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Diagnosis & Treatment

WHO Group 1: Pulmonary Arterial Hypertension

Overview | Definition | Epidemiology | Pathophysiology | Diagnostic Evaluation and Right Heart Catheterization  | Treatment

WHO Group 1 PAH

Overview

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload, which in turn leads to RV enlargement, RV dysfunction and clinical symptoms.1

PAH can occur without any associated systemic diseases (idiopathic PAH), may be secondary to drug/toxin exposure or congenital heart disease, or may be present in association with a variety of systemic conditions which result in a common pathophysiology at the level of the pulmonary vasculature. These include connective tissue diseases such as scleroderma, cirrhosis with portal hypertension, or HIV infection.2,3

Symptoms of PAH may be nonspecific but the most frequently reported symptoms include the following4:

  • Progressive exercise intolerance
  • Fatigue
  • Dyspnea
  • Exertional chest discomfort
  • Light-headedness or syncope

Patients may also report:

  • Hemoptysis
  • Abdominal distention
  • Palpitations
  • Peripheral leg edema 

Because these symptoms may be nonspecific and often occur in relatively young, otherwise healthy-appearing people, there is often a substantial lead time, in some cases up to 2 to 3 years, between the onset of clinical symptoms and establishment of the diagnosis of PAH5,6 and frequently patients with PAH will have advanced symptoms at initial presentation.7,8

PAH (WHO Group 1) is 1 of 5 groups of pulmonary hypertension (PH) as currently defined; it is important to realize that patients with suspected PAH should undergo a detailed evaluation to exclude other forms of PH such as left-heart related PH (WHO Group 2), chronic respiratory disorders (WHO Group 3), chronic thromboembolic pulmonary hypertension (WHO Group 4) and miscellaneous forms of PH such as sarcoidosis or pulmonary Langerhans' cell histiocytosis (WHO Group 5).1-3

Definition

Clinically, PAH is defined on right heart catheterization as:

  • Mean pulmonary artery pressure (mPAP) ≥ 25mmHg
  • Pulmonary occlusion wedge pressure (PAOP) <15mmHg
  • Pulmonary vascular resistance > 3 Wood Units
  • The absence of overt left-sided heart disease, severe lung disease, or known chronic thromboembolic disease.

Epidemiology

PAH encompasses a number of disorders with somewhat varied epidemiology, depending on the particular PAH subgroup referenced.

  • Pulmonary hypertension is actually relatively common – however, most patients with pulmonary hypertension do not have PAH.
  • PAH is a rare disorder with overall prevalence of between 15-50 cases per million9
  • In certain high risk populations, the prevalence of PAH is much higher:
    • Systemic sclerosis: 7-12%10, 11
    • Sickle cell disease/hemolytic anemia: 4%12
    • HIV infection: 0.5%13
  • Overall PAH is 2 to 4 fold more common in women vs. men9
  • Though symptoms can occur at any age, the disease is most commonly manifest in the 4th or 5th decade of life
  • Idiopathic PAH makes up nearly 50% of the cases of PAH with associated PAH accounting for the remainder

Pathophysiology 

Although the exact molecular basis of the PAH remains to be elucidated, several molecular pathways have been implicated in the pathophysiology of PAH.14

The initial inciting event in PAH is felt to be pulmonary endothelial cell injury. This in turn triggers a molecular cascade which eventually results in a distal small vessel arteriopathy characterized by medial hypertrophy, intimal proliferation and thickening, microthrombi formation, and ultimately plexiform lesions.15

  • Nitric oxide (NO): endogenous pulmonary vasodilator which also possesses anti-proliferative properties and a relative deficiency of endothelial NO in the pulmonary vasculature may be one mechanism which contributes to the development of PAH.
  • Endogenous prostacyclins: systemic and pulmonary vasodilators, anti-proliferative agents and also have antithrombotic/antiplatelet effects. Relative deficiency or down-regulation of endogenous prostacyclin may contribute to the development of PAH.
  • Endothelin-1: an endogenous vasoconstrictor and up-regulation of endogenous endothelin-1 may also contribute to the pathogenesis of PAH.16-18

The small vessel arteriopathy in PAH leads to a progressive rise in RV afterload and pulmonary vascular resistance (PVR). As a result, the RV undergoes stereotypical changes including RV hypertrophy, RV dilatation and ultimately RV dysfunction. If PAH is left untreated, RV failure will ultimately result which may be manifested as syncope, angina, edema and abdominal distention. Right ventricular failure is the most common cause of death in patients with PAH.19

Diagnostic Evaluation and Right Heart Catheterization

Patients with suspected PAH should have a comprehensive evaluation to exclude other forms of PH, to evaluate for associated systemic diseases, and to establish a baseline for risk stratification.1, 18

  • Patients with PAH should have a transthoracic echocardiogram to exclude overt left-sided myocardial and valvular heart disease, and to evaluate RV size and function. 
  • A high resolution CT scan of the chest and pulmonary function testing with diffusion capacity are required to exclude obstructive and interstitial lung disease. 
  • Chronic thromboembolic disease must be excluded with V/Q scanning. 
  • Serologic testing including rheumatologic serologies, hepatitis serologies and HIV testing should also be undertaken.

All patients with suspected PAH should undergo right heart catheterization (RHC) to confirm the diagnosis, typically prior to initiating pulmonary vasodilator therapy. If a particular patient has a number of risk factors for left heart related PH such as hypertension, diabetes, obesity and sleep apnea, a normal saline fluid challenge or exercise hemodynamic study should be considered to exclude left-heart related PH.16, 18

Treatment

Without treatment, PAH is a progressive, life-threatening condition. In the seminal NIH Registry of patients with PAH prior to the era of pulmonary vasodilator therapy, median survival was 3 years from diagnosis.20
Fortunately, in the last two decades since the approval of intravenous epoprostenol, the first medication available to treat PAH, there has been a dramatic advance in the number of therapies available to treat this disease.
In addition to standard background therapies such as diuretics, digoxin, and anticoagulation  in patients with idiopathic PAH, there are now four classes of drugs approved for the treatment of PAH which modulate molecular pathways implicated in the pathogenesis of the disease.

  • Phosphodiesterase type 5 inhibitors (PDE-5i) (e.g., sildenafil, tadalafil): oral medications originally developed for the treatment of erectile dysfunction, which modulate the nitric oxide pathway by inhibiting the breakdown of cyclic GMP in pulmonary vascular endothelial cells, resulting in vasodilatation. These agents have been demonstrated to improve exercise capacity and delay clinical worsening in PAH.
  • Soluble Guanylate Cyclase Agonist (e.g., riociguat): oral medication that increases levels of cyclic GMP in the pulmonary vasculature through nitric oxide dependent and independent mechanisms and has been shown to improve exercise capacity and delay clinical worsening.
  • Endothelin receptor antagonists (ERAs) (e.g., ambrisentan, bosentan and macitentan): oral agents that block of the effects of endogenous endothelin-1 in either selective or nonselective fashion. These agents have been shown to improve exercise capacity and prevent clinical worsening in patients with PAH.
  • Synthetic Prostacyclins (e.g., epoprostenol, treprostinil, iloprost): there are several formulations of synthetic prostacyclins now available for the treatment of PAH. These range from parenteral agents such as epoprostenol, either in its original intravenous formulation or in a newer room temperature stable formulation, or treprostinil which is available for both intravenous and subcutaneous administration. Intravenous epoprostenol is the only medication shown to improve survival in PAH patients vs. historical controls. Prostacyclins can also be delivered by an inhaled route typically 4-6 times per day with either inhaled treprostinil or iloprost. Most recently, an oral form of treprostinil was approved for further treatment of PAH to improve functional capacity in monotherapy.

In terms of selecting the most appropriate therapy for an individual patient, treatment should be tailored to the patient’s clinical status and risk of morbidity and mortality. Risk assessment can be made based on16, 18, 21, 22:

  • Subjective symptoms
    • Functional class
    • Hemodynamic variables
    • Hospitalization
  • Prognostic equation
    • REVEAL Risk Calculator
    • French PAH equation.

For patients with advanced symptoms of PAH, a parenteral prostacyclin is typically recommended. For patients with less severe symptoms (WHO Functional Class I-II) or low risk REVEAL score, consideration of oral therapy, either alone or in combination may be appropriate.16, 18 

In patients who have refractory symptoms despite maximally tolerated PAH specific therapy, bilateral lung transplantation is a potentially curative therapy in the select patients who are transplant eligible. Atrial septostomy is a palliative procedure in patients with refractory NYHA Functional Class IV symptoms and/or syncopal events, provided significant hypoxemia is not present.23

Author

Amresh Raina, MD
Allegheny General Hospital
April 30, 2015 

REFERENCES

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  2. Proceedings of the 4th World Symposium on Pulmonary Hypertension, February 2008, Dana Point, California, USA. J Am Coll Cardiol. 2009;54(1 Suppl):S1-117. PMID: 19630151
  3. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43-54. PMID: 19555858
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  8. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-30. PMID: 16456139
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  10. Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52(12):3792-800. PMID: 16320330
  11. Tueller C, Stricker H, Soccal P, Tamm M, Aubert JD, Maggiorini M, et al. Epidemiology of pulmonary hypertension: new data from the Swiss registry. Swiss Med Wkly. 2008;138(25-26):379-84. PMID: 18587690
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  13. Sitbon O, Lascoux-Combe C, Delfraissy JF, Yeni PG, Raffi F, De Zuttere D, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177(1):108-13. PMID: 17932378
  14. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121(18):2045-66. PMID: 20458021
  15. Pietra GG, Edwards WD, Kay JM, Rich S, Kernis J, Schloo B, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation. 1989;80(5):1198-206. PMID: 2805258
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