Pulmonary hypertension

Pulmonary hypertension
Synonyms Pulmonary arterial hypertension,[1] Ayerza syndrome[2]
Micrograph showing arteries in pulmonary hypertensive with marked thickening of the walls.
Specialty Pulmonology, cardiology
Usual onset 20 to 60 years old[3]
Duration Long term[1]
Causes Unknown[1]
Risk factors Family history, pulmonary embolism, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes[4][3]
Diagnostic method Following ruling out other potential causes[1]
Treatment Supportive care, medications, lung transplant[1][5]
Medication Epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafil[1]
Frequency 1,000 new cases a year (US)[2]

Pulmonary hypertension (PH or PHTN) is an increase of blood pressure in the arteries of the lungs.[6] Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and a fast heartbeat.[6][2] The condition may make it difficult to exercise.[6] Onset is typically gradual.[7]

The cause is often unknown.[1] Risk factors include a family history, prior blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes, and problems with the mitral valve.[4][3] The underlying mechanism typically involves inflammation of the arteries in the lungs.[4] Diagnosis involves first ruling out other potential causes.[1]

There is no cure.[6] Treatment depends on the type of disease.[5] A number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit clotting may be used.[1] Medications specifically for the condition include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil.[1] A lung transplant maybe an option in certain cases.[5]

While the exact frequency of the condition is unknown, it is estimated that about 1,000 new cases occur a year in the United States.[3][2] Females are more often affected than males.[2] Onset is typically between 20 and 60 years of age.[3] It was first identified by Ernst von Romberg in 1891.[8][1]

Signs and symptoms

The symptoms of pulmonary hypertension include the following:[9][10][11]

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting.[10] 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.[12] 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.[13]

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 atrium. Signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux.[10][11][14] Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.[10][11][15]

Causes

In terms of causes and classification,[16] a 1973 meeting organized by the World Health Organization was the first to attempt classification of pulmonary hypertension. A distinction was made between primary and secondary PH, and primary PH was divided in the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms.[17] A second conference in 1998 at Évian-les-Bains also addressed the causes of secondary PH (i.e. those due to other medical conditions),[18] and the classification was refined further at the third,[19] fourth,[20] and fifth [21] World Symposia on PAH based on new understandings of disease mechanisms. The revised system developed at the fifth World Symposium on PAH in Nice was adapted further in subsequent European guidelines for the diagnosis and treatment of pulmonary hypertension, and provides the current framework for understanding pulmonary hypertension.[21][22]

Classification

It can be one of seven different types.[23][21] The Nice 2013 Updated Clinical Classification system (with adaptations from the more recent European guidelines shown in italics) can be summarized as follows:[21][22]

Pathogenesis

Right ventricle (on left side)

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, much as it is 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).[24][25] Over time, vascular remodeling causes the affected blood vessels to become progressively stiffer and thicker. 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.[26][27] 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.[26][25][27] 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 pump to supply sufficient oxygen to the rest of the body, especially during physical activity.[28][29][30]

In PVOD (WHO Group 1'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels.[31] 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.[26]

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.[32] 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).[22][33][34]

In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group 3), 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.[30][35][36][37]

In CTEPH (WHO Group 4), 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.[38][39]

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.[40] 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.[41]

Nitric oxide-soluble guanylate cyclase pathway

In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in presence of oxygen.[42]

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).[43] 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.[44] Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.[45]

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.[46][47]

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, 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.[48][49]

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.[50][51] The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane.[50] fac

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.[50][52] 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.[50][52] 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.[26][50] 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.[50] 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.[53]

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

In terms of the diagnosis of pulmonary hypertension, which can be of several types, a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or miscellaneous varieties. Further procedures are required to confirm the presence of pulmonary hypertension and exclude other possible diagnoses. These generally include pulmonary function tests; blood tests to exclude HIV, autoimmune diseases, and liver disease; electrocardiography (ECG); arterial blood gas measurements; X-rays of the chest (followed by high-resolution CT scanning if interstitial lung disease is suspected); and ventilation-perfusion or V/Q scanning to exclude chronic thromboembolic pulmonary hypertension.[54][55] Clinical improvement is often measured by a "six-minute walk test", i.e. the distance a patient can walk in six minutes. Stability and improvement in this measurement correlate with better survival.[56]

Diagnosis of PAH requires the presence of pulmonary hypertension. Although pulmonary arterial pressure can be estimated on the basis of echocardiography,[57] pressure measurements with a Swan-Ganz catheter through the right side of the heart provide the most definite assessment.[58] Diagnosis of PAH requires right-sided cardiac catheterization; a Swan-Ganz catheter can also measure the cardiac output, which is far more important in measuring disease severity than the pulmonary arterial pressure.[58] Normal pulmonary arterial pressure in a person living at sea level has a mean value of 8–20 mm Hg (1066–2666 Pa) at rest. Pulmonary hypertension is present when mean pulmonary artery pressure exceeds 25 mm Hg (3300 Pa) at rest.[59]

Physical examination

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

A physical examination is performed to look for typical signs of pulmonary hypertension (described above),[55] and a detailed family history is established to determine whether the disease might be heritable.[60][61][62] 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.[11][63][64] 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.[64]

Echocardiography

A meta-analysis of doppler echocardiography for predicting right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively.[65]

Treatment

Treatment of pulmonary hypertension is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. The treatment is to optimize left ventricular function by the use of diuretics, digoxins, blood thinners, or to repair/replace the mitral valve or aortic valve.[68] 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 pulmonary arterial hypertension.[69] 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.[69] Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.[69]

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.[15] 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.[70] Of these, only half of the patients are responsive to calcium channel blockers in the long term.[71]

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.[72]

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.[73]

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.[74] 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

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,[75] 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.[76]

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.[77] PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.[78]

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.[79] Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy.[80] However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.[81]

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.[82]

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 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.[83]

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.[84]

Monitoring

Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,[69][85] patients are normally monitored through commonly available tests such as:

Prognosis

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).[86] A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% patients were alive at 2 years.[87] 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%.[88] 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.[89][90][91]

Epidemiology

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).[92]

Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients;[93] in rheumatoid arthritis it is rare.[94] However, in systemic lupus erythematosus it is 4 to 14%,[95] and in sickle cell disease, it ranges from 20 to 40%.[96] Up to 4% of people who suffer a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension.[97] A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure.[98] On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension.[99]

Notable cases

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Pulmonary Arterial Hypertension - NORD (National Organization for Rare Disorders)". NORD. 2015. Retrieved 30 July 2017.
  2. 1 2 3 4 5 "Pulmonary arterial hypertension". Genetics Home Reference. January 2016. Retrieved 30 July 2017.
  3. 1 2 3 4 5 "Who Is at Risk for Pulmonary Hypertension? - NHLBI, NIH". NHLBI. 2 August 2011. Retrieved 30 July 2017.
  4. 1 2 3 "What Causes Pulmonary Hypertension? - NHLBI, NIH". NHLBI. 2 August 2011. Retrieved 30 July 2017.
  5. 1 2 3 "How Is Pulmonary Hypertension Treated? - NHLBI, NIH". NHLBI. 2 August 2011. Retrieved 30 July 2017.
  6. 1 2 3 4 "What Is Pulmonary Hypertension? - NHLBI, NIH". NHLBI. 2 August 2011. Retrieved 30 July 2017.
  7. ↑ "How Is Pulmonary Hypertension Diagnosed? - NHLBI, NIH". NHLBI. 2 August 2011. Retrieved 30 July 2017.
  8. ↑ von Romberg, Ernst (1891–1892). "Über Sklerose der Lungenarterie". Dtsch Arch Klin Med (in German). 48: 197–206.
  9. ↑ "What Are the Signs and Symptoms of Pulmonary Hypertension? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2015-12-30.
  10. 1 2 3 4 Galie N, Humbert M, Vachiery JL, et al. (1 January 2016). "2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)". European Heart Journal. 37 (1): 67–119. ISSN 1522-9645. PMID 26320113. doi:10.1093/eurheartj/ehv317.
  11. 1 2 3 4 McLaughlin VV, Archer SL, Badesch DB, et al. (28 April 2009). "ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association". Journal of the American College of Cardiology. 53 (17): 1573–1619. ISSN 1558-3597. PMID 19389575. doi:10.1016/j.jacc.2009.01.004.
  12. ↑ Diller, Gerhard-Paul; Gatzoulis, Michael A. (27 February 2007). "Pulmonary vascular disease in adults with congenital heart disease". Circulation. 115 (8): 1039–1050. ISSN 1524-4539. PMID 17325254. doi:10.1161/CIRCULATIONAHA.105.592386.
  13. ↑ Fang JC, DeMarco T, Givertz MM, et al. (1 September 2012). "World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation". The Journal of Heart and Lung Transplantation: The Official Publication of the International Society for Heart Transplantation. 31 (9): 913–933. ISSN 1557-3117. PMID 22884380. doi:10.1016/j.healun.2012.06.002.
  14. ↑ Yusuf, Salim; Cairns, John; Camm, John; Fallen, Ernest L.; Gersh, Bernard J. (2011-09-07). Evidence-Based Cardiology. John Wiley & Sons. p. 70.3(figure). ISBN 9781444359459.
  15. 1 2 "Primary Pulmonary Hypertension Clinical Presentation: History, Physical Examination, Complications". emedicine.medscape.com. Retrieved 2015-12-30.
  16. ↑ "National Guideline Clearinghouse | ACR Appropriateness Criteria® pulmonary hypertension.". www.guideline.gov. Retrieved 2015-12-31.
  17. ↑ Hatano S, Strasser R (1975). Primary pulmonary hypertension. Geneva: World Health Organization.
  18. ↑ Rich S, Rubin LJ, Abenhail L, et al. (1998). Executive summary from the World Symposium on Primary Pulmonary Hypertension (Evian, France, September 6–10, 1998). Geneva: The World Health Organization. Archived from the original on April 8, 2002.
  19. ↑ Simonneau G, Galie N, Rubin LJ, et al. (2004). Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 43 (12 Suppl S): 5S-12S. doi: 10.1016/j.jacc.2004.02.037
  20. ↑ Simonneau G, Robbins IM, Beghetti M, et al. (2009). Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 54 (1 Suppl): S43-54. doi: 10.1016/j.jacc.2009.04.012. Address to be added as hyperlink from title if possible
  21. 1 2 3 4 Simonneau G, Gatzoulis MA, Adatia I, et al. (2013). Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 62 (25 Suppl): D34-41. doi: 10.1016/j.jacc.2013.10.029
  22. 1 2 3 Galie N, Humbert M, Vachiery JL, et al. (2015). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. doi: 10.1093/eurheartj/ehv317
  23. ↑ Simonneau G, Robbins I, Beghetti M, et al. (30 June 2009). "Updated Clinical classification of pulmonary hypertension". J. Am. Coll. Cardiol. 54 (1 Suppl S): S43–S54. PMID 19555858. doi:10.1016/j.jacc.2009.04.012.
  24. ↑ Tuder RM, Archer SL, Dorfmuller P, et al. (2013). Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 62 (25 Suppl): D4-12. doi: 10.1016/j.jacc.2013.10.025. PMID 3970402.
  25. 1 2 Vonk-Noordegraaf A, Haddad F, Chin KM, et al. (2013). Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 62 (25 Suppl): D22-33. doi: 10.1016/j.jacc.2013.10.027
  26. 1 2 3 4 McLaughlin VV, Archer SL, Badesch DB, et al. (2009). ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 53 (17): 1573-619. doi: 10.1016/j.jacc.2009.01.004
  27. 1 2 Galie N, Hoeper MM, Humbert M, et al. (2009). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 34 (6): 1219-63. doi: 10.1183/09031936.00139009
  28. ↑ Yuan, Jason X.-J.; Rubin, Lewis J. (2005-02-08). "Pathogenesis of Pulmonary Arterial Hypertension The Need for Multiple Hits". Circulation. 111 (5): 534–538. ISSN 0009-7322. PMID 15699271. doi:10.1161/01.CIR.0000156326.48823.55.
  29. ↑ Tuder, Rubin M.; Marecki, John C.; Richter, Amy; Fijalkowska, Iwona; Flores, Sonia (2007-03-01). "Pathology of Pulmonary Hypertension". Clinics in chest medicine. 28 (1): 23–vii. ISSN 0272-5231. PMC 1924722 Freely accessible. PMID 17338926. doi:10.1016/j.ccm.2006.11.010.
  30. 1 2 Simonneau G, Robbins IM, Beghetti M, et al. (2009). Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 54 (1 Suppl): S43-54. doi: 10.1016/j.jacc.2009.04.012
  31. ↑ Montani D, Price LC, Dorfmuller P, et al. (2009). Pulmonary veno-occlusive disease. Eur Respir J. 33 (1): 189-200. doi: 10.1183/09031936.00090608
  32. ↑ Guazzi, Marco; Galiè, Nazzareno (2012-12-01). "Pulmonary hypertension in left heart disease". European Respiratory Review. 21 (126): 338–346. ISSN 0905-9180. PMID 23204122. doi:10.1183/09059180.00004612.
  33. ↑ Fang JC, DeMarco T, Givertz MM, et al. (2012). World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 31 (9): 913-33. doi: 10.1016/j.healun.2012.06.002
  34. ↑ Vachiery JL, Adir Y, Barbera JA, et al. (2013). Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 62 (25 Suppl): D100-8. doi: 10.1016/j.jacc.2013.10.033
  35. ↑ Ward JP, McMurtry IF (2009). Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem. Curr Opin Pharmacol. 9 (3): 287-96. doi: 10.1016/j.coph.2009.02.006. PMID 2692823
  36. ↑ Sommer, N.; Dietrich, A.; Schermuly, R. T.; Ghofrani, H. A.; Gudermann, T.; Schulz, R.; Seeger, W.; Grimminger, F.; Weissmann, N. (2008-12-01). "Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms". European Respiratory Journal. 32 (6): 1639–1651. ISSN 0903-1936. PMID 19043010. doi:10.1183/09031936.00013908.
  37. ↑ Stenmark, Kurt R.; Fagan, Karen A.; Frid, Maria G. (2006-09-29). "Hypoxia-Induced Pulmonary Vascular Remodeling Cellular and Molecular Mechanisms". Circulation Research. 99 (7): 675–691. ISSN 0009-7330. PMID 17008597. doi:10.1161/01.RES.0000243584.45145.3f.
  38. ↑ McNeil, Keith; Dunning, John (2007-09-01). "Chronic thromboembolic pulmonary hypertension (CTEPH)". Heart. 93 (9): 1152–1158. ISSN 1355-6037. PMC 1955041 Freely accessible. PMID 17699182. doi:10.1136/hrt.2004.053603.
  39. ↑ Hoeper MM, Mayer E, Simonneau G, Rubin LJ (2006). Chronic thromboembolic pulmonary hypertension. Circulation. 113 (16): 2011-20. doi: 10.1161/CIRCULATIONAHA.105.602565
  40. ↑ Budhiraja, Rohit; Tuder, Rubin M.; Hassoun, Paul M. (2004-01-20). "Endothelial Dysfunction in Pulmonary Hypertension". Circulation. 109 (2): 159–165. ISSN 0009-7322. PMID 14734504. doi:10.1161/01.CIR.0000102381.57477.50.
  41. ↑ Budhiraja R, Tuder RM, Hassoun. PM. Endothelial dysfunction in pulmonary hypertension. Circulation. 2004;109:159–165.
  42. ↑ Förstermann, Ulrich; Münzel, Thomas (2006-04-04). "Endothelial Nitric Oxide Synthase in Vascular Disease From Marvel to Menace". Circulation. 113 (13): 1708–1714. ISSN 0009-7322. PMID 16585403. doi:10.1161/CIRCULATIONAHA.105.602532.
  43. ↑ Murad F (2006). Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med. 355 (19): 2003-11. doi: 10.1056/NEJMsa063904
  44. ↑ Francis SH, Busch JL, Corbin JD, Sibley D (2010). cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 62 (3): 525-63. doi: 10.1124/pr.110.002907. PMID 2964902
  45. ↑ Stasch JP, Pacher P, Evgenov OV (2011). Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 123 (20): 2263-73. doi: 10.1161/CIRCULATIONAHA.110.981738. PMID 3103045
  46. ↑ Ghofrani HA, Pepke-Zaba J, Barbera JA, et al. (2004). Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol. 43 (12 Suppl S): 68S-72S. doi: 10.1016/j.jacc.2004.02.031
  47. ↑ Francis SH, Busch JL, Corbin JD, Sibley D (2010). cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 62 (3): 525-63. doi: 10.1124/pr.110.002907. PMID 296490
  48. ↑ McLaughlin VV, McGoon MD (2006). Pulmonary arterial hypertension. Circulation. 114 (13): 1417-31. doi: 10.1161/CIRCULATIONAHA.104.503540
  49. ↑ Fonseca C, Abraham D, Renzoni EA (2011). Endothelin in pulmonary fibrosis. Am J Respir Cell Mol Biol. 44 (1): 1-10. doi: 10.1165/rcmb.2009-0388TR
  50. 1 2 3 4 5 6 Archer SL, Weir EK, Wilkins MR (2010). Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 121 (18): 2045-66. doi: 10.1161/CIRCULATIONAHA.108.847707. PMID 2869481
  51. ↑ Gomberg-Maitland M, Olschewski H (2008). Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J. 31 (4): 891-901. doi: 10.1183/09031936.00097107
  52. 1 2 Gomberg-Maitland M, Bull TM, Saggar R, et al. (2013). New trial designs and potential therapies for pulmonary artery hypertension. J Am Coll Cardiol. 62 (25 Suppl): D82-91. doi: 10.1016/j.jacc.2013.10.026. PMID 4117578
  53. ↑ onk-Noordegraaf A, Haddad F, Chin KM, et al. (2013). Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 62 (25 Suppl): D22-33. doi: 10.1016/j.jacc.2013.10.027
  54. ↑ Members, Authors/Task Force; Galiè, Nazzareno; Hoeper, Marius M.; Humbert, Marc; Torbicki, Adam; Vachiery, Jean-Luc; Barbera, Joan Albert; Beghetti, Maurice; Corris, Paul (2009-10-01). "Guidelines for the diagnosis and treatment of pulmonary hypertension". European Heart Journal. 30 (20): 2493–2537. ISSN 0195-668X. PMID 19713419. doi:10.1093/eurheartj/ehp297.
  55. 1 2 "How Is Pulmonary Hypertension Diagnosed? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2015-12-30.
  56. ↑ "Guidelines:Six-minute Walk Test" (PDF). American Thoracic Society. 2002. Retrieved 31 December 2015.
  57. ↑ Bossone, Eduardo (2011). "Echocardiography in Pulmonary Arterial Hypertension:From Diagnosis to Prognosis" (PDF). Journal of the American Society of Cardiology. Retrieved 31 December 2015.
  58. 1 2 "Swan-Ganz - right heart catheterization: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov. Retrieved 2015-12-30.
  59. ↑ Badesch, DB; Champion, HC; Sanchez, MA; Hoeper, MM; Loyd, JE; Manes, A; McGoon, M; Naeije, R; Olschewski, H; Oudiz, RJ; Torbicki, A (Jun 30, 2009). "Diagnosis and assessment of pulmonary arterial hypertension.". Journal of the American College of Cardiology. 54 (1 Suppl): S55–66. PMID 19555859. doi:10.1016/j.jacc.2009.04.011.
  60. ↑ "Pulmonary arterial hypertension". Genetics Home Reference. 2015-12-28. Retrieved 2015-12-30.
  61. ↑ 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.|Online 2015
  62. ↑ Hoeper MM, Bogaard HJ, Condliffe R, et al. (24 December 2013). "Definitions and diagnosis of pulmonary hypertension". Journal of the American College of Cardiology. 62 (25 Suppl): D42–50. ISSN 1558-3597. PMID 24355641. doi:10.1016/j.jacc.2013.10.032.
  63. ↑ Klepper, Michael J.; Cobert, Barton (2010-10-25). Drug Safety Data: How to Analyze, Summarize and Interpret to Determine Risk. Jones & Bartlett Learning. p. 86. ISBN 9780763769123.
  64. 1 2 Simonneau G, Gatzoulis MA, Adatia I, et al. (24 December 2013). "Updated clinical classification of pulmonary hypertension". Journal of the American College of Cardiology. 62 (25 Suppl): D34–41. ISSN 1558-3597. PMID 24355639. doi:10.1016/j.jacc.2013.10.029.
  65. ↑ Taleb M, Khuder S, Tinkel J, Khouri SJ (2013). "The diagnostic accuracy of Doppler echocardiography in assessment of pulmonary artery systolic pressure: a meta-analysis.". Echocardiography. 30 (3): 258–65. PMID 23227919. doi:10.1111/echo.12061.
  66. 1 2 3 4 "UOTW #29 - Ultrasound of the Week". Ultrasound of the Week. 16 December 2014. Retrieved 27 May 2017.
  67. ↑ "UOTW #65 - Ultrasound of the Week". Ultrasound of the Week. 20 December 2015. Retrieved 27 May 2017.
  68. ↑ "How Is Pulmonary Hypertension Treated? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2015-12-30.
  69. 1 2 3 4 American College of Chest Physicians; American Thoracic Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American College of Chest Physicians and American Thoracic Society, retrieved 6 January 2013, which cites
    • McLaughlin, V. V.; Archer, S. L.; Badesch, D. B.; Barst, R. J.; Farber, H. W.; Lindner, J. R.; Mathier, M. A.; McGoon, M. D.; Park, M. H.; Rosenson, R. S.; Rubin, L. J.; Tapson, V. F.; Varga, J.; Harrington, R. A.; Anderson, J. L.; Bates, E. R.; Bridges, C. R.; Eisenberg, M. J.; Ferrari, V. A.; Grines, C. L.; Hlatky, M. A.; Jacobs, A. K.; Kaul, S.; Lichtenberg, R. C.; Lindner, J. R.; Moliterno, D. J.; Mukherjee, D.; Pohost, G. M.; Rosenson, R. S.; Schofield, R. S. (2009). "ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association". Circulation. 119 (16): 2250–2294. PMID 19332472. doi:10.1161/CIRCULATIONAHA.109.192230.*Galie, N.; Hoeper, M. M.; Humbert, M.; Torbicki, A.; Vachiery, J. -L.; Barbera, J. A.; Beghetti, M.; Corris, P.; Gaine, S.; Gibbs, J. S.; Gomez-Sanchez, M. A.; Jondeau, G.; Klepetko, W.; Opitz, C.; Peacock, A.; Rubin, L.; Zellweger, M.; Simonneau, G.; Vahanian, A.; Auricchio, A.; Bax, J.; Ceconi, C.; Dean, V.; Filippatos, G.; Funck-Brentano, C.; Hobbs, R.; Kearney, P.; McDonagh, T.; McGregor, K.; Popescu, B. A.; et al. (2009). "Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)". European Heart Journal. 30 (20): 2493–2537. PMID 19713419. doi:10.1093/eurheartj/ehp297.*Hoeper, M. M.; Barberà, J. A.; Channick, R. N.; Hassoun, P. M.; Lang, I. M.; Manes, A.; Martinez, F. J.; Naeije, R.; Olschewski, H.; Pepke-Zaba, J.; Redfield, M. M.; Robbins, I. M.; Souza, R. R.; Torbicki, A.; McGoon, M. (2009). "Diagnosis, Assessment, and Treatment of Non-Pulmonary Arterial Hypertension Pulmonary Hypertension". Journal of the American College of Cardiology. 54 (1 Suppl): S85–S96. PMID 19555862. doi:10.1016/j.jacc.2009.04.008.
  70. ↑ Barst RJ, McGoon M, Torbicki A, et al. (June 2004). "Diagnosis and differential assessment of pulmonary arterial hypertension". J. Am. Coll. Cardiol. 43 (12 Suppl S): 40S–47S. PMID 15194177. doi:10.1016/j.jacc.2004.02.032.
  71. ↑ Sitbon O, Humbert M, Jaïs X, et al. (June 2005). "Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension". Circulation. 111 (23): 3105–11. PMID 15939821. doi:10.1161/CIRCULATIONAHA.104.488486.
  72. ↑ Torres F (2007). "Systematic review of randomised, double-blind clinical trials of oral agents conducted in patients with pulmonary arterial hypertension". Int. J. Clin. Pract. 61 (10): 1756–65. PMID 17877662. doi:10.1111/j.1742-1241.2007.01545.x.
  73. ↑ Raja, Shahzad G.; Raja, Shahbaz M. (2011-11-01). "Treating pulmonary arterial hypertension: current treatments and future prospects". Therapeutic Advances in Chronic Disease. 2 (6): 359–370. ISSN 2040-6223. PMC 3513893 Freely accessible. PMID 23251761. doi:10.1177/2040622311420773.
  74. ↑ "Treatment of pulmonary arterial hypertension: The role of prostacyclin and prostaglandin analogs - Respiratory Medicine". www.resmedjournal.com. Retrieved 2015-12-30.
  75. ↑ "UPDATE 1-Encysive gets Canadian approval for hypertension drug". Reuters. 2008-05-30. Retrieved 2007-07-08.
  76. ↑ "U.S. Food and Drug Administration Approves Gilead's Letairis Treatment of Pulmonary Arterial Hypertension" (Press release). Gilead Sciences. 2007-06-15. Retrieved 2007-06-16.
  77. ↑ "FDA approves Adcirca (tadalafil) tablets for pulmonary arterial hypertension" (Press release). 2009-05-26. Retrieved 2010-12-06.
  78. ↑ Duarte, Julio D; Hanson, Rebekah L; Machado, Roberto F (2013-05-01). "Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics". Future cardiology. 9 (3): 335–349. ISSN 1479-6678. PMC 3864092 Freely accessible. PMID 23668740. doi:10.2217/fca.13.6.
  79. ↑ Forgue ST, Patterson BE, Bedding AW, et al. (2005). "Tadalafil pharmacokinetics in healthy subjects". Br J Clin Pharmacol. 61: 280–288. doi:10.1111/j.1365-2125.2005.02553.x.
  80. ↑ Sally A. Arif, PharmD, BCPS (Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, Illinois, and Department of Pharmacy, Rush University Medical Center, Chicago, Illinois); and Henry Poon, PharmD, BCPS (Department of Pharmacy, James J. Peters VA Medical Center, Bronx, New York). Tadalafil: A Long-Acting Phosphodiesterase-5 Inhibitor for the Treatment of Pulmonary Arterial Hypertension. 2011;33:993–1004
  81. ↑ Galié N, Brundage BH, Ghofrani HA, et al. (2009). "Tadalafil therapy for pulmonary arterial hypertension". Circulation. 119: 2894–2903. doi:10.1161/circulationaha.108.839274.
  82. ↑ Lasker, George F; Maley, Jason H; Pankey, Edward A; Kadowitz, Philip J (2011-04-01). "Targeting soluble guanylate cyclase for the treatment of pulmonary hypertension". Expert review of respiratory medicine. 5 (2): 153–161. ISSN 1747-6348. PMC 3108035 Freely accessible. PMID 21510726. doi:10.1586/ers.11.9.
  83. ↑ "2006 OPTN/SRTR Annual Report". US Scientific Registry of Transplant Recipients. 2006-05-01. Retrieved 2007-03-28.
  84. ↑ Cerveri, I; D’Armini, A M; Viganò, M (2003-04-01). "Pulmonary thromboendarterectomy almost 50 years after the first surgical attempts". Heart. 89 (4): 369–370. ISSN 1355-6037. PMC 1769265 Freely accessible. PMID 12639858. doi:10.1136/heart.89.4.369.
  85. ↑ American College of Chest Physicians; American Thoracic Society (September 2013), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, American College of Chest Physicians and American Thoracic Society, retrieved 6 January 2013
  86. ↑ "Pulmonary Hypertension. About Pulmonary Hypertension | Patient". Patient. Retrieved 2015-12-30.
  87. ↑ McLaughlin VV, Sitbon O, Badesch DB, et al. (2005). "Survival with first-line bosentan in patients with primary pulmonary hypertension". Eur. Respir. J. 25 (2): 244–9. PMID 15684287. doi:10.1183/09031936.05.00054804.
  88. ↑ Benza RL; Miller DP; Barst RJ; Badesch DB; Frost AE; McGoon MD. (August 2012). "An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.". Chest. 142 (2): 448–56. PMID 22281797. doi:10.1378/chest.11-1460. [FREE]
  89. ↑ Kaufman, Matthew H.; Latha Stead; Feig, Robert (2007). First aid for the obstetrics & gynecology clerkship. New York: McGraw-Hill, Medical Pub. Division. p. 100. ISBN 0-07-144874-8.
  90. ↑ Ghosh, Amit K. (2008). Mayo Clinic Internal Medicine Review: Eighth Edition (Mayo Clinic Internal Medicine Review). Informa Healthcare. p. 55. ISBN 1-4200-8478-X.
  91. ↑ British Journal of Anaesthesia: "Primary pulmonary hypertension in pregnancy; a role for novel vasodilators" March 19, 2011
  92. ↑ "Primary Pulmonary Hypertension: Practice Essentials, Background, Pathophysiology".
  93. ↑ York, Michael; Farber, Harrison W. (November 2011). "Pulmonary Hypertension: Screening and Evaluation in Scleroderma". Current Opinion in Rheumatology. 23 (6): 536–544. doi:10.1097/BOR.0b013e32834ba6a7. Retrieved 8 January 2016.
  94. ↑ Nannini, Carlotta. "Lung Disease in Rheumatoid Arthritis". MedScape.com. MedScape. Retrieved 31 December 2015.
  95. ↑ Mittoo, Shikha. "Pulmonary Manifestations of Systemic Lupus Erythematosus". MedScape.com. MedScape. Retrieved 31 December 2015.
  96. ↑ Lee, M (2007). "Pulmonary Hypertension in Sickle Cell Disease" (PDF). Clinical Advances in Hematology & Oncology. Retrieved 31 December 2015.
  97. ↑ Hoeper, Marius M.; Mayer, Eckhard; Simonneau, Gérald; Rubin, Lewis J. (2006-04-25). "Chronic Thromboembolic Pulmonary Hypertension". Circulation. 113 (16): 2011–2020. ISSN 0009-7322. PMID 16636189. doi:10.1161/CIRCULATIONAHA.105.602565.
  98. ↑ Minai, Omar A.; Chaouat, Ari; Adnot, Serge (2010-06-01). "Pulmonary hypertension in copd: Epidemiology, significance, and management: pulmonary vascular disease: the global perspective". Chest. 137 (6_suppl): 39S–51S. ISSN 0012-3692. PMID 20522579. doi:10.1378/chest.10-0087.
  99. ↑ Balachandran, Jay S.; Masa, Juan Fernando; Mokhlesi, Babak (2014-09-01). "Obesity Hypoventilation Syndrome Epidemiology and Diagnosis". Sleep medicine clinics. 9 (3): 341–347. ISSN 1556-407X. PMC 4210766 Freely accessible. PMID 25360072. doi:10.1016/j.jsmc.2014.05.007.
  100. ↑ "Elaine Kaufman, famed Elaine's restaurateur, dies at age 81". Daily News. Retrieved 27 September 2016.
  101. ↑ "Why I Only Have One Kid, If You Insist on Asking". Yahoo News. Retrieved 27 September 2016.
  102. ↑ FOLKART, BURT A. (21 June 1990). "Ina Balin, 52; Movie and TV Actress Sought Lung Implant". Los Angeles Times. Retrieved 27 September 2016.
  103. ↑ Phull, Hardeep (July 26, 2016). "She’s tethered to an oxygen tank, but her singing career is soaring". New York Post.
  104. ↑ Insdorf, Annette (November 10, 2013). "The Challenges of Chloe Temtchine". The Huffington Post.
  105. ↑ "Autopsy: The Last Hours of Natalie Cole." Autopsy. Nar. Eric Meyers. Exec. Prod. Ed Taylor and Michael Kelpie. Reelz, 27 May 2017. Television.

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