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Pulmonary hypertension with a focus on pulmonary arterial hypertension and pulmonary hypertension secondary to clots

Pulmonary hypertension can be described as the increased pressure the heart must pump against to move the blood from the right side of the heart to the lungs for oxygenation through the pulmonary arteries. The persistent elevation of right ventricular afterload (force the heart must pump against to push the blood through to pulmonary circulation) associated with this condition can eventually lead to right sided heart failure. Symptoms and signs of right sided heart failure include: fluid accumulation in legs, feet, and perhaps the abdomen, liver, lower back; fatigue; irregular heartbeat; may have prominent vessels in the neck. Pulmonary hypertension has several causes, and it is important physicians identify the origin in order to initiate appropriate therapy.

Pictures below depict blood flow through the heart to the lungs (pulmonary arteries circled in yellow added by this author) and narrowing of a pulmonary artery (pictures from U.S. National Library of Medicine. Available at: http://www.nlm.nih.gov/medlineplus/ency/encyclopedia.)

Pulmonary hypertension (PH) includes several subtypes. Pulmonary arterial hypertension is made up of primary pulmonary hypertension ([PPH or IPAH] no cause has been identified) and pulmonary arterial hypertension secondary to certain health conditions or drugs (PAH). Other types of pulmonary hypertension include: pulmonary venous hypertension (PVH), pulmonary hypertension related to respiratory diseases or low oxygenation, pulmonary hypertension caused by chronic thrombotic and/or embolic disease ([clots] CTEPH). The focus of this article will be on general characteristics of pulmonary hypertension and treatment of both pulmonary arterial hypertension with or without an identifiable cause and pulmonary hypertension caused by chronic thrombotic and/or embolic disease (blood clots).

Most patients present with nonspecific symptoms no matter what the origin is. Initially, shortness of breath followed by chest pain and fainting episodes could occur in individuals with pulmonary hypertension. Physicians will run several screenings to determine if the source of symptoms is due to pulmonary hypertension. Imaging of the chest, lung function tests, ECG, blood and urine tests are all part of the assessment process.

Primary pulmonary hypertension is pulmonary arterial hypertension due to an unidentified cause. Some identifiable causes of pulmonary arterial hypertension include the following conditions:¹ collagen vascular disease (rheumatoid arthritis, lupus, scleroderma [connective tissue disease caused by changes in skin, blood vessels, muscles, and internal organs], dermatomyositis [inflammatory diseases of muscle and skin], polyarteritis nodosa [blood vessels that are damaged by immune cell attack]), congenital systemic to pulmonary shunts, portal hypertension (compromised circulation from the gi tract to the liver), HIV infection, some possible drug causes (amphetamines, cocaine, chemotherapies), and persistent pulmonary hypertension of the newborn.

Pulmonary hypertension secondary to chronic thrombotic/embolic disease is thought to be caused by unresolved pulmonary embolisms, although this is controversial. These individuals may have received treatment with warfarin or other anticoagulation for a specified time, but the clot was never fully dissolved, leaving the remnants to cause a partial blockage, increasing the pressure of the circulation system between the heart and the lungs. Other predispositions to this disease that have been identified are the presence of a lupus anticoagulant or anticardiolipin antibodies in 10-24% of patients.

Treatment options for chronic thrombotic pulmonary hypertension² include surgical removal of the clot as first line in patients who qualify, medical therapies if not a candidate for surgery or for use until surgery can be performed, and a lung transplant or heart lung transplant in those with an inoperable obstruction and/or those who have exhausted drug therapies. Pulmonary arterial hypertension (either unknown or known cause) treatment² involves various drug therapies and transplant if medications no longer manage symptoms.

Patients of any age with chronic proximal pulmonary thromboembolic disease should be considered for pulmonary thromboendarterctomy (surgery) as initial treatment option. Proximal pulmonary thromboembolic disease is an obstruction (clot) in the central pulmonary arteries. If a patient has distal pulmonary thromboembolic disease, surgeons will likely be unable to reach the involved area to remove the clot. Thromboendarterctomy surgery involves a dissection of the clotted material as well as a portion of the pulmonary arterial bed itself. This procedure should improve pulmonary artery pressures, which will improve right ventricular function and is perhaps a curative surgery.

Pharmacological treatment of pulmonary arterial and chronic thrombotic pulmonary hypertension may include life long anticoagulation therapy with warfarin (Coumadinâ). The therapeutic range should be an INR between 2 and 3. INR (international normalized ratio) is a measurement of how long it takes for the blood to clot. Patients maintained within the range of 2 and 3 should provide adequate reduction of the bodies’ ability to clot (2-3 times longer to clot compared to those not taking warfarin), therefore decreasing the likelihood of clotting. Some patients will require a higher range for this same effect. Warfarin therapy has been shown to almost double 3-year survival in primary pulmonary hypertension (unknown cause). Anticoagulation with warfarin in patients with pulmonary hypertension secondary to clots and primary pulmonary hypertension of unknown cause is recommended if not contraindicated (active bleed) due to the possible association of these types with a defect in fibrinolysis (clot disintegration) causing a hypercoagulable state (more likely to form a clot) and blood not moving efficiently through the heart-lung circulation. Patients with primary arterial hypertension linked to scleroderma or congenital heart disease should also be considered for warfarin therapy.Finally, individuals who are receiving the IV infusion of epoprostenol (FlolanÒ) should be anticoagulated due to a risk of clotting from the inserted catheter delivering the medicine.

Oxygen therapy may be beneficial for those with primary pulmonary hypertension who have had oxygen saturation testing overnight and have been shown to have an associated low oxygen level with their condition. Low levels of oxygen contribute to the poor circulating ability of the pulmonary arteries and could make pulmonary hypertension even worse. Oxygen saturations should be >90% with oxygen therapy for benefit.

Vasodilators such as calcium channel blockers [diltiazem (CardizemÒ, TiazacÒ, others), nifedipine, (AdalatÒ, ProcardiaÒ), amlodipine (NorvascÒ)] and prostaglandin therapy [epoprostenol (FlolanÒ), treprostinil (RemodulinÒ), iloprost (VentavisÒ)] are useful if there is an associated narrowing of the arteries (vasoconstriction) no matter what the cause of pulmonary hypertension. Patients would have to be tested to see if they respond to short acting vasodilators before calcium channel blockers could be initiated. The selection of calcium channel blockers for specific patients may be chosen based on heart rate. Nifedipine might be favored for those with a slow heart rate and diltiazem for a faster heart rate. All calcium channel blockers used for this condition should be started at a low dose and increased over time as tolerated and based on response. Calcium channel blockers should only be used for patients who meet certain criteria, including a specified cardiac index, oxygen saturation and/or right atrial pressure, and have had a response to a challenge with vasodilators. Epoprostenol is a very effective prostaglandin vasodilator, but it is a complicated therapy. It must be delivered by continuous IV infusion to the patient via a catheter and must be kept cold prior to and during the infusion. Treprostinil is a subcutaneous injection that is stable at room temperature. Its limitations include pain at the site of injection. Iloprost is an inhaled prostaglandin therapy. It must be inhaled via a nebulizer 6-9 times daily for the medication to be effective. Beraprost is an orally available prostaglandin that is approved for use in Japan and is also being evaluated in Europe. In addition to vasodilation, prostaglandins inhibit platelet aggregation, reduce blood vessel cell injury, and decrease the likelihood of forming clots. Prostaglandin therapy is recommended in those with primary pulmonary hypertension and those with chronic thromboembolic disease if it is inoperable or as a bridge to pulmonary thromboendarterectomy, a potentially curative surgery. Vasodilators (calcium channel blockers and prostaglandin therapy) can improve symptoms, allow blood to flow more efficiently between the heart and lungs, and increase survival.

Endothelin receptor antagonists [bosentan (TracleerÒ)] are an option for patients with pulmonary arterial hypertension. This medication and another agent currently being studied (sitaxsentan) have been shown to increase exercise tolerance and decrease the rate of deterioration associated with pulmonary hypertension through blocking two different receptors to varying degrees.

Sildenafil (ViagraÒ but will have a different brand name if approved for this condition) is currently being studied to determine if it has some utility in individuals with chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. Although more clinical trials are needed to prove its efficacy, a 6-month study has demonstrated an improvement in parameters of pressure and cardiac index in patients with chronic thromboembolic pulmonary hypertension (caused by clots). It may be an option when other therapies fail or in combination with other available agents when more evidence becomes available.

Supportive care for those who have manifestations of right-sided heart failure can include diuretic therapy to reduce water retention and digoxin to improve heart contractions.

The medication selections and combinations are highly individualized depending on the severity and cause of a patient’s condition. Many special populations or circumstances an individual may have (children, HIV, pregnancy, liver disease, etc) will also direct therapy choices.

Lung or lung heart transplantation is an option for pulmonary hypertension patients who have maximized medication and surgery options but remain symptomatic and have progressive disease.

Pulmonary arterial hypertension with or without an identifiable cause (primary pulmonary hypertension =cause unknown) and chronic thromboembolic pulmonary hypertension are different types of pulmonary hypertension. There are some disease processes and/or conditions associated with triggering pulmonary arterial hypertension. The disease process associated with chronic thromboembolic pulmonary hypertension is controversial, but it has been proposed to be linked with unresolved pulmonary embolisms. Treatment includes surgery, drug therapies, and lung or lung heart transplantation. Medications that are commonly used for pulmonary hypertension include: warfarin, vasodilators (calcium channel blockers, prostaglandins) in patients that have narrowing of the pulmonary arteries, oxygen if hypoxic (low oxygen concentration in the blood), endothelin receptor antagonists, and possible use of sildenafil in the future. The goal of any therapy selected remains the same: decrease pulmonary pressures, improve cardiac output (the blood flow out of the heart), and increase survival and quality of life.

For more information, please refer to the pulmonary hypertension association (PHA)

References

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