Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon disease but an important one for several reasons – it is substantially under recognized, it may result in progressive and disabling symptoms, the natural history is progression to death, but there is a highly effective operation (Pulmonary Endarterectomy) that may abolish symptoms and reverse the unfavorable natural history.
Pathology of Chronic Thromboembolic Pulmonary Hypertension
Approximately 96% of patients who have had an acute pulmonary embolus will undergo spontaneous lysis with complete resolution. A small proportion of patients who have a pulmonary embolus may still have reduced functional capacity and may even have measurable limitations in cardiopulmonary function, and of these patients a proportion will go on to develop chronic thromboembolic pulmonary hypertension. The process that underpins failure to lyse clots is abnormal thrombus, abnormal lytic mechanisms and in a small proportion of patients definable hypercoagulable disorders. The unlysed embolus lodges at a branch point in the pulmonary arteries and propagates down the branches and forms scar tissue that may result in bands and webs across the pulmonary artery or in some cases blind fibrous pouches. One of the features of the process is the opening of channels (called recanalization) through the obstructing thromboembolic disease and the importance of this is that the contrast material from a CT scan or nuclear medicine perfusion scan infiltrates through these channels and consequently the burden of thromboembolic disease maybe underappreciated on the imaging study. Because of the obstruction the blood pressure in the pulmonary arteries begins to rise and the consequence of this is that the very small vessels in the lung in areas that are unobstructed by thromboembolic disease begin to thicken, this process known as pulmonary vascular remodeling. This increases the resistance of blood flow and drives the pulmonary artery pressure higher. Therefore there are 2 processes that are involved in the CTEPH:
- The large vessel obstruction from the thromboembolic material.
- The excessive thickening of the walls of the very small vessels.
The other abnormality involving the small vessels of the lung is that there are multiple small connections formed between the small arteries and veins of the lung.
As the resistance in the pulmonary circuit increases the right ventricle that is only meant to generate pressures of 20-30 mmHg is now having to generate much higher pressures to overcome the resistance in the vessels of the lung and as a consequence the wall of the right ventricle becomes progressively thicker to compensate for the higher stress on the wall of the right ventricle. Eventually however this compensatory mechanism fails and the right ventricle becomes progressively enlarged and its function declines. Patients with longstanding severe CTEPH often first present with a right ventricle that is extremely large, thick walled with very poor function.
Prognosis of Chronic Thromboembolic Pulmonary Hypertension
The prognosis of patients with CTEPH is directly related to the severity of the pulmonary hypertension (blood pressure in the lungs) and when the pulmonary artery pressure reaches the same level as the systemic blood pressure the patient has approximately 20% chance of surviving 2 years. CTEPH is a progressive condition.
Clinical Presentation of Chronic Thromboembolic Pulmonary Hypertension
Only 40-50% of patients with CTEPH give a history of having either a deep venous thrombosis or a pulmonary embolus in the past. From the time of the pulmonary embolus that fails to lyse there is a “honeymoon period” of months to years until symptoms develop. The initial symptoms are often very non-specific in nature which frequently contributes to the diagnostic delay experienced by most patients. The patient slowly develops progressive symptoms, often over years with effort shortness of breath and fatigue, cough and when the pulmonary artery pressure becomes very high, fainting. Fifty percent of patients with severe pulmonary hypertension may experience a non-specific type of chest pain or chest tightness. As the right ventricle fails, signs of right ventricular failure including swelling of the legs and accumulation of fluid in the abdominal cavity (known as ascites) will develop.
Diagnosing Chronic Thromboembolic Pulmonary Hypertension
The VQ scan can distinguish between large and small vessel occlusive disease and is the best screening test for CTEPH. A normal scan rules out CTEPH. However the VQ scan may significantly underestimate the burden of vascular obstruction. The typical appearance of the VQ scan in CTEPH is large perfusion defects with normal ventilation.
The echocardiogram is a good screening test for pulmonary hypertension. In patients with longstanding CTEPH, the echocardiogram will invariably show a very adversely remodelled right ventricle that is dilated and poorly functioning and because of the high pressure that it is generating will compress the left ventricle. There may also be severe leakage of the tricuspid valve.
A CT scan is helpful for surgical decision making to detect larger areas of pulmonary infarction that may limit the degree of symptomatic benefit of pulmonary endarterectomy and would need to be factored into the decision making for the operation. Following confirmation of CTEPH the key imaging study for surgical decision making is a pulmonary angiogram. The pulmonary angiogram can be performed either as a formal study with a catheter in the pulmonary artery (heart catheterisation), by magnetic resonance or by CT and the choice depends very much on the experience of the CTEPH centre. The appearances are similar and they show webs, bands, filling defects, blind pouches, cut-off of vessels and areas of the lung with absent perfusion.
Medical Treatment of Chronic Thromboembolic Pulmonary Hypertension
The most effective therapy for CTEPH is pulmonary endarterectomy and therefore the entire therapeutic strategy is directed towards answering the question “Will this patient benefit from pulmonary endarterectomy?”. The benefit of pulmonary endarterectomy is so great that if pulmonary endarterectomy is not advised by a surgical centre that a second opinion be obtained from a more experienced centre.
All patients with CTEPH require life-long anticoagulation. Inferior vena cava filters were at one time felt to be mandatory in patients undergoing pulmonary endarterectomy although this is no longer felt to be the case. Inferior vena cava filters should be reserved for patients who are going to undergo pulmonary endarterectomy who are at increased risk of recurrent embolization including those with hypercoagulable disorders, particularly those with unprovoked deep venous thrombosis.
The only currently approved drug for CTEPH is riociguat which does improve exercise tolerance. A variety of other pulmonary vasodilator drugs may be tried such as endothelin antagonists but they are usually ineffective. As right ventricular failure advances, diuretics will be required. The place of medical therapy is in patients in whom pulmonary endarterectomy is inadvisable (either because of inoperability or unacceptable comorbidity) and in patients with residual pulmonary hypertension after a pulmonary endarterectomy.
Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension
Given the magnitude of the operation an extensive evaluation is required to confirm that a patient has technically operable disease, that sufficient thromboembolic disease is present that if removed will benefit the patient both symptomatically and hemodynamically, that there are no other major dysfunctional organ systems that would preclude operation (liver and kidneys in particular in the context of CTEPH) and that the patient has sufficient physical reserves for the operation and post-operative course. It should be mentioned that patients with longstanding CTEPH with very high pulmonary artery pressure may have an extremely poorly performing right ventricle which could be regarded as unacceptable right ventricular function for a successful pulmonary endarterectomy. However there is no degree of right ventricular dysfunction that will contraindicate a pulmonary endarterectomy as after an effective operation right ventricular dysfunction will reverse extraordinarily rapidly.
Although some of the details of the operation may differ between experienced centres the principles remain the same. The operation is performed with a median sternotomy (an incision that is used for most heart surgery) and cardiopulmonary bypass (which is used for most heart surgery). The bronchial arteries (the arteries from the aorta which supply the airways of the lung) in CTEPH become dilated and carry considerably more blood than normal. These so called collateral vessels can carry so much extra blood to the pulmonary arteries that visualisation for the surgeon out in the pulmonary arteries would be totally obscured. For that reason the patient needs to be cooled to a low temperature (20 degrees C) and the heart/lung machine switched off (circulatory arrest). Protection of the brain and spinal cord is an important issue in this operation where circulatory arrest is used and there are number of strategies for neurological protection. One strategy that is commonly used is to use circulatory arrest for 20 minute intervals followed by reperfusion of the entire body for 10 minute intervals. Another strategy is to perfuse the brain continuously as visualisation permits. The pulmonary artery on each side is opened and the correct plane in the wall of the pulmonary artery established. The correct plane is within the middle layer of the arterial wall called the media and the dissection then proceeds into all of the branches and sub-branches of the pulmonary artery removing fibrous pouches, webs, bands and thrombus that is often found sitting on top of blind pouches. The pulmonary artery incisions are closed, cardio pulmonary bypass resumed, the patient re-warmed, and the patient separated from cardio pulmonary bypass. There are many nuances in the surgical decision making, performance of the operation and post-operative care and this operation is best performed in an experienced centre with a team approach from surgery, anesthesia, pulmonary medicine and intensive care.
Post-Operative Results of Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension
The operative risk in experienced centres is between 1% and 5%. However there are of course patients who have more complex forms of the disease such as thromboembolic disease well out into the small vessels of the lung, patients who have severe pulmonary vascular remodelling, patients who have very poor right ventricular function and patients who have severe subsystem dysfunction or comorbid disease where the risk may be substantially higher. The long-term results of the operation are outstanding particularly in patients who have normalisation or near normalisation of their pulmonary artery pressures and the right ventricle after the operation for CTEPH.