Pulmonary Arterial Hypertension: It's Seeing You!

Donald J. Brown DVM, PhD, DACVIM-C  (edited 11/2009)

Pulmonary hypertension (PHT) is an elevation of the arterial pressure in the pulmonary circulation.  Don't confuse this with pulmonary congestion (elevated pulmonary venous pressure) although the two may coincide and the latter may contribute to the former.  Normal pulmonary arterial pressure is dramatically lower than systemic with a peak systolic pressure of 20-30 mmHg and mean of 8-16 as determined by cardiac catheterization in normal dogs.  With a mean left atrial pressure of roughly 10 mmHg, the mean pressure to drive the entire cardiac output through the pulmonary circulation is only about 5-10 mmHg at rest; the vascular resistance is on the order of 10-20 times lower than the systemic circulation.  It is now known that pulmonary arterial pressure gradually increases with age in people and it is likely that a similar phenomenon occurs with dogs and/or cats.

The pulmonary circulation also has a tremendous reserve capacity.  With exercise or increased pulmonary flow, this circulation is able to dilate and recruit latent vascular channels.  Vascular resistance decreases significantly with exercise so that only a mild increase in driving pressure is required to accommodate the additional blood flow.  Approximately 50% of the pulmonary vasculature must be occluded before pulmonary artery pressure begins to increase at rest.

Secondary PHT is a potential complication of a wide range of disease conditions of the cardiovascular or respiratory systems.    While primary PHT occurs in humans, it is rare in dogs and cats unless "persistent fetal circulation" is included in the category. Pulmonary vascular resistance is very high during fetal development as there is no benefit in perfusing the airless lung prior to birth. Pulmonary vascular resistance falls dramatically with the initial inflation and oxygenation of the lungs.  This may fail to occur with certain congenital defects, notably patent ductus arteriosus, resulting in "persistent fetal circulation".   This is the reason for right to left shunting in typical cases of reverse PDA (as opposed to reversal of a L to R PDA).  Dramatic right ventricular hypertrophy and the lack of left-sided dilation accompany the condition under these circumstances. 

Cor pulmonale refers to right ventricular heart disease, including hypertrophy and potentially right-sided heart failure, secondary to pulmonary hypertension.  As a matter of pre-determined taxonomy, cor pulmonale is a term that does not include or apply to PHT resulting from congenital heart disease or pulmonary overcirculation.  Disease conditions associated with secondary PHT include:

  • Chronic left-sided congestive heart failure, particularly marked mitral valve regurgitation from degenerative valve disease
  • Congenital heart disease resulting in pulmonary overcirculation (e.g. ASD, PDA, VSD)
  • Chronic upper airway obstruction (laryngeal paralysis, brachiocephalic syndrome, collapsing trachea/bronchi)
  • Chronic obstructive pulmonary disease (chronic pneumonia, chronic sterile or infectious bronchitis, pulmonary fibrosis)
  • Other causes of respiratory dysfunction such as malformation of the thoracic bellows (e.g. pectus excavatum ),  sleep apnea in people
  • Dirofilaria immitis or Angiostrongylus vasorum infections
  • Chronic decreased ambient inspired oxygen, most typically associated with altitudes above 7500 feet.
  • Acute pulmonary thromboembolism (PTE) which is usually secondary to abnormalities of coagulation (protein losing nephropathy, protein losing enteropathy, disseminated intravascular coagulation, pancreatitis, dirofilariasis, hyperadrenocorticism, neoplasia, immune mediated hemolytic anemia, other congenital or acquired coagulation defects)
  • Adult Respiratory Distress Syndrome (ARDS) secondary to septic shock, pancreatitis, or other conditions resulting in acute severe systemic inflammation.  
  • In humans, an appetite suppressant drug called Fen-phen (fenfluramine) was associated with valvular heart disease and pulmonary hypertension.  The drug caused increased levels of serotonin (5-hydroxytryptamine).  It has since been withdrawn.


There is an old saying in human cardiology: "The most common cause of right-sided heart disease is left-sided heart disease."  This is because severe left-sided heart disease commonly results in pulmonary hypertension.  PHT secondary to degenerative mitral valve disease is very common in dogs and many cases progress to this stage if they survive long enough. 
In general, patients with PHT may present with a wide range of historical abnormalities:

  • Exercise intolerance with respiratory manifestations 
  • Chronic coughing, dyspnea, or other respiratory signs
  • Inadequate parasite prevention program
  • Syncope, most typically associated with exertion
  • Abdominal distention (organomegaly or ascites secondary to right heart failure)
  • Signs referable to the primary condition (e.g. from hemolytic anemia, hyperadrenocorticism, neoplasia, history of congenital heart disease, etc.)

Clinical signs of PHT depend essentially on the underlying primary disease, as suggested above, or may be the result of PHT itself which is a debilitating or life threatening condition that can result in respiratory failure.   Physical findings also are related to the underlying cause for PHT and may distract the clinician from pursuing PHT has a specific entity contributing to the patient's malaise.

  • With cor pulmonale: abdominal distention, jugular distention, ascites, split second heart sound 
  • Pulmonary crackles and wheezes
  • Dyspnea, cyanosis, respiratory failure
  • Tachycardia, pale mucous membranes, diminished pulse strength
  • Heart murmur/thrill associated with tricuspid regurgitation
  • Heart murmur/thrill associated with mitral regurgitation or other evidence of primary left-sided heart disease.
  • Clinical signs referable to the primary, causative condition (e.g. petechia, systemic infection, vomiting/pancreatitis, signs referable to congenital heart disease)

The pulmonary vascular response to hypoxia is vasoconstriction, i.e. opposite to the systemic circulation.  Mechanisms of PHT include chronic hypoxia (chronic respiratory disease or high altitude), increased pulmonary blood flow (usually secondary to congenital heart disease with a left to right shunt) intravascular or extravascular obliteration/obstruction of a significant portion of the circulation (pulmonary masses, chronic or acute pulmonary thromboembolism, parasitic infestation, interstitial fibrosis), and pulmonary vascular remodeling, i.e. intrinsic restructuring of the vasculature resulting in an increased vascular resistance.  The latter may result whenever there is sufficient chronicity.  

Left-sided heart disease with elevated left atrial pressure physically necessitates an increase in pulmonary arterial pressure for continued forward blood flow.  Mitral regurgitation increases the left atrial pressure, causing the V wave of the left atrial pressure tracing.  The magnitude of this phenomenon is often not appreciated; the pressure V wave can be greater than 60 mmHg!  An average pulmonary venous pressure of this magnitude is incompatible with life as it results in unmanageable pulmonary edema.  However a pulsatile pressure of this magnitude apparently can be tolerated although it is associated with severe mitral regurgitation.  This left atrial pressure wave also contributes to the right ventricular afterload.  Right ventricular pressure is necessarily elevated in systole for forward flow to occur in the face of this dramatic left atrial pressure elevation.  However the elevated venous pressure can also trigger biochemical events that result in vascular remodeling and increased arterial vascular resistance, thereby compounding the problem.

Mechanisms by which vascular remodeling is initiated likely include both mechanical and biochemical activators that trigger a proliferative vascular response.  Heartworm disease pathophysiology, for example, involves release of platelet derived growth factor (PDGF) in response to endothelial damage, collagen exposure, and platelet activation.  Other mediators in the response may include vasoconstrictor prostaglandins, endothelin, angiotensin II, serotonin, reduced NO (nitric oxide) expression, mitogens such as vascular endothelial growth factor (VEGF) and catecholamines.

In congenital heart disease (ASD, VSD, PDA most typically), chronic overcirculation of the lungs of sufficient severity may result in pulmonary hypertension and Eisenmenger physiology; the latter occurs when pulmonary pressures approach systemic values and a reverse, i.e. right to left shunt may ensue.  Effects on the pulmonary vasculature have been well documented in human pediatric cardiology and a classification system has been derived based on progressive pathologic changes (Heath and Edwards) as follows:

  • I. Hypertrophy of media of small muscular pulmonary arteries and pulmonary arterioles.
  • II. Intimal cellular proliferation is added to the medial hypertrophy.
  • III. Advanced medial thickening with hypertrophy and hyperplasia, together with progressive intimal proliferation and concentric fibrosis resulting in obliteration of many arterioles and small arteries. 
  • IV. Dilation and so-called plexiform lesions of the muscular pulmonary arteries and arterioles.  Vascular channels are separated by proliferating endothelial cells that often contain thrombi.
  • V. Complex plexiform, angiomatous, and cavernous lesions with hyalinization of intimal fibrosis.
  • VI. Necrotizing arteritis.

The initial database for evaluation of PHT depends on initial clinical signs as suggested above.  However a chemistry profile, CBC, urinalysis, and thoracic radiographs are typically indicated from the outset.  There may be a history of chronic cough and nuisance or insidious respiratory signs that have not been fully diagnosed.  Because it is not on the "radar screen", PHT may be severe by the time of initial diagnosis.
General  tests for the underlying causes of PHT often involve some combination of the following:

  • Complete blood count
  • Chemistry profile
  • Urinalysis, +/- urine culture and sensitivity, +/- urine protein/creatinine ratio
  • Heartworm test
  • Thoracic radiography
  • Echocardiography with Doppler ( often diagnostic for PHT and some of its causes)
  • Fecal  zinc sulfate flotation or Baermann technique (GI parasites, Oslerus osleri, Paragonimus kellicotti, Capillaria aerophila, Filaroides hirthi, Crenosoma vulpis, or Aelurostrongylus abstrusus)
  • Transtracheal wash or bronchoalveolar lavage with cytology/culture and sensitivity
  • Cervical fluoroscopy ( collapsing airway syndrome)
  • Bronchoscopy/ laryngoscopy ( laryngeal paralysis, airway obstruction,  large airway disease, brachiocephalic syndrome)
  • Computed tomography ( with contrast,  for interstitial fibrosis, vascular obstruction, neoplasia )
  • Dexamethasone suppression test, +/- ACTH level (for hyperadrenocorticism)
  • Tests for immune mediated hemolytic anemia, pancreatitis, sepsis, etc. (other predisposing diseases for pulmonary thromboembolism)
  • Pulse oximetry, arterial blood gas determination
  • Coagulation profile ( for evidence of coagulation disorders, platelet abnormalities, or DIC)
  • D-dimer test ( for active coagulation /thrombus formation and dissolution)
  • Thromboelastography (TEG, for evaluation of hyper/hypocoagulability, coagulation function)
  • Biopsy of discrete pulmonary masses


Confirmation of PHT is by cardiac catheterization, which remains the gold standard for diagnosis, but recognition in veterinary medicine has increased greatly since the advent of Doppler echocardiography.   Particularly valuable is tricuspid regurgitation or pulmonic insufficiency flow velocity quantification.  Blood flow accelerations within the heart are largely the result of pressure forces, i.e. pressure gradients acting on blood elements.  Tricuspid regurgitation driven by a normal right ventricular to atrial pressure gradient, for example, results in a peak systolic velocity of 2-3 m/sec in rough terms.  The modified Bernoulli equation, P = 4 V2, applied to this velocity yields a pressure gradient range (RVP - RAP) of 16 - 36 mmHg.  Technically, an estimate of the right atrial pressure (RAP) must be added to the Doppler-derived value to obtain be RVP.  RA pressure may be clinically significant in the presence of right heart failure and failure to add this quantity results in a degree of underestimation of PHT severity.  A similar method is applied to a jet of pulmonic insufficiency to obtain a diastolic pressure gradient between the main pulmonary artery and right ventricle.  It is typical for PHT to result in tricuspid regurgitation and/or pulmonic insufficiency, at least to the extent that a diagnostic regurgitant jet is available.   Echocardiography also allows for the evaluation of both right and left sided heart disease, determination of parasitic burden (dirofilariasis), diagnosis and evaluation of congenital heart disease, etc..  On occasion, but it may be possible to visualize intravascular thrombi if they occur in the proximal pulmonary arteries.  Bottom line: echo Doppler is often quite informative.


Two-dimensional echocardiograms from a dog with chronic respiratory disease demonstrating common abnormalities in PHT including right ventricular dilation with flattening of the interventricular septum ( left ) and pulmonary artery dilation ( right ).

 

Color flow ( left ) and continuous wave spectral Doppler recordings (right) of pulmonic insufficiency demonstrating pulmonary hypertension in the above dog.  Maximum velocity of the PI jet is approximately 3.5 m/sec which corresponds to a diastolic pressure gradient of roughly 50 mmHg between the pulmonary artery and right ventricle.  PA pressure may be significantly higher than this if diastolic RV pressure is elevated.

 

Color flow ( left ) and continuous wave spectral Doppler recordings (right) of tricuspid regurgitation demonstrating pulmonary hypertension in the above dog.  Maximum velocity of the TR jet is approximately 5 m/sec corresponding to a systolic pressure gradient of 100 mmHg between the right ventricle and right atrium.  PA pressure may be significantly higher than this if systolic RA pressure is elevated.  Pulmonic stenosis must be ruled out as a cause for RV pressure elevation in such a case.

Specific tests to evaluate PHT may involve some combination of the following:

  • Echocardiography with Doppler, including evaluation of response to oxygen, calcium channel blockers,  phosphodiesterase inhibitors (e.g. sildenafil), eicosanoids,  and others.
  • Pulmonary function testing ( for chronic obstructive pulmonary disease)
  • Cardiac catheterization (definitive diagnosis,  evaluation of response to therapy), pulmonary angiography or CT angiography
  • Pulmonary ventilation perfusion scintigraphy
  • Pulse oximetry, arterial blood gas determination
  • Pulmonary biopsy

The prevention and treatment of pulmonary hypertension includes rigorous therapy for the underlying cause in all cases to the extent possible.  Sadly, this is not always effective and the condition may be progressive.  There is very little evidence-based information in veterinary medicine to suggest appropriate therapy or accurate prognosis.  Pulmonary hypertension in association with respiratory failure or right-sided congestive heart failure may be regarded as extremely serious with a guarded to poor prognosis in the absence of a treatable underlying cause.  

Based on recommendations in the human medical literature, treatment of dogs with pimobendan, judicious dosages of furosemide, and an angiotensin converting enzyme inhibitor +/- spironolactone may be considered as a starting point for symptomatic treatment of significant PHT.  These medications are the same as current "standard therapy" for congestive heart failure and would be obvious choices if left heart failure were the cause of PHT.  The rationale for this approach is not as obvious for other causes of PHT, but there is a need for inotropic support of the right ventricle and pimobendan is the logical choice in veterinary medicine. The author has observed examples of marked reduction of PHT with the addition of pimobendan alone in cases of PHT secondary to mitral regurgitation.  While pimobendan may have some direct vasodilating effects on the pulmonary circulation, my suspicion is that the drug may occasionally improve mitral regurgitation, by decreasing cardiac size, as a more important mechanism for reducing PHT in degenerative mitral valve disease.  It's been suggested that the ( human) right ventricle  cannot generate a pressure greater than 50 mmHg without hypertrophy; i.e. the RV is extremely taxed to generate the pressures often present with PHT.  Diuretics also appear to be of marked symptomatic benefit in people, possibly related to dyspnea resulting from increased left ventricular filling pressure and/or increased right ventricular wall stress.  Diuretics also are an obvious choice if right-sided heart failure is present.  Angiotensin and aldosterone elevation are also implicated in the elevated pulmonary vascular resistance and symptoms in people.

More specific therapy could certainly include the use of inhaled oxygen which is both a pulmonary vasodilator and a treatment for respiratory failure.  Oxygen therapy is certainly indicated for dogs and cats with acute respiratory decompensation of any cause.  Home oxygen therapy is an option that may be feasible for a subgroup of patients and clients that do not consider this an extreme measure. 

Anticoagulants are a consideration for human patients and are certainly appropriate for a subgroup of veterinary patients with PHT if hypercoagulability is a contributor.  However it is likely that coagulation abnormalities contribute in many cases of PHT, regardless of the etiology.  Anticoagulants may be considered as a general treatment for PHT, based on recommendations in human medicine, but there are no data currently to support usage in dogs with PHT and treatment can be very expensive.  For chronic/at-home therapy, low molecular weight heparin injections and/or anti-platelet drugs such as clopidogrel (Plavix) are considerations for dogs and cats whereas vitamin K antagonists such as warfarin,  most commonly used in people, are not as readily adapted.  Low dose aspirin may be considered as a low-cost substitute for clopidogrel.  Heparin may be  relatively ineffective when anti-thrombin III deficiency is present as an underlying coagulation defect.

Vasodilator calcium channel blockers (e.g. amlodipine) are a practical therapeutic consideration in human cases where response to therapy has been verified.  Failure to identify "responders", however, can result in excess morbidity and mortality associated with the treatment, possibly related to negative inotropic effects on the right ventricle and reflex sympathetic stimulation which can worsen PHT.  Dosages associated with reduction of PHT may be significantly greater than standard dosage.  A recommended approach is to start at 0.05 mg/kg q 24 h and titrate upwards, based on response, while avoiding systemic hypotension.

There has been recent enthusiasm in the veterinary literature for treating severe PHT with type 5 phosphodiesterase inhibitors such as sildenafil (1-2 mg/kg BID, Viagra ) and others.   PDE-5 inhibitors are relatively specific for dilation of the pulmonary vasculature.  This somewhat promising approach is currently moderately expensive and certainly is not effective in all cases.  Because of its expense and lack of safety and efficacy data, the author's approach is to discuss this option with owners and consider a therapeutic trial if the expense is not prohibitive.  Clear improvement in clinical signs may be of sufficient value to justify the expense in individual cases.  These drugs essentially increase the levels of NO (nitric oxide) and concurrent use with nitrates (nitroglycerin, nitroprusside) warrents caution or contraindication.  Note that the use of sildenafil is now recommended by some cardiologists for treatment of late stage mitral regurgitation secondary to chronic valve disease.

 Other approaches use in human medicine are currently cost prohibitive or impractical for small animals.  These include continuous central venous infusion of prostacyclins such as epoprostenol ( other prostenoids are being evaluated including an orally active drug called beraprost),  inhalation of nitric oxide, and endothelin antagonists such as bosentan, sitaxentan, ambrisentan, or darusentan.  At the moment of this writing, you can purchase #20 generic bosentan, 125 mg tablets from Northwest Pharmacy for $1479.99.  Lung transplant is a consideration for severe cases.

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