Pulmonary Hypertension

CHAPTER 58

PULMONARY HYPERTENSION Zeenat Safdar, MD, FCCP, FACP, FPVRI 1. W  hat is the hemodynamic criteria used to define pulmonary arterial hypertension? At the Fourth World Symposium on Pulmonary Hypertension, the definition of pulmonary arterial hypertension (PAH) was updated as the mean pulmonary arterial pressure equal to or more than 25 mm Hg at rest, with a pulmonary arterial wedge or left atrial pressure equal to or less than 15 mm Hg. The exercise and pulmonary vascular resistance criteria were removed from this updated definition due to the poor availability of evidence. Right-sided heart catheterization (RHC) is the diagnostic gold standard to confirm PAH diagnosis. During the RHC, pulmonary artery pressures, right atrial pressure, right ventricle (RV) pressure, cardiac output, cardiac index, and pulmonary artery wedge pressures are measured; and vasodilator testing and shunt calculation (if indicated) are undertaken. 2. W  hat are the usual physical findings in patients with pulmonary hypertension? The most common findings on physical examination include the following: n Loud pulmonic valve closure sound (P2) n Right ventricular heave n Murmur of tricuspid regurgitation (a systolic murmur over the left lower sternal border) n Murmur of pulmonic insufficiency (a diastolic murmur over the left sternal border) n Jugular venous distension (indicating elevated central venous pressures) n Peripheral edema n Hepatomegaly n Hepatojugular reflux n Ascites n Cyanosis 3. H  ow is PAH classified? At the Fourth World Conference on Pulmonary Hypertension (held in Dana Point, Calif., in 2008), the term familial PAH was replaced by hereditary PAH, and schistosomiasis and chronic hemolytic anemia were added to Group 1 PAH. Current classification is outlined in Box 58-1. Pulmonary hypertension is classified as pulmonary arterial hypertension (Group 1), pulmonary hypertension resulting from left heart disease (Group 2), pulmonary hypertension resulting from lung diseases and/or hypoxia (Group 3), chronic thromboembolic pulmonary hypertension (CTEPH) (Group 4), and pulmonary hypertension with unclear multifactorial mechanisms (Group 5). 4. Is pulmonary hypertension a genetic disease? About 6% of patients with PAH have hereditary PAH. Mutations in the gene encoding bone morphogenetic receptor 2 (BMPR2) were found in approximately 70% of families with hereditary PAH and in 20% to 30% of patients with idiopathic PAH. Due to incomplete penetrance, most patients with this mutation never develop the disease. A subject with a mutation has a 10% to 20% estimated lifetime risk of acquiring PAH.

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Box 58-1 UPDATED PULMONARY HYPERTENSION CLASSIFICATION Group 1. Pulmonary Arterial Hypertension (PAH) n Idiopathic PAH n Heritable: BMPR2, Alk1, unknown n Drug- and toxin-induced n PAH associated with: n Collagen vascular disease n Congenital heart disease n Human immunodeficiency virus (HIV) n Schistosomiasis n Portal hypertension n Chronic hemolytic anemia n Persistent pulmonary hypertension of newborn n 1′ Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis Group 2. Pulmonary Hypertension Resulting from Left Heart Disease Systolic dysfunction n Diastolic dysfunction n Valvular disease n

Group 3. Pulmonary Hypertension Resulting from Lung Disease and/or Hypoxia n COPD n Interstitial lung disease n Other pulmonary disease with mixed restrictive and obstructive pattern n Sleep-disordered breathing n Alveolar hypoventilation disorders n Chronic exposure to high altitude n Developmental abnormalities Group 4. Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Group 5. Pulmonary Hypertension with Unclear Multifactorial Mechanisms n Hematological disorders: myeloproliferative disorders, splenectomy n Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis n Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders n Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis From Dana Point, 2008. Simonneau G, Robbins I M, Beghetti M, et al: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 54:S43–S54, 2009.

5. W  hat should the clinical evaluation for possible pulmonary hypertension include? Evaluation should begin with a thorough history and physical examination. Possible causes of PAH should be addressed in the history. In addition, travel to or residence in an area endemic for schistosomiasis should be considered. All patients should receive a basic initial screening evaluation, consisting of collagen vascular disease serologic testing, human immunodeficiency virus (HIV) test˙ Q˙ ) scan, ing, hepatitis panel, chest radiograph, pulmonary function testing, ventilation-perfusion ( V/ hypercoagulable work-up (if indicated), electrocardiogram, and echocardiogram. Patients with no clues to the cause on history or physical examination should be given a broad, detailed evaluation; patients with a suspected secondary cause should receive a focused evaluation to verify that cause, followed by the broad evaluation if necessary. In addition to these tests, arterial

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TABLE 58-1. CONDITIONS AND SYMPTOMS ASSOCIATED WITH PULMONARY HYPERTENSION CATEGORY

CONDITIONS OR SYMPTOMS

Heart Failure (Systolic or Diastolic) Current Smoking

Dyspnea, exercise intolerance, angina, prior myocardial infarctions, systemic hypertension, valvular heart disease Shortness of breath, “smokers cough”, hypoxia

Obstructive Sleep Apnea

Snoring, excessive somnolence, witnessed apneic episodes

Autoimmune Diseases

History of skin changes, arthritis, gastrointestinal problems, and renal disease

Chronic Thromboembolic Disease

Prior history of pulmonary embolism, deep vein thrombosis, and genetic or acquired hypercoagulable conditions

Drug History

Illicit drug abuse, prior anorexiant use, and herbal products

Chronic Liver Disease

History of jaundice, ascites, chronic viral hepatitis, and alcohol abuse. Symptoms of portal hypertension, including abdominal distention and gastrointestinal bleed

HIV Infection

Risky sexual behavior, intravenous drug abuse and needle sharing

Congenital Diseases

History of congenital heart disease and intracardiac shunts, family history of sickle cell disease

HIV, Human immunodeficiency virus.

blood gases and pulmonary angiography may be indicated. If undertaken, pulmonary angiography should be performed by a radiologist experienced in working with pulmonary hypertension patients. Conditions and symptoms associated with pulmonary hypertension are listed in Table 58-1. An assessment of the patient’s functional status and six-minute walk test should also be performed. Table 58-2 lists the World Health Organization (WHO) classification of functional status of patients with pulmonary hypertension. 6. W  hich connective tissue diseases most commonly cause pulmonary hypertension? n Systemic sclerosis (especially CREST syndrome) n Mixed connective tissue disease n Systemic lupus erythematosus n Rheumatoid arthritis n Dermatomyositis and polymyositis n Sjögren syndrome 7. W  hat population group is most commonly affected by PAH? Although PAH occurs in both genders and virtually all age groups, it has a tendency to affect females. The modern U.S. PAH patient population is older (mean age at diagnosis is 47 years) and has a female preponderance. According to a French registry, female-to-male predominance is 1.7:1, whereas according to the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) data, the female-to-male ratio is 3.6:1. REVEAL registry is a multicenter, observational U.S. based registry of PAH patients initiated in 2006 and data from this registry shows that factors associated with increased mortality include men older than 60 years of age, hereditary PAH, pulmonary vascular resistance (PVR) greater than 32 Woods units, portopulmonary hypertension, and New York Heart Association (NYHA)/WHO functional class IV (Table 58-3).

PULMONARY HYPERTENSION

TABLE 58-2. WORLD HEALTH ORGANIZATION CLASSIFICATION OF FUNCTIONAL STATUS OF PATIENTS WITH PULMONARY HYPERTENSION CLASS

DESCRIPTION

I

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. Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.

II

III

Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.

IV

Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right-sided heart failure. Dyspnea or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Modified from Rubin LJ: Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines, Chest 126:7S-10S, 2004.

TABLE 58-3. HEMODYNAMIC DEFINITION OF PULMONARY HYPERTENSION PULMONARY HYPERTENSION

MEAN PAP ≥ 25 mm Hg

PH Group

Precapillary pulmonary hypertension

Mean PAP ≥ 25 mm Hg PCWP ≤ 15 mm Hg Cardiac output normal or reduced Mean PAP ≥ 25 mm Hg PCWP > 15 mm Hg Cardiac output normal or reduced or increased

Group 1. PAH Group 3. PH due to lung disease Group 4. CTEPH Group 5. PH multifactorial etiology Group 2. PH due to left heart disease

Postcapillary pulmonary hypertension

CTEPH, chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension.

8. Is surgical therapy now an option for patients with pulmonary hypertension secondary to chronic recurrent thromboembolism? ˙ Q˙ scan suggestive of CTEPH must have a pulmonary angiogram for accuA patient with PAH and a V/ rate diagnosis and assessment of resectability of the thrombi. It is now possible to surgically remove an organized thrombus from the proximal pulmonary arteries of such patients. Operative mortality is low in most experienced centers, and lifelong anticoagulation and inferior vena cava (IVC) filter placement are essential for such patients. 9. W  hat is the average survival outlook for a PAH patient? According to the National Institutes of Health Registry on Primary Pulmonary Hypertension, in the past, the median survival was approximately 2.8 years from the date of diagnosis. With the availability of

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new therapeutic modalities, survival has improved. According to the French registry, the 1-year survival is 88% and according to REVEAL registry, the 1-year survival is 85% and 5-year survival is 57%. 10. W  hat is considered conventional therapy for patients with PAH? Conventional therapy for patients with PAH includes the following: n Supplemental oxygen as needed to maintain an oxygen saturation of at least 91% n Diuretics if the patient has clinically significant edema or ascites n Anticoagulation in the absence of contraindications n Digoxin is used occasionally to improve RV function 11. A  re calcium channel blockers used in the treatment of PAH? Calcium channel blockers (CCBs) are only used in patients with a documented vasodilator response to a short-acting vasodilator at the time of an RHC. This comprises 6% of all PAH patients; of these patients, 50% continue to be sustained responders. CCBs should not be empirically used in patients without the demonstration of vasoreactivity. If patients have a favorable response to acutely administered vasodilators, this predicts a response to CCBs. The 1-, 3-, and 5-year survival in patients on a CCB was 94% for all three time periods, as compared with 68%, 47%, and 38%, respectively, in those classified as nonresponders. If patients do not have a favorable response to acutely administered vasodilators, consider treatment with an endothelin receptor antagonist, a phostodiesterase-5 inhibitor, or prostacyclin therapy. 12. W  hat is considered a favorable response to acutely administered vasodilators? A positive vasodilator response is defined as a fall in mean pulmonary artery pressure of at least 10 mm Hg to 40 mm Hg or less with an increased or unchanged cardiac output. Approximately 6% to 10% of PAH patients will have an acute positive response; however, only half of these patients will have a sustained response to CCBs. Only patients with a positive response should be considered candidates for a trial of an oral CCB. The agents used to determine vasoreactivity include intravenous epoprostenol and inhaled nitric oxide. 13. W  hat are the approved therapies to treat PAH? Currently nine U.S. Food and Drug Administration (FDA)-approved therapies target the three identified pathways involved in the pathogenesis of PAH. Table 58-4 lists the FDA-approved drugs to treat pulmonary arterial hypertension. n Endothelin receptor antagonists. Endothelin-1, a potent vasoconstrictor, acts as a mitogen, induces fibrosis, and leads to the proliferation of vascular smooth muscle cells. The effects of endothelin-1 are mediated through the activation of ETA and ETB receptors. Differential activation of ETA and ETB receptors leads to the vasoconstricting and vascular proliferative actions of endothelin-1. Bosentan is a dual endothelin receptor blocker, whereas ambrisentan is an ETA blocker. n Prostacyclins. Prostacyclin is the main product of arachidonic acid in the vascular endothelium. By the production of cyclic adenosine monophosphate (cAMP), prostacyclin promotes pulmonary vascular relaxation and inhibits growth of smooth muscle cells. In addition, prostacyclin is a powerful inhibitor of platelet aggregation. There are three prostacyclins approved for therapy; these include intravenous, subcutaneous, and inhaled treprostinil, intravenous epoprostenol, and inhaled iloprost. n Phosphodiestersae-5 (PDE-5) inhibitors. Phosphodiestersae-5 (PDE-5) inhibitors block the breakdown of cyclic guanosine monophosphate (cGMP) in the vascular endothelium, resulting in increased activity of endogenous nitric oxide that enhances pulmonary vasodilation. Sildenafil and tadalafil are the PDE-5 inhibitors approved to treat PAH in U.S. 14. W  hat are the complications associated with prostanoid therapy? Because prostanoids are nonselective vasodilators, a common complication is systemic hypotension. Other commonly reported side effects include flushing, headaches, nausea, diarrhea, leg pain, and jaw pain. Because intravenous administration of prostacyclin requires central venous access, line infections (especially gram negative sepsis related to treprostinil use) and catheter-associated

TABLE 58-4. FDA-APPROVED DRUGS TO TREAT PULMONARY ARTERIAL HYPERTENSION CLASS

PDE-5 INHIBITORS

ENDOTHELIN RECEPTOR ­ANTAGONISTS

Mode of action

Block degradation of cGMP

Individual Drugs

Tadalafil

Sildenafil

Competitive antagonists of endothelin receptor Ambrisentan Bosentan

Individual dose

40 mg

20 mg

5-10 mg

Frequency of administration

Daily

tid

Elimination half-life

17.5 h

Route of administration Side-effects

PROSTACYCLINS Provide exogenous prostacyclin Treprostinil

Iloprost

Tyvaso

62.5-125 mg

0.5>100 mg/kg/ min

0.5>100 mg/kg/ min

2.5 or 5 mcg

9-12 breaths

Daily

bid

Continuous infusion

Continuous infusion

Every 2 hr

4 times daily

3-5 h

15 h

5.4 h

2-3 min

3-4 h

20-30 min

3-4 h

Oral

Oral

Oral

Oral

IV

IV, SC

INH

INH

Headache, myalgia, back pain, flushing, dyspepsia, diarrhea, nausea, pain in extremities

Headache, myalgia, back pain, flushing, dyspepsia, diarrhea

Peripheral edema, headaches, dizziness, nasal congestion

Peripheral edema, headaches, dizziness, cough, syncope, abnormal hepatic function

Headache, flushing, jaw pain, anxiety, nervousness, diarrhea, flu-like symptoms, nausea and vomiting

Headache, diarrhea, nausea, jaw pain, flu-like symptoms; SC infusion: site pain, reactions, and bleeding

Headache, flushing, flu-like symptoms, nausea and vomiting, jaw muscle spasm, cough, tongue pain, and syncope

Cough, headache, pharyngolaryngeal pain, throat irritation, nausea, flushing, and syncope

cGMP, Cyclic guanosine monophosphate; FDA, U.S. Food and Drug Administration; INH, inhalation treatment; IV, intravenous infusion; PDE-5, phosphodiesterase 5; SC, subcutaneous infusion.

PULMONARY HYPERTENSION

Epoprostenol

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thrombosis are common. Proper care of the catheter and anticoagulation help lessen these risks, but there is still the chance for significant and life-threatening complications. 15. H  ow do I treat the pulmonary hypertension associated with CREST syndrome? Pulmonary hypertension is a common, life-threatening complication of CREST syndrome and accounts for the significant morbidity and mortality of this disease. Orally available vasodilators have been notoriously ineffective in the treatment of pulmonary hypertension associated with CREST. Recently, infused prostacyclin has been shown to improve the functional status of patients with CREST and pulmonary hypertension and is being used in the clinical setting more commonly. 16. Is transplantation possible in patients with PAH? Yes. Lung transplantation is an option in carefully selected patients, especially those who do not respond to aggressive PAH treatment. A combined heart and lung transplant is no longer believed to be required, because the right ventricle appears to recover function after lung transplantation. Occasionally, heart-lung transplantation is required in patients with uncorrectable congenital heart defects (e.g., Eisenmenger syndrome).

BIBLIOGRAPHY, SUGGESTED READINGS, AND WEBSITES 1. 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 334:296–302, 1996. 2. Benza RL, Miller DP, Gomberg-Maitland M, et al: Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management ­(REVEAL). Circulation 122:164–172. 3. Channick RN, Simonneau G, Sitbon O, et al: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study, Lancet 358:1119–1123, 2001. 4. Galiè N, Brundage BH, Ghofrani HA, et al: Tadalafil therapy for pulmonary arterial hypertension, Circulation 119:2894–2903, 2009. 5. Galiè N, Ghofrani HA, Torbicki A, et al: Sildenafil citrate therapy for pulmonary arterial hypertension, N Engl J Med 353:2148–2157, 2005. 6. 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 117:2966–2968, 2008. 7. Humbert M, Sitbon O, Chaouat A, et al: Pulmonary Arterial Hypertension in France: results from a National Registry, Am J Respir Crit Care Med 173:1023–1030, 2006. 8. McGoon M, Gutterman M, Steen V, et al: Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines, Chest 126:14S–34S, 2004. 9. McLaughlin VV, Archer SL, Badesch DB, et al: 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 53:1573–1619, 2009. 10. Miyamoto S, Nagaya N, Satoh T, et al: Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing, Am J Respir Crit Care Med 161:487–492, 2000. 11. Oudiz RJ: Primary Pulmonary Hypertension. Available at: http://emedicine.medscape.com/article/301450-overview. Accessed March 26, 2013. 12. Simonneau G, Barst RJ, Galiè 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 165:800–804, 2002. 13. Simonneau G, Robbins IM, Beghetti M, et al: Updated clinical classification of pulmonary hypertension, J Am Coll Cardiol 54:S43–S54, 2009. 14. Sitbon O, Humbert M, Jais X, et al: Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension, Circulation 111:3105–3111, 2005. 15. 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 40:780–788, 2002.