inflammation, and fibrosis. it also acts on etb receptors in endothelial cells; this leads to the release of both vasoconstrictors and vasodilators from those cells, and clears endothelin-1 from the system. prostacyclin and thromboxane prostacyclin is synthesized from arachidonic acid in endothelial cells. in vascular smooth muscle cells, prostacyclin binds mainly to the prostaglandin i receptor. this sends a signal to increase adenylate cyclase activity, which leads to increased synthesis of cyclic adenosine monophosphate (camp). this in turn leads to increased camp-dependent protein kinase or pka (protein kinase a) activity, ultimately promoting vasodilation and inhibiting cell proliferation. prostacyclin signaling also leads to anti-thrombotic, anti-fibrotic, and anti-inflammatory effects. levels of camp (which mediates most of the biological effects of prostacyclin) are reduced by phosphodiesterases 3 and 4. the vasoconstrictor thromboxane is also synthesized from arachidonic acid. in pah, the balance is shifted away from synthesis of prostacyclin toward synthesis of thromboxane. other pathways the three pathways described above are all targeted by currently available medical therapies for pah. however, several other pathways have been identified that are also altered in pah and are being investigated as potential targets for future therapies. for example, the mitochondrial enzyme pyruvate dehydrogenase kinase (pdk) is pathologically activated in pah, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in pah, while expression of its receptor is increased. plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with pah, although the role played by serotonin in the pathogenesis of pah remains uncertain. the expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in pah. other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include opg and trail. focusing only on the pulmonary vasculature provides an incomplete picture of pah; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. the molecular pathology of pah in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems. importantly, right ventricular remodeling is associated with increased apoptosis; this is in contrast to pulmonary vascular remodeling which involves inhibition of apoptosis. diagnosis phonocardiogram and jugular venous pulse tracing from a middle-aged man with pulmonary hypertension caused by cardiomyopathy. the jugular venous pulse tracing demonstrates a prominent a wave without a c or v wave being observed. the phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops. pulmonary artery catheter severe tricuspid regurgitation in terms of the diagnosis of pulmonary hypertension, it has five major types, and a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or unclear multifactorial varieties. pah is diagnosed after exclusion of other possible causes of pulmonary hypertension. physical examination a physical examination is performed to look for typical signs of pulmonary hypertension (described above), and a detailed family history is established to determine whether the disease might be heritable. a history of exposure to drugs such as benfluorex (a fenfluramine derivative), dasatinib, cocaine, methamphetamine, ethanol leading to cirrhosis, and tobacco leading to emphysema is considered significant. use of selective serotonin reuptake inhibitors during pregnancy (particularly late pregnancy) is associated with an increased risk of the baby developing persistent pulmonary hypertension of the newborn. echocardiography if pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step. a meta-analysis of doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively. thus, doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catheterization (described below) remains the gold standard for diagnosis of pah. echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension. 4-month-old with pulmonary hypertension as seen on ultrasound exclude other diseases if the echocardiogram is compatible with a diagnosis of pulmonary hypertension, common causes of pulmonary hypertension (left heart disease and lung disease) are considered and further tests are performed accordingly. these tests generally include electrocardiography (ecg), pulmonary function tests including lung diffusion capacity for carbon monoxide and arterial blood gas measurements, x-rays of the chest and high-resolution computed tomography (ct) scanning. ventilation/perfusion scintigraphy if heart disease and lung disease have been excluded, a ventilation/perfusion scan is performed to rule out cteph. if unmatched perfusion defects are found, further evaluation by ct pulmonary angiography, right heart catheterization, and selective pulmonary angiography is performed. ct scan pulmonary artery hypertension and emphysema as seen on a ct scan with contrast signs of pulmonary hypertension on ct scan of the chest are: enlargement of the pulmonary trunk (measured at its bifurcation). it is, however, a poor predictor of pulmonary hypertension in patients with interstitial lung disease. a diameter of more than 27 mm for women and 29 mm for men is suggested as a cutoff. a cutoff of 31.6 mm may be a more statistically robust in individuals without interstitial lung disease. increased ratio of the diameter of the main pulmonary artery (pulmonary trunk) to the ascending aorta (measured at its bifurcation). a ratio of 1.0 is suggested as a cutoff in adults. cutoff ~1.09 in children. increased diameter ratio of segmental arteries to bronchi. this finding in three or four lobes, in the presence of a dilated pulmonary trunk (≥29 mm), and absence of significant structural lung disease confers a specificity of 100% for pulmonary hypertension. mural calcification in central pulmonary arteries is most frequently seen in patients with eisenmenger's syndrome. right heart catheterization although pulmonary arterial pressure (pap) can be estimated on the basis of echocardiography, pressure measurements with a swan-ganz catheter inserted through the right side of the heart provide the most definite assessment. pulmonary hypertension is defined as a mean pap of at least 20 mm hg (3300 pa) at rest, and pah is defined as precapillary pulmonary hypertension (i.e. mean pap ≥ 20 mm hg with pulmonary arterial occlusion pressure ≤ 15 mm hg and pulmonary vascular resistance > 3 wood units). paop and pvr cannot be measured directly with echocardiography. therefore, diagnosis of pah requires right-sided cardiac catheterization. a swan-ganz catheter can also measure the cardiac output; this can be used to calculate the cardiac index, which is far more important in measuring disease severity than the pulmonary arterial pressure. mean pap (mpap) should not be confused with systolic pap (spap), which is often reported on echocardiogram reports. a systolic pressure of 40 mm hg typically implies a mean pressure of more than 25 mm hg. roughly, mpap = 0.61•spap + 2. due to the invasive nature of this procedure, the use of computational fluid dynamics based hemodynamic indices have been postulated. other for people considered likely to have pah based on the above tests, the specific associated condition is then determined based on the physical examination, medical/family history and further specific diagnostic tests (for example, serological tests to detect underlying connective tissue disease, hiv infection or hepatitis, ultrasonography to confirm the presence of portal hypertension, echocardiography/cardiac magnetic resonance imaging for congenital heart disease, laboratory tests for schistosomiasis, and high-resolution ct for pvod and pulmonary capillary hemangiomatosis). routine lung biopsy is discouraged in patients with pah, because of the risk to the patient and because the findings are unlikely to alter the diagnosis and treatment. treatment treatment of pulmonary hypertension is determined by whether the ph is arterial, venous, hypoxic, thromboembolic, or miscellaneous. if it is caused by left heart disease, the treatment is to optimize left ventricular function by the use of medication or to repair/replace the mitral valve or aortic valve. patients with left heart failure or hypoxemic lung diseases (groups ii or iii pulmonary hypertension) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonists, as these are approved for the different condition called primary pulmonary arterial hypertension. to make the distinction, doctors at a minimum will conduct cardiac catheterization of the right heart, echocardiography, chest ct, a six-minute walk test, and pulmonary function testing. using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources. high-dose calcium channel blockers are useful in only 5% of ipah patients who are vasoreactive by swan-ganz catheter. unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive pah, leading to excess morbidity and mortality. the criteria for vasoreactivity have changed. only those patients whose mean pulmonary artery pressure falls by more than 10 mm hg to less than 40 mm hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. of these, only half of the patients are responsive to calcium channel blockers in the long term. a number of agents have recently been introduced for primary and secondary pah. the trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectivity is the "six-minute walk test". many have no data on mortality benefit or time to progression. vasoactive substances many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 (pde-5) inhibitors, and prostacyclin derivatives. prostaglandins prostacyclin (prostaglandin i2) is commonly considered the most effective treatment for pah. epoprostenol (synthetic prostacyclin) is given via continuous infusion that requires a semi-permanent central venous catheter. this delivery system can cause sepsis and thrombosis. prostacyclin is unstable, and therefore has to be kept on ice during administration. since it has a half-life of 3 to 5 minutes, the infusion has to be continuous, and interruption can be fatal. other prostanoids have therefore been developed. treprostinil can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. an increased risk of sepsis with intravenous remodulin has been reported by the cdc. iloprost is also used in europe intravenously and has a longer half life. iloprost was the only inhaled form of prostacyclin approved for use in the us and europe, until the inhaled form of treprostinil was approved by the fda in july 2009. endothelin receptor antagonists moderate quality evidence suggests that endothelin receptor antagonists improve exercise capacity and decrease symptoms severity. the dual (eta and etb) endothelin receptor antagonist bosentan was approved in 2001. sitaxentan (thelin) was approved for use in canada, australia, and the european union, but not in the united states. in 2010, pfizer withdrew thelin worldwide because of fatal liver complications. a similar drug, ambrisentan is marketed as letairis in the u.s. by gilead sciences. s phosphodiesterase type 5 inhibitors the u.s. fda approved sildenafil, a selective inhibitor of cgmp specific phosphodiesterase type 5 (pde5), for the treatment of pah in 2005. it is marketed for pah as revatio. in 2009, they also approved tadalafil, another pde5 inhibitor, marketed under the name adcirca. pde5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). the t1/2 (biological half-life) hovers around 17.5 hours in healthy subjects. moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy. however, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia. activators of soluble guanylate cyclase soluble guanylate cyclase (sgc) is the intracellular receptor for no. as of april 2009, the sgc activators cinaciguat and riociguat were undergoing clinical trials for the treatment of pah. surgical atrial septostomy is a surgical procedure that creates a communication between the right and left atria. it relieves pressure on the right side of the heart, but at the cost of lower