Secondary Pulmonary Hypertension
- Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Ryland P Byrd, Jr, MD more...
Pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise, is often characterized by a progressive and sustained increase in pulmonary vascular resistance that eventually may lead to right ventricular (RV) failure. It can be a life-threatening condition if untreated. Treatment success rates vary according to the specific cause.
Cardiac disorders, pulmonary diseases, or both in combination are the most common causes of secondary pulmonary arterial hypertension (SPAH) (see the images below). Cardiac diseases produce PH via volume or pressure overload, though subsequent intimal proliferation of pulmonary resistance vessels adds an obstructive element. Perivascular parenchymal changes, along with pulmonary vasoconstriction, are the mechanisms of PH in respiratory diseases.
Therapy for PH is targeted at the underlying cause and its effects on the cardiovascular system. Novel therapeutic agents, such as prostacyclin and others undergoing clinical trials, have led to the possibility of specific therapies for these once untreatable disorders.
For patient education resources, see the Lung and Airway Center.
Pulmonary hypertension was previously divided into two categories, primary and secondary, depending on whether a specific cause could be identified. In 1998, the World Health Organization (WHO) proposed a clinical classification of pulmonary hypertension into five main groups on the basis of similarities in pathophysiology, clinical presentation, and therapeutic options. This classification was later revised in Venice in 2003 and again in Dana Point in 2008 to further clarify classifications.
Group 1, pulmonary arterial hypertension (PAH), is further divided into the following 4 subgroups:
Subgroup 1 - Idiopathic PAH (IPAH)
Subgroup 2 - Heritable PAH, including those with BMPR2 and ALK2 gene mutations
Subgroup 3 - Drug- and toxin-induced PAH (Aminorex, fenfluramine derivatives, and toxic rapeseed oil have been identified as definite risk factors for PAH.  )
Subgroup 4 - Conditions with known localization of lesions in the small pulmonary arterioles, including collagen-vascular disease (scleroderma/CREST syndrome), congenital left-to-right shunts, portopulmonary hypertension, HIV-associated pulmonary hypertension, schistosomiasis, and chronic hemolytic anemia
Subgroup 5 – Persistent pulmonary hypertension of the newborn
Group 2, pulmonary hypertension owing to left-sided heart disease, consists of left-sided myocardial and valvular diseases and extrinsic compression of the pulmonary veins (eg, tumors) and pulmonary veno-occlusive disease.
Group 3, pulmonary hypertension owing to lung diseases and/or hypoxia, consists of diseases that cause inadequate arterial oxygenation. Such conditions include lung disease (eg, chronic obstructive pulmonary disease [COPD] and interstitial lung disease), impaired respiration (eg, obstructive sleep apnea [OSA] and alveolar hypoventilation disorders), and long-term exposure to high altitude.
Group 4, chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH occurs in a minority of patients after acute embolism. Approximately 0.1% of survivors develop progressive pulmonary hypertension. Fewer than 1% of these patients have deficiencies of antithrombin 3, protein C, or protein S. No consistent defect in fibrinolytic activity has been identified.
Pathologically, these patients have a full range of pulmonary hypertensive lesions, including plexogenic lesions in the small pulmonary arteries. These patients present with progressive dyspnea and exercise intolerance. Physical examination findings demonstrate RV failure and PAH.
Group 5, pulmonary hypertension with unclear or multifactorial etiologies, is further divided into the following 4 subgroups:
Subgroup 1 - Hematologic disorders, including myeloproliferative disorders
Subgroup 2 - Systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis
Subgroup 3 - Metabolic disorders, including glycogen storage disease, Gaucher disease, and thyroid disorders
Subgroup 4 - Miscellaneous conditions, including tumor obstruction, mediastinal fibrosis, and chronic renal failure on dialysis
On the basis of information adapted from the executive summary of the world symposium on Primary Pulmonary Hypertension in Evian, France, in 1998, pulmonary hypertension may be divided into the following functional classes:
Class I – These are patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope in patients.
Class II – These are patients with pulmonary hypertension resulting in slight limitation of physical activity. The patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
Class III – These are patients with pulmonary hypertension resulting in marked limitation of physical activity. Patients are comfortable at rest, but even less-than-ordinary activity causes undue dyspnea or fatigue, chest pain, or near-syncope.
Class IV – These are patients with pulmonary hypertension who are unable to perform any physical activity without symptoms. These patients manifest signs of right-sided heart failure, dyspnea or fatigue may even be present at rest, and discomfort is increased by any physical activity.
The overall prevalence of pulmonary hypertension in the general population is unknown, owing to the heterogeneity of the disease. In specific subgroups of pulmonary hypertension patients, studies have estimated the prevalence as follows:
A systematic review of several studies of patients with OSA estimated the prevalence of pulmonary hypertension to be 15-20%. 
A systematic review of several studies among patients with COPD estimated the prevalence of pulmonary hypertension to be 10-30%. 
In scleroderma patients, the incidence has been estimated to be 6-60% of all patients, with the variance based on the extent of disease. 
Increasing pulmonary arterial pressure is associated with a progressive decline in survival for patients with COPD or interstitial lung diseases. The prognosis of patients with SPAH is variable and depends on the severity of hemodynamic derangement and the underlying primary disorder.
Patients with severe pulmonary hypertension or right-sided heart failure survive approximately one year. Patients with moderate elevations in pulmonary arterial pressure (mean pressure below 55 mm Hg) and preserved right-sided heart function have a median survival of three years from diagnosis.
On the basis of Centers for Disease Control and Prevention (CDC) Pulmonary Hypertension Surveillance from 1980 to 2002, the following mortality data were reported :
The age-standardized death rates for the total US population increased from 5.2 to 5.4 deaths per 100,000 population.
The main increase in death rates was seen among women, with an increase from 3.3 to 5.5 deaths per 100,000 population, and blacks, with an increase from 4.6 to 7.3 deaths per 100,000 population.
The death rate in males decreased over this time, from 8.2 to 5.4 deaths per 100,000 population.
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30. 54(1 Suppl):S43-54. [Medline].
Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest. 1990 Jan. 97(1):27-32. [Medline].
Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008 Jan 1. 177(1):108-13. [Medline].
Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest. 1991 Nov. 100(5):1268-71. [Medline].
Kessler R, Chaouat A, Weitzenblum E, et al. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J. 1996 Apr. 9(4):787-94. [Medline].
Elwing J, Panos RJ. Pulmonary hypertension associated with COPD. Int J Chron Obstruct Pulmon Dis. 2008. 3(1):55-70. [Medline]. [Full Text].
Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest. 1996 Dec. 110(6):1515-9. [Medline].
Hyduk, A, Croft, JB, Ayala, C, et al. Pulmonary hypertension surveillance--United States, 1980-2002. MMWR Surveill Summ. 2005. 54:1.
Soon E, Treacy CM, Toshner MR, MacKenzie-Ross R, Manglam V, Busbridge M, et al. Unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension. Thorax. 2011 Apr. 66(4):326-32. [Medline].
Arkles JS, Opotowsky AR, Ojeda J, Rogers F, Liu T, Prassana V, et al. Shape of the right ventricular Doppler envelope predicts hemodynamics and right heart function in pulmonary hypertension. Am J Respir Crit Care Med. 2011 Jan 15. 183(2):268-76. [Medline].
Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. 1998 Aug. 12(2):265-70. [Medline].
Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992 Jul 9. 327(2):76-81. [Medline].
Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005 Jun 14. 111(23):3105-11. [Medline].
Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17. 353(20):2148-57. [Medline].
Lee AJ, Chiao TB, Tsang MP. Sildenafil for pulmonary hypertension. Ann Pharmacother. 2005 May. 39(5):869-84. [Medline].
Reichenberger F, Voswinckel R, Enke B, et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J. 2007 Nov. 30(5):922-7. [Medline].
Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J. 2006 Apr. 151(4):851.e1-5. [Medline].
Fraisse A, Butrous G, Taylor MB, Oakes M, Dilleen M, Wessel DL. Intravenous sildenafil for postoperative pulmonary hypertension in children with congenital heart disease. Intensive Care Med. 2011 Mar. 37(3):502-9. [Medline]. [Full Text].
Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009 Jun 9. 119(22):2894-903. [Medline].
Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011 Jun 15. 183(12):1723-9. [Medline].
Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. 2007 Mar. 29(3):469-75. [Medline].
Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008 Oct 21. 149(8):521-30. [Medline].
Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, McLaughlin VV, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015 Aug 27. 373 (9):834-44. [Medline].
Hughes RJ, Jais X, Bonderman D, et al. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J. 2006 Jul. 28(1):138-43. [Medline].
Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother. 2003 Jul-Aug. 37(7-8):1055-62. [Medline].
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21. 346(12):896-903. [Medline].
Sharma S, Kashour T, Philipp R. Secondary pulmonary arterial hypertension: treated with endothelin receptor blockade. Tex Heart Inst J. 2005. 32(3):405-10. [Medline].
Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008 Jun 10. 117(23):3010-9. [Medline].
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29. 369(9):809-18. [Medline].
Stiles S. SERAPHIN: Macitentan, Novel Endothelin-Receptor Antagonist, Boosts PAH Outcomes. Medscape Medical News. Available at http://www.medscape.com/viewarticle/810215. Accessed: October 23, 2013.
Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. 1999 Apr 13. 99(14):1858-65. [Medline].
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996 Feb 1. 334(5):296-302. [Medline].
Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990 Apr 1. 112(7):485-91. [Medline].
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002 Aug 21. 40(4):780-8. [Medline].
Aguilar RV, Farber HW. Epoprostenol (prostacyclin) therapy in HIV-associated pulmonary hypertension. Am J Respir Crit Care Med. 2000 Nov. 162(5):1846-50. [Medline].
Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002 Mar 15. 165(6):800-4. [Medline].
Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. 2006 Jun. 129(6):1636-43. [Medline].
McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010 May 4. 55(18):1915-22. [Medline].
Jing ZC, Parikh K, Pulido T, Jerjes-Sanchez C, White RJ, Allen R, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation. 2013 Feb 5. 127(5):624-33. [Medline].
Tapson VF, Torres F, Kermeen F, Keogh AM, Allen RP, Frantz RP, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest. 2012 Dec. 142(6):1383-90. [Medline].
Tapson VF, Jing ZC, Xu KF, Pan L, Feldman J, Kiely DG, et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013 Sep. 144(3):952-8. [Medline].
Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002 Aug 1. 347(5):322-9. [Medline].
Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. 2005 Sep. 26(18):1895-902. [Medline].
Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galiè N, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015 Dec 24. 373 (26):2522-33. [Medline].
Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25. 369(4):319-29. [Medline].
Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25. 369(4):330-40. [Medline].
Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998 Sep. 114(3):787-92. [Medline].
Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. 2006 Aug. 130(2):545-52. [Medline].
Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J. 2006 Nov. 28(5):999-1004. [Medline].
Mellemkjaer S, Ilkjaer LB, Klaaborg KE, et al. Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Ten years experience in Denmark. Scand Cardiovasc J. 2006 Feb. 40(1):49-53. [Medline].
Thistlethwaite PA, Kemp A, Du L, Madani MM, Jamieson SW. Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. 2006 Feb. 131(2):307-13. [Medline].
[Guideline] Cassatt JC, Marini CP, Bender JW. The reversible reduction of horse metmyoglobin by the iron(II) complex of trans-1,2-diaminocyclohexane-N,N,N,n-tetraacetate. Biochemistry. 1975 Dec 16. 14(25):5470-5. [Medline].
[Guideline] Goss DJ, Parkhurst LJ, Gorisch H. Kinetic light scattering studies on the dissociation of hemoglobin from Lumbricus terrestris. Biochemistry. 1975 Dec 16. 14(25):5461-4. [Medline].
[Guideline] Martin JK, Luthra MG, Wells MA, Watts RP, Hanahan DJ. Phospholipase A2 as a probe of phospholipid distribution in erythrocyte membranes. Factors influencing the apparent specificity of the reaction. Biochemistry. 1975 Dec 16. 14(25):5400-8. [Medline].
[Guideline] Mockrin SC, Byers LD, Koshland DE Jr. Subunit interactions in yeast glyceraldehyde-3-phosphate dehydrogenase. Biochemistry. 1975 Dec 16. 14(25):5428-37. [Medline].