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Մասնակից:Անահիտ Հովսեփի Գևորգյան/Ավազարկղ

Վիքիպեդիայից՝ ազատ հանրագիտարանից



Molecular pathology[խմբագրել | խմբագրել կոդը]

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.[1] Moreover, there is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These results in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with PAH.[1]

Nitric oxide-soluble guanylate cyclase pathway[խմբագրել | խմբագրել կոդը]

In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in presence of oxygen.[2]

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).[3] 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.[4] Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.[5]

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.[6][7]

Endothelin[խմբագրել | խմբագրել կոդը]

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, 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.[8][9]

Prostacyclin (and thromboxane)[խմբագրել | խմբագրել կոդը]

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.[10][11] The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane.[10]

Other pathways[խմբագրել | խմբագրել կոդը]

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.[10][12] 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.[10][12] 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.[13][10] 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.[10] Other factors underlying the proliferative state of pulmonary vascular smooth muscle cells include OPG[14] and TRAIL[15]. 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.[16]

Diagnosis[խմբագրել | խմբագրել կոդը]

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.[13]

Physical examination[խմբագրել | խմբագրել կոդը]

A physical examination is performed to look for typical signs of pulmonary hypertension (described above),[17] and a detailed family history is established to determine whether the disease might be heritable.[18][19][20] 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.[13][21][22] 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.[22]

Echocardiography[խմբագրել | խմբագրել կոդը]

If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step.[23][13][20] A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively.[24] Thus, Doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catherization (described below) remains the gold standard for diagnosis of PAH.[23][13] Echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension.[23]

  • 4 month old with pulmonary hypertension as seen on ultrasound[25]
  • 4 month old with pulmonary hypertension as seen on ultrasound[25]
  • 4 month old with pulmonary hypertension as seen on ultrasound[25]
  • 4 month old with pulmonary hypertension as seen on ultrasound[25]
    4 month old with pulmonary hypertension as seen on ultrasound[25]
  • Long standing pulmonary hypertension[26]

Exclude other diseases[խմբագրել | խմբագրել կոդը]

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.[23][13][20][27]

Ventilation/perfusion scintigraphy[խմբագրել | խմբագրել կոդը]

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.[23][20]

CT scan[խմբագրել | խմբագրել կոդը]

Pulmonary artery hypertension and emphysema as seen on a CT scan with contrast

Signs of pulmonary hypertension on CT scan of the chest are:

  • 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.[28]
  • Cutoff ~1.09 in children.[28]
  • 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.[28]
  • Mural calcification in central pulmonary arteries is most frequently seen in patients with Eisenmenger's syndrome.[28]

Right heart catheterization[խմբագրել | խմբագրել կոդը]

Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography,[29] pressure measurements with a Swan-Ganz catheter inserted through the right side of the heart provide the most definite assessment.[42] Pulmonary hypertension is defined as a mean PAP of at least 25 mm Hg (3300 Pa) at rest, and PAH is defined as precapillary pulmonary hypertension (i.e. mean PAP ≥ 25 mm Hg with pulmonary arterial occlusion pressure [PAOP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood Units).[20] 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.[23][30] 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.[31]

Other[խմբագրել | խմբագրել կոդը]

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.[23][32][20]

Treatment[խմբագրել | խմբագրել կոդը]

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.[33] 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.[34] 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.[34] Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.[34]

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.[35] 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.[36] Of these, only half of the patients are responsive to calcium channel blockers in the long term.[37]

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 "6 minute walk test". Many have no data on mortality benefit or time to progression.[38]

Vasoactive substances[խմբագրել | խմբագրել կոդը]

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.[39]

Prostaglandins[խմբագրել | խմբագրել կոդը]

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.[40] 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.Կաղապար:Medical citation needed

Endothelin receptor antagonists[խմբագրել | խմբագրել կոդը]

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,[41] 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.[42]

Phosphodiesterase type 5 inhibitors[խմբագրել | խմբագրել կոդը]

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.[43] PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.[44]

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.[45] Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy.[46] However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.[47]

Activators of soluble guanylate cyclase[խմբագրել | խմբագրել կոդը]

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.[48]

Surgical[խմբագրել | խմբագրել կոդը]

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 oxygen levels in blood (hypoxia). Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a post-surgical median survival of just over five years.[49]

Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a very difficult, major procedure that is currently performed in a few select centers.[50]

Monitoring[խմբագրել | խմբագրել կոդը]

Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,[34][51] patients are normally monitored through commonly available tests such as:[փա՞ստ]

* Pulse oximetry

Prognosis[խմբագրել | խմբագրել կոդը]

Cor pulmonale

The prognosis of pulmonary arterial hypertension (WHO Group I) has an untreated median survival of 2–3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale).[53] A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% patients were alive at 2 years.[54] With new therapies, survival rates are increasing. For 2,635 patients enrolled in The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) from March 2006 to December 2009, 1-, 3-, 5-, and 7-year survival rates were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91%, 74%, 65%, and 59%.[55] Levels of mortality are very high in pregnant women with severe pulmonary arterial hypertension (WHO Group I). Pregnancy is sometimes described as contraindicated in these women.[56][57][58]

Epidemiology[խմբագրել | խմբագրել կոդը]

The epidemiology of IPAH is about 125–150 deaths per year in the U.S., and worldwide the incidence is similar to the U.S. at 4 cases per million. However, in parts of Europe (France) indications are 6 cases per million of IPAH. Females have a higher incidence rate than males (2–9:1).[59]

Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients;[60] in rheumatoid arthritis it is rare.[61] However, in systemic lupus erythematosus it is 4 to 14%,[62] and in sickle cell disease, it ranges from 20 to 40%.[63] Up to 4% of people who suffer a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension.[64] A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure.[65] On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension.[66]

Research[խմբագրել | խմբագրել կոդը]

For people that inherited the disease, gene therapy is being studied.[67]

Notable cases[խմբագրել | խմբագրել կոդը]

See also[խմբագրել | խմբագրել կոդը]

References[խմբագրել | խմբագրել կոդը]

  1. ↑ 1,0 1,1 Budhiraja R, Tuder RM, Hassoun PM (January 2004). «Endothelial dysfunction in pulmonary hypertension». Circulation. 109 (2): 159–65. doi:10.1161/01.CIR.0000102381.57477.50. PMID 14734504.
  2. ↑ Förstermann U, Münzel T (April 2006). «Endothelial nitric oxide synthase in vascular disease: from marvel to menace». Circulation. 113 (13): 1708–14. doi:10.1161/CIRCULATIONAHA.105.602532. PMID 16585403.
  3. ↑ Murad F (November 2006). «Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development». The New England Journal of Medicine. 355 (19): 2003–11. doi:10.1056/NEJMsa063904. PMID 17093251.
  4. ↑ Thijs Plokker HW, Ernst SM, Bal ET, van den Berg EC, Mast GE, van der Feltz TA, և այլք: (2010). «Percutaneous transluminal coronary angioplasty in patients with unstable angina pectoris refractory to medical therapy: long-term clinical and angiographic results». Catheterization and Cardiovascular Diagnosis. 14 (1): 15–8. doi:10.1124/pr.110.002907. PMC 2964902. PMID 2964902.
  5. ↑ Zelia OP, Kovalenko FP (2011). «[Comparative efficiency of infecting laboratory animals via intravenous and subcutaneous administration of Schistosoma mansoni cercaria]». Parazitologiia. 20 (6): 461–5. doi:10.1161/CIRCULATIONAHA.110.981738. PMC 3103045. PMID 3103045.
  6. ↑ Ghofrani HA, Pepke-Zaba J, Barbera JA, Channick R, Keogh AM, Gomez-Sanchez MA, և այլք: (June 2004). «Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension». Journal of the American College of Cardiology. 43 (12 Suppl S): 68S–72S. doi:10.1016/j.jacc.2004.02.031. PMID 15194181.
  7. ↑ Macchi RL, Baerecke WE, Beigelis AA, Ribas LM (November 1979). «[Properties and gamma-2 phase in an amalgam with high copper content]». Revista de la Asociacion Odontologica Argentina. 67 (9): 643–6. doi:10.1124/pr.110.002907. PMC 2964902. PMID 296490.
  8. ↑ McLaughlin VV, McGoon MD (September 2006). «Pulmonary arterial hypertension». Circulation. 114 (13): 1417–31. doi:10.1161/CIRCULATIONAHA.104.503540. PMID 17000921.
  9. ↑ Fonseca C, Abraham D, Renzoni EA (January 2011). «Endothelin in pulmonary fibrosis». American Journal of Respiratory Cell and Molecular Biology. 44 (1): 1–10. doi:10.1165/rcmb.2009-0388TR. PMID 20448055.
  10. ↑ 10,0 10,1 10,2 10,3 10,4 10,5 Wood SF (January 1986). «Astemizole and terfenadine compared in hay fever». The Practitioner. 230 (1411): 41–4. doi:10.1161/CIRCULATIONAHA.108.847707. PMID 2869481.
  11. ↑ Gomberg-Maitland M, Olschewski H (April 2008). «Prostacyclin therapies for the treatment of pulmonary arterial hypertension». The European Respiratory Journal. 31 (4): 891–901. doi:10.1183/09031936.00097107. PMID 18378784.
  12. ↑ 12,0 12,1 Lenfant M (2013). «[Dihydrostreptomycin fixation on the ribosomes of E. coli]». Biochimie. 54 (2): 283–5. doi:10.1016/j.jacc.2013.10.026. PMID 4117578.
  13. ↑ 13,0 13,1 13,2 13,3 13,4 13,5 Քաղվածելու սխալ՝ Սխալ <ref> պիտակ՝ «pmid19389575» անվանումով ref-երը տեքստ չեն պարունակում:
  14. ↑ Lawrie, Allan (2014). «The role of the osteoprotegerin/tumor necrosis factor related apoptosis-inducing ligand axis in the pathogenesis of pulmonary arterial hypertension». Vascular Pharmacology. 63 (3): 114–117. doi:10.1016/j.vph.2014.10.002. ISSN 1537-1891. PMID 25446166.
  15. ↑ Braithwaite, Adam T.; Marriott, Helen M.; Lawrie, Allan (2018). «Divergent Roles for TRAIL in Lung Diseases». Frontiers in Medicine (English). 5: 212. doi:10.3389/fmed.2018.00212. ISSN 2296-858X. PMC 6072839. PMID 30101145.{{cite journal}}: CS1 սպաս․ չճանաչված լեզու (link) CS1 սպաս․ չպիտակված ազատ DOI (link)
  16. ↑ Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, և այլք: (December 2013). «Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology». Journal of the American College of Cardiology. 62 (25 Suppl): D22–33. doi:10.1016/j.jacc.2013.10.027. PMID 24355638.
  17. ↑ «How Is Pulmonary Hypertension Diagnosed? – NHLBI, NIH». www.nhlbi.nih.gov. Արխիվացված է օրիգինալից 2016-01-05-ին. Վերցված է 2015-12-30-ին. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)
  18. ↑ «Pulmonary arterial hypertension». Genetics Home Reference. 2015-12-28. Արխիվացված է օրիգինալից 2015-12-24-ին. Վերցված է 2015-12-30-ին. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)
  19. ↑ Austin, Eric D.; Loyd, James E.; Phillips, John A. (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora JH; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Heritable Pulmonary Arterial Hypertension. Seattle (WA): University of Washington, Seattle. PMID 20301658. Արխիվացված է օրիգինալից 2017-09-10-ին. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)|Online 2015
  20. ↑ 20,0 20,1 20,2 20,3 20,4 20,5 Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, և այլք: (December 2013). «Definitions and diagnosis of pulmonary hypertension». Journal of the American College of Cardiology. 62 (25 Suppl): D42–50. doi:10.1016/j.jacc.2013.10.032. PMID 24355641.
  21. ↑ Klepper, Michael J.; Cobert, Barton (2010-10-25). Drug Safety Data: How to Analyze, Summarize and Interpret to Determine Risk. Jones & Bartlett Learning. էջ 86. ISBN 9780763769123. Արխիվացված է օրիգինալից 2016-05-04-ին. {{cite book}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)
  22. ↑ 22,0 22,1 Քաղվածելու սխալ՝ Սխալ <ref> պիտակ՝ «pmid24355639» անվանումով ref-երը տեքստ չեն պարունակում:
  23. ↑ 23,0 23,1 23,2 23,3 23,4 23,5 23,6 Քաղվածելու սխալ՝ Սխալ <ref> պիտակ՝ «pmid26320113» անվանումով ref-երը տեքստ չեն պարունակում:
  24. ↑ Taleb M, Khuder S, Tinkel J, Khouri SJ (March 2013). «The diagnostic accuracy of Doppler echocardiography in assessment of pulmonary artery systolic pressure: a meta-analysis». Echocardiography. 30 (3): 258–65. doi:10.1111/echo.12061. PMID 23227919.
  25. ↑ 25,0 25,1 25,2 25,3 «UOTW #29 - Ultrasound of the Week». Ultrasound of the Week. 16 December 2014. Արխիվացված է օրիգինալից 9 May 2017-ին. Վերցված է 27 May 2017-ին. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)
  26. ↑ «UOTW #65 - Ultrasound of the Week». Ultrasound of the Week. 20 December 2015. Արխիվացված է օրիգինալից 3 November 2016-ին. Վերցված է 27 May 2017-ին. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (օգնություն)
  27. ↑ «How Is Pulmonary Hypertension Diagnosed?». National Heart, Lung, and Blood Institute.
  28. ↑ 28,0 28,1 28,2 28,3 28,4 28,5 28,6 Frank Gaillard. «Pulmonary hypertension». Radiopaedia. Վերցված է 2018-03-12-ին.
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