Journal of Veterinary Cardiology (2015) 17, 83e96

www.elsevier.com/locate/jvc

Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs: Repeatability and reference intervals Lance C. Visser, DVM, MS , Brian A. Scansen, DVM, MS*, Karsten E. Schober, DVM, PhD , John D. Bonagura, DVM, MS Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 601 Vernon L. Tharp Street, Columbus, OH 43210, USA Received 31 July 2014; received in revised form 29 September 2014; accepted 21 October 2014

KEYWORDS Canine; Cardiac; Reference range; Reproducibility; Right ventricle

Abstract Objectives: To determine the feasibility, repeatability, intra- and interobserver variability, and reference intervals for 5 echocardiographic indices of right ventricular (RV) systolic function: tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed wave tissue Doppler imagingderived systolic myocardial velocity of the lateral tricuspid annulus (S’), and speckle-tracking echocardiography-derived global longitudinal RV free wall strain and strain rate. To explore statistical relationships between RV systolic function and age, gender, heart rate, and bodyweight. Animals: 80 healthy adult dogs. Methods: Dogs underwent 2 echocardiographic examinations. Repeatability and intra-observer and inter-observer measurement variability were quantified by average coefficient of variation (CV). Relationships between RV function and age, heart rate and bodyweight were estimated by regression analysis. Results: All indices were acquired with clinically acceptable repeatability and intra- and inter-observer variability (CVs < 10%). No differences were identified between male and female dogs. Allometric scaling by bodyweight demonstrated significant, clinically relevant correlations between RV function and bodyweight (all p  0.001) as follows: TAPSE e strong positive correlation (r2 ¼ 0.75); S’ e moderate positive correlation (r2 ¼ 0.31); strain rate e moderate negative correlation

Presented in abstract form as an oral presentation at the 2014 ACVIM Forum, Nashville, TN. * Corresponding author. E-mail address: [email protected] (B.A. Scansen). http://dx.doi.org/10.1016/j.jvc.2014.10.003 1760-2734/ª 2014 Elsevier B.V. All rights reserved.

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L.C. Visser et al. (r2 ¼ 0.44); FAC and strain e weak negative correlations (r2 ¼ 0.22 and 0.14, respectively). Strain rate and FAC were positively correlated with heart rate (r 2 ¼ 0.35 and 0.31, respectively). Allometric scaling generated bodyweightbased reference intervals for these RV systolic function indices. Conclusions: Echocardiographic indices of RV systolic function are feasible to obtain, repeatable, and affected by bodyweight. Studies of these indices in dogs with cardiovascular disease are needed. ª 2014 Elsevier B.V. All rights reserved.

Abbreviations 2D CV FAC RV S’

two-dimensional coefficient of variation fractional area change right ventricular pulsed wave tissue Doppler imagingderived systolic myocardial velocity of the lateral tricuspid annulus SD standard deviation STE speckle tracking echocardiography TAPSE tricuspid annular plane systolic excursion TDI tissue Doppler imaging

Introduction The right ventricle is affected by a number of diseases, including pulmonary hypertension caused by lung disease, pulmonary vascular disease, or left-sided heart disease; right ventricular (RV) cardiomyopathies, such as arrhythmogenic RV cardiomyopathy; pericardial disease; pulmonary or tricuspid valve malformations; cardiac shunts; and complex congenital heart disease. The clinical recognition of RV dysfunction in veterinary medicine is underdeveloped and has traditionally relied on qualitative assessment or overt signs of rightsided congestive heart failure. The qualitative assessment of RV structure and function in human patients is inaccurate, with low interobserver agreement.1 Consequently, measured and calculated indices that quantify RV function might be clinically useful in identifying the presence and progression of RV dysfunction. The importance of the quantitative assessment of RV function is increasingly apparent in people affected with both cardiac and non-cardiac diseases.2 Quantitative analysis of RV function provides prognostic data and guides the clinical decision-making process not only in right heartspecific diseases3 but also left heart disorders,

including mitral and aortic valve disease4e6 and dilated cardiomyopathy,7e12 often independent of pulmonary hypertension status. Similar studies of quantitative RV function in dogs could potentially be of similar clinical value. However, when compared to the left ventricle, the assessment of RV function is more difficult owing to its complex geometry. Specific anatomical challenges include separate inflow and outflow regions, prominent endocardial trabeculations, ventricular interdependence, and the marked load-dependence of most indices of RV function.13 Echocardiography is the most practical method for assessment of RV structure and function in veterinary medicine as it is noninvasive, readily available, relatively inexpensive, and does not require general anesthesia. Both guidelines and reference intervals are available for a number of RV echocardiographic indices in people.14 Although each index has inherent advantages and disadvantages, nearly all human RV indices have been validated against a catheterization- or magnetic resonance imaging derived gold standard. These include the M-mode-derived tricuspid annular plane systolic excursion (TAPSE), the 2dimensional (2D) correlate to RV ejection fraction e percent fractional area change (FAC), tissue Doppler imaging (TDI)-derived systolic myocardial velocity of the lateral tricuspid annulus (S’), and speckle-tracking echocardiography (STE)-derived strain and strain rate.14e18 Aside from TAPSE,19 canine reference intervals for RV systolic function indices based on estimates of central tendencies in a large sample of the healthy canine population are lacking. Such reference intervals along with repeatability data are essential prior to widespread clinical application of echocardiographic indices in diseased dogs. As several echocardiographic indices of cardiac structure and function are known to be affected by age, gender and body size in humans20e27 and in animals,28e32 these variables also should be considered when establishing reference intervals. The impact of bodyweight particularly warrants

Echocardiographic reference intervals for RV function in dogs consideration for the most accurate assessment of reference intervals given the wide range of body sizes in dogs. The aforementioned considerations led us to evaluate 5 different, but complementary echocardiographic indices of RV systolic function. The first study objective was determination of the feasibility, repeatability and intra- and interobserver variability of TAPSE, FAC, S’, and STEderived global longitudinal RV free wall strain and strain rate. The second objective was to explore the statistical effects of age, gender, heart rate, and bodyweight on those indices. Finally, based on these data, clinically-applicable reference intervals were generated.

Animals, materials and methods All procedures in this study were approved by the Institutional Animal Care and Use Committee and the Veterinary Medical Center Clinical Research and Teaching Advisory Committee at The Ohio State University. Written consent authorizing participation of dogs in the study was obtained from all dog owners.

Animals A convenience sample of 80 privately-owned healthy, mature dogs 8 months of age and of varying breed and bodyweight (n ¼ 40 > 15 kg; n ¼ 40  15 kg) were recruited for this study from members of The Ohio State University College of Veterinary Medicine. Dogs were determined to be healthy and without cardiac or respiratory diseases based on medical history, routine physical examination, cardiovascular examination, and a thorough screening echocardiogram. Exclusion criteria for the study were: 1) pathologic heart murmur, gallop sound, or (non-sinus) arrhythmia; 2) history of respiratory disease; 3) taking medications known to affect the cardiovascular or respiratory systems; 4) uncooperative temperament that might require sedation for an echocardiogram; 5) Boxer dogs and English bulldogs (due to risk of occult arrhythmogenic RV cardiomyopathy); and 6) cardiac abnormalities identified on a baseline 2D, M-mode, and Doppler echocardiographic study. Right heart valve regurgitation evident on color Doppler echocardiography was defined as physiologic if silent to auscultation and associated with normal valve morphology. Dogs with physiologic tricuspid or pulmonary valve regurgitation were not excluded due to the high prevalence of this finding in healthy dogs.33

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Echocardiographic examination Conventional and Doppler echocardiography All echocardiographic studies were performed by the same investigator (LCV) using a GE Vivid 7 echocardiographic systema with transducer selection (4, 7, or 10 MHz nominal frequency) matched to the size of the dog and preset for optimal imaging. Echocardiographic recordings were made with a simultaneous ECG, and all raw data were captured digitally for off-line analysis at a digital workstation. Standard imaging planes34 were utilized with the dogs manually restrained in right and left lateral recumbency without the use of sedation. Echocardiographic indices of RV systolic function All the indices of RV systolic function were acquired from the left apical 4-chamber view optimized for the right heart. This involved transducer placement 1 intercostal space cranial to the standard left apical 4-chamber view with varying degrees of caudal angulation. Care was taken to maximize the RV longitudinal dimension and to exclude the left ventricular outflow tract to avoid foreshortening of the RV. The ultrasound system was adjusted to optimize RV myocardial and endomyocardial border resolution. The examiner attempted to record images during periods of quiet/calm respiration. At least 10 cardiac cycles of each RV function index were acquired and stored for off-line analysis. Measured images were chosen based on technical adequacy, without regard to the respiratory cycle as translational motion with ventilation precluded using consecutive cardiac cycles. The value recorded for each RV function index at each time point was determined from an average of 5 representative cardiac cycles. The heart rate value recorded represented the average heart rate of each of the 5 cardiac cycles used to determine the RV function index value. The TAPSE measurement consisted of quantifying the maximal longitudinal displacement of the lateral tricuspid valve annulus toward the RV apex during systole and was generated from M-mode recordings with the cursor as parallel as possible to the majority of the RV free wall (Fig. 1). In order to avoid underestimating TAPSE values, the anatomic M-mode technique35 was activated infrequently (80 frames/s). Strain and strain rate values were generated by the software for each of 3 myocardial segments (basilar, mid, and apical myocardium of the RV free wall) in addition to the global strain and strain rate from the entire RV (considered as a single segment and not a mean of the 3 segments). Only global longitudinal systolic strain and strain rate values of the RV free wall were used in this study and were determined as the maximal (most negative) systolic point on the respective global strain or strain rate curve prior to pulmonary valve closure (Figs. 5 and 6).

Repeatability, intra- and interobserver measurement variability Day-to-day repeatability (recording variability or reproducibility) of each RV function index was evaluated by having each dog undergo 2 echocardiographic studies performed between 3 and 20 days apart. Intraobserver measurement variability was determined by having the same individual (LCV) measure RV function indices from 6 randomly selected echocardiographic studies on 3 separate occasions. Interobserver measurement variability was determined by having 2 trained

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Figure 4 Representative 2D echocardiographic image of the right heart from the left apical four-chamber view optimized for the right ventricle in which longitudinal segments have been designated by the proprietary software as basilar inferior (basInf; yellow), mid inferior (midInf; light blue) and apical inferior (apInf; green) due to the left ventricular 2Ch algorithm (as there was no right ventricular speckle-tracking echocardiography algorithm at the time of study). The green colored bars with a “V” below the labeled segments indicate that tissue tracking by the software is adequate. RA, right atrium; RV, right ventricle.

individuals (LCV & BAS), blinded to each other’s measurements, measure all RV function indices from 6 randomly selected echocardiographic studies. The 6 selected echocardiographic studies used to determine the intra- and interobserver measurement variability were determined by randomlyc choosing 3 echocardiographic studies from dogs weighing 15 kg and 3 echocardiographic studies from dogs weighing >15 kg. Anatomic Mmode for TAPSE determination was not used in any of the 6 studies of measurement variability data, nor was a manual override for STE-derived strain and strain rate employed for these measurements.

Statistical analysis All statistical analyses were performed using commercial software packages.d,e For the purpose of the reference intervals, values for each RV function index and heart rate were generated as c

http://www.randomizer.org/. IBM SPSS Statistics, version 21, IBM Corp, Armonk, NY, USA. e MedCalc, version 12.7.4, MedCalc Software, Ostend, Belgium. d

the average of the 2 day-to-day repeatability data sets (pooled data) from each dog. Descriptive statistics (mean, median, standard deviation [SD], and 95% confidence intervals or interquartile range) were calculated for all RV function indices. Normality testing for continuous data consisted of visual inspection of the probability plots and the D’Agostino-Pearson test. A value of P < 0.05 was considered statistically significant. For all linear regression models, assumptions of linearity, homoscedasticity, and normality of the residuals were evaluated by inspection of the standardized residual plots and probability plots. Normality of the standardized residuals was also assessed with the D’Agostino-Pearson test. Standardized residual plots and Cook’s distances were used to identify possible outliers and influential data points on the model and if Cook’s distances of greater than 1.0 were encountered, the data point was excluded from further analysis.37 Multiple linear regression analysis was used to explore the relationship between the indices of RV systolic function and bodyweight (in kg), age (in months), and heart rate (in beats/min). An unpaired t-test (or ManneWhitney U test) was used to test for

Echocardiographic reference intervals for RV function in dogs

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Figure 5 Representative snapshot of the workstation output for right ventricular (RV) free wall longitudinal strain. A reference 2D image of the right heart can be seen in the upper left, a color map is shown in the lower left to display the change in strain over one cardiac cycle (red ¼ negative; blue ¼ positive), and the remainder of the snapshot includes 3 regional (basilar ¼ yellow, mid ¼ light blue, apical ¼ green) and global (dotted line) strain curves over time in relation to the ECG (bottom). Only systolic global longitudinal strain of the RV free wall prior to pulmonary valve closure was utilized in this study (arrow). The “AVC” corresponds to pulmonary valve closure (instead of aortic valve closure [AVC]) determined from a continuous wave Doppler recording of pulmonary outflow timed with the ECG. RA, right atrium; RV, right ventricle.

differences between male and female dogs for each RV function index. To account for differences that can be expected with the large variation in bodyweight of the dogs, weight-dependent regression-based reference intervals were determined. RV function indices were scaled to bodyweight and several regression models were tested for fit, including linear, second-order polynomial, third-order polynomial and allometric (power) models. For the purpose of this study, the simplest mathematical model (i.e., the model with the fewest number of predictors) achieving the highest degree of statistical significance (i.e., the largest F-statistic) and adjusted r2 value was considered the best model of fit. Constants for allometric modeling were derived using the logarithmic form of the allometric scaling equation: log (Y) ¼ log (a) þ b  log (M), where a is the proportionality constant, b is the scaling exponent, Y represents the RV function index, and M represents bodyweight.38 Simple linear regression analysis yields the constant b, which is the slope of the regression line and the constant a, which is the antilog (log1) of the y-intercept of the regression line. The 95% prediction intervals for the linear regression line of

best fit were then used to calculate the recommended lower and upper reference intervals. The average percent coefficient of variation (CV) was used to quantify day-to-day repeatability for the 2 time points, intraobserver measurement variability and interobserver measurement variability, where percent CV ¼ (SD of the measurements/average of measurements)  100.

Results Animals The study sample consisted of 80 dogs with a median age of 4.1 years (minimum ¼ 0.66 years; maximum ¼ 9 years; interquartile range ¼ 2.2e6.4 years) and a median bodyweight of 15.8 kg (minimum ¼ 3.9 kg; maximum ¼ 42.3 kg; interquartile range ¼ 8.2e27.2 kg). The mean heart rate during the studies was 106  22 beats/min (minimum ¼ 57 beats/min; maximum ¼ 158 beats/ min). Tricuspid regurgitation was observed by color Doppler imaging in 23 of 80 dogs (29%) and graded as mild in all cases. Thirty-six dogs were

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Figure 6 Representative snapshot of the workstation output for right ventricular (RV) free wall longitudinal strain rate. A reference 2D image of the right heart can again be seen in the upper left, a color map is shown in the lower left to display the change in strain rate over one cardiac cycle (red ¼ negative; blue ¼ positive), and the remainder of the snapshot includes 3 regional (basilar ¼ yellow, mid ¼ light blue, apical ¼ green) and global (dotted line) strain rate curves over time in relation to the ECG (bottom). Only systolic global longitudinal strain rate of the RV free wall was utilized in this study (arrow). The “AVC” corresponds to pulmonary valve closure (instead of aortic valve closure [AVC]. RA, right atrium; RV, right ventricle.

castrated males and 44 were spayed females. Forty-one dogs were mixed breeds, 5 were Pugs, 4 dogs each were Boston Terriers, Labrador Retrievers, Golden Retrievers, and Miniature Schnauzers, 2 dogs each were Cavalier King Charles Spaniels, Rat Terriers, Italian Greyhounds, Chihuahuas, Beagles, and German Shepherds. The other breeds (Border Collie, Wheaton Terrier, Bloodhound, Miniature Pinscher, Greyhound, Pembroke Welsh Corgi, English Setter, Toy Poodle, Pomeranian, and Papillon) were each represented once.

Table 1

Repeatability, intra- and interobserver measurement variability Each RV function index could be obtained in all dogs. Descriptive statistics for each of the RV function indices from the echocardiographic studies are summarized in Table 1. Average CV for repeatability, intra- and interobserver measurement variability of all RV function indices were considered low (

Echocardiographic assessment of right ventricular systolic function in conscious healthy dogs: repeatability and reference intervals.

To determine the feasibility, repeatability, intra- and interobserver variability, and reference intervals for 5 echocardiographic indices of right ve...
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