Pulmonary arterial hypertension (PHT)

• The pulmonary pressure results from the interaction between:
  • The pulmonary blood flow; this is the right ventricular cardiac output.
  • The arterial vascular resistance (pre-capillary pressure).
  • The venous vascular resistance (post-capillary pressure or left atrial pressure).
• Pulmonary  hypertension (PHT) is defined as pulmonary arterial systolic prssure >30 mmHg, pulmonary arterial diastolic pressure >15 mmHg, or pulmonary arterial mean pressure >20 mmHg.
• PHT is not a diagnosis but rather the result of several disease processes, often associated with poor prognosis.
• Cause: PHT results from:
  • Increased pulmonary vascular resistance.
  • Increased pulmonary blood flow.
  • Increased left atrial pressure.
  • Or any combination of the three.
• Severe PHT can cause right heart failure and tachypnea, with associated poor left-sided filling. As a consequence this may lead to poor left-sided cardiac output causing exercise intolerance and syncope.
• PHT is usually secondary to other disease conditions such as pulmonary thromboembolism, heartworm infestation, chronic respiratory disease, or left-sided heart failure.
• Treatment: involves addressing the primary cause, supplemental oxygen, and vasodilator therapy.
• Treatment of severe disease is often unrewarding.

• Many cases of mild to moderate PHT display no clinical signs or these may be subtle, including cough, shortness of breath, lethargy, exercise intolerance and sometimes syncope Syncope.
• Cases with chronic and advanced PHT may present with ascites, jugular distesion and pleural effusion Pleural: effusion.

• Patients with acute PHT may present with severe respiratory distress and hypoxia with or without signs of right-sided congestive heart failure Heart: congestive heart failure (ascites, pleural effusion). 
• Often, evidence of predisposing disease is present (ie heartworm disease Canine cardiopulmonary dirofilarisis causing coughing, hemoptysis).

• In the United States, the most common cause of PHT is heartworm disease Canine cardiopulmonary dirofilariasis, and patients living in heartworm endemic areas (ie Southeastern United States) are predisposed.
• Patients living at high altitudes may also have a higher incidence of clinically significant PHT.

• The age incidence of PHT is related to the underlying cause. Cases of PHT due to systemic disease such as hyperadrenocorticism Hyperadrenocorticism, pulmonary fibrosis Idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease are usually older.
• Patients with congenital cardiac shunting lesions (ie right-to-left PDA Patent ductus arteriosus) are generally young.

• PHT can be caused by several different abnormalities.
• Patients with left-to-right cardiac shunts have increased pulmonary blood flow, and if this flow exceeds the capacity of the pulmonary system, increased pulmonary artery pressures develop, and reversed, right-to-left shunts can occur.
• Patients with increased pulmonary vascular resistance may have experienced obstruction of the pulmonary vessels (ie pulmonary thromboembolism Lung: pulmonary thromboembolism), have abnormalities in circulating vasoactive substances (ie endothelin), have hypoxia induced vasoconstriction (ie chronic lung disease), or have increased pulmonary pressures due to elevated downstream left atrial pressures (ie mitral valve regurgitation of mitral valve stenosis Heart: mitral valve degenerative disease).
• All these different causes for PHT result in vasoconstriction, vascular smooth muscle proliferation and thrombosis affecting the pulmonary circulation vessels. Therefore, if left untreated, may become progressively more severe, irreversible and refractory to treatment.
• In cases where no underlying cause can be identified, a diagnosis of primary or idiopathic PHT is occasionally made.

Most common causes of PHT in practice

• Congenital abnormalities Congenital heart disease: overview: reversed patent ductus arteriosus is the most common congenital abnormality associated with PHT, but any other abnormality that causes pulmonary overcirulation from birth may fall in this category.
• Acquired:
  • Degenerative mitral valve disease is the most common acquired cardiac disease in the dog and, as consequence, this is also the most common cause of PHT.
  • The second most common is pulmonary parenchymal disease (pulmonary fibrosis, particularly common in West Highland White terriers) and other causes of chronic hypoxia (chronic bronchopneumopathy, upper airway disease, high altitude, etc).
  • Depending on the geographical area, lung worm (Angiostrongylus spp Angiostrongylosis) or heart worm (Dirofilaria spp) may also be common. 
  • Pulmonary thromboembolism is a frequent complication of several systemic diseases, including immune-mediated hemolytic anemia Anemia: immune-mediated hemolytic, neoplasia, protein-losing nephropathy Protein-losing nephropathy, protein-losing enteropathy Protein-losing enteropathy, pancreatitis Pancreatitis: acute Pancreatitis: chronic and sepsis Shock: septic.

• PHT causes pressure overload to the right ventricle, which suffers remodelling in the form of concentric hypertrophy (thickening of the ventricular walls) and dilation.
• Dilation of the tricuspid valve annulus can cause secondary tricuspid regurgitation Tricuspid valve dysplasia and further promote the development of right heart failure.
• Right heart failure secondary to PHT is commonly referred to as cor pulmonale Cor pulmonale.
• Due to the increased pressure, and in virtue of the Bernoulli equation, if systolic tricuspid regurgitation and diastolic pulmonic insufficiency are present, these will have faster velocities than normal and proportional to the severity of the PHT.
• In severe cases of PHT, the right heart cannot generate enough force to overcome the high pulmonary pressures → right sided cardiac output falls → left-sided cardiac output falls as consequence → weakness and fainting during exertion can occur.
• Once present, pulmonary hypertension can worsen due to abnormal blood flow, endothelial disruption, platelet aggregation, release of vasoactive substances such as endothelin, thromboxane A2, and serotonin, and further obstruction of vessels.

• The time course of disease is often dependent on the underlying disease.
• Many episodes of pulmonary thromboembolism are sudden and the patients present with acute signs while cases of chronic lung disease may slowly develop PHT over long periods of time.
• Reactive PHT or secondary to an increased left atrial pressure may be subtle and respond to treatment of congestive heart failure, at least initially. This chronic form is common in dogs with advanced degenerative mitral valve disease.

• Acute presentation: sudden onset of weakness, collapse, syncope, tachypnea, dyspnea, hemoptysis (in very severe cases), cyanosis, right-sided heart failure (ascites, pleural effusion, jugular venous distension).
• Chronic presentation: more insidious and subtle, with exercise intolerance, cough and slowing down on walks.

• See above

• Dyspnea, tachypnea, harsh lung sounds, inspiratory wheezes, crackles, and snaps, split second heart sound, murmur of tricuspid regurgitation (right apical systolic).

• Ascites, pleural effusion, jugular pulses, S3 gallop sound Murmur: overview.

• Thoracic radiographs Radiology: chest (excl heart and lungs) , cardiac ultrasound       , heartworm antigen test.

• ECG, standard laboratory evaluation (CBC Hematology: complete blood count (CBC) , serum chemistry, urinalysis Urinalysis ) to detect underlying diseases.

• Radionuclide lung scan, arterial blood gas analysis Arterial blood gas sampling.

• Pulmonary angiography, pulmonary artery catheterization.

• The right ventricle is dilated and hypertrophied.
• The main pulmonary artery segment is often dilated.
• In cases of thromboembolic disease, clots may be found in the main pulmonary artery or its branches.
• Ascites and pleural effusion may be present.

• Histological lesions of the pulmonary vessels include: medial hypertrophy, intimal fibrosis, plexiform lesions, and intimal proliferation.
• Development of plexiform lesions is thought to represent irreversible vascular damage and poor prognosis.

• Respiratory signs due to primary pulmonary disease but without PHT.

• Right heart failure due to degenerative tricuspid valve disease or pulmonic stenosis.
• Other causes of ascites: hypoalbuminemia, liver disease, etc.
• Other causes of syncope: vasovagal syncope, hypoxia, structural cardiac disease, etc.

• Supplemental oxygen can be used to promote pulmonary vasodilation.
• The response to this therapy is variable depending on the severity of PHT and underlying disease process.
• Cases of severe obstructive PHT may show little improvement with supplemental oxygen.

• Phosphodiesterase-5 inhibitors (sildenafil Sildenafil) prevents the formation of cGMP and inhibit vascular remodelling, promoting vasodilation in the lung vasculature.
• Phosphodiesterase-3 inhibitors (pimobendan Pimobendan) has a lower affinity for the pulmonary circulation vessels. It is certainly recommended for cases of reactive PHT (secondary to elevated left atrial pressure or left-sided congestive heart failure) but its efficacy as sole agent to treat PHT has not been evaluated.
• Non-selective phosphodiesterase inhibitors (theophylline) may also have a moderate to weak effect. Cases of PHT secondary to lung disease may benefit from its use.
• Prostacyclin analogues (eg epoprostenol) and endothelin antagonists (eg bosetan) are effective at treating experimental canine PHT but are extremely expensive and have not been used in practice.
• Supportive care with bronchodilators, anti-inflammatory, congestive heart failure medication or even painkillers may be indicated depending on the underlying cause for PHT.
• Exercise and activity restriction may help prevent episodes of syncope.

• Monitoring of respiratory effort, arterial blood gasses, and serial chest radiographs or echocardiograms may be indicated.

Treatment

• Long-term therapy for PHT usually involves treatment of the underlying cause.
• No long-term therapies for direct resolution of PHT are available.
• Empirical treatment with bronchodilators and vasodilators can be attempted.

• Serial echocardiograms can help determine heart size and facilitate indirect measurements of pulmonary artery pressures.

Monitoring

• Cases of mild to moderate PHT may not need specific treatment other than addressing the underlying disease.
• Cases of severe disease may require specific treatment for right-sided heart failure (diuretics Therapeutics: diuretic, ACE-inhibitors ACE inhibitor: overview) and abdominal or thoracic taps to remove fluid.

• The prognosis in cases of severe PHT with right heart failure is very poor.
• Most cases at the author's institution die within 4-6 months.
• Mild or moderate PHT may be successfully managed depending on the underlying cause.

• Refractory signs of right heart failure or weakness, disability from underlying disease process.

Refereed papers

• Recent references from PubMed and VetMedResource.
• Reinero C, Visser L C,  Heidi B. Kellihan H B, Masseau I, Rozanski E, Clercx C, Williams K, Abbott J, Borgarelli M, Scansen B A (2020) ACVIM consensus statement guidelines for the diagnosis, classification, treatment, and monitoring of pulmonary hypertension in dogs. J Vet Intern Med  doi: 10.1111/jvim.15725 PubMed.
• Kellihan H B & Stepien R L (2010) Pulmonary hypertension in dogs: diagnosis and therapy. Vet Clin North Am Small Anim Pract 40 (4), 623-641 PubMed.
• Stepien R L (2009) Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs. J Small Anim Pract 50 (Suppl 1), 34-43 PubMed.
• Mikhail G W & Prasad S K et al (2004) Clinical and hemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects. Eur Heart J 25 (5), 431-436 PubMed.
• Glaus T M, Hauser K & Hässig M et al (2003) Non-invasive measurement of the cardiovascular effects of chronic hypoxemia on dogs living at moderately high altitude. Vet Rec 152 (26), 800-803 PubMed.
• Rich S & McLaughlin V V (2003) Endothelin receptor blockers in cardiovascular disease. Circ 108 (18), 2184-2190 PubMed.
• Johnson L, Boon J & Orton E C (1999) Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary hypertension: 1992-1996. J Vet Intern Med 13 (5), 440-447 PubMed.
• Gavaghan B J, Lapointe J M & Thomas W P (1998) Acute onset of pulmonary necrotizing arteritis in a dogs with a left to right patent ductus arteriosus. Aust Vet J 76 (12), 786-791 PubMed.
• Rawlings C A (1978) Pulmonary vascular response of dogs with heartworm disease. Can J Comp Med 42 (4), 452-459 PubMed.

Other sources of information

• Fox P R, Sisson D D, Moise N S (eds) (1999) Textbook of Canine and Feline Cardiology, 2nd edn. WB Saunders, Philadelphia.
• Kittleson M D & Kienle R D (1998) Small Animal Cardiovascular Medicine. Mosby, St. Louis.
• Johnson L R, Hamlin R L (1995) Recognition and treatment of pulmonary hypertension. In:Current Veterinary Therapy XII: Small Animal Practice. WB Saunders, Philadephia. pp 887-892.