal mitral valve in dogs are limited to the results of a study in which seven Norfolk terriers made up the normal population.26 Additional study is warranted to determine whether breed-specific measurements provide a significant advantage in assessment of the normal mitral valve over the mixed population used to derive the reference intervals presented in this study. Comparisons between the mitral valve anatomy of the control group and the study groups presented here yielded expected differences. Increases in thickness, length and area of the anterior mitral valve leaflet were evident in more severely affected patients. These echocardiographic changes parallel the classic valvular remodeling reported on gross pathologic examination.3e5 Additionally, there was an increase in the diameter of the mitral valve annulus in both systole and diastole in patients with more advanced MMVD. Dilation of the mitral valve annulus in the more severely affected dogs in this study is consistent with the expected changes associated with chronic mitral regurgitation, volume overload, and enlargement of the left heart.5 All of the increases in each of the 5 measurements that were studied were significantly different when comparing the control group to the B2/C group with advanced MMVD. The only measurement that showed a significant difference between the control group and the B1 group, however, was AMVW. The lack of echocardiographic change related to the length and area of the anterior mitral valve leaflet in the B1 group may reflect the fact that more advanced disease is required before significant changes in these parameters can be appreciated by echocardiography, or may relate to an insufficient sample size of the B1 group. Annular dilation, on the other hand, would not be expected in ACVIM Stage B1 patients as this group was defined by the absence of chamber enlargement.
Figure 2 Control group data are presented in scatterplot form. The predicted value for each measurement is depicted by a solid line. Upper and lower 95%
prediction intervals are depicted by dashed lines. A: Anterior mitral valve leaflet length (AMVL); B: Anterior mitral valve leaflet width (AMVW); C: Anterior mitral valve leaflet area (AMVA); D: Mitral valve annulus diameter in diastole (MVAd); E: Mitral valve annulus diameter in systole (MVAs).
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs
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Table 2
Normal mitral valve measurements and 95% prediction intervals for dogs of varying weights.
BW (Kg)
AMVL (mm)
3 4 6 8 10 12 14 17 20 25 30 35 40 50 60
8.95 (5.54e12.36) 9.90 (6.55e13.25) 11.42 (8.14e14.70) 12.64 (9.42e15.87) 13.69 (10.49e16.89) 14.61 (11.43e17.79) 15.44 (12.26e18.61) 16.55 (13.37e19.72) 17.54 (14.35e20.73) 19.01 (15.79e22.23) 20.30 (17.03e23.56) 21.46 (18.14e24.78) 22.52 (19.13e25.90) 24.41 (20.90e27.93) 26.08 (22.43e29.73)
AMVW (mm) 0.87 0.99 1.17 1.31 1.44 1.55 1.65 1.79 1.92 2.10 2.26 2.41 2.55 2.80 3.01
(0.58e1.17) (0.69e1.28) (0.88e1.45) (1.03e1.60) (1.16e1.72) (1.27e1.83) (1.38e1.93) (1.51e2.07) (1.64e2.20) (1.82e2.38) (1.98e2.55) (2.12e2.70) (2.25e2.85) (2.49e3.10) (2.69e3.34)
AMVA (mm2)
MVAd (mm)
MVAs (mm)
6.01 (<12.68a) 7.44 (0.81e14.06) 10.08 (3.55e16.62) 12.54 (6.07e19.01) 14.86 (8.44e21.28) 17.08 (10.69e23.47) 19.22 (12.85e25.59) 22.31 (15.95e28.67) 25.28 (18.91e31.65) 30.02 (23.59e36.46) 34.56 (28.01e41.12) 38.94 (32.22e45.65) 43.18 (36.27e50.08) 51.32 (43.95e58.70) 59.12 (51.19e67.04)
13.60 (9.66e17.54) 15.11 (11.24e18.98) 17.53 (13.75e21.31) 19.48 (15.75e23.20) 21.14 (17.45e24.83) 22.60 (18.93e26.27) 23.92 (20.25e27.58) 25.69 (22.02e29.35) 27.27 (23.59e30.94) 29.60 (25.88e33.31) 31.65 (27.88e35.42) 33.50 (29.67e37.33) 35.19 (31.28e39.09) 38.20 (34.15e42.26) 40.85 (36.64e45.07)
11.41 (6.80e16.03) 12.72 (8.18e17.26) 14.84 (10.40e19.28) 16.56 (12.18e20.94) 18.04 (13.70e22.38) 19.36 (15.04e23.67) 20.54 (16.24e24.85) 22.15 (17.84e26.45) 23.59 (19.27e27.91) 25.73 (21.36e30.09) 27.62 (23.19e32.05) 29.33 (24.82e33.84) 30.90 (26.31e35.50) 33.72 (28.94e38.50) 36.22 (31.24e41.20)
AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole. a In dogs weighing 3 kg the lower 95% prediction interval for AMVA was negative in value, thus the range is represented within the table as < the upper 95% prediction interval.
Further investigation with a larger study population could help to clarify whether additional echocardiographic valvular changes can be identified when comparing normal dogs to those classified as ACVIM Stage B1. This is particularly relevant to routine screening of breeding dogs, where the ability to definitively identify early echocardiographic valvular changes referable to MMVD is especially important for accurate diagnosis and appropriate breeding recommendations. Due to the inherently diminutive size of the mitral valve leaflets, small changes in dimensions may reflect clinically relevant progression of pathology. The magnitude of differences between groups for many of the measurements in this study are on the order of millimeters and might be within the expected limits of measurement variability. Care must be taken to institute strict measurement standards for evaluation of these structures, lest measurement error obscure actual changes in valvular pathology. A transesophageal echocardiography study performed in humans has previously indicated that the diastolic thickness of the anterior mitral valve leaflet is greater in patients with mitral valve prolapse when compared to controls, while no significant difference was found when comparing measurements of systolic thickness between the groups.27 The increase in diastolic thickness was attributed to leaflet redundancy, overlap and deformation present only during this phase of the cardiac cycle.27 Systolic leaflet thickness was not
measured in the study presented here, nor was the degree of mitral valve prolapse quantified, thus we cannot establish whether concurrent mitral valve prolapse may have played a role in the apparent increases in mitral vale leaflet width and area in dogs with advanced MMVD. Given the established predilection for MMVD lesions in the dog to begin at the distal aspect of the valve near the line of closure, measurements taken during systole could obscure the thickest portion of the leaflet when the leaflet tips are fully apposed.5 Additionally, a comparative study between MMVD in humans and dogs indicated that the prevalence of marked mucoid degeneration and valvular deformity is common in dogs but rare in humans.4 These species differences suggest that observations specific to the measurement of the human mitral valve may not fully translate to similar measurements of the canine mitral valve. Further study is warranted for clarification. Comparison of the % CV between the parasternal long-axis 4-chamber view and the parasternal long-axis left ventricular outflow tract view in this study suggests that the parasternal long-axis 4-chamber view should be considered the preferred image plane for quantitative assessment of the mitral valve in the dog. The intraobserver and interobserver repeatability based on % CV were less than 10.4% for all measurements obtained from the parasternal long-axis 4-chamber view, with the exception of the interobserver repeatability of the AMVW. We suspect this has to do with
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Data are presented as mean (SD) in columns 1e3. Data in columns 4e6 present the difference of means between indicated groups (upper 95% confidence interval; lower 95% confidence interval). AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole; BW, body weight; CI, confidence interval. a significantly different from B2C (p < 0.01). b significantly different from B2C (p < 0.0001). c significantly different from B1 (p < 0.05).
(1.57; (0.68; (3.24; (2.64; (2.05; 0.95 0.48 2.21 1.89 1.4 0.14) 0.56) 1.83) 1.00) 0.80) (1.16; (0.89; (3.53; (2.24; (1.87; 0.65 0.73 2.68 1.62 1.33 0.99) 0.02) 0.68) 1.11) 0.79) (0.40; (0.47; (1.62; (0.58; (0.66; 0.30 0.25 0.47 0.26 0.07 (0.94) (0.34) (1.74) (1.13) (1.00) 6.46 1.29 5.13 10.63 8.48 AMVL/BW0.37 AMVW/BW0.41 AMVA/BW0.78 MVAd/BW0.37 MVAs/BW0.40
5.81 0.56 2.44 9.01 7.15
(0.52)a (0.04)b,c (0.32)b (0.52)b (0.60)b
5.51 0.81 2.92 8.75 7.08 s
(0.80)a (0.17)b (0.83)b (1.15)b (0.71)b
Control - B2/C Difference (95% CI) Control - B1 Difference (95% CI) B2/C B1 Control
Mitral valve measurements in 22 healthy dogs (control), 13 dogs in group B1, and 47 dogs in group B2/C. Table 3
0.33) 0.28) 1.18) 1.13) 0.75)
S. Wesselowski et al.
B1 e B2/C Difference (95% CI)
8
differences between observers in their choice of delineation between the edge of the valve leaflet and the many chordal attachments to the free edge of the valve. While this may reflect a limitation of this measurement if comparisons are made between observers, the intrabserver repeatability suggests that measurements obtained by the same observer do have value. Additionally, the RC for all measurements performed on the parasternal long-axis 4-chamber view suggest that minimal variability between measurements was attributable to differences between observers or within the same observer, with more variability attributed to the dog itself or to unexplained factors. This study has several limitations. Firstly, small sample size may have limited our ability to detect differences between the control group and the B1 group as previously mentioned. Additionally, the small sample size of the control population may have led to wider prediction intervals than those that could have been derived from investigation of a larger control group. Ideally, reference intervals should be derived from a much larger control population. Unfortunately, recruitment of cardiologically normal dogs without evidence of MMVD proved difficult during the study period. The mixed population of the control group may also represent a limitation, as breed specific measurements may be required for the most narrow prediction intervals. Another possible limitation relates to the potential introduction of unconscious bias due to an inability to blind the investigators to disease state or stage of disease. Finally, necropsy data was not available for study, thus direct comparisons between echocardiographic measurements and anatomic measurements could not be made. One previous study has shown no significant difference in echocardiographic measurement of mitral valve leaflet length obtained pre-mortem and anatomic measurements obtained postmortem, while measurements of leaflet area and width were not compared.28 The same study showed that echocardiographic measurements of the mitral valve annulus were significantly larger than the anatomic measurements, though the fixation process may have contributed to these differences.28 Despite these limitations, the data reported here does provide a starting point from which further study can continue to fine tune the echocardiographic delineation between normal and abnormal anatomy of the canine mitral valve. Repeatability data were obtained by repeated measurements of the same stored image loops, thus the ability of the same observer or a different observer to obtain similar measurements on new
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs images acquired at a different time was not evaluated. Furthermore, images were obtained from standard image planes that included full visualization of the left atrium and left ventricle in addition to the mitral valve itself. Images with a narrowed sector focusing on only the mitral valve itself or images obtained with magnification of the mitral valve may have improved resolution and repeatability. Finally, the differentiation of valvular thickening attributable to MMVD from that attributable to normal aging remains a significant challenge, with gross and histologic findings ascribed to each group bearing substantial similarities.29 The severity of mitral valve lesions in dogs with MMVD has previously been correlated to increasing age.3,30 Indeed, some have proposed that aging itself is likely a part of the pathogenesis of MMVD,4 though the complex etiology of MMVD in the dog remains unresolved. Within our study groups, age was lowest in the control group and highest in the B2/C group. The AMVW increased sequentially and significantly from the control group to the B1 group, and from the B1 group to the B2/C group. Without an age-matched control group it remains difficult to differentiate the degree of valvular thickening that is attributable to MMVD pathology alone versus that attributable to advancing age. Even with an age-matched control group, histologic study would likely be needed for further clarification, as some dogs that have been deemed normal based on physical exam and echocardiography have been shown to have mild to moderate myxomatous degeneration when examined histologically.31 In normal human hearts, age-related changes in mitral valve thickness have been investigated using autopsy specimens to stratify expected valve width across various age ranges.10 Similar investigation is warranted in veterinary medicine and could help clarify where to draw the line between normal aging change and true pathology.
Conclusions In conclusion, measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on the allometric relationship between mitral valve dimensions and body size. Reference intervals have been proposed over a range of body sizes. Relative to normal dogs, the diameter of the mitral valve annulus as well as the thickness, length and area of the anterior mitral valve leaflet are greater in patients with advanced MMVD.
9
Conflict of interest The authors declare no conflict of interest.
References 1. Detweiler DK, Patterson DF. The prevalence and types of cardiovascular disease in dogs. Ann N. Y Acad Sci 1965;127: 481e516. 2. Borgarelli M, Haggstrom J. Canine degenerative myxomatous mitral valve disease: natural history, clinical presentation and therapy. Vet Clin North Am Small Anim Pract 2010;40:651e663. 3. Whitney JC. Observations on the effect of age on the severity of heart valve lesions in the dog. J Small Anim Pract 1974;15:511e522. 4. Pomerance A, Whitney JC. Heart valve changes common to man and dog: a comparative study. Cardiovasc Res 1970;4: 61e66. 5. Buchanan JW. Chronic valvular disease (endocardiosis) in dogs. Adv Vet Sci Comp Med 1977;21:75e106. 6. Han RI, Black A, Culshaw G, French AT, Corcoran BM. Structural and cellular changes in canine myxomatous mitral valve disease: an image analysis study. J Heart Valve Dis 2010;19:60e70. 7. Pedersen HD, Haggstrom J. Mitral valve prolapse in the dog: a model of mitral valve prolapse in man. Cardiovasc Res 2000;47:234e243. 8. Fox PR. Pathology of myxomatous mitral valve disease in the dog. J Vet Cardiol 2012;14:103e126. 9. Babburi H, Oommen R, Brofferio A, Ilercil A, Frater R, Shirani J. Functional anatomy of the normal mitral apparatus: a transthoracic, two-dimensional echocardiographic study. J Heart Valve Dis 2003;12:180e185. 10. Sahasakul Y, Edwards WD, Naessens JM, Tajik AJ. Agerelated changes in aortic and mitral valve thickness: Implications for two-dimensional echocardiography based on an autopsy study of 200 normal human hearts. Am J Cardiol 1988;62:424e430. 11. Takamoto T, Nitta M, Tsujibayashi T, Taniguchi K, Marumo F. The prevalence and clinical features of pathologically abnormal mitral valve leaflets (myxomatous mitral valve) in the mitral valve prolapse syndrome: an echocardiographic and pathological comparative study. J Cardiol Suppl 1991; 25:75e86. 12. Bonow RO, Carabello BA, Kanu C, de Leon Jr AC, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS, Smith Jr SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Nishimura R, Page RL, Riegel B. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84e231. 13. Olsen LH, Martinussen T, Pedersen HD. Early echocardiographic predictors of myxomatous mitral valve disease in dachshunds. Vet Rec 2003;152:293e297.
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14. Boon JA. Veterinary echocardiography. 2nd ed. Ames, Iowa: Wiley-Blackwell; 2011. 15. Pedersen HD, Lorentzen KA, Kristensen BO. Observer variation in the two-dimensional echocardiographic evaluation of mitral valve prolapse in dogs. Vet Radiol Ultrasound 1996; 37:367e372. 16. Brown S, Atkins C, Bagley R, Carr A, Cowgill L, Davidson M, Egner B, Elliott J, Henik R, Labato M, Littman M, Polzin D, Ross L, Snyder P, Stepien R. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 2007;21:542e558. 17. Atkins C, Bonagura J, Ettinger S, Fox P, Gordon S, Haggstrom J, Hamlin R, Keene B, Luis-Fuentes V, Stepien R. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23: 1142e1150. 18. Wesselowski S, Borgarelli M, Bello NM, Abbott J. Discrepancies in identification of left atrial enlargement using left atrial volume versus left atrial-to-aortic root ratio in dogs. J Vet Intern Med 2014;28:1527e1533. 19. Cornell CC, Kittleson MD, Della Torre P, Haggstrom J, Lombard CW, Pedersen HD, Vollmar A, Wey A. Allometric scaling of M-mode cardiac measurements in normal adult dogs. J Vet Intern Med 2004;18:311e321. 20. Bland JM, Altman DG. Measuring agreement in method comparison studies. Stat Methods Med Res 1999;8:135e160. 21. Pinna GD, Maestri R, Torunski A, Danilowicz-Szymanowicz L, Szwoch M, La Rovere MT, Raczak G. Heart rate variability measures: a fresh look at reliability. Clin Sci 2007;113: 131e140. 22. Holt JP, Rhode EA, Kines H. Ventricular volumes and body weight in mammals. Am J Physiol 1968;215:704e715.
23. Holt JP, Rhode EA, Holt WW, Kines H. Geometric similarity of aorta, venae cavae, and certain of their branches in mammals. Am J Physiol 1981;241:R100eR104. 24. Gutgesell HP, Rembold CM. Growth of the human heart relative to body surface area. Am J Cardiol 1990;65:662e668. 25. Batterham AM, George KP, Whyte G, Sharma S, McKenna W. Scaling cardiac structural data by body dimensions: a review of theory, practice, and problems. Int J Sports Med 1999;20:495e502. 26. Trafny DJ, Freeman LM, Bulmer BJ, MacGregor JM, Rush JE, Meurs KM, Oyama MA. Auscultatory, echocardiographic, biochemical, nutritional, and environmental characteristics of mitral valve disease in Norfolk terriers. J Vet Cardiol 2012;14:261e267. 27. Louie EK, Langholz D, Mackin WJ, Wallis DE, Jacobs WR, Scanlon PJ. Transesophageal echocardiographic assessment of the contribution of intrinsic tissue thickness to the appearance of a thick mitral valve in patients with mitral valve prolapse. J Am Coll Cardiol 1996;28:465e471. 28. Borgarelli M, Tursi M, La Rosa G, Savarino P, Galloni M. Anatomic, histologic, and two-dimensionalechocardiographic evaluation of mitral valve anatomy in dogs. Am J Vet Res 2011;72:1186e1192. 29. Connell PS, Han RI, Grande-Allen KJ. Differentiating the aging of the mitral valve from human and canine myxomatous degeneration. J Vet Cardiol 2012;14:31e45. 30. Kogure K. Pathology of chronic mitral valvular disease in the dog. Nihon Juigaku Zasshi 1980;42:323e335. 31. Borgarelli M, Tursi M, Rosa GL, Savarino P, Galloni M. Anatomic, histologic, and two-dimensional-echocardiographic evaluation of mitral valve anatomy in dogs. Am J Vet Res 2011;72:1186e1192.
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Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease S. Wesselowski, DVM, MS*, M. Borgarelli, DMV, PhD , G. Menciotti, DVM , J. Abbott, DVM Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA 24061, USA Received 5 July 2014; received in revised form 8 January 2015; accepted 16 January 2015
KEYWORDS Canine; Anterior leaflet; Annulus; Reference intervals
Abstract Objectives: To further characterize the echocardiographic anatomy of the canine mitral valve apparatus in normal dogs and in dogs affected by myxomatous mitral valve disease (MMVD). Animals: Twenty-two normal dogs and 60 dogs with MMVD were prospectively studied. Methods: The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured in the control group and the affected group, as were the diameters of the mitral valve annulus in diastole (MVAd) and systole (MVAs). The dogs with MMVD were staged based on American College of Veterinary Internal Medicine (ACVIM) guidelines and separated into groups B1 and B2/C. All measurements were indexed to body weight based on empirically defined allometric relationships. Results: There was a statistically significant relationship between all log10 transformed mitral valve dimensions and body weight. The AMVL, AMVW, AMVA, MVAd and MVAs were all significantly greater in the B2/C group compared to the B1 and control groups. The AMVW was also significantly greater in the B1 group compared to the control group. Interobserver % coefficient of variation (% CV) was <10% for AMVL, AMVA, MVAd and MVAs, but was 29.6% for AMVW. Intraobserver % CV was <10.4% for all measurements. Conclusions: Measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on allometric relationships.
* Corresponding author. E-mail address: [email protected] (S. Wesselowski). http://dx.doi.org/10.1016/j.jvc.2015.01.003 1760-2734/ª 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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S. Wesselowski et al. Preliminary reference intervals have been proposed over a range of body sizes. Relative to normal dogs, AMVL, AMVW, AMVA, MVAd and MVAs are greater in patients with advanced MMVD. ª 2015 Elsevier B.V. All rights reserved.
Abbreviations ACVIM American College of Veterinary Internal Medicine AMVA anterior mitral valve leaflet area AMVL anterior mitral valve leaflet length AMVW anterior mitral valve leaflet width MMVD myxomatous mitral valve disease MVAd mitral valve annulus diameter in diastole MVAs mitral valve annulus diameter in systole RC repeatability coefficients % CV % coefficient of variation
Introduction The most common acquired cardiac disease in canine patients is myxomatous mitral valve disease (MMVD).1,2 Gross pathology of affected mitral valve leaflets exhibits a wide spectrum of lesion severity; some dogs develop only mild nodular thickening of the leaflets, while others are found to have lengthening or rupture of the chordae tendineae with elongated and severely thickened leaflets.3,4 Dilation of the mitral valve annulus also develops in association with long-standing mitral regurgitation due to MMVD.5 Histopathology of affected leaflets shows an accumulation of proteoglycans and glycosaminoglycans in combination with connective tissue derangements.4e8 Standardized echocardiographic criteria distinguish between normal and abnormal mitral valve morphology in humans, but despite the high prevalence of MMVD in dogs, similar criteria for use in canine echocardiography have not been established.9e11 The lack of objective or quantitative echocardiographic criteria has hampered systematic investigation of the relationships between structural mitral valve abnormalities and clinical assessments of disease severity. Additionally, the prognostic relevance of abnormal mitral valve anatomy associated with MMVD in dogs has not been fully evaluated. In humans, mitral valve leaflets measuring 5 mm or greater in width during diastole are known to be a predictor of
complications associated with MMVD.12 The prognostic relevance of systolic thickness of the anterior mitral valve leaflet has been investigated in dachshunds, but this variable was not predictive of increases in left atrial and left ventricular enddiastolic diameters over a 3-year period.13 Further study of prognostic indicators related to mitral valve anatomy in dogs is needed. The image plane utilized most commonly for evaluation of the mitral valve in people, especially with regard to diagnosis of mitral valve prolapse, is the parasternal long axis view. This view corresponds most closely to the veterinary image plane known as the right parasternal long-axis left ventricular outflow view, which allows visualization of the aorta in addition to the left atrium, left ventricle and mitral valve leaflets.14 The right parasternal long-axis 4-chamber view, though not a standard image plane in human cardiology, is also considered a standard echocardiographic view for assessment of the canine mitral valve.7,14,15 Both views provide visualization of the mitral valve apparatus; however, the optimal image plane for assessment of the mitral valve in dogs has not been critically assessed. The goals of this study were: 1) to evaluate the relationships between mitral valve measurements and body size; 2) to propose preliminary reference intervals for echocardiographic measurements of the anterior mitral valve leaflet and the mitral valve annulus in normal dogs; 3) to determine which echocardiographic view provides more repeatable measurements of the mitral valve apparatus in dogs, and 4) to compare these echocardiographic measurements among groups of dogs defined by clinical stage of MMVD.
Animals, materials and methods The control group was made up of healthy dogs owned by faculty, staff and students of the Virginia Maryland Regional College of Veterinary Medicine as well as dogs presenting for pre-breeding cardiac screening to both the Virginia Maryland Regional College of Veterinary Medicine and the Kansas State University Veterinary Teaching Hospital.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs These dogs were evaluated with approval of the Virginia Tech Institutional Animal Care and Use Committee and were deemed cardiologically normal based on physical examination, complete echocardiographic evaluation and Dopplera blood pressure measurement. An ultrasound unitb equipped with 1.5e10 MHz phased array transducers was used to obtain standard M-mode, 2D, and Doppler blood flow measurements with contemporaneous electrocardiographic monitoring. Harmonic transducer settings were utilized for all studies. The frame rate of acquired images varied according to the transducer that was utilized and the machine settings that were required for patients of different size. Doppler blood pressure measurements were performed compliant with previously published recommendations.16 Criteria for exclusion included auscultation of a mid-systolic click or left apical systolic murmur, echocardiographic evidence of mitral valve prolapse or mitral regurgitation assessed as greater than trivial in severity, or evidence of cardiovascular or systemic disease expected to affect cardiovascular function. The study group comprised client-owned dogs that were presented to the Virginia Maryland Regional College of Veterinary Medicine Veterinary Teaching Hospital or the Kansas State University Veterinary Teaching Hospital for evaluation of MMVD. All dogs had complete echocardiographic evaluation and measurement of Doppler blood pressure. Thoracic radiographs were obtained only if clinically indicated. The diagnosis of MMVD was based on the echocardiographic identification of mitral valve thickening and/or prolapse, typically in combination with the presence of mitral regurgitation. In 3 cases, mitral valve prolapse was identified in 2 or more image planes in the absence of mitral regurgitation. Dogs were classified according to previously published American College of Veterinary Internal Medicine (ACVIM) staging guidelines.17 The distinction between Stage B1 and Stage B2 was based on radiographic and/or echocardiographic findings. Patients for which the vertebral heart scale exceeded 10.5, the echocardiographic left atrial volume indexed to body weight was greater than 1.1 ml/kg18 or the left ventricular end-diastolic dimension exceeded the upper limit of a published reference interval19 were classified as Stage B2. Dogs classified as Stage B1 made up one group while Stage B2 and Stage C
a b
811-B, Parks Medical Electronics, Inc, Aloha, OR. Vivid 7; GE-Medical, Milwaukee, WI.
3 dogs were grouped together (B2/C) to represent patients with advanced disease and cardiac remodeling. Both the control population and the study population were previously utilized for a separate echocardiographic study.18 Measurements of the mitral valve were obtained in the 4-chamber, right parasternal long-axis view and in the right parasternal long-axis left ventricular outflow view. The length (AMVL), width (AMVW) and area (AMVA) of the anterior mitral valve leaflet were measured during diastole, when the leaflet was fully extended (Fig. 1A). The length of the leaflet was measured as a straight line from the hinge point of the mitral valve annulus to the tip of the leaflet when the leaflet was best visualized as a fully extended line during early or late diastole. The width was determined by measuring the widest part of the extended leaflet. Finally, the area of the leaflet was obtained using planimetry to trace its border. The mitral valve annulus was measured at both end-diastole (MVAd) and end-systole (MVAs) by measuring the distance from mitral valve hinge point to hinge point (Fig. 1B and C), with frame-by-frame advancement utilized to accurately identify each hinge point location. The first frame after mitral valve closure and the last frame prior to mitral valve opening defined end-diastole and end-systole, respectively. All measurements were repeated on 3 consecutive cardiac cycles and averaged. Average values were used in the statistical analysis. One operator (SW) obtained measurements on all dogs and these data were subject to the principal analyses. Measurements of the same stored images were repeated in a randomly selected subset of 6 control dogs by SW one week after the initial measurements. A second operator (MB) also obtained measurements from the stored images of those 6 dogs. These data were used to assess intraobserver and inter-observer repeatability. Because remodeling (Stage B2 and C) was obvious to the operator from the 2D echocardiographic image plane, blinding of the operator was not attempted.
Statistical analysis A relationship between mitral valve dimensions and body size was assumed. Therefore, exploratory analyses were used to identify the most appropriate measure of body size with which to index echocardiographic variables. More specifically, simple linear regression was used to evaluate relationships between echocardiographic variables and body-weights of the control group. This procedure was repeated with calculated body surface area serving as the explanatory variable. To
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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Figure 1 2-Dimensional right parasternal long-axis 4-chamber view demonstrating the measurement of A: anterior mitral valve leaflet length, width, and area, B: mitral valve annulus diameter in diastole, and C: mitral valve annulus diameter in systole.
explore the possibility of an allometric relationship between mitral valve dimensions and body size, log10 transformed echocardiographic dimensions were regressed against the log10 of body weight. For each variable, goodness of fit, defined by the coefficient of determination (R-squared), was greatest for the linear relationship between log10 transformed echocardiographic data and log10 of body weight. The parameters of the regression equation were used to define the terms of the allometric equation: y ¼ axb where y is the response variable, a is the proportionality constant, x is body-weight and b is the scaling exponent. For inter-group comparisons, echocardiographic variables were indexed to body weight raised to the scaling exponent defined by the aforementioned allometric relationship. Intraobserver and interobserver repeatability of variables obtained from the 4-chamber right parasternal long-axis view and from the right parasternal long-axis left ventricular outflow view were assessed through calculation of the % coefficient of variation (% CV). These values are presented in Table 1. Relative to those obtained from the right parasternal long-axis left ventricular outflow view, values of % CV were consistently lower for variables obtained from the 4-chamber right parasternal long-axis view. Additionally, right parasternal left ventricular outflow view images from five patients within the study group were of insufficient quality to obtain all measured variables. Therefore, further analyses were performed only on data obtained from the 4-chamber right parasternal long-axis image plane. Intraobserver and interobserver repeatability of variables obtained from the 4-chamber right
parasternal long-axis image plane were further characterized through calculation of repeatability coefficients (RC).20,21 Specifically, a mixed linear model that included the fixed effects of observer and time as well as the random effect of dog was developed. Variance components were derived from this model and used to calculate the RC. In some cases, measurement variability attributed to the operator was negligible and generated RC of zero. These data are presented in Table 1. Predicted values and 95% prediction intervals were derived from the allometric relationship between echocardiographic variables and bodysize and from these data, reference intervals for
Table 1 Percent coefficient of variation (% CV) and repeatability coefficients (RC) (linear dimensionsmm/area-mm2) of mitral valve measurements.
AMVL AMVW AMVA MVAd MVAs
CV(%) RC CV(%) RC CV(%) RC CV(%) RC CV(%) RC
Intraobserver
Interobserver
RP4
RPLVOT
RP4
RPLVOT
3.12 1.33 7.67 0.35 10.33 0.00 1.65 0.00 0.73 0.37
6.25
5.16 0.00 29.62 1.28 9.99 2.49 5.40 3.72 3.16 1.87
14.47
12.49 13.08 2.50 1.46
41.62 18.94 8.35 13.72
RP4, right parasternal 4-chamber view; RPLVOT, right parasternal left ventricular outflow tract view; Bold values: % CV; Italic values: RC; AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole.
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs ranges of body-weights were developed. Comparisons between study groups were by one-way analysis of variance for normally distributed data, and by a Kruskall-Wallis analysis of variance for data that were not normally distributed. When these tests disclosed a statistically significant difference between groups, post-hoc evaluation consisted of the Tukey’s HSD test or Steel-Dwass test as appropriate, based on distribution of data. Normally distributed data are presented as mean (SD) while non-normally distributed are presented as median (range). A p value of <0.05 was considered significant. Distributions of data and residual plots were graphically evaluated to ensure that the assumptions implicit in the use of statistical methods were met.
Results Twenty-two cardiologically normal dogs of 12 different breeds were enrolled in the control group. Ten dogs were of mixed breed origin, 2 were beagles, and the remaining 10 breeds were represented by 1 dog each. The mean age of the control group was 4.6 years (2.0 years) and median weight was 14.25 kg (4e37.1 kg). Sixty client-owned dogs with MMVD were enrolled in the study group. Twenty-seven breeds were represented, with the most common breeds being Cavalier King Charles spaniel (n ¼ 9), Toy Poodle (n ¼ 5), Pomeranian (n ¼ 4), Shih Tzu (n ¼ 3), Yorkshire terrier (n ¼ 3), and Labrador retriever (n ¼ 3). The median weight of the study group was 9.4 kg (2.5e51.5 kg) and the mean age was 10.5 years (2.7 years). Within the study group there were 13 dogs classified as ACVIM stage B1 and 47 classified as stage B2/C. The mean age of the dogs in group B1 was 8.3 years (2.5 years) and the mean age of the dogs in and in group B2/C was 11.1 years (2.5 years), both of which were significantly older than the mean age of dogs in the control group (p < 0.0001 and p < 0.001, respectively). Group B2/C dogs were also significantly older than those in group B1 (p ¼ 0.0011). The median body weight of dogs in group B1 was 17.4 kg (2.5e41.1 kg) and the median body weight of dogs in group B2/C was 7.7 kg (3.5e51.5 kg). There was no significant difference in body weight between the control group and group B1 (p ¼ 0.67), whereas body weight of group B2/C was significantly less than the weights of both the control group (p ¼ 0.027) and group B1 (p ¼ 0.028). There was a statistically significant relationship between all log transformed mitral valve
5 dimensions and body weight. Coefficients of determination (R-squared) for AMVL, AMVW, AMVA, MVAd and MVAs were 0.87, 0.93, 0.93, 0.93, and 0.88, respectively. The scaling exponents derived from these allometric relationships were close to the theoretical expectations of 0.33 for linear dimensions and 0.67 for areas; they were, respectively: 0.37, 0.41, 0.78, 0.37 and 0.4 for AMVL, AMVW, AMVA, MVAd and MVAs. Figure 2 relates measurements of AMVL, AMVW, AMVA, MVAd and MVAs from the control group to body-weight in scatterplot form. Table 2 shows predicted values for each mitral valve measurement for a range of body sizes. Comparisons of mitral valve measurements, indexed according to the empirically defined allometric relationship, are summarized in Table 3. The AMVL was significantly longer in the B2/C group compared to both the control group (p ¼ 0.0086) and the B1 group (p ¼ 0.0013). A significant difference between AMVL from the control group and dogs in stage B1 was not detected (p ¼ 0.56). The AMVW was significantly greater in the B2/C group compared to the control group (p < 0.001) and the B1 group (p < 0.001). Additionally, AMVW from the B1 group was significantly greater than AMVW from the control group (p ¼ 0.0296). The AMVA was significantly larger in the B2/C group than the control group (p < 0.001) and the B1 group (p < 0.001). There was no significant difference between the control group and the B1 group (p ¼ 0.5959) with respect to AMVA. MVAd was significantly greater in the B2/ C group than in the control group (p < 0.001) or the B1 group (p < 0.001), however there was no significant difference between the control group and the B1 group (p ¼ 0.7333). Finally, the dimension of the MVAs was also significantly greater in the B2/C group than the control group (p < 0.001) or the B1 group (p < 0.001). No significant difference in MVAs was found between the control group and the B1 group (p ¼ 0.9721).
Discussion The results of this study demonstrate an allometric relationship between mitral valve dimensions and body size. The scaling exponents derived for AMVL, AMVW, MVAd and MVAs were all close to the theoretical exponent of 1/3 expected for measurements related to body length, while the exponent derived for AMVA was close to the theoretical exponent of 2/3 for measurements related to body surface area. These findings are consistent with
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
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S. Wesselowski et al. data presented in previously published studies of allometric scaling.19,22e25 We have proposed reference intervals across a range of body sizes that provide the basis of standardized criteria that define the quantitative echocardiographic characteristics of the normal canine mitral valve. Previously published data on the echocardiographic anatomy of the normal mitral valve in dogs are limited to the results of a study in which seven Norfolk terriers made up the normal population.26 Additional study is warranted to determine whether breed-specific measurements provide a significant advantage in assessment of the normal mitral valve over the mixed population used to derive the reference intervals presented in this study. Comparisons between the mitral valve anatomy of the control group and the study groups presented here yielded expected differences. Increases in thickness, length and area of the anterior mitral valve leaflet were evident in more severely affected patients. These echocardiographic changes parallel the classic valvular remodeling reported on gross pathologic examination.3e5 Additionally, there was an increase in the diameter of the mitral valve annulus in both systole and diastole in patients with more advanced MMVD. Dilation of the mitral valve annulus in the more severely affected dogs in this study is consistent with the expected changes associated with chronic mitral regurgitation, volume overload, and enlargement of the left heart.5 All of the increases in each of the 5 measurements that were studied were significantly different when comparing the control group to the B2/C group with advanced MMVD. The only measurement that showed a significant difference between the control group and the B1 group, however, was AMVW. The lack of echocardiographic change related to the length and area of the anterior mitral valve leaflet in the B1 group may reflect the fact that more advanced disease is required before significant changes in these parameters can be appreciated by echocardiography, or may relate to an insufficient sample size of the B1 group. Annular dilation, on the other hand, would not be expected in ACVIM Stage B1 patients as this group was defined by the absence of chamber enlargement.
Figure 2 Control group data are presented in scatterplot form. The predicted value for each measurement is depicted by a solid line. Upper and lower 95%
prediction intervals are depicted by dashed lines. A: Anterior mitral valve leaflet length (AMVL); B: Anterior mitral valve leaflet width (AMVW); C: Anterior mitral valve leaflet area (AMVA); D: Mitral valve annulus diameter in diastole (MVAd); E: Mitral valve annulus diameter in systole (MVAs).
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs
7
Table 2
Normal mitral valve measurements and 95% prediction intervals for dogs of varying weights.
BW (Kg)
AMVL (mm)
3 4 6 8 10 12 14 17 20 25 30 35 40 50 60
8.95 (5.54e12.36) 9.90 (6.55e13.25) 11.42 (8.14e14.70) 12.64 (9.42e15.87) 13.69 (10.49e16.89) 14.61 (11.43e17.79) 15.44 (12.26e18.61) 16.55 (13.37e19.72) 17.54 (14.35e20.73) 19.01 (15.79e22.23) 20.30 (17.03e23.56) 21.46 (18.14e24.78) 22.52 (19.13e25.90) 24.41 (20.90e27.93) 26.08 (22.43e29.73)
AMVW (mm) 0.87 0.99 1.17 1.31 1.44 1.55 1.65 1.79 1.92 2.10 2.26 2.41 2.55 2.80 3.01
(0.58e1.17) (0.69e1.28) (0.88e1.45) (1.03e1.60) (1.16e1.72) (1.27e1.83) (1.38e1.93) (1.51e2.07) (1.64e2.20) (1.82e2.38) (1.98e2.55) (2.12e2.70) (2.25e2.85) (2.49e3.10) (2.69e3.34)
AMVA (mm2)
MVAd (mm)
MVAs (mm)
6.01 (<12.68a) 7.44 (0.81e14.06) 10.08 (3.55e16.62) 12.54 (6.07e19.01) 14.86 (8.44e21.28) 17.08 (10.69e23.47) 19.22 (12.85e25.59) 22.31 (15.95e28.67) 25.28 (18.91e31.65) 30.02 (23.59e36.46) 34.56 (28.01e41.12) 38.94 (32.22e45.65) 43.18 (36.27e50.08) 51.32 (43.95e58.70) 59.12 (51.19e67.04)
13.60 (9.66e17.54) 15.11 (11.24e18.98) 17.53 (13.75e21.31) 19.48 (15.75e23.20) 21.14 (17.45e24.83) 22.60 (18.93e26.27) 23.92 (20.25e27.58) 25.69 (22.02e29.35) 27.27 (23.59e30.94) 29.60 (25.88e33.31) 31.65 (27.88e35.42) 33.50 (29.67e37.33) 35.19 (31.28e39.09) 38.20 (34.15e42.26) 40.85 (36.64e45.07)
11.41 (6.80e16.03) 12.72 (8.18e17.26) 14.84 (10.40e19.28) 16.56 (12.18e20.94) 18.04 (13.70e22.38) 19.36 (15.04e23.67) 20.54 (16.24e24.85) 22.15 (17.84e26.45) 23.59 (19.27e27.91) 25.73 (21.36e30.09) 27.62 (23.19e32.05) 29.33 (24.82e33.84) 30.90 (26.31e35.50) 33.72 (28.94e38.50) 36.22 (31.24e41.20)
AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole. a In dogs weighing 3 kg the lower 95% prediction interval for AMVA was negative in value, thus the range is represented within the table as < the upper 95% prediction interval.
Further investigation with a larger study population could help to clarify whether additional echocardiographic valvular changes can be identified when comparing normal dogs to those classified as ACVIM Stage B1. This is particularly relevant to routine screening of breeding dogs, where the ability to definitively identify early echocardiographic valvular changes referable to MMVD is especially important for accurate diagnosis and appropriate breeding recommendations. Due to the inherently diminutive size of the mitral valve leaflets, small changes in dimensions may reflect clinically relevant progression of pathology. The magnitude of differences between groups for many of the measurements in this study are on the order of millimeters and might be within the expected limits of measurement variability. Care must be taken to institute strict measurement standards for evaluation of these structures, lest measurement error obscure actual changes in valvular pathology. A transesophageal echocardiography study performed in humans has previously indicated that the diastolic thickness of the anterior mitral valve leaflet is greater in patients with mitral valve prolapse when compared to controls, while no significant difference was found when comparing measurements of systolic thickness between the groups.27 The increase in diastolic thickness was attributed to leaflet redundancy, overlap and deformation present only during this phase of the cardiac cycle.27 Systolic leaflet thickness was not
measured in the study presented here, nor was the degree of mitral valve prolapse quantified, thus we cannot establish whether concurrent mitral valve prolapse may have played a role in the apparent increases in mitral vale leaflet width and area in dogs with advanced MMVD. Given the established predilection for MMVD lesions in the dog to begin at the distal aspect of the valve near the line of closure, measurements taken during systole could obscure the thickest portion of the leaflet when the leaflet tips are fully apposed.5 Additionally, a comparative study between MMVD in humans and dogs indicated that the prevalence of marked mucoid degeneration and valvular deformity is common in dogs but rare in humans.4 These species differences suggest that observations specific to the measurement of the human mitral valve may not fully translate to similar measurements of the canine mitral valve. Further study is warranted for clarification. Comparison of the % CV between the parasternal long-axis 4-chamber view and the parasternal long-axis left ventricular outflow tract view in this study suggests that the parasternal long-axis 4-chamber view should be considered the preferred image plane for quantitative assessment of the mitral valve in the dog. The intraobserver and interobserver repeatability based on % CV were less than 10.4% for all measurements obtained from the parasternal long-axis 4-chamber view, with the exception of the interobserver repeatability of the AMVW. We suspect this has to do with
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Data are presented as mean (SD) in columns 1e3. Data in columns 4e6 present the difference of means between indicated groups (upper 95% confidence interval; lower 95% confidence interval). AMVL, anterior mitral valve length; AMVW, anterior mitral valve width; AMVA, anterior mitral valve area; MVAd, mitral valve annulus diameter in diastole; MVAs, mitral valve annulus diameter in systole; BW, body weight; CI, confidence interval. a significantly different from B2C (p < 0.01). b significantly different from B2C (p < 0.0001). c significantly different from B1 (p < 0.05).
(1.57; (0.68; (3.24; (2.64; (2.05; 0.95 0.48 2.21 1.89 1.4 0.14) 0.56) 1.83) 1.00) 0.80) (1.16; (0.89; (3.53; (2.24; (1.87; 0.65 0.73 2.68 1.62 1.33 0.99) 0.02) 0.68) 1.11) 0.79) (0.40; (0.47; (1.62; (0.58; (0.66; 0.30 0.25 0.47 0.26 0.07 (0.94) (0.34) (1.74) (1.13) (1.00) 6.46 1.29 5.13 10.63 8.48 AMVL/BW0.37 AMVW/BW0.41 AMVA/BW0.78 MVAd/BW0.37 MVAs/BW0.40
5.81 0.56 2.44 9.01 7.15
(0.52)a (0.04)b,c (0.32)b (0.52)b (0.60)b
5.51 0.81 2.92 8.75 7.08 s
(0.80)a (0.17)b (0.83)b (1.15)b (0.71)b
Control - B2/C Difference (95% CI) Control - B1 Difference (95% CI) B2/C B1 Control
Mitral valve measurements in 22 healthy dogs (control), 13 dogs in group B1, and 47 dogs in group B2/C. Table 3
0.33) 0.28) 1.18) 1.13) 0.75)
S. Wesselowski et al.
B1 e B2/C Difference (95% CI)
8
differences between observers in their choice of delineation between the edge of the valve leaflet and the many chordal attachments to the free edge of the valve. While this may reflect a limitation of this measurement if comparisons are made between observers, the intrabserver repeatability suggests that measurements obtained by the same observer do have value. Additionally, the RC for all measurements performed on the parasternal long-axis 4-chamber view suggest that minimal variability between measurements was attributable to differences between observers or within the same observer, with more variability attributed to the dog itself or to unexplained factors. This study has several limitations. Firstly, small sample size may have limited our ability to detect differences between the control group and the B1 group as previously mentioned. Additionally, the small sample size of the control population may have led to wider prediction intervals than those that could have been derived from investigation of a larger control group. Ideally, reference intervals should be derived from a much larger control population. Unfortunately, recruitment of cardiologically normal dogs without evidence of MMVD proved difficult during the study period. The mixed population of the control group may also represent a limitation, as breed specific measurements may be required for the most narrow prediction intervals. Another possible limitation relates to the potential introduction of unconscious bias due to an inability to blind the investigators to disease state or stage of disease. Finally, necropsy data was not available for study, thus direct comparisons between echocardiographic measurements and anatomic measurements could not be made. One previous study has shown no significant difference in echocardiographic measurement of mitral valve leaflet length obtained pre-mortem and anatomic measurements obtained postmortem, while measurements of leaflet area and width were not compared.28 The same study showed that echocardiographic measurements of the mitral valve annulus were significantly larger than the anatomic measurements, though the fixation process may have contributed to these differences.28 Despite these limitations, the data reported here does provide a starting point from which further study can continue to fine tune the echocardiographic delineation between normal and abnormal anatomy of the canine mitral valve. Repeatability data were obtained by repeated measurements of the same stored image loops, thus the ability of the same observer or a different observer to obtain similar measurements on new
Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003
Mitral anatomy in dogs images acquired at a different time was not evaluated. Furthermore, images were obtained from standard image planes that included full visualization of the left atrium and left ventricle in addition to the mitral valve itself. Images with a narrowed sector focusing on only the mitral valve itself or images obtained with magnification of the mitral valve may have improved resolution and repeatability. Finally, the differentiation of valvular thickening attributable to MMVD from that attributable to normal aging remains a significant challenge, with gross and histologic findings ascribed to each group bearing substantial similarities.29 The severity of mitral valve lesions in dogs with MMVD has previously been correlated to increasing age.3,30 Indeed, some have proposed that aging itself is likely a part of the pathogenesis of MMVD,4 though the complex etiology of MMVD in the dog remains unresolved. Within our study groups, age was lowest in the control group and highest in the B2/C group. The AMVW increased sequentially and significantly from the control group to the B1 group, and from the B1 group to the B2/C group. Without an age-matched control group it remains difficult to differentiate the degree of valvular thickening that is attributable to MMVD pathology alone versus that attributable to advancing age. Even with an age-matched control group, histologic study would likely be needed for further clarification, as some dogs that have been deemed normal based on physical exam and echocardiography have been shown to have mild to moderate myxomatous degeneration when examined histologically.31 In normal human hearts, age-related changes in mitral valve thickness have been investigated using autopsy specimens to stratify expected valve width across various age ranges.10 Similar investigation is warranted in veterinary medicine and could help clarify where to draw the line between normal aging change and true pathology.
Conclusions In conclusion, measurements of the anterior mitral valve leaflet and the mitral valve annulus in the dog can be indexed to body weight based on the allometric relationship between mitral valve dimensions and body size. Reference intervals have been proposed over a range of body sizes. Relative to normal dogs, the diameter of the mitral valve annulus as well as the thickness, length and area of the anterior mitral valve leaflet are greater in patients with advanced MMVD.
9
Conflict of interest The authors declare no conflict of interest.
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Please cite this article in press as: Wesselowski S, et al., Echocardiographic anatomy of the mitral valve in healthy dogs and dogs with myxomatous mitral valve disease, Journal of Veterinary Cardiology (2015), http://dx.doi.org/10.1016/j.jvc.2015.01.003