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Abbreviations:
Ao aortic root diameter
AT acceleration time
CDMD chronic degenerative mitral valvular disease CV coefficient of variation
ECG electrocardiography
EF ejection fraction
ET ejection time
FS fractional shortening
IVS interventricular septum
LA left atrial diameter
LVD end-diastolic left ventricular basal diameter LVEDD left ventricular dimension at end-diastole LV-EI left ventricular eccentricity index
LVFW left ventricular free wall MEA mean electrical axis
MPA main pulmonary artery/aortic root diameter ratio
MR mitral valve regurgitation
PAH pulmonary artery hypertension PAP pulmonary arterial pressure
PH pulmonary hypertension
PR pulmonic valve regurgitation PVR pulmonary vascular resistance
RV right ventricular
RVD end-diastolic right ventricular basal diameter RVM right ventricular remodeling
SBP systemic blood pressure
SPAP systolic pulmonary artery pressure
TAPSE tricuspid valve regurgitation, tricuspid annular plane systolic excursion
TR tricuspid regurgitation
VHS vertebral heart scale
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Echocardiographic assessment of right heart indices in dogs with elevated pulmonary artery pressure associated with chronic respiratory disorders, heartworm disease and chronic degenerative mitral valvular disease Tzu-Chi Tai, Hui-Pi Huang
Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan.
Abstract
Background: Elevation of pulmonary arterial pressure (PAP) can be caused by pre- and post-capillary hemodynamic changes. Chronic elevated PAP may lead to right ventricular remodeling (RVM) and right heart failure.
Hypothesis: Different causes of elevated PAP in dogs may lead to diverse RVM.
Animals: 40 clinically healthy dogs and 169 dogs with tricuspid regurgitation.
Methods: Case-controlled, observational study. Dogs were examined and categorized as presenting normal (group 1, n=40); 169 dogs with tricuspid regurgitation (TR >1.5 m/s) were further categorized into group 2 (presented with chronic respiratory
disorders and left atrium to aorta ratio (LA/Ao) <1.7, n=33), group 3 (affected with heartworm disease, and LA/Ao <1.7, n=35), group 4 (presented with
mild-to-moderate chronic degenerative mitral valvular disease, CDMD, 1.5< LA/Ao
≤ 2, n=61), and group 5 (presented with severe CDMD, LA/Ao > 2, n=40). Right heart indices were measured by the echocardiography.
Results: The ratio of right to left ventricular basal diameter in right
ventricular-focused view was significant higher in groups 2 and 3 (P< .002 and P< .001, respectively). The ratio of main pulmonary artery to aortic root diameter, left ventricular compression quantified by eccentricity index were significantly higher in group 3 (P< .008 and P< .001, respectively ), and right ventricular acceleration to ejection time was significantly lower (P< .001) in group 3.
Conclusions: Among the three causes of elevated PAP; chronic respiratory disorders and heartworm disease had significant effect on echocardiographic indices of RV.
However, right heart indices derived from left heart measurements could be underestimated in dogs with CDMD.
Key words: dog, right heart, pulmonary hypertension, echocardiography.
Part of the study is going to present as a poster in the 22th European College of Veterinary Internal Medicine Congress, Maastricht, Netherlands. Sep. 6-8, 2012.
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Introduction
Pulmonary hypertension (PH) is defined as high diastolic or systolic pulmonary arterial pressure and may lead to right ventricular concentric or eccentric hypertrophy, right atrial enlargement, and right-sided heart failure.1,2 Elevation of PAP above normal constitutes PH and can be caused by pre- and post-capillary hemodynamic changes.3-5 Pulmonary hypertension is a well-recognized clinical condition in human patients and occurs as a primary or secondary disease of pulmonary vasculature.6,7 Primary pulmonary artery hypertension (PAH) has been described rarely in dogs.8 Left-sided heart failure caused by chronic degenerative mitral valvular disease (CDMD), myocardial disease, increased pulmonary blood flow, or increased pulmonary vascular resistance due to conditions such as obstructive pulmonary vascular disease, thromboembolic disease, pulmonary parenchymal disease, or chronic hypoxia are the common secondary causes of PH in dog.1,9-11 Chronic degenerative mitral valvular may lead to left heart dilation and increased left atrial pressure further causing elevated pulmonary venous pressure (post-capillary PH), pulmonary edema and hypoxia. Reactive pre-capillary PH may occur in the setting of left-heart failure when pulmonary artery vascular narrowing secondary to hypoxia and chronic post-capillary PH.3 Heart worm disease caused by Dirofilaria immitis is the most often reported cause of severe PH in dogs.12,13 The thromboembolism associated with dead adult worms, chronic inflammation, pulmonary vascular proliferation and dysfunction may cause pre-capillary PH in HWD.14 Chronic respiratory disorders such as tracheobronchial disease, brachycephalic syndrome and interstitial lung diseases result in chronic hypoxia, mechanical stress and inflammation and may lead to pre-capillary PH.7,10,15 In human patients with PH, the pathological changes in pulmonary vasculature are characterized by remodeling of small pulmonary arteries due to the proliferation of smooth muscle and endothelia cell, leading to hypertrophy
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of media and intima, and formation of plexiform lesions.14-17 Remodeling of pulmonary vessels leads to restrictions in pulmonary blood flow and progressive elevation in pulmonary vascular resistance (PVR) and PAP.5,7 Increased afterload resulted from increasing PVR and decreasing pulmonary vascular compliance is the primary cause of right ventricular adaption and ultimately failure in PH.17,18 Although changes in the pulmonary vasculature are the initial cause of PH, severity of
symptoms and survival are strongly associated with right ventricular function, and right heart failure is the main cause of death in human patients with PH.17
In recent years, echocardiography allows noninvasive estimates of PAP and evaluation of right heart function and structure.6,19,20 Doppler echocardiography assessment of tricuspid valve regurgitation (TR) or pulmonic valve regurgitation (PR) can be used to indirectly assess systolic PAP and diastolic PAP, respectively.1,6 These noninvasive estimates of PAP have been demonstrated to be strongly correlated with invasively measured PAP values in human patients.19 A number of echocardiographic right heart indices have been show potential prognostic values in human patients with PH, such as pericardial effusion, right atrial size, right ventricular (RV) diameter, tricuspid valve regurgitation, tricuspid annular plane systolic excursion (TAPSE), and eccentricity index.17 In dogs, several indirect markers of PH have been proposed, including observations of two-dimensional echocardiographic interventricular septal motion, right ventricular and main pulmonary artery size, Doppler derived TR and PR peak velocity, systolic time interval of pulmonary artery flow and RV myocardial velocities measured by tissue Doppler imaging.6,10,15,20 However, these finding in dogs are usually not quantitative values or only focus on one of PH causes.1,6,10,21 The quantitative echocardiographic measurements of right heart function and the usefulness of echocardiographic right heart indices as an assessment of right
ventricular remodeling (RVM) due to different etiologies of PH are rarely reported in
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the veterinary literatures. The aims of this study were to assess the echocardiographic right heart indices among different causes of elevated PAP in dogs.
Materials and Methods
Animals and criteria of inclusion
Medical records of client-owned dogs that echocardiographic examination was performed at the National Taiwan University Veterinary Hospital (NTUVH) between September 2009 and April 2012 were reviewed.
Dogs presented with obvious TR based on color-flow and continuous Doppler examinations were included. Dogs were excluded from this study if evidences of right bundle branch block was evident in electrocardiogram, or primary/secondary lung tumors were detected on chest radiography, or pulmonary stenosis were detected by standard echocardiography.
Forty client-owned clinical healthy dogs that were admitted to the NTUVH for annual wellness checkup during the same period of time were also included as control group (group 1). All these 40 dogs were free from any cardiac or respiratory disorders All dogs, both clinical healthy and diseased dogs included in this study were required to have medical record of complete physical examination, systolic blood pressure measurement, routine blood examination, chest radiography, electrocardiography (ECG), and echocardiography (two-dimensional, M-mode, and Doppler).
Procedures
In this study, the systemic blood pressure (SBP) measurement was measured by a Doppler flow detector by using a 9.5-MHz probe and an inflatable cuff attached to a sphygmomanometera. A standard 6-lead electrocardiogramb was recorded in right lateral recumbency. Thoracic radiographic measurements were made using electronic calipers of the digital thoracic radiographic system. Vertebral heart scale (VHS) was
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calculated from right lateral recumbent view (Fig 1).22 Echocardiography
examinations were performed in conscious dogs with undergoing continuous ECG monitoring and gently restrained in lateral recumbent positions using the two
dimensional (2D)-guided M mode and Doppler mode with ultrasound units equipped with 2-5 and 5-7.5 MHz phased-array transducersc. Two-dimensional
echocardiographic indices and left heart function assessment, including the left ventricular dimension at end-diastole (LVEDD) and end-systole (LVESD), the thickness of left ventricular free wall (LVFW) and interventricular septum (IVS) at end-diastole, E-point to septal separation (EPSS), ejection fraction (EF) and fractional shortening (FS), and left atrial/aortic root ratio (LA/Ao) were measured from the standard views obtained from the right parasternal images. In this study, left atrial size was categorized depending on the LA/Ao, as normal (LA/Ao < 1.5), mildly (1.5 ≤ LA/Ao ≤ 1.7), moderately (1.7 < LA/Ao ≤ 2), or severely enlarged (LA/Ao > 2).23 Two-dimensional echocardiographic right heart function assessment, the main pulmonary artery/aorta root ratio (MPA/Ao) was obtained by using the right parasternal transaortic short-axis view. The end-diastolic MPA diameter was
measured right under the closed pulmonic valve, the aortic diameter was measured on the same view, and the MPA/Ao ratio was calculated (Fig. 1).20 The end diastolic and systolic left ventricular eccentricity index (LV-EI) was measured as the ratio of the long axis to short axis diameters of the left ventricle in right parasternal short-axis view at mid-ventricular level (Fig. 2).24,25 In apical four-chamber view, tricuspid annular plane systolic excursion (TAPSE) was acquired by passing an M-mode cursor through the tricuspid annulus and measuring the distance of annular movement between end-diastole to end-systole (Fig.3).24,26 The relationship of TAPSE and aortic root diameter (Ao) was estimated by the ratio of TAPSE/Ao. The end-diastolic right to left ventricular basal diameter ratio (RVD/LVD) was defined as ratio of right to left
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ventricular basal short-axis dimension in apical four-chamber view with focus on the right ventricle (Fig. 4).26,27 The RVD/aortic root diameter (RVD/Ao) was also
calculated. The diastolic mitral/tricuspid flow velocities, mitral valve regurgitation and the aortic flow were measured from the standard left apical view. The pulmonary flow velocity profile was recorded from the standard right parasternal short-axis view at the basal level. The acceleration time (AT) of the pulmonary outflow was measured from the onset of pulsed Doppler to peak flow. The ejection time (ET) of the
pulmonary outflow was measured from the onset to the end of pulsed Doppler flow, and the right ventricular systolic time interval (AT/ET) was then calculated.10,20 Tricuspid regurgitation and pulmonic regurgitation (PR) were also quantitated by Doppler-derived echocardiography from the standard left apical and right parasternal views. Noninvasive prediction of systolic or diastolic PAP was estimated by
application of the modified Bernoulli equation based on the maximal velocity of TR or PR, respectively.19 In this study, elevated systolic pulmonary artery pressure (SPAP) was defined with affirmative identification of TR velocity > 1.5 m/sec by both
color-flow and continuous Doppler modes. TR velocity < 2 m/sec and ≥ 2 to < 3 m/sec was classified as normal-mild and moderate elevated SPAP, TR ≥ 3 m/sec (SPAP > 36 mmHg) was considered as severe PH.6,20
Measurement variability
Within-day variability was tested in 6 awake dogs. Repeated image acquisition for the right heart indices was performed in each dog at 3 nonconsecutive time points on a given day. The resulting mean values and standard deviations were used to determine the coefficient of variation (CV).28
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Statistical analysis
Data were expressed as the means ± standard deviations (SDs). The
Kolmogorov-Smirnov test was used for testing normal distribution of all data with commercial computer statistic softwared. Differences in continuous variables between groups were evaluated by one-way analysis of variance (ANOVA), followed if necessary by Student’s t-test with Bonferroni correction. Where the data were not normal distributed were analyzed by using Kruskal-Wallis test followed by the
post-hoc Mann-Whitney U-test. Receiver operating characteristic (ROC) analysis was used to evaluate the relationship between sensitivity and specificity.29 The Pearson product-moment and Spearman rank order correlation coefficient (r) were used to assess the relationship between variables. All tests were two-tailed. Significance was defined as P-value < 0.05.
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Results
Cases and Classification
A total of 169 dogs were fulfilled the inclusion criteria and enrolled in this study (Table 1). Tricuspid regurgitation or moderate-to-severe mitral valve regurgitation (MR) was detected during echocardiographic examinations in all these 169 dogs.
These cases were further categorized into four different groups based on the etiology of the disorders (Table2):
Group 2: cases of non-cardiac associated chronic respiratory disorders (n=33), all dogs in this group were presented with clinical signs: chronic exercise intolerance, shortness of breath, resting or exercise-induced cyanosis, dry cough, bilateral respiratory crackles, marked diffuse interstitial pulmonary infiltrates on thoracic radiographs. The findings of echocardiographic examinations in these dogs were TR without left sided congestive heart failure.10 In this group, five dogs with collapsed trachea, five with brachycephalic syndrome, 23 with lower airway diseases.
Group 3: cases of heartworm infestation but without moderate-to-severely enlarged left atrium (n=35). All dogs in this group were positive for circulating antigens of D. immitis detected by commercial ELISA kitse.
Group 4: cases of mild to moderate CDMD and enlarged left atrium (1.5 ≤ LA/Ao ≤ 2) with concomitant TR (n=61). Dogs in this group were no evidence of concurrent respiratory tract disease based on thoracic radiographs examination.
Group 5: cases of severe CDMD and markedly enlarged left atrium (LA/Ao > 2) with concomitant TR (n=40). Dogs in this group were no evidence of concurrent respiratory tract disease based on thoracic radiographs examination.
There was no statistical significance among five groups in sex distribution, but age of group1 was significantly lower compared with groups 2, 3, 4 and 5 (P< .001).
The body weight of groups 2 and 3 was significantly higher compared with groups 1,
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4 and 5 (P< .02).
Electrocardiography, Thoracic radiographic measurements
The electrocardiographic parameters: P wave amplitude, duration of P wave and QRS complex, PR and QT interval, mean electrical axis were not significantly different among these five groups. However, the amplitude of R wave in lead II of group 5 was significantly higher than groups 2 and 3 (P< .003) (Table 3).
The mean electrical axis (MEA) in groups 2 and 3 were slightly deviated toward right axis than other groups, however, these were within the reference range.30,31 Only 21% in group 2, 18% in groups 3, and 9% in group 4 and 3% in group 5 had right axis deviation (MEA > 100o). Overall, the sensitivity of right axis deviated MEA of
electrocardiogram to detect moderate-to-severe SPAP (TR > 2.8 m/s) was only 17.2%
with a specificity of 92.8%.
The VHS of group 5 was significantly higher than groups 1, 2, 3 and 4 (P< .001), the VHS of group 4 was also significantly higher than group 1 (P< .015).
Echocardiography
Two-dimensional (2D) Echocardiography (left heart function assessment)
Results of the two-dimensional echocardiographic indices are presented in Table 4. The left ventricular diameter and wall thickness, EPSS, EF and FS of groups 1, 2, 3 and 4 were within the reference ranges.32,33 In group 5, the left ventricular diameter was significantly increased as compared with groups 1, 2, 3 and 4 (P< .001).
Two-dimensional Echocardiography (right heart function assessment)
In group 3, the MAP/Ao and diastolic LV-EI were significantly higher than other groups (P< .008 and P< .001). The RVD/LVD was significantly higher in groups 2
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and 3 than groups 1, 4 and 5 (P< .02 and P< .001) and the RVD/Ao was significantly higher in group 3 than groups 1 and 4 (P< .019). There was no statistical significance among 5 groups in systolic LV-EI and TAPSE/Ao (Table 4).
Doppler hemodynamic assessment
In group 1, TR and PR was detected in 3 and 2 dogs, respectively, however, TR and PR was all less than 0.7 m/s.
In group 2, the mean TR velocity was 2.27 m/sec: 44%, 36% and 20% was classified as mild, moderate and severe regurgitation, respectively; and PR was detected in 18 of 33 dogs (mean velocity: 1.2 m/sec, ranged 0.23 to 4.2 m/sec) (Table 2). In group 3, the mean TR velocity was 2.44 m/sec: 24%, 52%, and 24% was classified as mild, moderate and severe regurgitation, respectively; and PR was detected in 20 of 35 dogs (mean velocity 1.33 m/sec, ranged 0.29 to 3.27 m/sec). In group 4, the mean TR velocity was 2.02 m/sec: 50%, 32%, and 16% was classified as mild, moderate and severe regurgitation, respectively; and PR was detected in 15 of 61 dogs (mean
velocity 0.84 m/sec, ranged 0.34 to 1.63 m/sec). In group 5, the mean TR velocity was 2.13 m/sec: 64%, 18% and 18% was classified as mild, moderate and severe
regurgitation, respectively; and PR was detected in 15 of 40 dogs (mean 0.92 m/sec, ranged 0.26 to 3.23 m/sec).
No significant differences of TR peak velocity and pulmonic regurgitation peak velocity (m/s) were found among groups 2, 3, 4 and 5.
Based on the causes of PAP development in this study, 59.8% (101/169), 20.7%
(35/169), 19.5% (33/169) was associated with CDMD, heartworm infestation, and chronic respiratory disorders, respectively.
In group 3, 4 and 5, the mitral regurgitation velocity was significantly higher than groups 1 and 2 (all P< .001). The ratio of mitral early and late diastolic peak
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velocity (Mitral E/A) in group 5 was significantly higher than groups 2, 3 and 4 (P< .01), and the AT/ET of pulmonary artery flow in group 3 was significantly lower than other groups (P< .001). There was no statistical significance among 5 groups in tricuspid early and late diastolic peak velocity (Tricuspid E/A), mean aortic and pulmonary flow velocity (Table 5).
The sensitivity to predict elevated PAP was 14% and 54% when AT/ET of pulmonary artery flow was set at ≤ 0.31 and ≤ 0.44, respectively (Table 5)
The correlations of elevated pulmonary artery pressure and electrocardiographic, radiographic, and echocardiographic indices
A significant positive correlation (P < .05) was found between SPAP and MAP/Ao, SPAP and RVD/Ao, SPAP and RVD/LVD, whereas a significant negative correlation (P < .05) was found between SPAP and AT/ET (Table 6).
The with-in day intra- and inter-observer variabilities of the right heart indices The with-in day intra- and inter-observer variabilities of the right heart indices are presented in Table7. All CV values of each right heart indices were lower than 16%.
Discussion
Prevalence of PH has been reported in dogs associated with respiratory disorders, HWD, and CDMD ranged 8 to 50%, 6 to 10%, and, 30 to 74%, respectively.4,6,15,20,34
The severity of systolic PAP estimated based on echocardiographic assessment with respiratory disorders, heartworm infestation and CDMD was classified as mild to moderate in most dogs.15 In the present study, CDMD also was the most common cause among these three causes of PH in our cases. Similarly, the severity of PH for
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most cases among these three causes was classified as mild to moderate. However frequency and severity of heartworm-related PH in this study were higher than the results of previous studies. The difference might be attributed to the high prevalence of dirofilariasis in Taiwan.35,36
The electrocardiographic changes have been reported in dogs with PH.6,37,38 These changes were not frequently noted in this study. Although the MEA in dogs with chronic respiratory and heartworm infestation were slightly deviated to right axis than other groups, it was within the reference range. The frequency of right axis deviation was lower than the result of a study that 42% of dogs was experimentally infested with D. immitis infestation in the pulmonary arteries.30 In this study, right axis deviated MEA of electrocardiogram was not sensitive to predict
moderate-to-severe elevated SPAP (TR > 2.8 m/s). In dogs with CDMD, the R wave amplitudes in lead I and II were increased significantly compared with dogs with respiratory disorders and HWD. Thus, the MEA could be affected by the left
ventricular enlargement.39 This result agreed with the findings of previous studies that the electrocardiogram is insufficiently sensitive to be a screening tool for detecting significant PH.6,37
The echocardiogram is the gold standard for noninvasive method applied in veterinary medicine for diagnosis of PH.3,38 Measurement of tricuspid valve
regurgitation maximal velocity, right ventricular systolic time intervals (AT and ET), and the acceleration time index (AT/ET) had been used to estimate systolic PA
pressures.6,10,20,34,40-42 Values of AT/ET ≤ 0.31 (sensitivity: 73% and specificity: 87%) and ≤ 0.44 (sensitivity: 71% and specificity: 71%) had been used to predict presence of PH, and these values were especially useful to diagnose the PH in dogs without
pressures.6,10,20,34,40-42 Values of AT/ET ≤ 0.31 (sensitivity: 73% and specificity: 87%) and ≤ 0.44 (sensitivity: 71% and specificity: 71%) had been used to predict presence of PH, and these values were especially useful to diagnose the PH in dogs without