Pulmonary hypertension (PH) is a well-recognized clinical

Transcription

1 J Vet Intern Med 999;3: Clinical Characteristics of 53 Dogs with Doppler-Derived Evidence of Pulmonary Hypertension: Lynelle Johnson, June Boon, and E. Christopher Orton Pulmonary hypertension occurs as a primary or secondary disorder of the pulmonary vasculature. Doppler echocardiography provides a noninvasive tool for the estimation of pulmonary arterial pressure when tricuspid regurgitation or pulmonic insufficiency is present. The cardiology database at Colorado State University was reviewed, and echocardiographic records from cases diagnosed with pulmonary hypertension were evaluated. Application of the modified Bernoulli equation to the maximal instantaneous velocity of a right-sided regurgitant jet provided evidence of pulmonary hypertension in 53 dogs over a 4-year period. Tricuspid regurgitant velocity 2.8 m/second or pulmonic insufficiency velocity 2.2 m/second was considered abnormal and indicative of pulmonary hypertension. Tricuspid regurgitant gradients in 5 dogs ranged from 32 to45 mm Hg (mean, 63.0 mm Hg; median, 57.0 mm Hg; 25th 75th percentiles, mm Hg). Pulmonic insufficiency gradients in 8 dogs ranged from 20 to 00 mm Hg (mean, 59.5 mm Hg; median, 6.5 mm Hg; 25th 75th percentiles, mm Hg). Affected dogs ranged in age from 2 months to 6 years. Clinical signs were characteristic of cardiopulmonary disease, but a relatively high frequency of syncope was noted (2 of 53 dogs, 23%). Pulmonary hypertension was probably due to increased pulmonary vascular resistance in 23 dogs, pulmonary overcirculation in 2 dogs, and pulmonary venous hypertension in 23 dogs. Five dogs lacked a clinically recognizable cardiopulmonary cause of pulmonary vascular disease. Our results suggest that pulmonary hypertension can occur as a complication of commonly encountered cardiopulmonary diseases, and that Doppler echocardiography can facilitate recognition of this condition. Key words: Bernoulli; Echocardiography; Hypoxia; Overcirculation; Regurgitation; Velocity. Pulmonary hypertension (PH) is a well-recognized clinical condition in human patients and occurs as a primary or secondary disease of the pulmonary vasculature. Primary or idiopathic PH is characterized by pathology in the tunica media of muscular pulmonary arteries and is described as a plexogenic pulmonary arteriopathy. PH also may occur secondary to abnormally high left atrial pressure, increased pulmonary blood flow, or increased pulmonary vascular resistance. 2 Increased pulmonary vascular resistance can be caused by obstructive or obliterative diseases of the vasculature, arterial vasoconstriction, or chronic pulmonary parenchymal disease. In veterinary medicine, the most well-recognized cause of pulmonary hypertension is heartworm disease. Embolism of dead heartworms causes acute clinical signs of pulmonary arterial hypertension, and mechanical occlusion of large pulmonary arteries is followed by proliferative intimal changes that lead to irreversible structural damage to the vasculature and sustained pulmonary hypertension. 3 5 Chronic parenchymal inflammation and fibrosis of the lung contribute to vascular dysfunction. 3,6 Mild PH also has been reported in dogs with left-sided heart failure caused by mitral regurgitation 7 and in those with congenital cardiac conditions, 8 0 but it has not been fully described in these diseases or in noncardiac conditions. Cardiac catheterization is required for definitive measurement of pulmonary arterial pressure, and pulmonary From the Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, MO (Johnson); and the Department of Clinical Sciences, Colorado State University, Fort Collins, CO (Boon, Orton). Presented in part at the 5th Annual Forum of the American College of Veterinary Internal Medicine, Lake Buena Vista, FL, May 997. Reprint requests: Lynelle Johnson, DVM, MS, E02 Veterinary Medicine Building, Department of Veterinary Biomedical Sciences, Columbia, MO 652; johnsonlr@missouri.edu. Submitted September 4, 998; Revised February 6, 999; Accepted March 9, 999. Copyright 999 by the American College of Veterinary Internal Medicine /99/ /$3.00/0 hypertension is characterized by systolic pressures 25 mm Hg. 2 Noninvasive prediction of pulmonary artery pressure is possible with Doppler echocardiography. In the absence of pulmonic stenosis, systolic or diastolic pulmonary arterial pressure can be estimated by application of the modified Bernoulli equation ( P 4 velocity in m/second 2 ) to the maximal velocity of tricuspid regurgitation or pulmonic insufficiency, respectively. 2 To date, this technique has not been widely reported in the clinical investigation of pulmonary hypertension in dogs. We describe the clinical, radiographic, and echocardiographic characteristics of PH diagnosed by Doppler echocardiography in a population of dogs with a low prevalence of naturally occurring heartworm disease. Materials and Methods Echocardiographic records at Colorado State University were searched for a diagnosis of pulmonary hypertension in dogs. During the time period during which Doppler technology was available ( ), 63 dogs with echocardiographic characteristics of PH were identified, and each echocardiographic report was evaluated for completeness. Ten dogs were excluded from analysis because of lack of a measured value for tricuspid regurgitant or pulmonic insufficiency velocity for calculation of the right ventricular-to-right atrial (RV-to- RA) or pulmonary artery-to-right ventricular (PA-to-RV) pressure gradient. Medical records and radiographs of the remaining 53 dogs were reviewed by one of the authors (LJ). History, signalment, and presenting complaints were noted. Abnormalities on cardiopulmonary examination, laboratory findings, radiographic findings, and results of ancillary tests were recorded. Median survival time was calculated for dogs with PH that died or were euthanized. Disease course was described by evaluating pressure gradients in dogs that died or were euthanized. Postmortem reports were available for review for 2 dogs. Fifty dogs were examined by ultrasonographer (JB) and 3 were examined by another. Complete 2-dimensional and Doppler echocardiographic studies were performed using an HP-Sonos 000 (Hewlett Packard, Andover, MA). Doppler studies were performed with a 2.5- or 3.5-MHz transducer to minimize signal-to-noise ratio. Standard echocardiographic views were obtained in all dogs, 3 and the view that provided optimal alignment with regurgitant flow was used to estimate the instantaneous RV-to-RA or PA-to-RV pressure gradient. Pulmonic

2 Pulmonary Hypertension in Dogs 44 Fig. Echocardiogram showing a 2-dimensional recording of tricuspid regurgitation from a left cranial parasternal short-axis view at the level of the aortic root. The flow profile shown below the 2-dimensional image discloses a regurgitant jet with a velocity of 4.0 m/ second, corresponding to a right ventricular-to-right atrial pressure gradient of 64 mm Hg. stenosis was ruled out in all dogs based on lack of deformity or narrowing of the pulmonic valve region, absence of poststenotic dilatation of the pulmonary artery, and normal excursion of the valve leaflets. Application of the modified Bernoulli equation ( P 4 velocity 2 ) to the maximal velocity of tricuspid regurgitation or pulmonic insufficiency was used to calculate RV-to-RA and PA-to-RV pressure gradients, respectively. A peak tricuspid regurgitant velocity 2.8 m/ second (Fig ) or pulmonic insufficiency velocity 2.2 m/second was considered abnormal and indicative of PH. Right atrial pressure was not predicted clinically for all dogs, and therefore could not be used for estimation of pulmonary artery pressure. Pressure gradients were reported as mean values with ranges and median values with 25th 75th percentiles to describe the population. Dogs were categorized as having mild PH (RV-to-RA gradient 50 mm Hg), moderate PH (5 75 mm Hg), or severe PH ( 75 mm Hg) to evaluate the frequency of some clinical findings. The pulmonary velocity profile was examined in the right ventricular outflow tract. The sample volume was placed immediately distal to the pulmonary valve and then advanced within the artery and moved from side to side until a clear laminar flow pattern with maximal velocity was recorded. The pulmonary artery velocity profile was subjectively assessed in 34 of 53 dogs and reported as type I, type II, or type III (Fig 2) according to standard descriptions. 4,5 In 5 of 53 dogs, subjective assessment of right ventricular chamber size and wall thickness was made by comparison with left ventricular parameters as described. 6 Right ventricular chamber size was reported as normal if it was less than or equal to one half of the size of the left ventricle in the right parasternal long-axis view of the left ventricular outflow tract. The right ventricle was considered moderately dilated if it was from 50 to 00% of left ventricular size, and severe dilatation was reported when right ventricular size exceeded that of the left ventricle. Effects of paradoxical septal motion on RV chamber size were considered in this subjective assessment. Right ventricular wall thickness less than one half of left ventricular free wall thickness was recorded as normal. Wall thickness greater than 0.5 but less than Fig 2. The top image shows the left cranial long-axis view of the pulmonary artery with the Doppler gate site for recording pulmonary velocity profiles. In the 3 lower figures, the type I profile represents normal pulmonary flow as described in human medicine, the type II profile depicts the rapid rate of rise in pulmonary flow associated with elevated pulmonary artery pressure, and the type III profile illustrates the rapid rise in pulmonary flow followed by delayed deceleration and midsystolic notching in the velocity profile..5 times the left ventricular free wall was deemed moderately hypertrophied, and severe hypertrophy was recorded when the right ventricular wall exceeded.5 times the thickness of the left ventricular free wall. Pathophysiologic mechanisms considered as possible causes for PH in this study included increased pulmonary vascular resistance due to chronic alveolar hypoxia (hypoxic vasoconstriction) or pulmonary vascular obstruction, pulmonary overcirculation, and chronically increased left atrial pressure. Data used to support the suspected mechanism of disease included clinical diagnosis, blood gas analysis, perfusion scan, radiographic evidence of pulmonary venous congestion or parenchymal infiltrates, echocardiographic findings of left atrial dilatation or cardiac shunt, historical evidence of heartworm disease or pulmonary thromboembolism, or postmortem results. Multiple mechanisms may have contributed to the clinical syndrome of PH in individual dogs; however, each case was assigned to a single category based on the primary suspected pathophysiology. Dogs that lacked a recognizable cause for PH were placed in an unclassified category. Results Animals From 992 to 996, 53 dogs had measurable increases in the calculated RV-to-RA or PA-to-RV pressure gradient

3 442 Johnson, Boon, and Orton Table. Frequency of clinical findings in 53 dogs with Doppler-derived evidence of pulmonary hypertension. Clinical Sign Presenting complaints Exercise intolerance Cough Dyspnea Syncope Physical examination findings Heart murmur Ascites Abnormal lung sounds Cyanosis Jugular venous distention Subcutaneous edema Radiographic findings Cardiomegaly Pulmonary infiltrates Large pulmonary arteries Pleural effusion Large pulmonary veins Large caudal vena cava Echocardiographic findings Type I pulmonary velocity profile Type II pulmonary velocity profile Type III pulmonary velocity profile Right ventricular dilatation Right ventricular hypertrophy Decreased left ventricular diastolic volume Paradoxical septal motion % (No. with Finding/Total No.) 45 (24/53) 30 (6/53) 28 (5/53) 23 (2/53) 83 (44/53) 26 (4/53) 23 (2/53) 5 (8/53) 9 (5/53) 6 (3/53) 84 (4/49) 65 (32/49) 3 (5/49) 4 (7/49) 2 (6/49) 2 (6/49) 0 (0/34) 56 (9/34) 44 (5/34) 53 (27/5) 49 (25/5) 40 (2/53) 5 (8/53) as determined by Doppler echocardiography. The population was composed of 26 males and 27 females. Affected dogs ranged from 2 months to 6 years in age, with 7 dogs less than year of age, 2 dogs between and 5 years, 6 dogs from 5 to 0 years, and 28 dogs 0 years of age. Of adult dogs diagnosed with PH, 0 of 46 (22%) were small ( 7.5 kg) dogs, 28 of 46 (6%) were medium sized ( kg), and 8 of 46 (7%) were large ( 20.5 kg) dogs. Four large-breed dogs were less than year of age at the time of diagnosis. Breeds represented more than once in the population included the Miniature Poodle (5), Cocker Spaniel (5), West Highland White Terrier (3), Scottish Terrier (2), Dachshund (2), Great Pyrenees (2), Golden Retriever (2), and Labrador Retriever (2). Outcome was available for 30 of 53 dogs. Twelve dogs were euthanized 220 days after the diagnosis of PH. Mean and median survival times were 35.0 and 3.5 days, and RV-to-RA pressure gradients ranged from 37 to 45 mm Hg (mean, 66 mm Hg; median, 62.5 mm Hg). Eight dogs with suspected PH died 47 days after diagnosis. Mean and median survival times were 4.4 and 3.0 days, and RV-to-RA pressure gradients in this group ranged from 39 to 22 mm Hg (mean, 65.6 mm Hg; median, 62.5 mm Hg). Ten dogs were alive from 4 to 600 days after Doppler evidence of PH was obtained, and RV-to-RA pressure gradients in this group ranged from 35 to 05 mm Hg with slightly lower mean (53.7 mm Hg) and median (49.0 mm Hg) values. Disease course did not seem to be related to the magnitude of the RV-to-RA gradient. Fig 3. The right ventricular-to-right atrial (RV-to-RV) pressure gradient was used to categorize patients as having mild pulmonary hypertension (RV-to-RA 50 mm Hg), moderate pulmonary hypertension (RV-to-RA 5 75 mm Hg), and severe pulmonary hypertension (RV-to-RA 75 mm Hg). Selected clinical, radiographic, and echocardiographic features were compared among groups. Clinical Findings Historical and Physical Findings. Four dogs had a history of heartworm disease month to 0 years before presentation. One dog received adulticidal therapy month before the diagnosis of PH. Presenting complaints for dogs suspected of PH included lethargy or exercise intolerance, cough, dyspnea, and syncope (Table ). Cardiac murmurs were reported in 44 of 53 dogs (83%). One dog had a diastolic pulmonic murmur, and the remainder had systolic murmurs described by the primary clinician as mitral (26 of 44 dogs, 59%), tricuspid (3 of 44 dogs, 30%), aortic (2 of 44 dogs, 5%), and systolic pulmonic (2 of 44 dogs, 5%). No murmur could be auscultated in 9 of 53 dogs (7%). Twelve dogs were tachycardic (heart rate 50 beats per minute) and 4 were bradycardic ( 80 beats per minute). Additional abnormalities on physical examination included ascites, adventitious lung sounds, cyanosis, jugular venous distention, and subcutaneous edema (Table ). Seven of 53 dogs (3%) were asymptomatic, and these dogs tended to have lower RV-to-RA pressure gradients, but clinical findings generally were not related to the RV-to-RA pressure gradient calculated (Fig 3). Clinical pathology. A CBC was performed in 36 dogs. Mild leukocytosis was found in 0 of 36 dogs (28%). Nucleated red blood cells, a potential indicator of hypoxia, were found in 0 of 36 dogs (28%). Blood gas evaluation was performed in 0 dogs, and hypoxemia was documented in 8 of 0 dogs (80%). The partial pressure of oxygen in arterial blood varied from 35.0 to 75.9 mm Hg (mean SD, mm Hg; predicted normal range, mm Hg). Partial pressure of carbon dioxide in arterial blood ranged from 22. to 55.2 mm Hg (mean SD, mm Hg; predicted normal range, mm Hg). Heartworm status was assessed in 8 dogs. A Knott s test

4 Pulmonary Hypertension in Dogs 443 Table 2. Pathophysiologic associations and clinical diseases in 53 dogs with Doppler-derived evidence of pulmonary hypertension. Fig 4. Distribution of Doppler-derived estimates of right ventricularto-right atrial (n 5) and pulmonary artery-to-right ventricular (n 8) pressure gradients in 53 dogs. Box and whiskers plots exhibit the entire range of data. The box encompasses the 25th 75th percentiles surrounding the median (indicated by the line within the box) and error bars include the 0th 90th percentiles. was negative in 6 of 7 dogs (94%), and occult heartworm antigen test results were negative in all 0 dogs. The sole positive Knott s test was in a research Beagle used as a donor of microfilaria. Radiography. Thoracic radiographs were abnormal in 48 of 49 dogs and the following were reported: cardiomegaly in 4 of 49 dogs (84%), pulmonary parenchymal infiltrates in 32 of 49 dogs (65%), large pulmonary arteries in 5 of 49 dogs (3%), pleural effusion in 7 of 49 dogs (4%), large pulmonary veins in 6 of 49 dogs (2%), and large caudal vena cava in 6 of 49 dogs (2%) (Table ). Hepatomegaly was noted in 2 dogs. Collapse of the trachea was detected during fluoroscopy in 2 dogs. Ancillary Diagnostics. Transtracheal wash was performed in 8 dogs. Inflammation was present in all 8 dogs, and 3 of 8 samples (38%) had cytologic evidence of previous airway hemorrhage. Five dogs had technetium lung scans performed and all documented perfusion deficits. Electrocardiograms were included in the cardiac evaluation of 8 of 53 dogs (34%). Evidence of chamber enlargement was seen in 0 of 8 dogs, with right atrial or left ventricular enlargement in 2 dogs each (%) and left atrial or right ventricular enlargement patterns in 3 dogs each (7%). Arrhythmias were detected in of 8 dogs, with atrial fibrillation (4 of 8 tracings, 22%) and sinus tachycardia (3 of 8 tracings, 7%) being most common. Paroxysmal atrial tachycardia, ventricular bigeminy, st-degree atrioventricular block, and bradycardia nonresponsive to atropine were found in dog each. Echocardiography. In 5 dogs, continuous-wave Doppler echocardiography suggested PH because of detection of tricuspid regurgitant velocity 2.8 m/second. RV-to-RA pressure gradients ranged from 32 to 45 mm Hg with a mean of 63.2 mm Hg (median, 57.0 mm Hg; 25th 75th percentiles, mm Hg) (Fig 4). Eight dogs were suspected to have PH based on detection of a pulmonic insufficiency jet 2.2 m/second. PA-to-RV pressure gradients ranged from 20 to 00 mm Hg with a mean of 59.5 mm Hg (median, 6.5 mm Hg; 25th 75th percentiles, mm Hg) (Fig 4). Disease Alveolar hypoxia Pulmonary fibrosis Pneumonia Tracheobronchial disease Chronic pulmonary disease Mineralization Neoplasia Vascular obstruction Heartworm disease Thromboembolism Pulmonary endarteritis Pulmonary overcirculation Confirmed right-to-left patent ductus arteriosus Eisenmenger s physiology Increased venous pressure Mitral valve disease Dilated cardiomyopathy Myocarditis Atrial distention with atrial fibrillation Unclassified Lymphosarcoma Diabetes mellitus Tricuspid dysplasia Digital tumor Perineal hernia No Pulmonary artery velocity profile was evaluated in 34 dogs and designated as type I in 0 of 34 tracings (0%), type II in 9 of 34 (56%), and type III in 5 of 34 (44%) (Table ). Right ventricular wall thickness was graded as normal in 26 of 5 dogs (5%), moderately thickened in 20 of 5 dogs (39%), and severely thickened in 5 of 5 dogs (0%). All dogs with severe right ventricular hypertrophy were year of age. Right ventricular chamber size was assessed as normal in 24 of 5 dogs (47%), moderately dilated in of 5 dogs (22%), and severely dilated in 6 of 5 dogs (3%). Dogs with mild, moderate, or severe PH had type II or III pulmonary velocity profiles and right ventricular abnormalities documented on echocardiography (Fig 3). Paradoxical septal motion suggestive of right ventricular pressure overload was detected in 8 of 53 dogs (5%) (Table ). Pathophysiology Increased pulmonary vascular resistance due to either hypoxic pulmonary disease or pulmonary vascular obstruction was considered the most likely cause of PH in 23 of 53 dogs (43%) (Table 2). In 2 of 53 dogs (23%), chronic alveolar hypoxia with subsequent vascular remodeling was considered the most likely factor contributing to abnormally high pulmonary artery pressure based on clinical history, blood gas data, radiographic changes, and histopathology. Clinical diagnoses in these patients included pulmonary fibrosis, pneumonia, and chronic tracheobronchial disease. RV-to-RA gradients in this group of dogs ranged from 39 to 22 mm Hg (mean 7.0 mm Hg; median, 67.5 mm Hg;

5 444 Johnson, Boon, and Orton 25th 75th percentiles, mm Hg) (Fig 5). PH was attributed to pulmonary vascular disease in of 53 dogs (2%). Five dogs had acute or chronic pulmonary thromboembolism, 5 dogs had acute heartworm embolization or chronic heartworm disease, and dog had obliterative pulmonary endarteritis of unknown cause on histopathology. RV-to-RA pressure gradients in this group ranged from 37 to 45 mm Hg (mean, 74.3 mm Hg; median, 70.5 mm Hg; 25th 75th percentiles, mm Hg) (Fig 5). PH was related to pulmonary overcirculation in dog with a confirmed right-to-left shunting patent ductus arteriosus and PA-to-RV pressure gradient of 00 mm Hg. A 2nd dog considered likely to have pulmonary overcirculation and Eisenmenger s physiology as a cause of PH had pressure gradients of 20 mm Hg (RV-to-RA) and 95 mm Hg (PA-to-RV). A chronic increase in left atrial pressure with subsequent pulmonary venous hypertension was considered the likely cause of pulmonary arterial hypertension in 23 of 53 dogs (43%). The RV-to-RA pressure gradient ranged from 33 to 00 mm Hg in this group (mean, 55.8 mm Hg; median, 56.0 mm Hg; 25th 75th percentiles, mm Hg) (Fig 5). Sixteen of 53 dogs (30%) had mitral regurgitation with left atrial dilatation or congestive heart failure. Four of 53 dogs (8%) had a final diagnosis of dilated cardiomyopathy, dog had lymphoplasmacytic myocarditis on necropsy, and dog had congestive heart failure with myocardial dysfunction. The other dog in this category had left atrial dilatation, atrial fibrillation, and tricuspid valve dysplasia. Five dogs lacked radiographic, echocardiographic, or postmortem evidence of pathology that could explain their abnormally high pulmonary artery pressures, and these dogs were placed in an unclassified category. The RV-to- RA pressure gradients in this group ranged from 32 to 60 mm Hg (mean and median, 45.0 mm Hg; 25th 75th percentiles, mm Hg). Final diagnoses in these dogs are listed in Table 2. Discussion Fig 5. Distribution of calculated right ventricular-to-right atrial pressure gradients for the pathophysiologic mechanisms suspected in 53 dogs. () Hypoxia (2 of 53 dogs). (2) Vascular obstruction ( of 53 dogs). (3) Pulmonary overcirculation (2 of 53 dogs). (4) Increased left atrial pressure (23 of 53 dogs). (5) Unclassified (5 of 53 dogs). Box and whiskers plots exhibit the entire range of data. The box encompasses the 25th 75th percentiles surrounding the median (indicated by the line within the box) and error bars include the 0th 90th percentiles. An * denotes pulmonary artery-to-right ventricular pressures. From 992 to 996, continuous-wave Doppler echocardiography was routinely performed during cardiac examinations at Colorado State University and could be used to detect pulmonary hypertension. Application of the modified Bernoulli equation to the maximal velocity of tricuspid regurgitant or pulmonic insufficient jets resulted in calculated RV-to-RA or PA-to-RV pressure gradients ranging from 20 to 45 mm Hg and 20 to 00 mm Hg in 53 dogs. Use of the modified Bernoulli equation has several procedural and inherent limitations. 2 The Doppler signal must be parallel to flow for accurate estimation of the pressure difference between 2 chambers. Misalignment with flow results in a lower predicted pressure gradient, and proper alignment with high-velocity jets depends both on the operator and patient. A single ultrasonographer performed most of the studies described here, and no dogs were sedated for examination, which facilitated interpretation and comparison of the echocardiographic reports. The pressure gradient calculated by the modified Bernoulli equation relies solely on the instantaneous regurgitant velocity measured and ignores the contribution of flow acceleration and viscous friction. 2 The modified Bernoulli equation also ignores the initial flow velocity present. When high-volume regurgitation is present, use of the modified Bernoulli equation may overestimate the pressure gradient. Limitations in the use of the Bernoulli equation may have been responsible for the lack of correlation between the magnitude of the RV-to-RA pressure gradient and severity of clinical signs, clinical outcome, or specific echocardiographic features in the population of dogs described. Also, in this retrospective study right atrial pressure was not estimated clinically in all patients and therefore did not enter into estimation of pulmonary artery pressure. However, use of the pressure gradient alone has been reported to predict pulmonary arterial hypertension accurately. Despite these limitations, Doppler echocardiography provided evidence of pulmonary hypertension in association with many commonly encountered cardiopulmonary diseases in the dogs of this study. Older dogs most often were affected and typically represented breeds commonly affected by valvular insufficiency or airway disease. Dogs year of age had several disease processes, and most were large-breed dogs including Great Pyrenees (2 of 7 dogs) and Labrador or Golden Retrievers (2 of 7 dogs). Diagnoses in young dogs included pulmonary vascular disease due to congenital heart disease or pulmonary endarteritis (3 of 7 dogs), pneumonia (2 of 7 dogs), dilated cardiomyopathy ( dog), and thrombosis in the right atrium ( dog). The major pathophysiologic mechanisms associated with pulmonary hypertension in human patients are increased left atrial pressure, pulmonary overcirculation, and increased pulmonary vascular resistance due to hypoxic vasoconstriction, obstructive vascular disease, or parenchymal disorders. In this study, only noninvasive diagnostic tests were performed and clinical criteria were used to define the mechanism most likely responsible for suspected PH. Left

6 Pulmonary Hypertension in Dogs 445 atrial pressure was not directly measured and therefore was inferred from the presence of an enlarged left atrium on radiography or echocardiography in the setting of chronic congestive heart failure. In a large number of dogs, pulmonary disorders were diagnosed based on a combination of blood gas analysis, radiographic and scintigraphic findings, and histopathologic information. Normal dogs exhibit only mild pulmonary vasoconstriction in response to hypoxia 7 ; however, chronic or intermittent global hypoxia can initiate or contribute to reactive PH in human patients 8 and may have an important impact on vascular function in dogs with chronic pulmonary disease. Additional factors may contribute to the pathogenesis of abnormally high pulmonary arterial pressures in dogs with pulmonary disease, including structural changes in the vasculature, 9 an imbalance of vasodilatory and vasoconstrictor mediators, genetic tendencies, or abnormal endothelial smooth muscle cell interactions. 20 In addition, high altitude has been clearly implicated as a factor in the generation of pulmonary hypertension in susceptible species 7 and may have played a role in the development of high pulmonary artery pressures in the dogs of this study, most of which lived at,500-m altitude. In humans, a genetic predisposition for PH has been proposed, and multiple factors are believed to contribute to induction of pulmonary hypertension. 2 Coexisting cardiopulmonary diseases, systemic inflammatory processes, or acidosis all may affect the development of increased pulmonary artery pressure. The contribution of multiple disease processes to the generation of PH could not be confirmed or excluded by review of the medical records of the dogs in this study, and therefore the most likely mechanism for PH was reported here. Chronic alveolar hypoxia with subsequent vascular remodeling was considered the most likely contributor to PH in 2 dogs. Pulmonary fibrosis was diagnosed in 3 dogs and documented by histopathology in 2 of 2 dogs that underwent postmortem examination. Pneumonia was diagnosed in 3 dogs and confirmed by histopathology in 2 of 2 dogs that underwent postmortem examination. Two of the 3 dogs with pneumonia were under 6 months of age and may have had retention of fetal characteristics in the vasculature that made them more susceptible to hypoxic vasoconstriction with vascular remodeling. In the remaining 6 dogs with presumed alveolar hypoxia, chronic tracheobronchial disease was present in 2 dogs, bronchial mineralization and pulmonary neoplasia were found in dog each, and a nonspecified chronic pulmonary disease was reported in 2 dogs. Persistent pulmonary inflammation with overexpression of growth factors and increased production of vasoactive mediators may contribute to the cascade of reactions that leads to structural alterations in vessels, increased pulmonary vascular resistance, and pulmonary hypertension. 2 Thus, chronic exposure to hypoxia in conjunction with ongoing pulmonary disease may lead to intermittent or sustained vasoconstriction with resultant vascular remodeling and induction of pulmonary hypertension. Pulmonary vascular disease leading to increased vascular resistance was considered the likely cause of PH in dogs. Chronic thromboembolic or heartworm disease was diagnosed in 5 dogs based on history and clinical findings. Acute pulmonary vascular obstruction due to thromboembolism or a heartworm embolus was thought to lead to pulmonary hypertension in 5 dogs. In a retrospective casematched study of human patients, echocardiographic findings were abnormal in 94% of patients with acute pulmonary embolization. 22 Abnormal findings in that study included tricuspid regurgitant velocity 2.5 m/second, dilatation of the right ventricle, and abnormal septal motion. These echocardiographic abnormalities were present in dogs with pulmonary embolism reported here. Echocardiography can be used to follow resolution of disease in acute pulmonary hypertension due to thromboembolism, 6 but in our population, only dog survived the embolic event. In this study, the highest pressure gradient detected by continuous-wave Doppler occurred in a dog with pulmonary vascular disease. The RV-to-RA gradient of 45 mm Hg was calculated in a 6-month-old Miniature Poodle with a diagnosis of severe, obliterative pulmonary endarteritis and hypertrophic changes in the tunica media of pulmonary vascular smooth muscle on postmortem examination. The etiology of this vasculitis could not be determined. Two dogs were suspected to have PH due to pulmonary overcirculation and Eisenmenger s physiology. A bubble study during echocardiography confirmed a right-to-left shunting patent ductus arteriosus in dog but definitive documentation of a shunt could not be obtained in the other dog. Eisenmenger s physiology can result when a large leftto-right shunt leads to flow-induced vascular damage, increased pulmonary vascular resistance, and reversal of flow. 2 Pulmonary hypertension resulting from increased pulmonary venous pressure was suspected in 6 dogs with mitral valve insufficiency, in 6 dogs with myocardial failure, and in dog with atrial fibrillation. Doppler-derived RV-to-RA pressure gradients in this group ranged from 33 to 00 mm Hg (mean, 57.8 mm Hg; median, 56.0 mm Hg). Chronic pulmonary venous hypertension can cause structural alterations in pulmonary capillaries with resultant muscularization of pulmonary resistance arterioles. 23 The prevalence of histopathologic abnormalities could not be determined in the present study because postmortem results only were available for 4 dogs with acquired cardiac disease and PH, although intimal proliferation was noted in the pulmonary artery of dog. Pulmonary vascular abnormalities have been reported in dogs with PH associated with congenital cardiac lesions, 8 but further study is required to determine the frequency of structural alterations in the pulmonary arterioles, capillaries, or venules of dogs with acquired heart disease. Five dogs did not have a classifiable cardiopulmonary condition that could be associated with abnormally high pulmonary artery pressures. Diagnoses in these dogs were diverse and included nonpulmonary neoplasia, diabetes mellitus, perineal hernia, and tricuspid dysplasia. No necropsy results were available for dogs in this group to identify potential causes for increased pulmonary arterial pressure. These dogs tended to exhibit lower RV-to-RA gradients and were less often symptomatic. The absence of a standardized diagnostic workup for all animals presented to the teaching hospital was an inherent limitation of this retrospective study. Not all dogs presented to Colorado State University for evaluation of respiratory

7 446 Johnson, Boon, and Orton conditions or cardiac disease had Doppler echocardiography performed, and therefore the true prevalence of PH in dogs is difficult to assess. However, the wide range of common diseases associated with pulmonary hypertension in this study suggests that PH may be more common than previously thought. Clinical signs in this population of dogs with PH were not specific for pulmonary hypertension. A relatively high frequency (23%) of syncope was noted, and this may have been related to cardiopulmonary dysfunction exacerbated by PH. Multiple pathogenetic mechanisms can contribute to collapse in dogs with cardiopulmonary disease. Hypoxemia associated with cardiac failure, respiratory insufficiency, or collapse of the left mainstem bronchus can cause syncopal episodes in affected dogs. Atrial fibrillation or paroxysmal atrial tachycardia was present in 3 dogs and may have contributed to collapse. Neurocardiogenic syncope due to inappropriate vasodilatation and bradycardia after sympathetic stimulation may be responsible for collapse in some dogs with cardiac disease 24 and could explain syncope in some dogs with PH. Poor left ventricular cardiac output and decreased cerebral blood flow associated with pressure overload of the right heart contribute to syncope in human patients with PH 2,6,25 and may have triggered collapse in some of the dogs reported here. Clinical signs of right heart failure including ascites, jugular venous distention, or subcutaneous edema were found in 6 of 53 dogs (30%). Clinical diagnoses for these dogs included biventricular heart failure in 4 of 6 dogs, acute pulmonary vascular obstruction in 4 of 6 dogs, and Eisenmenger s physiology in dog. Right heart failure was attributed to cor pulmonale in 7 of 6 dogs (44%) based on clinical and radiographic evidence of primary respiratory disease. Respiratory disorders associated with cor pulmonale included pulmonary fibrosis, pulmonary neoplasia, pulmonary mineralization, and chronic pulmonary disease from previous heartworm infection. Doppler-derived RV-to- RA pressure gradients in dogs with cor pulmonale ranged from 45 to 22 mm Hg (mean, 7.4 mm Hg; median, 62.0 mm Hg). The range of RV-to-RA pressure gradients in dogs with cor pulmonale overlapped that of animals that did not develop cor pulmonale, indicating that additional factors were important in generation of right-sided heart failure. Right ventricular ischemia, volume overload, acute versus chronic pressure load, or reactive pulmonary vasoconstriction can play a role in the development of cor pulmonale and may have been present in some of the dogs in this study. 2,9 Results of clinicopathologic testing and findings on thoracic radiography were nonspecific but facilitated identification of the primary disease condition. Thoracic radiographs were abnormal in almost all dogs (98%), with cardiomegaly reported most often (84%). Large pulmonary arteries were commonly noted (3% of dogs), but a case-controlled prospective trial would be required to establish the sensitivity of this finding for PH. Electrocardiographic changes characterized by right ventricular enlargement (deep S waves in lead I, II, III, and avf) or right atrial enlargement (P wave 0.4 mv) have been reported to occur with PH, 26 but classic ECG changes were noted infrequently in this study. Electrocardiograms were done in only one third of the dogs evaluated here, with evidence of right ventricular or right atrial enlargement noted in only 3 and 2 of 8 dogs, respectively. In 9 of the 0 dogs with suggested chamber enlargement on ECG, radiographic or echocardiographic studies also indicated atrial or ventricular enlargement. However, 8 of 8 dogs that lacked ECG characteristics of chamber enlargement also had evidence of cardiac enlargement on thoracic imaging, indicating that the ECG did not accurately predict changes in chamber dimension. A prospective study would be necessary to determine the frequency of ECG changes in dogs with pulmonary hypertension. Subjective changes in echocardiographic parameters aid in the diagnosis of PH in human patients 6 and may enhance suspicion for PH in veterinary patients. Pulmonary velocity profiles have not been critically evaluated in dogs, but in humans, type I profiles are found only in patients with normal pulmonary arterial pressure. 4 Type II and III velocity profiles often are found in humans with PH. These profiles exhibit a rapid acceleration phase due to an increased rate of rise in pulmonary vascular pressures, and a rapid deceleration or delayed deceleration with midsystolic notching is found. 4 In this study, pulsed-wave Doppler recordings disclosed type II and type III pulmonary velocity profiles in all dogs evaluated. Right ventricular wall thickness and chamber dimensions were abnormal in one half of the patients diagnosed with PH, but based on this study, PH cannot be ruled out when the right ventricle appears normal echocardiographically. As might be expected, severe right ventricular hypertrophy was found only in dogs year of age, suggesting that young animals have a different compensatory response to pressure or volume overload than do adults, or that sufficient time had not passed to allow development of right ventricular dilatation. In the current study, subjective assessment of left ventricular size suggested a reduction in left ventricular volume in approximately 40% of the dogs examined. Decreased filling of the left ventricle and paradoxical septal motion are suggestive of right ventricular pressure overload. Left ventricular diastolic function may be impaired because of ventricular interdependence 6 or by alterations in chamber stiffness. 25 Systolic time intervals can be obtained by Doppler echocardiography and provide objective evidence of pulmonary hypertension. Measurements of right ventricular preejection period, right ventricular ejection time, time to peak flow, and acceleration time index correlate with pulmonary artery pressure in some studies of both humans 4 and dogs. 5 A prospective study of systolic time intervals in PH would be valuable because these measurements are best evaluated using a high paper speed, averaging values over 5 0 beats, and excluding premature beats in the analysis. Although heartworm disease is a well-recognized cause of PH, our study suggests that PH may be more commonly associated with other respiratory and cardiac diseases than previously recognized. PH has been shown to be indicative of a poor prognosis in human patients with dilated cardiomyopathy, with a 40% increase in mortality and 49% increase in hospitalization rate after documentation of PH. 27 Information regarding prognosis for dogs with PH unrelated to heartworm disease is lacking. Early identification of pul-

8 Pulmonary Hypertension in Dogs 447 monary hypertension and appropriate therapeutic intervention may prolong survival and improve the quality of life for dogs with pulmonary hypertension. Increased suspicion for pulmonary hypertension and Doppler interrogation of tricuspid and pulmonic valves in dogs with cardiopulmonary conditions may identify PH as an important complicating feature of these diseases. Prospective evaluation of dogs at risk for pulmonary hypertension will provide useful information in determining the prognosis for affected animals and developing rational therapeutic protocols. Acknowledgments This work was supported by grants from the National Institutes of Health, Heart, Lung and Blood Institute (HL and HL-52490). We would like to thank Mr Howard Wilson at the University of Missouri for his assistance with figures. References. Edwards WD, Edwards JE. Clinical primary pulmonary hypertension: Three pathologic types. Circulation 977;56: Rich S, Braunwald E, Grossman W. Pulmonary hypertension. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine, 5th ed. Philadelphia, PA: WB Saunders; 997: Winter H. The pathology of canine dirofilariasis. Am J Vet Res 959;20: Castleman WL, Wong MM. Light and electron microscopic pulmonary lesions associated with retained microfilariae in canine occult dirofilariasis. Vet Pathol 982;9: Sasaki Y, Kitagawa H, Hirano Y. Relationship between pulmonary arterial pressure and lesions in the pulmonary arteries and parenchyma, and cardiac valves in canine dirofilariasis. J Vet Med Sci 992; 54: McManus EC, Pulliam JD. Histopathologic features of canine heartworm microfilarial infection after treatment with ivermectin. Am J Vet Res 984;45: O Grady MR. Pulmonary hypertension in dogs with mitral regurgitation. 2th Annual American College of Veterinary Medicine Forum, San Francisco, CA, June 2 5, Turk JR, Miller JB, Sande RD. Plexogenic pulmonary arteriopathy in a dog with ventricular septal defect and pulmonary hypertension. J Am Anim Hosp Assoc 982;8: Oswald GP, Orton EC. Patent ductus arteriosus and pulmonary hypertension in related Pembroke Welsh Corgis. J Am Vet Med Assoc 993;202: Lehmkuhl LB, Ware WA, Bonagura JD. Mitral stenosis in 5 dogs. J Vet Intern Med 994;8:2 7.. Berger M, Haimowitz A, Van Tosh A, et al. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol 985;6: Hatle L, Angelsen B. Doppler Ultrasound in Cardiology: Physical Principles and Clinical Application. Philadelphia, PA: Lea & Febiger; 982: Thomas WP, Gaber CE, Jacobs GJ, et al. Recommendations for standards in transthoracic two-dimensional echocardiography in the dog and cat. J Vet Intern Med 993;7: Martin-Duran R, Larman M, Trugeda A, et al. Comparison of Doppler-determined elevated arterial pressure with pressure measured at cardiac catheterization. Am J Cardiol 986;57: Uehara Y. An attempt to estimate pulmonary artery pressure in dogs by means of pulsed Doppler echocardiography. J Vet Med Sci 993;55: Jardin F, Dubourg O, Bourdarias JP. Echocardiographic pattern of acute cor pulmonale. Chest 997;: Tucker A, McMurtry IF, Reeves JT, et al. Lung vascular smooth muscle as a determinant of pulmonary hypertension at altitude. Am J Physiol 975;228: Fletcher EC, Luckett RA, Miller T, et al. Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 989;95: Schulman DS, Matthay RA. The right ventricle in pulmonary disease. Cardiol Clin 992;0: Maksimowich DS, Mupanomunda M, Williams JF, Kaiser L. Effect of heartworm infection on in vitro contractile response of canine pulmonary artery and vein. Am J Vet Res 997;58: Voelkel NF, Tuder RM. Cellular and molecular mechanisms in the pathogenesis of pulmonary hypertension. Eur Respir J 995;8: Nazeyrollas P, Mertz D, Chapoutot L, et al. Diagnostic accuracy of echocardiography Doppler in acute pulmonary embolism. Int J Cardiol 995;47: West JB, Mathieu-Costello O. Vulnerability of pulmonary capillaries in heart disease. Circulation 995;92: Calvert CA, Jacobs GJ, Pickus CW. Bradycardia-associated episodic weakness, syncope, and aborted sudden death in cardiomyopathic Doberman Pinschers. J Vet Intern Med 996;0: Gomez A, Unruh H, Mink SN. Altered left ventricular chamber stiffness and isovolumic relaxation in dogs with chronic pulmonary hypertension caused by emphysema. Circulation 993;87: Tilley LP. Essentials of Canine and Feline Electrocardiography, 3rd ed. Philadelphia, PA: Lea & Febiger; 992: Abramson SV, Burke JF, Kelly JJ, et al. Pulmonary hypertension predicts mortality and morbidity in patients with dilated cardiomyopathy. Ann Intern Med 992;6: