pulmonary hypertension pulmonary hypertension pulmonary hypertension (ph or phtn) is a condition of increased blood pressure in the arteries of the lungs. symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. the condition may make it difficult to exercise. onset is typically gradual. pulmonary hypertensionother namespulmonary arterial hypertension, ayerza syndromepulmonary hypertensionspecialtypulmonology, cardiologysymptomschest pain, fatigueusual onset20 to 60 years olddurationlong termcausesunknownrisk factorsfamily history, pulmonary embolism, hiv/aids, sickle cell disease, cocaine use, copd, sleep apnea, living at high altitudesdiagnostic methodfollowing ruling out other potential causestreatmentsupportive care, various medications, lung transplantationmedicationepoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafilfrequency1,000 new cases a year (us) according to the latest definition at the 6th world symposium of pulmonary hypertension, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmhg at rest, and pulmonary vascular resistance pvr >3 wood units. this was revised down from 25mmhg to improve sensitivity. furthermore, the initial cutoff of 25mmhg was purely arbitrary. the cause is often unknown. risk factors include a family history, prior pulmonary embolism (blood clots in the lungs), hiv/aids, sickle cell disease, cocaine use, chronic obstructive pulmonary disease, sleep apnea, living at high altitudes, and problems with the mitral valve. the underlying mechanism typically involves inflammation and subsequent remodeling of the arteries in the lungs. diagnosis involves first ruling out other potential causes. there is currently no cure for pulmonary hypertension, although research on a cure is ongoing. treatment depends on the type of disease. a number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit blood clotting may be used. medications specifically used to treat pulmonary hypertension include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil. lung transplantation may be an option in severe cases. the frequency of occurrence is estimated at 1,000 new cases per year in the united states. females are more often affected than males. onset is typically between 20 and 60 years of age. pulmonary hypertension was identified by ernst von romberg in 1891. classification according to who classification there are 5 groups of ph, where group i (pulmonary arterial hypertension) is further subdivided into group i' and group i'' classes. the most recent who classification system (with adaptations from the more recent esc/ers guidelines shown in italics) can be summarized as follows: who group i – pulmonary arterial hypertension (pah) idiopathic heritable (bmpr2, alk1, smad9, caveolin 1, kcnk3 mutations) drug- and toxin-induced (e.g., methamphetamine, amphetamine, or cocaine use ) associated conditions:connective tissue disease, hiv infection, portal hypertension, congenital heart diseases, schistosomiasis who group i' – pulmonary veno-occlusive disease (pvod), pulmonary capillary hemangiomatosis (pch) idiopathic heritable (eif2ak4 mutations) drugs, toxins and radiation-induced associated conditions:connective tissue disease, hiv infection who group i" – persistent pulmonary hypertension of the newborn who group ii – pulmonary hypertension secondary to left heart disease left ventricular systolic dysfunction left ventricular diastolic dysfunction valvular heart disease congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathy congenital/acquired pulmonary venous stenosis who group iii – pulmonary hypertension due to lung disease, chronic hypoxia chronic obstructive pulmonary disease (copd) interstitial lung disease mixed restrictive and obstructive pattern pulmonary diseases sleep-disordered breathing alveolar hypoventilation disorders chronic exposure to high altitude developmental abnormalities who group iv – chronic arterial obstruction chronic thromboembolic pulmonary hypertension (cteph) other pulmonary artery obstructions angiosarcoma or other tumor within the blood vessels arteritis congenital pulmonary artery stenosis parasitic infection (hydatidosis) who group v – pulmonary hypertension with unclear or multifactorial mechanisms hematologic diseases: chronic hemolytic anemia (including sickle cell disease) systemic diseases: sarcoidosis, pulmonary langerhans cell histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis metabolic disorders: glycogen storage disease, gaucher disease, thyroid diseases others: pulmonary tumoral thrombotic microangiopathy, fibrosing mediastinitis, chronic kidney failure, segmental pulmonary hypertension (pulmonary hypertension restricted to one or more lobes of the lungs) signs and symptoms the symptoms of pulmonary hypertension include the following: shortness of breath fatigue chest pain palpitations (heartbeat rate increased) right-sided abdominal pain poor appetite lightheadedness fainting swelling (legs/ankles) cyanosis less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting. coughing up of blood may occur in some patients, particularly those with specific subtypes of pulmonary hypertension such as heritable pulmonary arterial hypertension, eisenmenger syndrome and chronic thromboembolic pulmonary hypertension. pulmonary venous hypertension typically presents with shortness of breath while lying flat or sleeping (orthopnea or paroxysmal nocturnal dyspnea), while pulmonary arterial hypertension (pah) typically does not. other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular third heart sound, and parasternal heave indicating a hypertrophied right ventricle. signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux. evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension. causes pulmonary hypertension is a pathophysiologic condition with many possible causes. indeed, this condition frequently accompanies severe heart or lung conditions. a 1973 world health organization meeting was the first attempt to classify pulmonary hypertension by its cause, and a distinction was made between primary ph (resulting from a disease of the pulmonary arteries) and secondary ph (resulting secondary to other, non-vascular causes). further, primary ph was divided into the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms. in 1998, a second conference at évian-les-bains addressed the causes of secondary ph. subsequent third, fourth, and fifth (2013) world symposia on pah have further defined the classification of ph. the classification continues to evolve based on improved understanding of the disease mechanisms. most recently in 2015, the who guidelines were updated by the european society of cardiology (esc) and european respiratory society (ers). these guidelines are endorsed by the international society for heart and lung transplantation, and provide the current framework for understanding and treatment of pulmonary hypertension. genetics mutations in several genes have been associated with this condition these include bone morphogenetic protein receptor type 2 (bmpr2) and eukaryotic translation initiation factor 2 alpha kinase 4 gene (eif2ak4). pathogenesis right ventricle (on left side) micrograph showing arteries in pulmonary hypertensive with marked thickening of the walls. the pathogenesis of pulmonary arterial hypertension (who group i) involves the narrowing of blood vessels connected to and within the lungs. this makes it harder for the heart to pump blood through the lungs, as it is much harder to make water flow through a narrow pipe as opposed to a wide one. over time, the affected blood vessels become stiffer and thicker, in a process known as fibrosis. the mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors). this further increases the blood pressure within the lungs and impairs their blood flow. in common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart. the right ventricle is normally part of a low pressure system, with systolic ventricular pressures that are lower than those that the left ventricle normally encounters. as such, the right ventricle cannot cope as well with higher pressures, and although right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. as the blood flowing through the lungs decreases, the left side of the heart receives less blood. this blood may also carry less oxygen than normal. therefore, it becomes harder and harder for the left side of the heart to supply sufficient oxygen to the rest of the body, especially during physical activity. during the end-systolic volume phase of the cardiac cycle, the gaussian curvature and the mean curvature of right ventricular endocardial wall of ph patients was found to be significantly different as compared to controls. in pvod (who group i'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels. pvod shares several characteristics with pah, but there are also some important differences, for example differences in prognosis and response to medical therapy. persistent pulmonary hypertension of the newborn occurs when the circulatory system of a newborn baby fails to adapt to life outside the womb; it is characterized by high resistance to blood flow through the lungs, right-to-left cardiac shunting and severe hypoxemia. pathogenesis in pulmonary hypertension due to left heart disease (who group ii) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. this causes pulmonary edema and pleural effusions. in the absence of pulmonary blood vessel narrowing, the increased back pressure is described as 'isolated post-capillary pulmonary hypertension' (older terms include 'passive' or 'proportionate' pulmonary hypertension or 'pulmonary venous hypertension'). however, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. this is referred to as 'post-capillary pulmonary hypertension with a pre-capillary component' or 'combined post-capillary and pre-capillary pulmonary hypertension' (older terms include 'reactive' or 'out-of-proportion' pulmonary hypertension). in pulmonary hypertension due to lung diseases and/or hypoxia (who group iii), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. this phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response designed to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. when the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension. prolonged hypoxia also induces the transcription factor hif1a, which directly activates downstream growth factor signaling that causes irreversible proliferation and remodeling of pulmonary arterial endothelial cells, leading to chronic pulmonary arterial hypertension. in cteph (who group iv), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. this combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises. molecular pathology three major signaling pathways involved in the pathogenesis of pulmonary arterial hypertension the molecular mechanism of pulmonary arterial hypertension (pah) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin. moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (vegf). these result in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with pah. nitric oxide-soluble guanylate cyclase pathway in normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from l-arginine in the presence of oxygen. this nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cgmp) from guanosine triphosphate (gtp). the cgmp then activates cgmp-dependent kinase or pkg (protein kinase g). activated pkg promotes vasorelaxation (via a reduction of intracellular calcium levels), alters the expression of genes involved in smooth muscle cell contraction, migration and differentiation, and inhibits platelet activation. nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects. phosphodiesterase type 5 (pde5), which is abundant in the pulmonary tissue, hydrolyzes the cyclic bond of cgmp. consequently, the concentration of cgmp (and thus pkg activity) decreases. endothelin endothelin-1 is a peptide (comprising 21 amino acids) that is produced in endothelial cells. it acts on the endothelin receptors eta and etb in various cell types including vascular smooth muscle cells and fibroblasts, leading to vasoconstriction, hypertrophy, proliferation,