Pulmonary hypertension (PHT, pulmonary arterial hypertension or PAH) is a condition in which the blood pressure in the lungs is excessively elevated. The normal blood pressure in the pulmonary artery (PA) is no more than 30 mmHg systolic and 19 mmHg diastolic. Patients with severe PHT may have systolic pulmonary arterial pressures greater than 80 mmHg. Pulmonary hypertension is an important rule-out in patients presenting to the clinician with dyspnea, cyanosis and/or syncope, especially if appropriate medical therapy for any underlying heart and lung disease is failing to significantly improve symptoms. Pulmonary hypertension is most often diagnosed in small breed dogs, and is much less commonly seen in cats.
Primary vs. Secondary PHT:
Primary pulmonary hypertension occurs in the absence of obvious underlying lung or left heart disease and is thus idiopathic in origin. Secondary pulmonary hypertension occurs as a consequence of some other cardiopulmonary issue. Pulmonary hypertension may develop in response to chronic left-sided congestive heart failure (LCHF), in which case the degree of PHT tends to be modest. Pulmonary hypertension also commonly develops secondary to heartworm/thromboembolic disease and chronic lung/airway disease (airway collapse, chronic bronchitis/COPD, interstitial pulmonary fibrosis). Occasionally, PHT may develop as a result of reactive vasoconstriction secondary to acute pulmonary edema or high altitude. Most commonly, pulmonary hypertension develops over a long period of time as gradual hypertrophy of the pulmonary vascular smooth muscle occurs. These patients tend to have marked concentric right ventricular hypertrophy (RVH) as a result. This condition may rarely develop suddenly secondary to pulmonary thromboembolism, in which case right ventricular enlargement (RVE) without concurrent hypertrophy is typical. Patients with massive pulmonary thromboemboli typically have severe dyspnea and unfortunately tend to pass away suddenly. Congenital cyanotic heart disease with Eisenmenger’s physiology from increased pulmonary arterial flow and pressure (bidirectional ventricular or atrial septal defects, atrioventricular septal defects/endocardial “cushion” defects, right-to-left shunting patent ductus arteriosus, etc.) or chronic elevation of pulmonary venous pressure (mitral stenosis, cortriatriatum sinister) can be causes of PHT.
Luminal narrowing of the pulmonary arteries may occur to physical obstruction via thromboemboli or heartworm infestation. This narrows the cross-sectional area of the pulmonary arterial tree, increasing the vascular resistance, leading to increased pulmonary arterial pressures. Conditions that are associated with a prothrombotic state include hyperadrenocorticism, immune-mediated hemolytic anemia, protein-losing enteropathy or nephropathy, disseminated intravascular coagulation, sepsis, trauma and recent surgery. Most commonly, hypertrophy of pulmonary arterial vascular smooth muscle occurs in response to an imbalance of local vasodilators (prostacyclin, nitric oxide) and vasoconstrictors (thromboxane A2, also a platelet agonist) with endothelin-1 and serotonin contributing to smooth muscle proliferation. The resultant hypertrophy leads to increased stiffness and thus increased pulmonary arterial pressures. The increased pulmonary arterial pressures lead to ventilation:perfusion mismatch within the lungs which in turn leads to hypoxemia. Concurrent patchy alveolar infiltrates may develop in patients with pulmonary hypertensive crises, exacerbating hypoxemia via diffusion impairment, and may be misdiagnosed as cardiogenic pulmonary edema or pneumonia. The etiology of these infiltrates is incompletely understood, though theorized to represent atypical non-cardiogenic pulmonary edema resulting from non-uniform vasoconstriction with localized regions of overperfused lung tissue experiencing higher than normal hydrostatic pressure, compromising the integrity of the alveolar membrane.
Gross specimen from a patient with severe pulmonary hypertension present since birth. The right side of the heart is severely enlarged. Lower image, the lungs are opened, revealing thickened pulmonary arteries.
Patient Presentation/Physical Examination:
Patients with severe pulmonary hypertension often present to the veterinarian for exercise intolerance, difficult or labored breathing. In some cases, patients may have obvious oxygen depletion, and cyanosis of the tongue and gums may be apparent. Many patients may present with exertional-induced syncope. Patients with a history of chronic lung disease or LCHF usually have a history of chronic coughing. Crackles/rales may be evident on auscultation of the lungs, and a loud Grade III+/VI, R-sided systolic cardiac murmur may be noted. If a palpable thrill on the R hemithorax is noted, PHT should be suspected (rule-out a left-to-right shunting small ventricular septal defect). A split second heart sound may be noted and is the result of delayed closure of the pulmonic valve. This may be misinterpreted as a gallop if there is a wide split. A concurrent left-sided systolic murmur may be ausculted if coexistent heart disease (i.e. chronic mitral valvular disease) is present. Occasionally, cardiac auscultation will be unremarkable. A marked expiratory grunt and heave line may be noted in patients with chronic lung disease.
Blood testing is used to rule-out underlying heartworm infestation. Arterial blood gas may indicate hypoxemia. Serum NT-pro BNP may be elevated. Thoracic radiographs may show dilated pulmonary arteries with occasional heart enlargement. Severe cardiomegaly with left atrial enlargement is generally present if PHT is secondary to chronic LCHF. Changes consistent with chronic lung disease (i.e. a diffuse bronchointerstitial pattern, bronchiectasis) or airway collapse may be present. Diffuse or patchy alveolar infiltrates may be present. Chest films may rarely be within normal limits. The diagnosis of pulmonary hypertension is best made with invasive catheterization of the main pulmonary artery with a direct blood pressure measurement. This is typically not practical in patients with severe respiratory distress, as it requires general anesthesia in dogs and specialized equipment (fluoroscopy). The best way to non-invasively diagnose this condition is through the use of echocardiography (ultrasound of the heart), however well-known significant limitations are present when utilizing this technique. Concurrent underlying structural heart disease is assessed for simultaneously. Most of the time, tricuspid regurgitant velocities are obtained using continuous wave Doppler. The peak velocity (V) in m/s is then used in the modified Bernoulli equation (pressure gradient in mmHg = 4* V2) to estimate the pressure gradient (the difference in systolic pressure of the right ventricle and the right atrium). Usually the right atrial pressure (RAP) is considered to be 0-5 mmHg, and the subjective size of the right atrium is used to estimate RAP, which may be added to the pressure gradient. If right-sided CHF is present (i.e. cardiogenic pleural/pericardial effusion/ascites), with severe right atrial enlargement then the RAP is usually in excess of 10 mmHg and should be included in the estimate of right ventricular systolic pressure (RVSP). Pulmonic stenosis must be excluded, as its presence would normally be expected to increase the RVSP. In the absence of pulmonic stenosis, elevated RVSP is indicative of PHT. The estimated RVSP should normally be less than 40 mmHg (some authors state 31 mmHg). Patient with estimated RVSPs in the 40-50 mmHg range are considered to have mild PHT. Moderate PHT is denoted by RVSP in the 50-80 mmHg (or 50-75 mmHg) range, and those patients with severe PHT have RVSPs > 80 mmHg (or > 75 mmHg). Generally speaking, the ultrasonographer is most likely to underestimate the true peak RVSP. This is especially easy to do when the full envelope of tricuspid regurgitation on Doppler is not able to be visualized. The mean pulmonary arterial pressure (mean PAP) may be estimated via Doppler if pulmonic insufficiency (PI or pulmonic regurgitation/PR) is present. The peak diastolic pressure gradient (difference in diastolic pressure between the pulmonary artery and the diastolic pressure of the right ventricle) roughly equals the mean pulmonary arterial pressure. If no tricuspid regurgitation or pulmonic insufficiency is present, the echocardiographer will not be able to estimate RVSP or mean PAP, and thus cannot exclude PHT. It is critically important in these situations for the echocardiographer to assess for other signs of PHT (i.e. RVH, RVE, diastolic septal wall flattening, dilation of the MPA/proximal branch PAs, etc.) if PHT is suspected. Typically, the severity of PHT is almost always underestimated, and if the patient’s clinical signs fit with more severe PHT than what can be documented via echo, then appropriate treatment is warranted. Stress may elicit mild PHT, and is suspected when no secondary structural changes to the heart are evident, and the systemic blood pressure is concurrently mild to moderately elevated in patients visibly agitated for restraint during echocardiography.
Thoracic radiographs of a dog with severe pulmonary hypertension. The pulmonary arteries are dilated. A diffuse interstitial pattern in the caudodorsal lung field suggests chronic lung disease.
Echocardiographs of a dog with pulmonary hypertension. The right ventricular free wall (RVFW) is thickened. The main pulmonary artery (MPA) and right and left pulmonary artery branches (RPA, LPA) are dilated. (RVFW: right ventricular free wall, RV: right ventricle, IVS: interventricular septum, LVFW: left ventricular free wall, RA: right atrium, RVOT: right ventricular outflow tract, Ao: aorta, PV: pulmonic valve).
Echocardiographs from a dog with pulmonary hypertension. To the left, continuous wave Doppler shows a peak tricuspid regurgitation (TR) velocity of 4.14 m/s, consistent with a pressure gradient of 68.4 mmHg and an RVSP of at least 73.4 mmHg (assuming RAP of 5 mmHg). To the right, the peak diastolic pulmonic regurgitation measures to be 2.89 m/s, consistent with a pressure gradient and estimated mean pulmonary arterial pressure of 33.5 mmHg. The pulmonary arterial outflows (right ventricular outflow tract/RVOT) velocities are normal at 0.71 m/s, excluding pulmonic stenosis.
Specific therapy for PHT is indicated if patients are documented to have moderate to severe PHT and/or are symptomatic for PHT. Mildly affected patients generally do not warrant therapy outside of that for associated conditions. The treatment of PHT involves medical management of any underlying causes (i.e. medical therapy for heart failure or lung/airway disease if present), oxygen therapy in severely affected patients and specific medical therapy for pulmonary hypertension. Inhaled or injectable (prostacyclin) used in human patients with PHT are impractical or cost-prohibitively expensive (i.e. endothelial antagonists such as bosentan) to use in veterinary patients. Oral guanylate cyclase stimulators (riociguat) have not been studied in dogs. Diltiazem may help in a very small subset of human patients with PHT and is not generally successfully used in dogs. The use of phosphodiesterase inhibitors is most often advocated, though not all patients with PHT will respond. The most commonly used medication is sildenafil (VIAGRA®, REVATIO®). A phosphodiesterase V inhibitor, sildenafil acts directly on the pulmonary arteries to help them relaxby increasing concentrations of cyclic guanosine monophosphate via increasing nitric oxide activity, and may improve the symptoms of patients suffering from severe pulmonary hypertension. Significant improvement may take a few days to a week to occur. Other phosphodiesterase inhibitors may be used in different situations, however tadalafil and vardenafil have not been extensively studied in dogs with naturally-occurring PHT. Pimobendan (VETMEDIN®), a phosphodiesterase III inhibitor, may be prescribed if the patient has concurrent heart failure, and theophylline (THEO-DUR®) may be used in patients with chronic lung disease often with prednisone and cough suppressants (i.e. hydrocodone). Patients with active left-heart failure with cardiogenic pulmonary edema should generally not be treated with sildenafil if the PHT is only mild-moderate. These patients need furosemide, pimobendan, enalapril, etc.. If the PHT is severe, often associated with right-sided congestive heart failure (RCHF) or biventricular failure (BVF), then sildenafil may be considered. Patients typically do NOT show a measurable decrease in estimated RVSP or mean PAP via echo with medical therapy, so the numbers should not necessarily be used to guide therapy. Patients with concurrent RCHF should receive furosemide +/- enalapril, spironolactone, etc.. Sildenafil alone will not resolve ascites/pleural/pericardial effusion/subcutaneous edema secondary to RCHF/BVF.
The prognosis for patients with pulmonary hypertension depends on many different factors. Patients that have treatable underlying causes may do well for some period of time, depending on the severity of the underlying condition. Cases that have no obvious underlying cause (primary pulmonary hypertension) generally have a guarded prognosis. Patients that cannot be weaned off of supplemental oxygen have a grave prognosis. Generally speaking, the owners of patients with PHT and severe symptoms including cyanosis, oxygen-dependent crises, dyspnea and syncope should be counseled so they understand their pet has severe heart and lung disease which is ultimately incurable, may or may not respond to medical management, putting the pet is at risk for sudden cardiac death. Human patients in similar situations typically are placed on a heart and lung transplant list, and explaining this to owners tends to help them understand the severity of the disease the patient is facing and foster realistic expectations. That said, many patients even with severe PHT may respond favorably to medical management for months, and in some cases even years. Consultation with a veterinary cardiologist is recommended for patients with known or suspected pulmonary arterial hypertension.
A complete list of references will be provided upon request.
Dr. Schroeder is a board-certified veterinary cardiologist that has been serving South Florida since 2006. A graduate of Kansas State University College of Veterinary Medicine in 2002, Dr. Schroeder then served a 1 year internship at Veterinary Specialists of South Florida and went on to complete a residency in cardiology at California Animal Hospital in Los Angeles under the tutelage of the renowned veterinary cardiologist and author, Stephen Ettinger. Dr. Schroeder works full-time at LeadER Animal Specialty Hospital in Cooper City and part-time at Animal Specialty Hospital of Florida in Naples and sees appointments by referral.