Pulmonary Hypertension in Dogs

Pulmonary hypertension (PH) is defined as an abnormally increased pressure in the pulmonary vasculature.¹ The prevalence of PH in dogs depends on many factors, including geographic area (e.g., living at altitude versus sea level, prevalence of pathogens such as Dirofilaria immitis) and breed demographics. Anecdotally, its incidence has increased, likely due to increased awareness and recognition of associated clinical signs, as well as more widespread accessibility to specialty diagnostic tests such as echocardiography. In humans, PH is defined as a mean pulmonary arterial pressure higher than 25 mm Hg at rest, while in veterinary patients, the pulmonary arterial pressures are estimated using Doppler echocardiography and PH is defined as a systolic pulmonary arterial pressure greater than 30 mm Hg.

High pulmonary arterial pressure is not associated with a single defined pathophysiologic process and requires further investigation into the underlying cause. Identification of a likely cause is important in the long-term management of dogs with PH, as treatment approach and prognosis vary greatly based on the primary cause.

Clinical Signs of Pulmonary Hypertension

The clinical signs of PH are nonspecific and can depend on the underlying cause, which adds to the challenge of identifying affected dogs. Signs that are most strongly suggestive of PH include syncope (especially with exertion), respiratory distress at rest or after activity, and the presence of right-sided congestive heart failure (CHF) signs (e.g., ascites).^1-5 Other signs that are less specific but still supportive of PH include increased respiratory rate or effort at rest, prolonged tachypnea after exercise or activity, and cyanotic mucous membranes.

Additional signs may be present depending on the underlying cause and severity of PH. For example, hind-limb collapse is commonly reported in cases of reverse-shunting patent ductus arteriosus, and coughing is reported in cases with underlying respiratory disease.^2,4,6

On physical examination, a loud, right apical murmur radiating to the left, caused by tricuspid regurgitation, is commonly auscultated in patients with PH.^2,5,7-9 A split S₂ sound can also be auscultated in some animals; this finding is associated with delayed closure of the pulmonary valve relative to the aortic valve, given the increased right ventricular afterload.^5,7 Tachycardia, tachypnea, and jugular vein pulsation may be observed. However, these findings are nonpathognomonic and nonspecific and should be used in combination with diagnostic tools to assess the full clinical presentation. Other physical examination findings may depend on the underlying cause and severity of PH.

Causes of Pulmonary Hypertension

The factors that affect pulmonary arterial pressure—pulmonary flow (Qp), pulmonary vascular resistance (PVR), and pulmonary capillary wedge pressure (PCWP)—are shown in FIGURE 1, along with examples of underlying conditions that can elevate each factor to contribute to PH. PCWP is a surrogate for pulmonary venous and, often, left atrial pressures (in the absence of obstructive venous lesions proximal to the left atrium). PH secondary to increased pulmonary venous pressure is referred to as postcapillary PH, whereas PH secondary to increased PVR in the absence of increased pulmonary venous pressures is referred to as precapillary PH.

In humans, causes of PH were historically categorized as either primary or secondary. More recently, they have been further classified into 5 groups based on similarities in pathology, hemodynamic consequences, and therapeutic approaches.¹⁰ A recent American College of Veterinary Internal Medicine (ACVIM) consensus statement on PH in dogs proposed a similar 6-group classification scheme for use in veterinary medicine.¹

Group 1

Group 1 is composed of causes capable of increasing PVR, including heritable diseases, certain drugs or toxins (e.g., dexfenfluramine, fenfluramine), systemic-to-pulmonary (left-to-right) congenital shunts, and idiopathic causes. In cases of systemic-to-pulmonary congenital shunt, the increase in Qp, which in some cases can be more than double the systemic blood flow, increases shear stress on the pulmonary vascular endothelium. This subsequently stimulates vascular remodeling in the pulmonary circulation, leading to increased PVR and, when severe, Eisenmenger’s physiology (shunt reversal).⁶

Group 2

Group 2 describes PH secondary to left-sided heart disease, the estimated most common cause of PH in dogs.^8,11 Any heart disease severe enough to progress to significant left-sided volume overload, left atrial hypertension, and enlargement can cause pulmonary venous hypertension and postcapillary PH. Chronically, the pulmonary arteries may “react” to this increase in pressure as well as hypoxia (in patients with pulmonary edema) and undergo structural changes that increase PVR, resulting in combined (pre- and postcapillary) PH.⁸ Although PH is most commonly seen in dogs with myxomatous mitral valve degeneration, additional causes include dilated cardiomyopathy and mitral valve dysplasia.^8,11

Group 3

Group 3 describes PH secondary to respiratory disease, hypoxia, or both. In contrast to what happens in the systemic circulation, when the pulmonary circulation is faced with hypoxia, it undergoes vasoconstriction to improve ventilation-perfusion matching. Disease processes such as chronic obstructive airway disorders or primary pulmonary parenchymal disease, or chronic exposure to high altitude, can result in chronic hypoxia and pulmonary vasoconstriction.^12,13 Excessive volume in vessels receiving diverted blood may result in vascular structural remodeling and increased PVR, worsening PH.² These disorders are thought to be an underestimated cause of PH due to the difficulty of their definitive diagnosis in veterinary medicine.¹

Group 4

Group 4 describes PH resulting from pulmonary emboli, thrombi, or thromboemboli, in either the acute or chronic setting. Occlusion of part of the pulmonary arteries increases PVR. Many diseases have been associated with thromboembolic disease, including immune-mediated diseases, neoplasia, sepsis, pancreatitis, protein-losing diseases, and infectious diseases.^14,15

Group 5

Group 5 is unique to veterinary medicine and describes PH induced by heartworm disease (Dirofilaria) or Angiostrongylus infection. PVR increases after worm-induced myointimal proliferation, inflammation, fibrosis, and thromboembolism develop within the pulmonary arteries.^16,17

Group 6

Group 6 describes PH with multifactorial mechanisms, including masses that compress the pulmonary vasculature and combinations of diseases in groups 1 through 5.

Diagnosis of Pulmonary Hypertension

Given the wide variety of diseases that can lead to the development of PH, systemic evaluation is warranted to investigate the cause in an individual patient. However, diagnosis of the underlying cause is often challenging and can be elusive in some cases despite thorough evaluation. Diagnostic efforts should concentrate on identifying severity of PH, presence of right-sided CHF, and other factors that may affect prognosis. Many patients are classified as having “idiopathic” PH, but it is more likely that the cause is not clinically identified due to the limitations of diagnostics in veterinary medicine compared to human medicine.¹ For example, diagnostics such as ventilation-perfusion lung scan, pulmonary function testing (e.g., spirometry, exercise testing), and computed tomography pulmonary angiography are commonly included in the diagnostic approach to PH in humans but not routinely performed or practical in most veterinary patients.¹⁸

Right Heart Catheterization

Right heart catheterization is the gold standard for the diagnosis of PH.^7,19 It is seldom performed in veterinary medicine due to the invasiveness of the procedure, cost, and inherent risks. Nevertheless, it is considered indicated in some patients, particularly animals with congenital heart disease when intervention is being planned and accurate assessment of the PVR is necessary.

Imaging

Echocardiography

In most veterinary patients with suspected PH, hemodynamic parameters are estimated with Doppler echocardiography, a minimally invasive method with acceptable reliability despite its limitations.^19,20 Numerous quantitative echocardiographic parameters are used to assess the severity of PH, with the peak tricuspid regurgitation velocity being the most used and relied upon. Briefly, quantification of the peak tricuspid regurgitation velocity is used to estimate the pressure difference, or pressure gradient (PG), between the right atrium and right ventricle during ventricular systole, using the simplified Bernoulli equation (PG = 4V²; V = peak tricuspid regurgitation velocity in m/s). In the absence of a right ventricular outflow tract obstruction such as a double-chamber right ventricle or pulmonic stenosis, the PG plus the estimated right atrial pressure yields the estimated systolic pulmonary artery pressure.^7,8 Echocardiography can also be used to estimate the mean and diastolic pulmonary artery pressures by quantifying the velocity of the pulmonic valve insufficiency, with the early and end-diastolic peak velocities used to estimate the mean and diastolic pulmonary artery pressures, respectively.^7,8

In addition to estimation of systolic, mean, and diastolic pulmonary artery pressures, echocardiography is used to evaluate for additional changes suggestive of PH (BOX 1). A recent ACVIM consensus statement recommended the use of both tricuspid regurgitation velocity and the number of echocardiographic signs of PH to determine the echocardiographic probability of PH (low, moderate, or high).¹ Echocardiography is also used to evaluate for the presence of left-to-right shunting defects, left atrial hypertension, heartworm disease, thromboembolic disease, and compressive mass lesions.

Radiography

Thoracic radiographs may show right atrial, ventricular, and pulmonary artery enlargement (reverse D sign) in cases of moderate to severe PH (FIGURE 2). Changes to the pulmonary vasculature (arteries versus both arteries and veins), as well as left-sided heart changes and changes in the aspect of the lung parenchyma, depend on the type of PH. It is important to note that some dogs may develop pulmonary infiltrates consistent with noncardiogenic pulmonary edema as a direct result of severe PH.² Additional radiographic features of pulmonary hypertension are discussed in a recent review article.²¹

Figure 2. Thoracic radiographs from a dog with severe pulmonary hypertension (PH) secondary to heartworm disease. (A) Note the dilated cranial lobar artery (lines) and the bilateral, unstructured interstitial pulmonary pattern (oval) likely representing pneumonitis. Moderate hepatomegaly is also seen (asterisk).

Figure 2B. Note the mild, right-sided cardiomegaly (blue arrowheads) and dilated main pulmonary artery (white arrowheads), all suggestive of but not specific to PH.

Ultrasonography

Point-of-care ultrasonography can be used to identify some of the signs in BOX 1 (e.g., interventricular septal flattening, right ventricular hypertrophy) and increase the index of suspicion for PH (VIDEO 1).^22,23

Electrocardiography

Electrocardiography may reveal tall P waves suggestive of right atrial enlargement and signs of right axis deviation (tall R wave in lead aVR and deep S waves in leads I, II, III, and aVF) due to right ventricular enlargement. Furthermore, it may help identify rhythm disorders that can contribute to clinical signs in dogs with PH (FIGURE 3). However, these findings are not sensitive or specific and do not provide any additional useful information to differentiate between the types of PH.

Figure 3. Electrocardiogram from a dog with severe pulmonary hypertension. There is an underlying normal sinus rhythm with a single atrial premature complex (asterisk). The mean electrical axis is deviated to the right (deep S waves in leads I, II, III, and aVF [arrow]; tallest R wave in lead aVR), suggestive of right ventricular hypertrophy. Intermittent first-degree atrioventricular block is observed (arrowhead).

Laboratory Testing

N-terminal pro-brain natriuretic peptide (NT-proBNP) has been found to be significantly higher in dogs with PH and concurrent respiratory signs compared with dogs that have respiratory signs without PH.²⁴ Additionally, NT-proBNP may be useful in predicting the severity of PH. However, a high NT-proBNP is not specific for PH and should not be used to discriminate between underlying causes of PH.

Other laboratory testing results, including complete blood count, chemistry profile, urinalysis, and urine protein:creatinine ratio, do not add to the definitive diagnosis of PH but may reflect the underlying disease.

Treatment of Pulmonary Hypertension

The prognosis of dogs with PH depends on the underlying cause. Dogs with right-sided heart failure secondary to PH often have a worse prognosis.

Vasodilators

The 3 main pathways affecting pulmonary vascular tone are the nitric oxide (NO), endothelin, and prostacyclin pathways. As such, the development of drugs for PH has targeted these pathways.

Sildenafil is the most commonly used pulmonary vasodilator in veterinary medicine.^4,5,7,8,25 It is a phosphodiesterase-5 (PDE5) inhibitor that decreases the breakdown of cyclic guanosine monophosphate, leading to NO-mediated vasodilation. Sildenafil has a relatively short half-life and is typically administered every 8 hours.²⁶ Tadalafil has a longer duration of action, can be administered every 24 hours, and can be considered a viable alternative.²⁷ Additionally, because NO is endogenously synthesized from L-arginine and oxygen by endothelial NO synthase, treatment with sildenafil or tadalafil may be potentiated by L-arginine supplementation.^28,29 A study found that some dogs may not experience improvement and were found to have a worse quality-of-life score after PDE5 inhibitor therapy due to an underlying gene polymorphism.³⁰

Bosentan is a dual endothelin-1 (ET-1) receptor inhibitor, and ambrisentan is an ET-1 receptor A antagonist. These vasodilators are used in human medicine but are currently not used in veterinary medicine due to their high cost; however, a recent report described clinical improvement in 5 dogs with severe PH refractory to sildenafil after receiving ambrisentan.³¹ Therapies targeting the prostacyclin pathways (e.g., epoprostenol, iloprost) were first-line therapies for PH in humans before PDE5 inhibitors and ET-1 receptor blockers but have not been used in veterinary medicine due to their short half-life and need for continuous-rate infusion.

Even though vasodilators are indicated in most dogs with PH, some exceptions apply. Treatment should be implemented based on the top diagnostic differential regarding the type of PH, and the underlying cause should be specifically treated, when possible.

Shunt Occlusion

For hemodynamically significant shunting lesions (e.g., patent ductus arteriosus, ventricular septal defect), closure or occlusion of the shunt is recommended as long as the shunting is exclusively left to right. Pulmonary vasodilators are not recommended in these cases (as the increase in pressure is driven by the increased Qp) unless the shunting becomes bidirectional or right to left due to the development of significant PVR. Closure or occlusion of bidirectional or right-to-left shunts is contraindicated (as this leads to an acute increase in afterload to the right heart, often resulting in right-sided heart failure), and management of these shunts consists of monitoring and therapy for polycythemia with phlebotomy and/or hydroxyurea in addition to pulmonary vasodilators.^6,32 In some rare cases, severe PH improves after therapy with vasodilators and closure could be safely performed.³³ Dogs with other underlying causes of PH belonging to group 1 (inherited, idiopathic) are managed with pulmonary vasodilators.

Management of Left Atrial Hypertension

In cases of PH due to left atrial hypertension, the authors elect to treat left-sided CHF, if present; increase the pimobendan dose; or achieve additional afterload reduction with amlodipine, in an effort to reduce left atrial pressures and therefore pulmonary venous pressures.^8,34 The use of pulmonary vasodilators is not recommended as first-line therapy in these cases, given that pulmonary vasodilators increase preload to the left side of the heart, which may exacerbate left atrial hypertension and lead to decompensation or worsening of left-sided heart disease and heart failure.

If no clinical improvement is appreciated after pimobendan therapy with or without therapy for CHF, starting and up-titrating low-dose sildenafil can be considered. The owners should be counseled on the importance of monitoring resting respiratory rate and clinical signs to allow for prompt intervention with treatment for CHF, if it is precipitated. In some cases, depending on the cause of left atrial hypertension (e.g., mitral valve degeneration, mitral valve dysplasia), open-heart surgery for valve repair can be considered; however, in some dogs, PH persists despite the decrease in pulmonary venous hypertension due to nonreversible pulmonary arterial remodeling.³⁵

Management of Pulmonary Hypertension

Patients With Respiratory Disease

Patients with underlying respiratory disease should be treated supportively with a combination of environmental modifications, bronchodilators, cough suppressants, sedatives, antimicrobials, anti-inflammatories, and a weight loss plan, among other treatment modalities depending upon the underlying cause. Some dogs may need additional intervention such as tracheal stent placement for management of severe tracheal collapse or surgery for correction of obstructive anatomy leading to brachycephalic obstructive airway syndrome. Treatment with sildenafil is recommended, as it was found to be an independent variable predicting survival in a multivariable analysis and to improve quality of life in dogs with PH secondary to respiratory disease.^4,12

Patients With Vascular Obstruction

Antithrombotic agents, including antiplatelet (e.g., clopidogrel) and anticoagulant (e.g., rivaroxaban, enoxaparin) therapies, are indicated along with vasodilators for patients with suspected or confirmed pulmonary thromboembolism.³⁶ If the underlying cause of hypercoagulability can be identified, additional treatment to address the specific cause is indicated. In patients with acute pulmonary thromboembolism, immediate use of systemic or local (catheter-delivered) tissue plasminogen activator can be considered in specialized centers.³⁷ Treatment of dogs with Dirofilaria or Angiostrongylus infection should be implemented according to the available respective guidelines.^17,38 Specific guidance regarding the use of vasodilators in these patients is not available, but the authors commonly add sildenafil to the medical regimen of dogs with severe PH secondary to parasitic infections. Endovascular, surgical, or radiation therapy should be implemented for compressive mass lesions.

Patients With Dyspnea

Oxygen supplementation is imperative for dyspneic patients, except for patients with right-to-left shunting lesions. Oxygen also acts as a pulmonary vasodilator in patients experiencing acute decompensation. At-home oxygen supplementation for dogs is feasible and can be considered for the short term. However, the authors discuss quality of life with pet owners when long-term at-home oxygen supplementation is required.

Supportive Care

Exercise restriction should be implemented for patients with severe PH, as exertion will increase pulmonary pressures and decrease cardiac output, increasing the risk for syncope. Additionally, air travel and high altitude should be avoided, as they may also increase pulmonary pressures. The risks and rewards of moving forward with elective procedures that require general anesthesia should be carefully considered.

In patients with right-sided heart failure and cavity effusion, thoracocentesis and/or abdominocentesis to improve patient comfort and respiratory excursion/effort may be indicated along with diuretics, pimobendan, and renin-angiotensin-aldosterone system–modulating drugs.

Summary

PH can develop secondary to a variety of conditions, and its associated clinical signs are nonspecific. Diagnostic efforts should concentrate on identifying the underlying cause and severity of PH. Therapy should be targeted at the suspected or confirmed underlying cause, with the goal of managing clinical signs. The prognosis of dogs with PH depends on the underlying cause. Dogs with right-sided heart failure secondary to PH often have a worse prognosis.