Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease

Journal of Veterinary Cardiology (2016) -, -e- www.elsevier.com/locate/jvc Left atrial volume and function in dogs with naturally occurring myxomat...

769KB Sizes 0 Downloads 81 Views

Journal of Veterinary Cardiology (2016)

-, -e-

www.elsevier.com/locate/jvc

Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease ¨llmer, DVM, PhD a,*, J.L. Willesen, DVM, PhD a, M. Ho A. Tolver, MSc, PhD b, J. Koch, DVM, PhD a a

Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark b Department of Mathematics and Statistics, Faculty of Sciences, University of Copenhagen, Copenhagen, Denmark Received 4 March 2016; received in revised form 10 July 2016; accepted 19 August 2016

KEYWORDS Biplane area-length method; Left atrial size; Volumetric function; Active left atrial emptying fraction; Congestive heart failure

Abstract Objective: Myxomatous mitral valve disease (MMVD) induces progressive left atrial (LA) enlargement. The LA modulates left ventricular filling and performance through its reservoir, conduit, and contractile function. Assessment of LA size and function may provide valuable information on the level of cardiac compensation. Left atrial function in dogs with naturally occurring MMVD remains largely unexplored. The objective of this study was to evaluate LA volume and function in dogs with naturally occurring MMVD. Animals: This prospective study included 205 client-owned dogs of different breeds, 114 healthy dogs, and 91 dogs with MMVD of different disease severities. Methods: Using two-dimensional echocardiography, the biplane area-length method was applied to assess LA volume and calculate volumetric indices of LA reservoir, conduit, and contractile function. Results: Left atrial volume and LA stroke volume increased, whereas LA reservoir and contractile function decreased with increasing disease severity. A maximal LA volume <2.25mL/kg was the optimal cut off identified for excluding congestive heart failure in dogs with chronic MMVD with a sensitivity of 96% and a specificity of 100%. An active LA emptying fraction <24% and/or a LA expansion index <126% were suggestive of congestive heart failure in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% and a sensitivity of 82% and a specificity of 82%, respectively.

* Corresponding author. E-mail address: [email protected] (M. Ho ¨llmer). http://dx.doi.org/10.1016/j.jvc.2016.08.006 1760-2734/ª 2016 Elsevier B.V. All rights reserved.

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

2

M. Ho ¨llmer et al. Conclusion: Dogs with MMVD appear to have larger LA volumes with poorer LA function. Deteriorating LA function, characterized by a decreasing reservoir and active contractile function, was evident in dogs with MMVD with increasing disease severity. ª 2016 Elsevier B.V. All rights reserved.

Abbreviations 2D two-dimensional BW body weight CI confidence interval CHF congestive heart failure ECG electrocardiogram HR heart rate LA left atrial/atrium LAE left atrial emptying LAEF left atrial emptying fraction LA P-volume preatrial contraction volume LASV left atrial stroke volume LV left ventricle/ventricular LVIDd left ventricular internal dimension in diastole LVSF left ventricular systolic function MMVD myxomatous mitral valve disease MR mitral regurgitation Peak E peak velocity of early diastolic transmitral flow Peak E0 peak early tissue Doppler mitral annulus velocity Peak TR peak velocity of tricuspid regurgitation ROC receiver operating characteristic SF shortening fraction TR tricuspid regurgitation

Introduction Myxomatous mitral valve disease (MMVD) is the most commonly acquired heart disease in dogs [1]. Dogs with MMVD usually remain asymptomatic for a long time, but eventually the hemodynamic changes resulting from mitral regurgitation (MR) may progress to congestive heart failure (CHF) [2]. Mitral regurgitation induces progressive cardiac remodeling, characterized by left atrial (LA) dilation and eccentric hypertrophy of the left ventricle (LV) [3]. Conventional indices of LV function are difficult to interpret in MMVD and the normal or increased shortening and ejection fractions may mask underlying ventricular dysfunction [3,4]. Therefore, identification of other features indicative of disease progression is important.

The LA plays an important role in cardiac performance by modulating LV filling through its reservoir, conduit, and contractile functions [5,6]. Therefore, assessment of LA size and function may provide valuable information on the level of cardiac compensation. In addition, LA size has been recognized as a strong predictor of outcome in dogs with MMVD [7,8]. However, little is known about LA volume and function in dogs with naturally occurring MMVD. Left atrial volumes and functions can be evaluated using two-dimensional (2D) or threedimensional echocardiography. Recently, reference values for LA volume and function in healthy dogs using the 2D biplane area-length method were established, and the method was shown to be a feasible and reproducible method for LA assessment in dogs [9,10]. To investigate the effect of MMVD on atrial volume and function, we conducted a study in a group of dogs with naturally occurring MMVD of different disease severities. We hypothesized that there would be differences in LA volume and function between the different stages of MMVD, with deteriorating atrial function with increasing disease severity. Accordingly, the aims of this study were (1) to characterize LA volume, reservoir, conduit, and contractile function using the 2D biplane area-length method in dogs with MMVD, and (2) to determine an optimal cut-off value of LA indices to identify the absence or presence of CHF in dogs with chronic MMVD.

Materials and methods Animals This prospective study included 205 client-owned dogs, 91 dogs with MMVD, and 114 healthy control dogs. None of the dogs included in the study had received any medication in the 4 weeks before the initial examination. Control dogs were considered healthy based on the absence of owner-reported clinical signs and unremarkable serum biochemical and C-reactive protein results, together with normal results from

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

Left atrial volume and function in dogs physical, electrocardiogram (ECG), M-mode, 2D, and Doppler examinations. Most control dogs were part of a previous study that established reference values for LA volume in dogs using the biplane area-length method [9]. Diagnostic criteria for MMVD included thickened and/or prolapsed mitral valve leaflets and MR detected on color Doppler [11]. If signs of respiratory problems were reported by the owner and/ or observed during the clinical examination, and/or echocardiographic findings indicative of pulmonary hypertension (tricuspid regurgitation > 3m/s) were identified, thoracic radiographs were taken. Dogs with MMVD were staged according to the American College of Veterinary Internal Medicine classification system [12]. Asymptomatic dogs (stage B) were further subclassified into stage B1 (normal cardiac size) and stage B2 (enlarged heart) [12]. Cardiac enlargement was defined by LV internal end-diastolic dimension above the respective reference ranges and/or maximal LA volume > 0.92mL/kg (LA enlargement was defined as the indexed maximal LA volume above the 95th percentile in a group of healthy dogs) [9,13]. Dogs with CHF were defined as having clinical signs of CHF (e.g. cough, dyspnea, exercise intolerance), echocardiographic changes compatible with CHF (e.g. LA enlargement, increased transmitral valve flow velocity, presence of postcapillary venous pulmonary hypertension), radiographic signs of pulmonary edema (e.g. LA enlargement, pulmonary venous congestion, interstitial/alveolar pulmonary infiltrates), and response to diuretic treatment. Dogs with comorbidities were excluded. The study was approved by the Ethical Committee at the Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Denmark (Ref: 18/2008).

Echocardiography All echocardiographic studies were performed by a single cardiac sonographer using a Vivid 7 ultrasonographic system (GE Healthcare) equipped with a 4M MHz and a 5S MHz phased-array transducer. All dogs were examined gently restrained without sedation in right and left lateral recumbency. Each dog underwent a complete echocardiographic examination, which included transthoracic 2D, M-mode, spectral, and color flow Doppler imaging with continuous ECG monitoring according to recommendations [14,15]. Left ventricular wall and chamber dimensions were measured from the right parasternal long-

3 axis view. Mitral inflow was assessed by pulsedwave Doppler echocardiography from the apical four-chamber view. From the mitral inflow profile, the E-wave velocity and A-wave velocity were measured. The ratio between peak early (E) and late (A) diastolic LV filling velocities was used to assess LV diastolic function. All echocardiographic analyses were carried out offline by one operator blinded to the disease status of the dogs on images stored as digital data using the EchoPAC for PC, version 113 (GE Healthcare). All measurements were made on three consecutive cardiac cycles, and mean values were used in the statistical analysis.

LA volume and function Left atrial volumes were measured using the biplane area-length method from the left apical four- and two-chamber views with the dog in left lateral recumbent position as previously described in dogs [9]. Left atrial volumes were calculated as: 8 ðA1  A2 Þ=½ðL1 þ L2 Þ=2 3p ¼ ð0:85  A1  A2 Þ=½ðL1 þ L2 Þ=2

LA volume ¼

where A1 is the planimetered area and L1 the length in the apical four-chamber view, A2 the planimetered area and L2 the length in the apical two-chamber view. The LA area was traced along the inner border of the atrial wall, excluding the confluence of the pulmonary veins and the LA appendage. A straight line connecting both hinge points of the mitral leaflets was taken as the border to the left ventricle, thus excluding the funnel of the mitral valve leaflets from the LA tracing. The length was measured from the center of the mitral annular plane to the superior border of the chamber [16,17]. Left atrial measurements were done at three time-points (1) immediately before the mitral valve opening (maximal LA volume); (2) at the onset of the P-wave on the ECG (preatrial contraction volume or LA P-volume); and (3) at mitral valve closure (minimal LA volume). All LA volumes and LA stroke volumes were indexed to body weight (BW) [9]. From these volumes, several variables were derived to assess reservoir, conduit, and contractile function (Table 1) [6,18,19]. The reproducibility and the feasibility of the biplane area-length measurements of LA volume and function in dogs have previously been reported in studies conducted in our group [9,20].

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

4

M. Ho ¨llmer et al. Table 1

Left atrial function assessment and related calculations.

Reservoir function

Conduit function

Contractile function

Total LASV ¼ maximal LA volume  minimal LA volume

Passive LA stroke volume ¼ maximal LA volume  LA P-volume

Active LA stroke volume ¼ LA P-volume  minimal LA volume

LA expansion index (compliance) ¼ LASV/minimal LA volume (%)

Passive LA emptying percentage of total emptying ¼ passive LASV/ total LASV (%)

Active LA emptying percentage of total emptying ¼ active LASV/total LASV (%)

Total LA emptying fraction ¼ LASV/ maximal LA volume (%)

Passive LA emptying fraction ¼ passive LASV/maximal LA volume (%)

Active LA emptying fraction ¼ active LASV/LA P-volume (%)

Statistical analysis Fisher’s exact tests were used to compare healthy dogs and dogs with MMVD with respect to sex. Continuous variables were compared using one-way analysis of variance to test for differences between healthy dogs and dogs with MMVD (stage B1, B2, or C). Post hoc pairwise comparisons between MMVD groups were made using either t-test or Fisher’s exact test on 22 tables and the p values were adjusted using Holm’s method to maintain the prespecified significance level. Non-normally distributed variables (age, heart rate [HR], BW, LA volumes, and LA stroke volumes) were logtransformed before analysis. Normally distributed variables were presented as mean  standard deviation (SD), whereas non-normally distributed variables were reported as median (range). Linear regression was used to examine the association between indexed total LA stroke volume and indexed maximal LA volume. A regression model including a quadratic term was used to determine

the association between total LA emptying fraction and indexed LA volumes, HR, and age. We report the coefficient of determination (R2) for the quadratic model and the p value for testing the linear association. The capability of LA volumes and LA function parameters to differentiate dogs with asymptomatic MMVD with an enlarged LA (stage B2) from those with MMVD in CHF (stage C) was assessed by receiver operating characteristic (ROC) curve analysis. A significant predictor was defined as having an area under the curve significantly greater than 0.5 and we report the 95% confidence interval (CI). Statistical significance was set at p<0.05 for all analyses. The statistical analyses were performed using R: A Language and Environment for Statistical Computing.

Results The 114 healthy control dogs consisted of 23 Chihuahuas, 24 Border terriers, 21 Cavalier King Charles spaniels, 19 Dachshunds, 20 Petit Basset

Table 2 Demographic data and selected conventional echocardiographic variables of control dogs and dogs with MMVD included in the study.

n Age (years) Body weight (kg) Female n (%) Male n (%) Heart rate (/min) LVIDd (mm) LVSF (%) Peak E (m/s) E/A TR (%) Peak TR (m/s)

Control dogs

Dogs with MMVD (stage B1)

Dogs with MMVD (stage B2)

Dogs with MMVD (stage C2)

114 3.5 (1.2e15.4)a 7.8 (1.9e24.0)a 57 (50%)a 57 (50%)a 119 (71e194)a 24.6 (13.7e36.2) 39 (28e47) 0.70 (0.45e1.03) 1.31 (1.09e73) / /

41 8.6 (2.2e13.8)b 9.0 (2.0e23.4)ab 23 (56%)a 18 (44%)a 128 (72e179)a 24.8 (17.4e36.1) 41 (27e51) 0.74 (0.54e1.18) 1.35 (1.04e1.79) 73 2.52 (2.08e3.01)

27 10.2 (3.6e15.5)b 10.7 (2.6e21.5)b 8 (30%)a 19 (70%)a 114 (63e204)a 31.3 (23.5e45.1) 44 (31e57) 0.90 (0.53e1.50) 1.37 (1.08e2.10) 75 2.56 (1.89e3.23)

23 9.4 (7.0e13.3)b 9.8 (2.8e17.3)ab 10 (43%)a 13 (57%)a 152 (111e201)b 36.4 (27.8e42.7) 51 (42e62) 1.92 (1.50e2.40) 1.72 (1.08e2.71) 86 3.64 (3.31e4.53)

Data are presented as median (range). Means not sharing a letter in their superscript are significantly different (p<0.05) after adjustment for multiplicity using Holm’s method.

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

Indexed LA stroke volumes increased with the severity of MMVD (Table 3). Total LA stroke volume showed a positive linear correlation with maximal LA volume (Fig. 1). On the other hand, total LA emptying fraction showed a decreasing tendency with disease severity and increasing LA volumes. Total LA emptying fraction showed an inverse

0.14 0.19 0.35 0.41 (0.08e0.48)a (0.02e0.46)b (0.15e1.32)c (0.31e2.80)d 0.23 0.19 0.45 1.25 0.4 (0.16e0.66)a 0.42 (0.19e0.70)a 0.75 (0.50e1.84)b 1.80 (0.90e3.78)c (0.07e0.48)a (0.08e0.34)a (0.24e0.93)b (0.91e4.00)c 0.18 0.21 0.46 1.75 (0.14e0.79)a (0.15e0.72)b (0.51e1.38)c (1.34e5.32)d 0.34 0.41 0.88 2.60

Passive LA stroke volume (mL/kg) Total LA stroke volume (mL/kg) Minimal LA volume (mL/kg) Preatrial contraction volume (mL/kg) Maximal LA volume (mL/kg)

0.60 (0.31e1.01)a 0.66 (0.27e0.92)a 1.31 (0.95e2.61)a* 3.79 (2.46e7.02)b Control dogs Dogs with MMVD (stage B1) Dogs with MMVD (stage B2) Dogs with MMVD (stage C)

LA function

Indexed LA volumes and indexed LA stroke volumes in control dogs and dogs with MMVD.

Left atrial volumes in dogs with MMVD varied widely. The increase in maximal LA volume was accompanied by an increase in LA P-volume and minimal LA volume. The maximal LA volume was on average increased five-fold and the minimal LA volume was on average increased nine-fold in dogs with CHF (stage C) compared with control dogs. All three LA volumes were significantly larger in dogs with CHF (stage C) than stage B2 dogs (overall p<0.01). Table 3 summarizes the differences in LA volumes between dogs with different degrees of MMVD and controls. A maximal LA volume <2.25mL/kg was the optimal cut off identified by the ROC analysis for excluding CHF in dogs with MMVD with a sensitivity of 96% and a specificity of 100% (area under the ROC curve ¼ 0.995 and 95% CI ¼ 0.917e1.000). A minimal LA volume <0.87mL/kg was the optimal cut off identified for excluding CHF in dogs with MMVD with a sensitivity of 96% and a specificity of 100% (area under the ROC curve ¼ 0.998 and 95% CI ¼ 0.924e1.000).

Table 3

LA volume

Active LA stroke volume (mL/kg)

Griffon Vendeen, and one dog each of seven other breeds. Dogs diagnosed with MMVD were 28 Cavalier King Charles Spaniels, 23 Dachshunds, 10 Chihuahuas, seven Petit Basset Griffon Vendeen, six Danish Swedish farm dogs, four mixed breed dogs, and one dog each of 13 other breeds. Of the 91 dogs with MMVD, 68 dogs were classified as asymptomatic (41 stage B1 and 27 stage B2) and 23 were classified with CHF (stage C). Sex distribution and BW did not significantly differ between control dogs and dogs with MMVD or between the different MMVD disease groups. Dogs with MMVD were significantly older than healthy control dogs (p<0.01). Heart rate was significantly higher for dogs with CHF (stage C) compared with control dogs and asymptomatic dogs with MMVD (stages B1 and B2) (overall p<0.01). All dogs had a normal or increased LV fractional shortening. None of the dogs had an E/A ratio <1. Demographic and conventional echocardiographic data are summarized in Table 2.

Data are presented as median (range). Means not sharing a letter in their superscript are significantly different (p<0.05) after adjustment for multiplicity using Holm’s method. a*: Maximal LA volume was used to subclassify dogs with MMVD stage B to stages B1 and B2, and thus statistical analyses for comparisons of these measurements were not performed.

5 (0.04e0.37)a (0.04e0.48)a (0.17e0.64)b (0.15e2.09)c

Left atrial volume and function in dogs

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

6

M. Ho ¨llmer et al.

A

Figure 1 Relation between total left atrial (LA) stroke volume and maximal LA volume based on back transformation of a linear regression model fitted to logtransformed values.

relation to maximal LA volume (p<0.01, R2 ¼ 0.35; Fig. 2), LA P-volume (p<0.01, R2 ¼ 0.44), minimal LA volume (p<0.01, R2 ¼ 0.52; Fig. 2) and age (p<0.01, R2 ¼ 0.08), whereas HR showed no significant relation with total LA emptying fraction. Total LA emptying fraction and LA expansion index (compliance) were significantly reduced in stage B2 dogs (p¼0.01) and further reduced in stage C dogs (p<0.01) in comparison with control dogs. Both measures of LA reservoir function were significantly lower in dogs with CHF (stage C) than in stage B1 and B2 dogs (p<0.01; Table 4 and Fig. 3). Active LA emptying fraction initially showed an increasing tendency in stage B1 dogs (p¼0.36) compared with control dogs, but significantly decreased in stage C dogs (p<0.01) compared with control dogs, stage B1 and B2 dogs (Table 4 and Fig. 3). Passive LA emptying fraction significantly decreased in stage B1 dogs (p¼0.02), and remained unchanged in stage B2 (p¼0.65) and class C dogs (p¼0.20) compared with control dogs (Table 4 and Fig. 3). The functional distribution of LA volumes changed in dogs with MMVD with increasing disease severity. The residual volume (minimal LA volume) constituted an increasing percentage of LA volume, whereas the percentage of LA volume dedicated to total stroke volume decreased. The individual contribution of passive and active emptying to the total stroke volume was changed with increasing disease severity (Fig. 4).

B

Figure 2 Inverse relations between total left atrial (LA) emptying fraction and (A) maximal LA volume and (B) minimal LA volume.

An active LA emptying fraction <24% was suggestive of CHF in dogs with chronic MMVD with a sensitivity of 77% and a specificity of 89% (area under the ROC curve ¼ 0.901 and 95% CI ¼ 0.781e0.967). An LA expansion index <126% was suggestive of CHF in dogs with chronic MMVD with a sensitivity of 82% and a specificity of 82% (area under the ROC curve ¼ 0.875 and 95% CI ¼ 0.750e0.952).

Discussion The main findings of the present study in dogs with naturally occurring MMVD indicate that: (1) LA

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

Left atrial volume and function in dogs Table 4

7

Left atrial function in control dogs and dogs with MMVD. Reservoir function

Control dogs Dogs with MMVD (stage B1) Dogs with MMVD (stage B2) Dogs with MMVD (stage C)

Conduit function

Contractile function

Total LAEF (%)

LA expansion index (%)

Passive LAEF (%)

Passive LAE of total emptying (%)

Active LAEF (%)

Active LAE of total emptying (%)

68  8a 66  7ab

228  83a 204  62ab

41  11a 34  13b

60  14a 52  19b

45  11a 47  11a

40  14a 48  19b

63  8b

181  60b

37  10ab

60  13ab

40  11a

40  13a

48  12c

101  44c

34  12ab

71  16c

21  11b

29  16c

Data are presented as mean  SD. Means not sharing a letter in their superscript are significantly different (p<0.05) after adjustment for multiplicity using Holm’s method.

Figure 3 Box and whisker plot for left atrial (LA) function in control dogs and dogs with different degrees of myxomatous mitral valve disease (MMVD). Total LA emptying fraction (A) and LA expansion index (B) were used to assess reservoir function; active LA emptying fraction to assess contractile function (C) and passive LA emptying fraction to assess conduit function (D).

volumes and LA stroke volumes increased with increasing disease severity; (2) LA reservoir and contractile function decreased with increasing disease severity; and (3) maximal and minimal LA volumes were specific and sensitive markers for excluding CHF in dogs with chronic MMVD. The large LA volumes and the elevated LA stroke volumes in dogs with MMVD are primarily a reflection of volume overload due to regurgitant

flow from the LV [21,22]. The enlarged LA in MMVD initially appears to provide an important compensating mechanism by preventing pulmonary congestion, and by maintaining an adequate ventricular filling volume [23e25]. All three LA volumes increased with increasing disease severity in dogs with MMVD, and all three LA volumes were significantly larger in dogs with CHF than in asymptomatic dogs with MMVD.

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

8

M. Ho ¨llmer et al.

Figure 4 Proportions of maximal LA volume used as active and passive stroke volume and residual volume in control dogs and dogs with different degrees of myxomatous mitral valve disease (MMVD).

Similar to a human study by Blondheim et al. [26], the minimal LA volume increased on average by more than maximal LA volume, and the minimal LA volume showed a higher correlation with decreasing total LA emptying fraction than maximal LA volume. Most studies rely only on maximal LA volume as a prognostic marker, but a recent study suggests that minimal LA volume is superior to maximal LA volume as a marker of outcome [27]. The large minimal LA volume might represent chronic LV diastolic dysfunction and end-diastolic LV filling pressures eliciting LA pressure [28]. Even if volume overload is the primary mechanism for LA enlargement in MMVD, is has been suggested that pressure overload might have an influence, especially in late disease stages [25,28]. However, none of the dogs with MMVD in this study had a mitral E/A < 1 suggestive of diastolic dysfunction. During LV systole, the LA acts as a reservoir for blood from the pulmonary veins [29]. In the present study, reservoir function, assessed using total LA emptying fraction and LA expansion index (compliance), decreased significantly with increasing disease severity in dogs with chronic MMVD. Although an initial increase in LA compliance in mild MR has been reported in humans and dogs [4,24], a decreased LA reservoir function is usually evident in severe MR [4,30]. Contrary to this, a recent study found a wide variation of total LA emptying fraction and no significant differences between dogs with and without MMVD [31]. Ultrastructural changes of the LA myocardium, including interstitial fibrosis, myocyte hypertrophy, and chronic inflammatory changes, might be an important pathophysiological feature in the

reduction of compliance [6,30,32]. A reduction in the reservoir function of the LA may result in a profound impairment of LA filling, with consequent stasis in pulmonary venous flow, and subsequent development of pulmonary congestion [19]. Furthermore, a decreasing total LA ejection fraction indicates generalized decreasing efficacy of the LA [33]. After the reservoir phase, during early ventricular diastole, the LA functions as a conduit for blood passively transiting from the pulmonary veins to the LV [5,29]. In the present study, passive LA emptying fraction remained unchanged in asymptomatic dogs with LA enlargement and dogs with CHF compared with the control dogs, whereas the passive filling contribution to total LV filling constituted an increasing percentage with increased disease severity, which is in agreement with previous studies in dogs and humans [4,34]. The increased conduit function compensates for the reduced contractile function, but over time this is an insufficient compensation for the decreased active LA contraction, and cardiac output falls [5]. One study in humans reported a reduced conduit function of the LA in severe MR explaining this finding with increasing early diastolic LV filling pressures [30]. In late ventricular diastole, active LA contraction finalizes the process of LV filling [5,29]. In the present study, the LA contractile function initially showed a transient increase and then a stepwise decline in asymptomatic dogs with LA enlargement and further declined in dogs with CHF. This is in agreement with several studies in both animals and humans with MR [24,30]. The initially

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

Left atrial volume and function in dogs increased contractile function with mild MR is presumably caused by a state of enhanced preload resulting in higher contractility because of the FrankeStarling mechanism [4,35]. The impaired contractile function of the LA with aggravation of chronic MMVD may be due to a combination of fibrosis, increased afterload (high LV end-diastolic filling pressure) and exhaustion of the Franke Starling mechanism by severe volume overload [4,30,36]. Left atrial contractile dysfunction may contribute to pulmonary hypertension and development of pulmonary congestion [37]. A maximal LA volume < 2.25mL/kg and a minimal LA volume < 0.87mL/kg may be used as cut off values for excluding CHF in dogs with chronic MMVD with high sensitivity and specificity. Using LA volumes for prediction of CHF in dogs with MMVD is more difficult, as there are substantial differences between dog’s capacity to compensate for MR. Furthermore, the speed of progression and chronicity of disease is crucial. In a dog with an enlarged LA, the evaluation of functional indices might provide valuable supplementary information. An LA expansion index <126% and/or an active LA emptying fraction <24% were suggestive of CHF in dogs with chronic MMVD with a reasonable sensitivity and specificity. Doppler echocardiographic indices of LV filling and LA pressure have been used to predict CHF in dogs with MMVD. In one study [38], the ratio between peak velocity of early diastolic transmitral flow (E) to peak early tissue Doppler mitral annulus velocity (E0 ) identified CHF with a sensitivity of 80% and a specificity of 83%, and in another study [39] peak E and the E/E0 predicted CHF with a sensitivity of 96% and a specificity of 71%, respectively a sensitivity of 75% and a specificity of 91%, which is similar to the performance of the functional LA indices in our study. However, the use of E/E0 as a reliable indicator of increased filling pressures and congestion is questionable in the setting of MMVD with volume overload and only mildly affected diastolic function [39]. Another potentially useful variable is the ratio between E and isovolumetric relaxation time that in one study performed better than the volumetric indices of LA function in our study in predicting CHF in dogs with MMVD (sensitivity of 92% and specificity of 96%) [39]. In human medicine, it was shown that when evaluating volumetric indices of LA function, reservoir function (i.e. LA expansion index) had the highest predictive value, followed by contractile function (i.e. active LA emptying fraction) for the presence of mitral surgery indications in MR [30]. In dogs, LA contractile function (i.e. active LA emptying fraction) was identified as an

9 independent predictor of mortality in dogs with MMVD [40]. Thus, the evaluation of LA function may be an important tool for identifying asymptomatic MMVD dogs at higher risk of early decompensation. Left atrial function assessment may also have an important prognostic value in dogs with CHF and may be valuable for monitoring treatment response in dogs with MMVD. Serial assessment of LA volume and function during treatment may document improvement of the remodeling or treatment failure, and thus be a promising tool for tailoring treatment regimens in the individual dog with MMVD. Some limitations to the present study should be acknowledged. First, blood pressure was not measured in all dogs and possible hypertension might have influenced LA size. Second, no invasive assessment or tissue Doppler analyses of LA functional indices or diastolic dysfunction were performed to prove the determinants of reduced LA function. Third, to firmly establish the cut-off values of LA volumes and LA functions presented in this study for differentiating dogs with MMVD that were not in CHF from those that were in CHF, our findings require validation in a large canine population with and without cardiac treatment for CHF.

Conclusion Our study provides new insight into LA volume and function in dogs with different degrees of naturally occurring MMVD. Absolute LA volumes and LA functions can be determined using the biplane area-length method. Dogs with MMVD appear to have larger LA volumes with poorer LA function. This study demonstrated a decrease in reservoir and active contractile function with increasing disease severity in dogs with MMVD, despite increased reservoir and contractile volumes.

Conflicts of Interest The authors do not have any conflicts of interest to disclose.

Acknowledgments Funding was provided by a PhD grant from the University of Copenhagen. The skillful technical assistance of Michelle Dupont and the kind cooperation of the owners and their wonderful dogs are greatly appreciated. Preliminary results were presented as an abstract at the BSAVA Congress, Birmingham, 3e6 April 2014.

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

10

M. Ho ¨llmer et al.

References [1] Detweiler DK, Patterson DF. The prevalence and types of cardiovascular disease in dogs. Ann N Y Acad Sci 1965;127: 481e516. [2] Urabe Y, Mann DL, Kent RL, Nakano K, Tomanek RJ, Carabello BA, Cooper G. Cellular and ventricular contractile dysfunction in experimental canine mitral regurgitation. Circ Res 1992;70:131e47. [3] Bonagura JD, Schober KE. Can ventricular function be assessed by echocardiography in chronic canine mitral valve disease. J Small Anim Pract 2009;50:12e24. [4] Borg AN, Pearce KA, Williams SG, Ray SG. Left atrial function and deformation in chronic primary mitral regurgitation. Eur J Echocardiogr 2009;10:833e40. [5] Hoit BD, Gabel M. Influence of left ventricular dysfunction on the role of atrial contraction: an echocardiographichemodynamic study in dogs. J Am Coll Card 2000;36: 1713e9. [6] To AC, Flamm SD, Marwick TH, Klein AL. Clinical utility of multimodality LA imaging: assessment of size, function, and structure. J Am Coll Cardiol Img 2011;4:788e98. [7] Borgarelli M, Savarino P, Crosara S, Santilli RA, Chiavegato D, Poggi M, Bellino C, La Rosa G, Zanatta R, Ha ¨ggstro ¨m J, Tarducci R. Survival characteristics and prognostic variables of dogs with mitral regurgitation attributable to myxomatous valve disease. J Vet Intern Med 2008;22:120e8. [8] Borgarelli M, Crosara S, Lamb K, Crosara S, La Rosa G, Savarino P, Haggstrom J. Survival characteristics and prognostic variables of dogs with preclinical chronic degenerative mitral valve disease attributable to myxomatous degeneration. J Vet Intern Med 2012;26:69e75. [9] Ho ¨llmer M, Willesen JL, Tolver A, Koch J. Left atrial volume and phasic function in clinically healthy dogs of 12 different breeds. Vet J 2013;197:639e45. [10] 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;28:1527e33. [11] Ha ¨ggstro ¨m J, Boswood A, O’Grady M, Jo ¨ns O, Smith S, Swift S, Borgarelli M, Gavaghan B, Kresken JG, Patteson M, ˚blad B, Bussadori CM, Glaus T, Kovacevic A, Rapp M, A Santilli RA, Tidholm A, Eriksson A, Belanger MC, Deinert M, Little CJ, Kvart C, French A, Rønn-Landbo M, Wess G, Eggertsdottir A, Lynne O’Sullivan M, Schneider M, Lombard CW, Dukes-McEwan J, Willis R, Louvet A, DiFruscia R. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study. J Vet Intern Med 2013;27:1441e51. [12] Atkins C, Bonagura J, Ettinger S, Fox P, Gordon S, Ha ¨ggstro ¨m J, Hamlin R, Keene R, Luis-Fuentes V, Stepien R. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med 2009;23:1142e50. [13] Cornell CC, Kittleson MD, Della Torre P, Ha ¨ggstro ¨m 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;18:311e21. [14] Thomas WP, Gaber CE, Jacobs GJ, Kaplan PM, Lombard CW, Moise NS, Moses BL. Recommendations for standards in transthoracic two-dimensional echocardiography in dogs and cats. J Vet Intern Med 1993;7:247e52. [15] Quinones M, Otto C, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler

[16]

[17]

[18]

[19]

[20]

[21] [22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

echocardiography: a report from the Doppler quantification task force of the nomenclature and standards committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15:167e84. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440e63. Leung DY, Boyd A, Ng AA, Chi C, Thomas L. Echocardiographic evaluation of left atrial size and function: current understanding, pathophysiologic correlates, and prognostic implications. Am Heart J 2008;156:1056e64. Nikitin NP, Witte KK, Thackray SD, Goodge LJ, Clark AL, Cleland JG. Effect of age and sex on left atrial morphology and function. Eur J Echocardiogr 2003;4:36e42. Morris DA, Gailani M, Vaz Pe ´rez A, Blaschke F, Dietz R, Haverkamp W, Ozcelik C. Left atrial systolic and diastolic dysfunction in heart failure with normal left ventricular ejection fraction. J Am Soc Echocardiogr 2011;24:651e62. Ho ¨llmer M, Willesen JL, Tolver A, Koch J. Comparison of four echocardiographic methods to determine left atrial size in dogs. J Vet Cardiol 2016;18:137e45. Hawley RR, Dodge HT, Graham TP. Left atrial volume and its changes in heart disease. Circulation 1966;34:989e96. Ren JF, Kotler MN, DePace NL, Mintz GS, Kimbiris D, Kalman P, Ross J. Two-dimensional echocardiographic determination of left atrial emptying volume: a noninvasive index in quantifying the degree of nonrheumatic mitral regurgitation. J Am Coll Cardiol 1983;2:729e36. Braunwald E, Awe WC. The syndrome of severe mitral regurgitation with normal left atrial pressure. Circulation 1963;27:29e35. Kihara Y, Sasayama S, Miyazaki S, Onodera T, Susawa T, Nakamura Y, Fuyiwara H, Kawai C. Role of the left atrium in adaption of the heart to chronic mitral regurgitation in conscious dogs. Circ Res 1988;62:543e53. Le Tourneau T, Messika-Zeitoun D, Russo A, Detaint D, Topilsky Y, Mahoney DW, Suri R, Enriquez-Sarano M. Impact of left atrial volume on clinical outcome in organic mitral regurgitation. J Am Coll Cardiol 2010;56:570e8. Blondheim DS, Osipov A, Meisel SR, Frimerman A, Shochat M, Shotan A. Relation of left atrial size to function as determined by transesophageal echocardiography. Am J Cardiol 2005;96:457e63. Fatema K, Barnes ME, Bailey KR, Abhayaratna WP, Cha S, Seward JB, Tsang TS. Minimum vs. maximum left atrial volume for prediction of first atrial fibrillation or flutter in an elderly cohort: a prospective study. Eur J Echocardiogr 2009;10:282e6. Hsiao SH, Huang WC, Lin KL, Chiou KR, Kuo FY, Lin SK, Cheng CC. Left atrial distensibility and left ventricular filling pressure in acute versus chronic severe mitral regurgitation. Am J Cardiol 2010;105:709e15. Murray JA, Kennedy JW, Figley MM. Quantitative angiocardiography II. The normal left atrial volume in man. Circulation 1968;37:800e4. Debonnaire P, Leong DP, Witkowski TG, Al Amri I, Joyce E, Katsanos S, Schalij MJ, Bax JJ, Delgado V, Marsan NA. Left atrial function by two-dimensional speckle-tracking echocardiography in patients with severe organic mitral regurgitation: association with guidelines-based surgical

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006

Left atrial volume and function in dogs

[31]

[32]

[33]

[34]

[35]

11

indication and postoperative (long-term) survival. J Am Soc Echocardiogr 2013;26:1053e62. Tidholm A, Ho ¨glund K, Ha ¨ggstro ¨m J, Bodega ˚rd-Westling A, Ljungvall I. Left atrial ejection fraction assessed by realtime 3-dimensional echocardiography in normal dogs and dogs with myxomatous mitral valve disease. J Vet Intern Med 2013;27:884e9. Verheule S, Wilson E, Everett T, Shanbhag S, Golden C, Olgin J. Alterations in atrial electrophysiology and tissue structure in a canine model of chronic atrial dilation due to mitral regurgitation. Circulation 2003;107:2615e22. Tsai C, Hung C, Hou CJ, Hung T, Yeh H, Tsai C. Real-time three-dimensional echocardiography in the evaluation of left atrial structure and function in normal, aging, hypertensive and heart failure patients: new insights into left atrial adaptation and remodeling. Int J Gerontol 2009;3: 53e65. Katayama K, Tajimi T, Guth BD, Matsuzaki M, Lee JD, Seitelberger R, Peterson KL. Early diastolic filling dynamics during experimental mitral regurgitation in the conscious dog. Circulation 1988;78:390e400. Braunwald E, Frahms CJ. Studies on Starling laws of the heart: IV. Observations on the hemodynamic functions of the left atrium in man. Circulation 1961;24:633e42.

[36] Cameli M, Lisi M, Righini FM, Mondillo S. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 2013;111: 595e601. [37] Saraiva RM, Yamano T, Matsumura Y. Left atrial function assessed by real-time 3-dimensional echocardiography is related to right ventricular systolic pressure in chronic mitral regurgitation. Am Heart J 2009;158:309e16. [38] Teshima K, Asano K, Sasaki Y, Kato Y, Kutara K, Edamura K, Hasegawa A, Tanaka S. Assessment of left ventricular function using pulsed tissue Doppler imaging in healthy dogs and dogs with spontaneous mitral regurgitation. J Vet Med Sci 2005;67:1207e15. [39] Schober KE, Hart TM, Stern JA, Li X, Samii VF, Zekas LJ, Scansen BA, Bonagura JD. Detection of congestive heart failure in dogs by Doppler echocardiography. J Vet Intern Med 2010;24:1358e68. [40] Nakamura K, Osuga S, Suzuki K, Morita T, Yokoyama N, Ohta H, Yamasaki M, Takiguchi M. Prognostic value of left atrial function in dogs with chronic mitral valvular heart disease. J Vet Intern Med 2014;28:1746e52.

Available online at www.sciencedirect.com

ScienceDirect

Please cite this article in press as: Ho ¨llmer M, et al., Left atrial volume and function in dogs with naturally occurring myxomatous mitral valve disease, Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.08.006