All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- Pulmonary Hypertension From The Lancet, August 12, 1998 by Sean P. Gaine ------------------------------------------------------- Definitions: Alkalosis = abnormally alkaline (having high pH) Capillaries = smallest blood vessels Endothelium = the flattened cells lining blood vessels Hypertrophy = unusual enlargement or over-development Intracellular = happening inside one cell Primary = spontaneous; cause unknown Pulmonary = of with the lungs Raynaud's = condition of spasming capillaries mainly in fingers and toes on exposure to cold - causes whiteness, pain, loss of blood flow Secondary = caused by another disease or condition Vascular = of the blood vessels Vasoconstriction = narrowing of blood vessel's diameter Vasodilators = substances that cause blood vessels to expand their diameter ------------------------------------------------------ SHORT VERSION Primary pulmonary hypertension (PPH) is a progressive disease of high pulmonary artery pressure. PPH reduces right heart function due to increased right ventricle afterload. It occurs most often in young and middle-aged women. Average survival from first symptoms is 2-3 years. The cause of PPH is unknown, although inherited (familial) disease may account for 10% of cases. Current theories focus on improper interaction between cells in the blood vessel wall and smooth muscle cells. Injuries to cells lining blood vessels may cause too much of certain substances to be produced, causing blood vessels to constrict (vasoconstriction). Testing for PPH mainly just decides what the problem is NOT. Cath is necessary to measure blood flow and to check reactions to certain drugs. Lowered pulmonary vascular resistance in response to drugs that dilate blood vessels occurs in about 30% of patients. This indicates a good response to therapy with calcium channel blockers. For patients who don't respond to such a drug "challenge," constant IV epoprostenol (prostacyclin) may improve blood flow and abiltiy to exercise. This may also increase survival in people with severe PPH (heart class 3-4). LONG VERSION History In 1967, an epidemic of PH in Europe was blamed on widespread use of the appetite suppressant aminorex fumarate. Study of the harmful effects of appetite suppressants in PPH has led to their withdrawal from North American and European markets. What is PH? PH is defined as an average pulmonary artery pressure of more than 25 mm Hg at rest or 30 mm Hg during exercise. Although there are many ways of classifying PH, it is usually classed as either primary or secondary. A diagnosis of primary PH is made when all types of secondary PH have been ruled out. The estimated PPH rate is 1-2 cases per million people per year in the general population. Average age at diagnosis is 36 years, although it can occur at any age. More women get PPH than men. Race has no bearing on risk of PPH. Familial PPH acounts for about 10% of cases. The How and Why of PPH The pulmonary vessel is a high-flow, low-pressure circuit. Features of PPH include smooth muscle enlargement, abnormal growth of the cells lining the blood vessels, and blood clots. More complex lesions can also occur, including aneurysm-type enlargements. PPH has 3 distinct types or patterns: 1) plexogenic arteriopathy (30-60% of PPH patients) 2) thrombotic arteriopathy (40-50% of PPH patients) 3) veno-occlusive disease (less than 10% of PPH patients) These patterns are difficult to tell apart. PPH findings can be graded on a 6-point scale (grade 1 - grade 6) based how severe the disease is. There is no correlation between this scale and pulmonary artery pressure. The cause of PPH is unknown. Only small percentages of people in high-risk groups (users of appetite suppressants and HIV infected people) develop PH. There may be genetic tendencies. In families, PPH occurs at younger ages and is more severe in each succeeding generation. PPH has many possible "triggers" 1) swallowed substances such as appetite suppressants 2) monocrotaline extracts 3) inhaled solvents 4) methamphetamine or cocaine 5) contaminated rapeseed oil and L-tryptophan 6) infections such as HIV 7) inflammatory disorders 8) autoimmune thyroid disease Vasoconstriction and blood vessel enlargement happen early in PPH. Less endothelium-produced vasodilators occur. High amounts of vasoconstrictors may be produced. Endothelial-produced nitric oxide levels are lower in the pulmonary arteries of PPH patients. Blood levels of endothelin 1 - a pulmonary vasoconstrictor - are higher. Serotonin levels are high in PPH and remain high even after lung transplant. The appetite suppressants fenfluramine and dexfenfluramine - which inhibit serotonin reuptake - may trigger PPH in some people. Calcium in the cells controls smooth muscle contraction and growth. Certain channels involved in this calcium use may be defective in PPH patients. Vasoconstriction is followed by abnormal growth of cells lining the blood vessels, and by fibrosis and blood clots. Increased production of growth factor (VEGF) may play a part in changes to the blood vessels. Symptoms The earliest symptom in most PPH cases is gradual onset of shortness of breath after physical exertion. Thus diagnosis is often delayed, sometimes for more than 2 years after onset of symptoms. Other common symptoms include chest pain, fainting or near-fainting, fatigue, and swelling of feet or ankles. Raynaud's phenomenon is seen in in 10% of patients, almost all women. Hoarseness occurs from compression of the left recurrent laryngeal nerve by an enlarged pulmonary artery (Ortner's syndrome). Diagnosis PPH can mimic obstructive sleep apnea or left-ventricular diastolic dysfunction (CHF). Signs of PPH depend on how severe it is. The most common signs are a strong second heart sound and a right-ventricular S4 gallop (See Jon's CHF FAQ). When right-sided heart failure develops, pressure in the jugular vein rises. Diagnostic testing is to exclude all possible causes of high pulmonary pressure and to measure severity. First, blood tests should include liver function tests and tests for HIV. Blood studies should check for collagen vascular disease. PPH patients may test positive for antinuclear antibodies. Chest x-rays will show prominent central pulmonary arteries and clear lungs. Chest x-rays can also exclude other causes of high pulmonary pressure such as certain forms of lung disease. EKGs commonly show right ventricular enlargement and T-wave changes suggesting strain. Echocardiogram (see Jon's CHF Tests pages) may raise the possibility of pulmonary hypertension, and can help exclude congenital heart disease as a cause, or mitral valve disease or left ventricular dysfunction. Echo can show enlargement of the right heart chambers, and improper movement of the heart wall. Impaired left ventricle filling may also be seen. Echo also allows response to therapy to be measured. Echo can estimate pulmonary artery systolic pressures. Lung function tests (such as Vo2max) should be done to exclude airway disorders. Arterial blood gases can show chronic respiratory alkalosis. Severe lack of oxygen in the blood is caused by decreased heart output. The 6 minute walk test gives useful information. The ventilation-perfusion lung scan is required to exclude chronic blood clotting problems. Sleep tests may be needed since 10-20% of patients with sleep apnea have PH. Heart cath (see Jon's CHF Tests pages) is the most important test. Cath is necessary to fully measure right and left heart blood flow, presence of shunts, and reactions to acute drug therapy. Pulmonary flow should be thoroughly measured, since such measures can be used to determine possible survival. Response to immediate use of vasodilators predicts long-term response to oral vasodilator therapy. To lessen risk, short-acting drugs like inhaled nitric oxide, IV prostacyclin, or adenosine are used. Lung biopsy is rarely necessary in diagnosing PPH and should be used only when a diagnosis is unclear. Treatment Although there is no cure for PPH, there have been advances in treatment. Physical activity should be limited, and drugs that can aggravate PH should be avoided such as many decongestants, and beta-blockers. Drugs that interfere with warfarin, such as non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided. Places with low levels of oxygen, such as high altitudes or unpressurised aircraft, may make PPH worse, and some patients may need extra oxygen. Pregnancy is a very bad idea. The importance of birth control should be emphasized, but birth control pills should not be taken by PPH patients since they increase the risk of blood clots. Hormone-replacement therapy does not seem harmful. Using vasodilators is based on the idea that vasoconstriction always occurs with PPH. Almost every type of vasodilator has been tried, but there have been no randomised trials of oral vasodilator drugs for PPH. Non-controlled studies have shown improved blood flow, better exercise tolerance, and better survival rates in patients taking oral vasodilators. However, these drugs can cause unpredictable results, so a trial with short-acting agents should be done during right heart cath before oral therapy is started. A substantial reduction in pulmonary artery pressure without worsening heart function in response to nitric oxide predicts good long-term response to calcium channel blockers. However, less than 30% of patients fall into this "responder" category. Calcium channel blocker doses given for PPH are higher than what is used for high blood pressure. The most commonly used drugs are nifedipine and diltiazem, but newer drugs like nicardipine and amlodipine are also used to treat PPH. Suddenly stopping calcium channel blockers can lead to rebound PH, which can be fatal. Although increased cardiac output may lead to fewer symptoms on exertion, right ventricular work may actually be increased with these drugs, which can lead to right-heart failure. Patients with low blood pressure, oxygen desaturation, or lessened cardiac output are not likely to benefit from vasodilator meds. In such people, such drugs can actually make them worse. Continuous IV epoprostenol (prostacyclin) can improve blood flow and exercise tolerance, and prolong survival in severe PPH (heart class 3-4) that has not responded to standard meds. Since the half-life of epoprostenol in the blood is only 3-5 minutes, it has to be given by continuous intravenous infusion. Side effects include jaw pain, headache, rash, diarrhea, and joint pain, particularly in ankles and feet. More serious side-effects are caused by the drug delivery system, and include catheter-related infections and pump malfunction which suddenly stops drug delivery and can be fatal. More on Drug Treatment Blood clots are one effect of PPH. Two uncontrolled trials show improved survival for PPH patients treated with blood thinners. We recommend that INR stay between 1:5 and 2:5 with warfarin use. Heparin can be used but osteoporosis is a side effect of long-term heparin use. Diuretics are used to control edema (high dose calcium channel blockers can cause drug-induced edema). Spironolactone (Aldactone) is helpful if a patient has stomach edema. Treatment with digoxin may help counter the tendency of calcium channel blockers to reduce the heart's pumping strength. Surgeries The first successful heart-lung transplant was done on a patient with PPH. However, if normal pulmonary artery pressures are restored, right-ventricular dysfunction is reversible. Single or double lung transplant is now done for patients with severe PPH. Life expectancy after lung transplant is shorter than for heart, liver, or kidney transplant, especially for PPH patients. Blade-balloon atrial septostomy lowers right heart filling pressures in patients with severe right-sided heart failure. The technique is also used in patients who faint due to underfilling of the left heart. A right to left shunt in the atria allows decompression of the right heart and improved filling of the left chambers. The oxygen desaturation which results should be offset by improvement in cardic output. Prognosis The prognosis for untreated PPH is poor. In a series of 137 cases from the UK, average survival time was 3.4 years. Among 200 patients in the USA, average life expectancy was 2.5 years from PPH diagnosis. Research in France gave similar results. A National Institutes of Health study showed 64% survival at one year and 48% survival at 3 years. The results were not affected by age, age at onset, sex, symptom duration, family history, use of birth control pills, pregnancy, or smoking. PPH patients who respond to calcium-channel blockers have a 95% chance of a 5-year life expectancy when blood thinners are also used. Epoprostenol has increased survival in patients who don't respond to oral meds. Experimental Therapies New therapies are directed at underlying systems and improving drug delivery. Encouraging results with epoprostenol in patients with advanced non-vasoconstrictive PPH suggest that PPH may someday be reversible. Treatments now being developed include thromboxane-synthesis inhibitors, phosphodiesterase inhibitors, endothelin-receptor antagonists, and prostacyclin analogues. Cicaprost, an oral prostacyclin analogue, is available in Japan, although its long-term effectiveness remains to be seen. Inhaler therapy with iloprost (a prostacyclin analogue) is being tested in a large trial in Europe. A new long-acting prostacyclin analogue named 15AU81 (UT-15) is under development. Treatment with inhaled nitric oxide has not yet been discounted as a possible therapy. Gene therapy may also be possible.