Survival characteristics and prognostic importance of echocardiographic measurements of right heart size and function in dogs with pulmonary hypertension

Abstract Background The clinical relevance of echocardiographic measurements of right heart size and function in dogs with pulmonary hypertension (PH) is unknown. Objective To determine if echocardiographic measurements of right heart size and right ventricular (RV) function are associated with survival times in dogs with PH. Animals Eighty‐two client‐owned dogs. Methods Retrospective study where data from medical records and baseline echocardiographic examinations were collected and measured in a standardized manner. Owners or primary veterinarians were contacted for outcome data. Results Enlargement of the right atrium (88%), RV (69%), and pulmonary artery (72%) was common. One‐third of the cases had reduced RV function quantified by two‐dimensional echocardiography‐derived tricuspid annular plane systolic excursion (TAPSE). Decreased TAPSE was significantly (P = .008) more common in dogs with PH not secondary to left heart disease (LHD; 43%) compared to dogs with PH secondary to LHD (14%) but median survival times (182, 95% confidence interval [CI] = 39‐309 versus 298, 95% CI = 85‐314 days, respectively) were not significantly different (P = .78). Right atrial area (hazard ratio [HR] = 2.72, 95% CI = 1.58‐4.70), TAPSE < 3.23 mm/kg0.284 (HR = 2.19, 95% CI = 1.28‐3.74), and right heart failure (HR = 2.05, 95% CI = 1.18‐3.57) were independently associated with shorter survival time (P ≤ .04). Conclusions and Clinical Importance Right atrial area, RV function (TAPSE < 3.23 mm/kg0.284), and right heart failure offer clinically relevant prognostic information in dogs with PH. Results support the quantitative assessment of right heart size and function in dogs with PH.


| INTRODUCTION
Pulmonary hypertension (PH) is a secondary complication of many commonly encountered cardiopulmonary disorders and is an increasingly recognized clinically important finding in dogs. [1][2][3][4][5] It is commonly associated with and can lead to clinical signs such as exercise intolerance, breathing difficulty, and exertional syncope and can cause right heart failure. [4][5][6][7][8][9][10] Reports have suggested that a tricuspid regurgitation pressure gradient (PG) > 55 mm Hg and ≥47 mm Hg is associated with an increased risk of death in dogs with myxomatous mitral valve disease (MMVD) 5 and respiratory disease/hypoxia, 4  is the primary metric used to estimate pulmonary arterial pressure and helps to assess the echocardiographic probability a dog has PH. 2 Doppler echocardiography has limitations and therefore might be inaccurate 11 and imprecise. 12,13 Several additional echocardiographic measurements of right heart size and function can be utilized to aid the echocardiographic assessment of PH. These measurements are largely based on characteristic cardiac changes that occur secondary to PH and have been previously evaluated in dogs diagnosed with PH. For example, the pulmonary artery might dilate, 7,14 exhibit reduced distensibility (quantified by the right pulmonary artery distensibility [RPAD] index), [14][15][16][17] or both. The blood flow profile in the pulmonary artery might exhibit a shortened acceleration time when indexed to ejection time (AT/ET). 7,14,18 The right atrium (RA), 19 right ventricle (RV), 20 or both might become dilated. The RV might exhibit systolic dysfunction when, for example, quantified by tricuspid annular plane systolic excursion (TAPSE). 21,22 In addition to assessing the likelihood a dog has PH, these quantitative right heart measurements might help determine the clinical severity and prognosis of dog with PH.
Longitudinal studies on dogs with PH that describe survival characteristics and the prognostic value of echocardiographic measurements of right heart size and function will likely provide clinically useful information, regardless of the underlying etiology of disease.
Such measurements have been demonstrated to be powerful prognostic indicators in humans with PH. 23,24 Identifying echocardiographic variables associated with survival time in dogs might aid clinical recommendations, identify future therapeutic targets, or both. Therefore, the primary objective of our study was to determine if echocardiographic measurements of right heart size and function are associated with survival times in dogs with PH. We also sought to compare echocardiographic measurements of right heart size and function in dogs with PH secondary to left heart disease (LHD) to dogs with PH not secondary to LHD. Last, we sought to determine the prevalence of right heart remodeling and RV dysfunction in dogs diagnosed with PH.

| Animals
The echocardiography database at the University of California, Davis, Veterinary Medical Teaching Hospital was searched for dogs diagnosed with PH between January 2015 and July 2018. Dogs were enrolled on a consecutive basis provided the inclusion criteria and none of the exclusion criteria were met.

| Inclusion criteria
Dogs had to have a complete two-dimensional and Doppler echocardiographic examination using standardized imaging planes 25 that included adequate visualization of right heart structures. Dogs had to have at least three tricuspid regurgitation jets recorded to allow measurement of TRV. The peak TRV determined using continuous wave Doppler that was recorded in the echocardiography report had to be >3.4 m/s. 2 The TRV profiles had to be clearly visible and their contour had to comply with known hemodynamic principals.

| Exclusion criteria
Dogs were excluded if they had a RV outflow tract obstruction (eg, pulmonary valve stenosis), if they had intracardiac heartworms and underwent interventional heartworm retrieval, if they were diagnosed with congenital cardiac shunt, or if they had a sustained or clinically important arrhythmia (eg, dogs that underwent treatment or pacing for an arrhythmia).

| Echocardiographic measurements and calculations
All echocardiographic examinations were performed by one of the authors (a board-certified cardiologist) or a cardiology resident trained by the author. All echocardiographic assessments, measurements, and calculations were performed by a single investigator (L. C. V.) at an off-cart workstation (Syngo Dynamic Workplace, Siemens Medical Solutions, Inc, Malvem, Pennsylvania). All echocardiographic studies were measured in the same order. The TRV recorded for study purposes was measured last. It was measured using continuous-wave Doppler recordings from the imaging plane that permitted the fastest jet profile. The TRV was converted to a tricuspid regurgitation The right parasternal short-axis basilar view optimized for the RV outflow tract that permitted adequate visualization of the pulmonary trunk and right pulmonary artery was used for the following measurements. Diameter of the pulmonary valve was measured in early diastole and indexed to the aorta root measurement (PV/Ao) as described above for LA/Ao. Pulmonary regurgitation velocity was measured in early diastole, if present. The ratio of acceleration time to ejection time (AT/ET) of pulsed-wave Doppler recordings of blood flow was measured at the level of the pulmonary valve. 18 Right pulmonary artery distensibility index was measured as previously described. 14 Internal diameter of the minimum diastolic and maximum systolic right pulmonary artery was quantified at the same location on the right pulmonary artery. The RPAD index was calculated according to the formula: RPAD index = (maximum diameter of the right pulmonary artery in systole − minimum diameter of the right pulmonary artery in diastole)/maximum diameter of the right pulmonary artery in systole.
A left apical 4-chamber view, usually optimized for the right heart, was utilized for measurements of right atrial and ventricular size and RV function. Maximum right atrial (end-systolic) and ventricular (end-diastolic) area (RAA and RVAd, respectively) were quantified using planimetry as previously described. 33 Right ventricular systolic function was quantified with TAPSE using two-dimensional echocardiography. 34 Table 2 for the remainder of the key. "-" = variables not included in the final model. Abbreviations: CI, confidence interval; HR, hazard ratio. a Overall model P = .002. b 4 dogs were excluded from the survival analysis because they did not survive to discharge.

| Statistical analysis
interventional retrieval. Three dogs were excluded because of a congenital cardiac shunt; 1 with a left-to-right shunting atrial septal defect and 2 with a right-to-left shunting patent ductus arteriosus.
Thus, 82 dogs were enrolled in our study and a summary of clinical findings is presented in Table 1. Breeds that were represented more than once included the Chihuahua (14), Shih Tzu (7), Maltese (6)
When these predictors (in addition to TAPSE and right heart failure) were carried forward into the second multivariable analysis, only RAA (P = .02) was independently associated with survival time ( Table 4)

| DISCUSSION
Our study showed that echocardiographic evidence of right heart enlargement is common in dogs with PH, regardless of the underlying etiology. Enlargement of the RA, RV, or PA was identified in at least 69% of all cases and RV systolic dysfunction was identified in onethird of cases. Right ventricular function was significantly worse in dogs with PH not secondary to LHD when compared to dogs with PH secondary to LHD. However, survival times were not significantly different between dogs with PH secondary to LHD (ie, MMVD) and dogs with PH not secondary to LHD. Last, right atrial size (RAA) and decreased RV function (TAPSE < 3.23 mm/kg 0.284 ) in addition to right heart failure were independently associated with reduced survival time in dogs with PH. These findings provide clinically relevant prognostic information and highlight the importance of quantifying right heart size and function (RAA and TAPSE, respectively) in dogs with PH related to any underlying cause.
Numerous studies have documented that RA enlargement (increased RAA), 19 RV enlargement (increased RVAd), 20 PA enlargement (increased PV/Ao), 7,14 and reduced RPAD index [14][15][16][17] are common in dogs with PH and that RV systolic dysfunction (reduced TAPSE) occurs in some dogs with PH. 21 In conclusion, our study suggests that increased right atrial size