The silent killer: pulmonary hypertension (Proceedings)

Pulmonary hypertension (PH) is defined by a systolic pulmonary artery pressure greater than 25 mmHg. The incidence of PH is difficult to define due to lack of clinical awareness, non-specific clinical signs, and difficulty in confirming the diagnosis. Unfortunately, many patients with PH are diagnosed late in the course of disease when irreversible vascular pathology has developed. PH results from many diseases and pathophysiologic mechanisms, and most commonly occurs secondary to chronic cardiopulmonary disease.

The vascular endothelium mediates vascular tone and remodeling through release of several neurohormonal factors, and endothelial injury plays a key role in development of PH. Normally, there is a balance between locally acting vasodilators including prostacyclin (PGI2) and nitric oxide (NO) versus potent vasoconstricting substances including thromboxane, endothelin-I (ET-1), and angiotensin II (AT-II). Endothelial dysfunction in PH contributes to smooth muscle cell proliferation (increased ET-I, AT-II, reduced NO), increased production of vasoconstrictor mediators including ET-1 and AT-II, and decreased synthesis of vasodilating substances including PGI2 and NO.

Classification of PH through hemodynamic and pathophysiologic mechanisms helps to guide interventional treatment. Mean pulmonary artery pressure (MPAP) is related to pulmonary blood flow (PBF) and pulmonary vascular resistance (PVR) by the equation MPAP= (PVR x PBF) + pulmonary capillary wedge pressure (PCWP). Abnormalities of any component of this equation can cause PH.

Pre-capillary PH occurs due to abnormalities of the pulmonary arterial vascular bed and is characterized by increased systolic, mean, and diastolic PAP, increased PVR, and normal PCWP. PVR is closely related to total cross sectional area of the small muscular arteries and arterioles. Given the high-capacitance of the pulmonary vasculature, ≥ 50% of the pulmonary vasculature must be destroyed before PH develops. Diseases that cause pre-capillary PH include: primary pulmonary hypertension (PPH), Eisenmenger syndrome, chronic pulmonary disorders, pulmonary thromboembolism (PTE), and peripheral pulmonary artery branch stenosis. PPH is ill-defined in veterinary medicine. PTE is a secondary condition. Immune mediated hemolytic anemia (IMHA), neoplasia, cardiac disease, protein-losing nephropathy or enteropathy, hyperadrenocorticism, disseminated intravascular coagulation, sepsis, trauma, and recent surgery are associated with PTE in dogs and cats. Eisenmenger syndrome is an irreversible, obliterative pulmonary vascular disease that results from severe left to right shunting congenital heart disease that reverse to shunt right to left. Chronic respiratory disorders may result in PH in some individuals through hypoxic pulmonary vasoconstriction, extramural compression of the pulmonary arterioles, and destruction of pulmonary microvasculature. In absence of pulmonary arterial pathologic changes (plexiform lesions, necrotizing arteritis, hyalinizing fibrosis), PH due to hypoxic vasoconstriction may be dynamic and respond to therapeutic intervention.

In post-capillary PH, PAP passively increases due to elevated PCWP. PA diastolic pressure is within 5 mmHg of the PCWP, and PVR is normal. Left sided congestive heart failure (CHF) is the most common cause of increased PCWP and may result from severe mitral valve disease, dilated cardiomyopathy, or diastolic heart disease. A mixed hemodynamic response may be seen with chronic elevations in PCWP and consists of a disproportionate elevation in PA pressures in comparison to elevated PCWP. The mechanism for increased PVR in response to elevated PCWP is not entirely clear but likely involves endothelin-1 release, endothelial dysfunction and abnormal pulmonary vasodilatory reserve. Based on clinical experience, a low percentage of dogs with severe mitral regurgitation likely have a mixed hemodynamic response of PH.

Pulmonary blood flow (PBF) can be increased selectively by left to right shunting congenital heart diseases (ASD, VSD, PDA) and some patients are at risk for development of Eisenmengers physiology. PBF is also increased by high output cardiac disease (arteriovenous fistula, chronic anemia, and hyperthyroidism), however most patients do not develop recognizable PH. Pneumonectomy leads to selective increases in pulmonary blood flow, but PH is not recognized as a complication in dogs.

Cor pulmonale is an adaptive mechanism by which the right ventricle responds to PH resulting from chronic pulmonary disease. The most common cause of cor pulmonale in veterinary medicine is heartworm disease in dogs. PH leads to acquired pressure overload of the right ventricle characterized by concentric hypertrophy and chamber dilation. RV myocardial failure may occur due to inadequate reduction of wall stress and may be worsened by myocardial ischemia from reduced right coronary artery perfusion pressure. The extent of concentric hypertrophy and dilation of the RV ventricle depends on the age of the animal, the severity and duration of pressure overload, and the time course of progression.

Clinical abnormalities

The most common presenting complaints are cough, tachypnea, dyspnea, and syncope. Right sided CHF may be seen as ascites, jugular venous distension, +/- pleural effusion, +/- peripheral edema. Often a right sided systolic murmur is present, and left apical systolic murmur is present if there is mitral regurgitation. A split S2 heart sound may be heard. Often there are marked adventitious pulmonary sounds in animals with severe underlying pulmonary parenchymal or bronchial disease.

A minimum database (CBC, chemistry, urinalysis) and heartworm test should be performed to identify underlying diseases that may be associated with PH. Hypoxemia and acidosis should be identified since hypoxemia can cause PH and both may worsen PH. Arterial blood gas analysis is often abnormal in dogs with PTE, and common abnormalities include hypoxemia, hypocapnea, and increased alveolar-to-arterial gradient. However, normal arterial oxygenation does not exclude the diagnosis of PTE. If there is proteinuria, urine protein creatinine (UPC) ratio should be measured, and if abnormal then plasma anti-thrombin III should be measured. Hyperadrenocorticism should be evaluated if there are corresponding clinical signs. Plasma D-dimer is a useful screening test in people and animals for PTE. D-dimer is a breakdown product of cross-linked fibrin (from a stabilized clot), which is produced when fibrin is degraded by plasmin. Plasma D-dimer is used in the diagnosis of PTE in humans, with 96% sensitivity and 52% specificity. D-dimer appears to be highly sensitive (100%) for diagnosis of pulmonary thromboembolism in dogs, since all 20 dogs had elevated D-dimer > 500 ng/dl in one study. Larger studies need to be conducted to verify these early findings. The author has had two cases where there was an abnormal perfusion scan indicative of PTE in the face of normal D-dimer concentration. Elevated D-dimer is not specific for PTE, and may be increased with DIC, hepatic disease, or other fibronolytic conditions.

Thoracic radiographs most commonly show cardiomegaly. Identification of RV enlargement and dilated central pulmonary arteries with rapid tapering towards the periphery should greatly increase clinical suspicion of severe PH. Eisenmengers syndrome is characterized by pulmonary undercirculation and right heart enlargement. Substantial left atrial enlargement and perihilar to caudo-dorsal pulmonary infiltrates indicate left sided CHF and possible post-capillary PH. Thoracic radiographs may be unremarkable in animals with PTE.

Echocardiography is an essential tool for noninvasive diagnosis of pulmonary hypertension. Right ventricular concentric and eccentric hypertrophy, pulmonary artery dilation, and variable degrees of tricuspid regurgitation are seen in animals with PH. Measurement of the tricuspid regurgitation velocity allows non-invasive estimation of pulmonary artery systolic pressure, and assessment of the severity of PH. Measurement of an increased TR pressure gradient of >30 mmHg is indicative of PH, with arbitrary cutoffs of 30- 50 mmHg mild; 50-75 mmHg moderate4, and >75 mmHg severe. Measurement of pulmonic insufficiency velocity likewise yields an estimated pulmonary artery diastolic pressure. Identification of heartworms or proximal pulmonary artery thrombi may be possible. It is important to assess whether there is significant left heart disease or Eisenmengers syndrome.

Right heart catheterization is the gold standard for diagnosing PH and determining the hemodynamic classification, but is rarely done. Unfortunately, sedation or general anesthesia is required in veterinary patients who are at increased risk for anesthetic complications. Cardiac output and pressures can be measured, allowing calculation of PVR. Selective pulmonary artery angiograms may identify intraluminal filling defects due to a pulmonary thrombus.

Perfusion scanning with an intravenous injection of technesium magroaggregated albumin, is a safe, non-invasive technique for evaluation of PTE. Perfusion deficits may occur in regions of thrombosis or in non-ventilated regions with reflex vasoconstriction. Definitive positive V:Q scans are defined as multiple segmental or lobar perfusion defects in areas of normal ventilation and no radiographic evidence of pulmonary infiltrates. Unfortunately, results may be vague and not clearly document PTE. While V:Q scans are commonly used in human medicine to increase the likelihood of documenting PTE, fewer than half of people with PTE have a high probability scan.

Diagnosis of primary respiratory diseases by bronchoscopy, bronchoalveolar lavage, or trans-tracheal wash is indicated if there are significant pulmonary abnormalities on thoracic radiographs. Often patients are not stable enough to endure these diagnostic tests, and broad spectrum treatment of primary respiratory disease with antibiotics, bronchodilators, +/- steroids may necessary.

Treatment of PH is aimed at correcting the specific hemodynamic abnormality. Left CHF is treated with diuretics, angiotensin converting enzyme (ACE) inhibitors, pimobendan, and possibly careful use of afterload reducing agents (amlodipine or hydralazine). Resolution of symptomatic CHF often reduces post-capillary PH and clinical signs of syncope. Surgical or interventional techniques may be used to correct left to right shunting congenital heart diseases but should never be attempted in patients with right to left shunts since it will hasten death. Cautious use of diuretics and ACE-inhibitors are indicated for right heart failure, since patients may develop symptomatic hypotension if they become significantly volume underloaded in the face of fixed PVR. ACE-inhibitors have been shown to delay pulmonary vascular remodeling in experimental animals and have produced beneficial hemodynamic effects in people with cor pulmonale. Digoxin improved cardiac output and reduced circulating norepinephrine concentration in people with primary PH and symptomatic right heart failure, and could be considered for treatment of severe PH and right heart failure in veterinary patients. Although high risk patients, treatment of dogs with heartworm disease with the split protocol of melarsomine and anti-inflammatory doses of prednisone is recommended since there may be improvement in the PH post-treatment.

Treatment of pre-capillary PH or persistent post-capillary PH is aimed at reducing PVR and RV pressure overload with the use of selective pulmonary vasodilator therapy. In veterinary medicine, the most common pulmonary vasodilator used for treatment of PH is sildenafil, a phosphodiesterase V inhibitor. Phosphodiesterase V inhibitors lead to selective increases in cGMP in the pulmonary vasculature, leading to increased nitric oxide and pulmonary arteriolar vasodilation. Sildenafil has been used with some frequency in veterinary medicine for treatment of PH in dogs, with anecdotal reports of reduced symptoms and improved exercise capacity. The half life of sildenafil in dogs is 6.1 hours compared to 3.7 hours in people. Optimal dosing frequency has not been defined for dogs. In people, it is given orally every 8 hours. Pharmacodynamic studies are lacking in people and in dogs. Dogs are often arbitrarily given 1 mg/kg PO BID- TID. Mild to moderate pulmonary arteriolar vasodilation occurs, which decreases pulmonary vascular resistance and pulmonary artery pressure. Sildenafil may reverse pathologic pulmonary arteriolar remodeling and smooth muscle hypertrophy through nitric oxide and cyclic GMP modulation of smooth muscle cell hypertrophy, which is also beneficial for patients with pulmonary hypertension. In dogs, sildenafil may also reduce systemic vascular resistance which could exacerbate systemic hypotension, although there are contradictory results in several experimental studies. Sildenafil has been shown to reduce the severity of pulmonary hypertension in people as well as dogs, and improve QOL, reduce syncopal episodes, reduce dyspnea, and increase exercise capacity.(12;13) Only one abstract is available regarding the use of sildenafil in dogs with PH. A retrospective, open label, unblinded study evaluated sildenafil in 9 dogs with PH. Doses were variable (0.5- 2.7 mg/kg TID to q 24 hours). PA pressure was either directly measured or indirectly estimated by CW Doppler measurement of the tricuspid regurgitation velocity in 7 dogs. Sildenafil reduced PA systolic pressure by approximately 18% (median decrease of 19 mmHg) compared to baseline. Other studies show variable results of sildenafil on PA pressures estimated by TR pressure gradient on echocardiography, but clinical improvement seems to be a consistent finding among studies. There is a need for more veterinary studies evaluating the effect of PDE5 inhibitors in dogs with PH, as well as other pulmonary vasodilator therapy such as endothelin receptor antagonists (bosentan), beraprost (an oral prostacyclin analog), or other phosphodiesterase V inhibitors such as tadalafil.

In human medicine, early and aggressive thrombolytic treatment of PTE is reserved for hemodynamically unstable (i.e. low output) patients. In hemodynamically stable people with massive PTE, there was no benefit in thrombolytic therapy over anticoagulant therapy with heparin. Thrombolytic therapy is uncommonly used in veterinary medicine, and may include tissue plasminogen activator, streptokinase, or urokinase. Anticoagulants are necessary, and options include: unfractionated heparin, low molecular weight heparin, or warfarin. Treatment should also be focused on the underlying systemic disease (if identified) that may have been responsible for PTE.

Prognosis for pulmonary hypertension causing cor pulmonale is poor to grave, and typical survival times are days to several months, typically less than 6 months for those with significant cor pulmonale and dyspnea. Reported survival times range from 3 to 734 days, although severity of PH ranged in those studies.