Screening, Referral and Diagnosis of Pulmonary Arterial Hypertension

Screening, Referral and Diagnosis of Pulmonary Arterial Hypertension
TERESA DE MARCO, MD Professor of Clinical Medicine Director, Heart Failure and Pulmonary Hypertension Program Medical Director, Heart Transplantation University of California, San Francisco Medical Center San Francisco, California

Learning Objectives (CME, CE, CPE)
At the completion of this educational activity, participants should be able to: Identify patients who are at higher risk for PAH Identify the common presenting symptoms for PAH Discuss the diagnostic workup for symptoms suggestive of PAH, and the appropriate use of various tests Identify when a patient with suspected PAH should be referred to a PAH-specific specialty center Slide: Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: Identify patients who are at higher risk for PAH. Identify the common presenting symptoms for PAH. Discuss the diagnostic workup for symptoms suggestive of PAH, and the appropriate use of various tests. Identify when a patient with suspected PAH should be referred to a PAH-specific specialty center.

Clinical Classification of Pulmonary Arterial Hypertension (PAH)

PAH: Definition on Right Heart Catheterization
Increased mean pulmonary arterial pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise Normal pulmonary artery wedge pressure (PAWP) <15 mm Hg Pulmonary hypertension is a syndrome characterized by increased mean pulmonary arterial pressure over 25 mmHg at rest or over 30 mmHg during activity and increased pulmonary vascular resistance over 3WU (Wood’s units). The cause can range from simple transmission of elevated pressure in the left heart to complicated primary disease of the pulmonary arteries, which often progresses quickly and may have a fatal outcome several years after the first symptoms appeared. Reference: Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998;352: Increased pulmonary vascular resistance (PVR) >3 Wood units Gaine SP, et al. Lancet. 1998;352:

Revised Clinical Classification of Pulmonary Hypertension: 2003 Venice
PAH Idiopathic (IPAH) Familial (FPAH) Associated with (APAH) Connective tissue disease Congenital systemic-to-pulmonary shunts Portal hypertension HIV infection Drugs and toxins Other Thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease (PVOD) Pulmonary capillary hemangiomatosis (PCH) Persistent pulmonary hypertension of the newborn (PPHN) Following the Third World Conference on Pulmonary Arterial Hypertension (PAH) in Venice, Italy in 2003, the following classification for PAH syndromes were adopted. The remainder of this lecture will focus primarily on these forms of PAH. Reference: Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S. Simonneau G, et al. J Am Coll Cardiol. 2004;43:5S-12S.

Pulmonary hypertension with left heart disease Left-sided atrial or ventricular heart disease Left-sided valvular heart disease Pulmonary hypertension associated with lung diseases and/or hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Following the Third World Conference on Pulmonary Arterial Hypertension (PAH) in Venice, Italy in 2003, the following classification for PAH syndromes were adopted. Reference: Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S. Simonneau G, et al. J Am Coll Cardiol. 2004;43:5S-12S.

Pulmonary hypertension due to chronic thrombotic and/or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Non-thrombotic pulmonary embolism Tumor, parasites, foreign material Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) Following the Third World Conference on Pulmonary Arterial Hypertension (PAH) in Venice, Italy in 2003, the following classification for PAH syndromes were adopted. Reference: Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43:5S–12S. Simonneau G, et al. J Am Coll Cardiol. 2004;43:5S-12S.

Pulmonary Hypertension Connection Registry: Etiology of PAH
The Pulmonary Hypertension Connection Registry is a US-based registry of patients enrolled at a PAH tertiary care practice in 3 Chicago-area hospitals. From 1982 to 2006, 578 patients were followed; 77% were female. Almost half were diagnosed with idiopathic or familial PAH (IPAH, FPAH). The median age was 48 years. Eighty percent were diagnosed with NYHA Class III or IV symptoms. Most strikingly, 80% of patients referred were inappropriately receiving calcium channel blockers at the time of their referral. Reference: Thenappan T, Shah SJ, Rich S, et al. A USA-based registry for pulmonary arterial hypertension: Eur Respir J. 2007;30: n=578; female-male ratio: 77% - 33% Calcium channel blocker use at referral: 80% Thenappan T. Eur Respir J. 2007;30:

REVEAL Database: Most Frequent Symptoms at Diagnosis
Dyspnea at rest Cough Dizzy/lightheaded Presyncope/syncope Edema Chest pain/discomfort Other Fatigue Dyspnea on exertion IPAH APAH The REVEAL database reported initial presenting symptoms among 1479 patients enrolled. As can be seen here, symptoms did not differ between patients who were found to have IPAH versus those whose PAH was associated with other medical conditions (APAH). Elliott CG, Farber H, Frost A, et al. REVEAL registry: medical history and time to diagnosis of enrolled patients. Chest. 2007;132(4 suppl):631S. Incidence (%) n=1479. Elliott CG, et al. Chest. 2007;132(4 suppl):631S.

Survival in PAH by Etiology
1 2 3 4 5 Years 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Percent Survival Congenital Heart Disease Portopulmonary IPAH Connective Tissue Disease HIV Survival of patients diagnosed with PAH depends on the etiology of their disease, as well as potential underlying conditions, including HIV disease, which may impact on survival. Untreated PAH is associated with a poor prognosis. Median life expectancy of untreated idiopathic PAH is 2.8 years from diagnosis from right ventricular failure caused by a progressive increase in pulmonary artery pressure and pulmonary vascular resistance. Reference: McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:78S–92S. Park MH. Medical management of pulmonary arterial hypertension. In: Kasper DL, Braunwald D, Fauci AS, Hauser SL, Longo DL, Jameson JL, Isselbacher KJ, eds. Harris’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill Available online at Accessed March 15, 2007. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115: IPAH, idiopathic pulmonary arterial hypertension. McLaughlin VV, et al. Chest. 2004;126:78S-92S.

Screening for PAH in At-Risk Populations

Screening for PAH Requires High Index of Suspicion for Clinician
Diagnosis is complex IPAH and FPAH remain diagnoses of exclusion Early symptoms likely to be attributed to variety of more-common conditions Echocardiography is most commonly used screening tool Right heart cardiac catheterization required for diagnosis Best limited to centers of excellence PAH is a rare condition. Screening for PAH in patients presenting with nonspecific complaints requires a high index of suspicion, since early symptoms are more likely to be attributed to a variety of more-common conditions. On average, it takes patients 2 years from the onset of symptoms to receive a definitive diagnosis of PAH. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Alternative Diagnoses of Patients Referred to PAH Specialty Clinic
ILD VTE Other Structural Heart Disease OSA LV Dysfunction Obstructive Lung Disease All Alternative Diagnoses 85% of patients referred to a specialty PAH center for evaluation of potential PAH were determined to have an alternative diagnosis. These data represent 268 referrals made over a 2 year period. The most common reason for referral was an abnormal echocardiogram. 45% of patients were referred to the center by primary care clinicians, 15% by cardiologists, 10% by rheumatologists, and 5% by pulmonologists. The rest (25%) were referred by other specialties or self referred. PAH was ruled out with a normal echocardiogram in 76% and by right heart catheterization in 24% of patients. Obstructive lung disease was the most common alternative diagnosis established in these patients. Reference: Moghbelli MH, Heresi GA, Newman J, et al. Alternative Diagnoses in Patients Referred to a Pulmonary Hypertension Program. Am J Respir Crit Care Med. 2008;177:A923. n=268, all patients referred to PAH specialty center. Moghbelli MH, et al. Am J Respir Crit Care Med. 2008;177:A923.

FPAH Genetic Screening and Counseling
BMPR mutations found in 70% of FPAH patients Penetrance is low: Only 20% of BMPR germline mutation carriers will develop PAH “Second hit” theory implicates other pathways, including serotonin transport At present, no guidelines exist regarding routine genetic testing and counseling for patients with FPAH Although a substantial proportion of PAH appears to have a familial pattern, there is still no clear guidance with regard to routine genetic screening and testing for FPAH. Since only 20% of carriers of the common BMPR mutations will develop PAH, researchers have theorized that a “second hit” is required for PAH to develop. The serotonin transport mechanism has been implicated as one of the “second hit” mechanisms, in part because of the relationship between anorexigen use and PAH. Humbert M. Update in pulmonary arterial hypertension Am J Respir Crit Care Med. 2008;177:574–579. Humbert M. Am J Respir Crit Care Med. 2008;177:

Screening for PAH Associated With Connective Tissue Disorders
Doppler echo recommended for patients at high risk of PAH DLCO recommended every 6–12 months to improve detection of pulmonary vascular or interstitial disease Progress has been made recently in determining the prevalence and clinical course of PAH in persons with connective tissue disorders. Contrary to previously published reports, the prevalence of pulmonary hypertension associated with connective tissue diseases appears to be lower than generally accepted. The natural history and prognosis of PAH, primarily the setting of systemic sclerosis, is worse than seen in patients with idiopathic pulmonary hypertension. Fortunately, disease-modifying therapies substantially improves the prognosis for patients with systemic sclerosis-associated pulmonary hypertension. Reference: Coghlan JG, Handler C. Connective tissue associated pulmonary arterial hypertension. Lupus. 2006;15: Coghlan JG, et al. Lupus. 2006;15:

PAH and HIV Infection Sex-standardized incidence is between 68 to 138 cases per 100,000 HIV seropositive patients PY (versus 0.16 cases per 100,000 PY in the general population) Females have 1.7x risk of PAH than males Higher prevalence among injection drug users AIDS diagnosis and low CD4 cell counts associated with higher incidence of IPAH No apparent impact of antiretroviral therapy on IPAH occurrence Approximately 2/3 of patients with HIV who develop PAH succumb to complications of PAH A correlation between persons with HIV infection and PAH has been noted for several years. The sex-standardized incidence of PAH in HIV infected individuals is between 68 and 138 cases per 100,000 patients, with females having a 1.7 fold increased risk than males. The pathogenesis of PAH in HIV disease is unclear, but it does not appear that HIV affects the vascular endothelium. There is a higher prevalence of PAH among injection drug users infected with HIV disease, but the majority of PAH appears to be unrelated to causes such as methamphetamine or cocaine use. Two-thirds of patients identified with PAH succumb to PAH-related complications and not other HIV-related diseases. Reference: Mary-Krause M, Lascoux-Combe C, Simon A, et al. What about primary pulmonary hypertension in HIV infection in the era of combination antiretroviral therapy? J Intern AIDS Soc. 2008;11(Suppl 1):Abstract P299. Limsukon A, Saeed AI, Ramasamy V, et al. HIV-related pulmonary hypertension. Mt Sinai J Med. 2006;73: Mary-Krause M. J Intern AIDS Soc. 2008;11(suppl 1):Abstract P299. Limsukon A, et al. Mt Sinai J Med. 2006;73:

Diagnosis of PAH

PAH Diagnostic Guidelines: Decision Analysis
Unexplained Symptoms of Dyspnea on Exertion, Syncope/Near Syncope, Fatigue Initial steps in identifying a potential PAH patient include obtaining a full clinical history and physical exam as well as a chest X-ray and ECG. CXR is obtained to reveal features supportive of a diagnosis of PAH and to lead to diagnosis of underlying diseases. ECG is performed to screen for a spectrum of cardiac anatomic and arrhythmic problems. It lacks the sensitivity to screen for PAH but contributes prognostic information. If PAH is likely, Doppler echocardiography as a non-invasive screening test that can detect PAH is recommended; however, this method is imprecise in determining actual pressures compared to invasive evaluation. Doppler echocardiography is recommended to evaluate the level of RVSP, and assess the presence of anatomic abnormalities such as RA/RV enlargement (RAE/RVE) and pericardial effusion. An estimate of systolic PAP can also be determined. Doppler echocardiography is also recommended to look for LV systolic and diastolic dysfunction, chamber enlargement, or valvular heart disease, as well as to look for evidence of intracardiac shunting. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. Clinical History, Examination, Chest X-Ray, ECG McGoon M, et al. Chest. 2004;126:14S-34S.

Physical Findings Consistent With PAH
Accentuated pulmonary component of second heart sound (P2) at apex Noted in 90% of patients with IPAH Early systolic ejection click Midsystolic ejection murmur Left parasternal lift Right ventricle S4 gallop Prominent jugular “a” wave Auscultation may provide some key clues to guide clinician thinking in the early detection of PAH. For example, an accentuated pulmonary component of the second heart sound audible at the apex is noted in 90% of patients with IPAH. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Physical Findings Consistent With PAH
Diastolic murmur of pulmonary regurgitation Holosystolic murmur of tricuspid valve regurgitation Signs of right ventricular failure Right-sided third heart sound Jugular venous distention Peripheral edema, ascites Cool extremities Indicative of reduced cardiac output and peripheral vasoconstriction These physical findings are suggestive of severe or advanced PAH. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Other Physical Findings: Differential Diagnosis/PAH Etiology
Cyanosis Right-to-left shunt Clubbing Rare in IPAH Congenital heart or pulmonary veno-occlusive disease Rales, fine rales, abnormal breath sounds Pulmonary congestion, parenchymal airway disease, PVOD, PCH, etc. Obesity, kyphoscoliosis, enlarged tonsils Hypoventilatory disorders Sclerodermal skin changes, rashes, nail-fold capillary abnormalities Associated connective tissue disorder Peripheral venous insufficiency Venous thrombosis, pulmonary thromboembolic Other physical findings may indicate etiology of PAH, or assist in the differential diagnosis. Clubbing, for example, is rare in IPAH, but can indicate congenital heart or pulmonary veno-occlusive disease. Cyanosis is seen more often in right-to-left shunts than in other forms of PAH. Other physical findings may indicate lung disease, connective tissue disorders or thromboembolic disease. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Screening Tests for PAH: Electrocardiogram
Insufficiently sensitive as a screening tool May indicate right-heart disease May provide prognostic information PAH is a diagnosis of exclusion. However, ECG tracings may indicate right-heart disease and guide the clinician to further evaluation. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Electrocardiogram Associated With Right Ventricular Hypertrophy (RVH)
Image courtesy of Vallerie McLaughlin, MD

Electrocardiogram Associated With Right Bundle Branch Block Plus RVH

Screening Tests for PAH: Chest X-Ray Findings Consistent With PAH
Enlarged main and hilar pulmonary artery shadows “Pruning” of peripheral pulmonary vasculature Right ventricular enlargement Symptomatic patients may have normal chest x-ray Chest x-ray may reveal underlying causes of PH Chest X-ray findings suggestive of PAH may show enlarged main and hilar pulmonary artery shadows, or pruning of the peripheral pulmonary vasculature and/or right ventricular enlargement. However, many patients with symptomatic PAH do not have abnormal X-rays. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Chest X-Ray Consistent With PH
1. Findings that suggest PAH Enlarged main and hilar pulmonary artery shadows “Pruning” of peripheral pulmonary vasculature Right ventricular enlargement 2. Many patients with symptomatic disease have normal CXR 3. CXR may also reveal underlying causes of PAH Image courtesy of Vallerie McLaughlin, MD

MRI of Pulmonary Artery Distensibility: Preliminary Findings
Potential Noninvasive Surrogate Marker of Acute Vasodilator Challenge mPAD (%) Mean pulmonary artery distensibility as measured by MRI may have utility as a noninvasive surrogate marker for response to acute vasodilator challenge following diagnostic right-heart catheterization for PAH. In this series, a >10% mPA distensibility within 48 hours of catheterization correlated with response to acute vasodilator challenge. An arbitrary cut-off value of 10% mPAD to differentiate between responders and nonresponders, with 100% sensitivity (95% confidence interval of 61–100%) and 56% specificity (33–77%). The 10% cut-off value also was associated with a positive predictive value of 36% (15–65%) and a negative predictive value of 100% (77– 100%). These preliminary results need to be validated before being put into widespread clinical practice. Jardim C, Rochitte CE, Humbert M, et al. Pulmonary artery distensibility in pulmonary arterial hypertension: an MRI pilot study. Eur Respir J. 2007;29:476–481. Nonresponders Responders N = 19. P=0.01. 10% pulmonary artery distensibility predicted response to acute vasodilator challenge with 100% sensitivity and 56% specificity. Jardim C, et al. Eur Respir J. 2007;29:

Clinical History, Examination, Chest X-Ray, ECG Is There a Reason to Suspect PH? Initial steps in identifying a potential PAH patient include obtaining a full clinical history and physical exam as well as a chest X-ray and ECG. CXR is obtained to reveal features supportive of a diagnosis of PAH and to lead to diagnosis of underlying diseases. ECG is performed to screen for a spectrum of cardiac anatomic and arrhythmic problems. It lacks the sensitivity to screen for PAH but contributes prognostic information. If PAH is likely, Doppler echocardiography as a non-invasive screening test that can detect PAH is recommended; however, this method is imprecise in determining actual pressures compared to invasive evaluation. Doppler echocardiography is recommended to evaluate the level of RVSP, and assess the presence of anatomic abnormalities such as RA/RV enlargement (RAE/RVE) and pericardial effusion. An estimate of systolic PAP can also be determined. Doppler echocardiography is also recommended to look for LV systolic and diastolic dysfunction, chamber enlargement, or valvular heart disease, as well as to look for evidence of intracardiac shunting. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. Yes No Echocardiography Work-Up for Other Conditions McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiography for Suspected PH RH Analysis CHD Analysis LH Analysis If PAH is likely, Doppler echocardiography as a non-invasive screening test that can detect PAH is recommended; however, this method is imprecise in determining actual pressures compared to invasive evaluation. Doppler echocardiography is recommended to evaluate the level of RVSP, and assess the presence of anatomic abnormalities such as RA/RV enlargement (RAE/RVE) and pericardial effusion. An estimate of systolic PAP can also be determined. Doppler echocardiography is also recommended to look for LV systolic and diastolic dysfunction, chamber enlargement, or valvular heart disease, as well as to look for evidence of intracardiac shunting. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. TRV to Estimate RVSP, RVE, RAE, RV Dysfunction Abnormal Morphology, Shunt LV Systolic Diastolic Dysfunction Valvular Dysfunction McGoon M, et al. Chest. 2004;126:14S-34S.

Echocardiograph: Parasternal Long Axis

Echocardiograph: Parasternal Short Axis

Echocardiograph: Apical Four Chamber

Echocardiograph: Tricuspid Regurgitation
Modified Bernoulli’s Equation: 4 x (V)² + RAP = RVSP (PASP) V=tricuspid jet velocity (m/s); RAP= right atrial pressure; RVSP=right ventricular systolic pressure; PASP=pulmonary artery systolic pressure. Image courtesy of Vallerie McLaughlin, MD

Calculations of Estimated Pulmonary Artery Pressures (PAP) by Doppler Echo
Measurement Calculation sPAP 4 x TR peak velocity2 + “RAP” mPAP 79 – 0.45 (RVOT AT) 4 x peak pulmonary regurgitation velocity2 Pulmonary end diastolic pressure 4 x (pulmonary regurgitation end-diastolic velocity)2 + “RAP” Doppler echocardiography allows an accurate estimate of PAP, as tricuspid regurgitation (TR) peak velocity and RV outflow tract (RVOT) acceleration time (AT) have linear positive and negative correlations with pulmonary artery systolic pressure (sPAP) and median PAP (mPAP). As shown in these calculations, the peak early diastolic and the end-diastolic velocities of pulmonary regurgitation correlate with mPAP and pulmonary artery end-diastolic pressure. Reference: Bossone E, Bodini BD, Mazza A, et al. Pulmonary arterial hypertension: the key role of echocardiography. Chest. 2005;127: TR=tricuspid regurgitant jet velocity m/sec. “RAP”=estimated right atrial pressure. RVOT AT=right ventricular outflow tract acceleration time. Bossone E, et al. Chest. 2005;127:

Limitations of Echocardiography in Diagnosing PH
15% of patients will not display TR jets Saline contrast can enhance TR jet Not all congenital heart lesions will be obvious Poor method to measure LH filling pressure or cardiac output (CO) Small errors in TRV tracing can significantly alter results TRV can underestimate RVSP or overestimate RVSP While echocardiography is an extremely useful screening tool, it is not diagnostic for PH. Up to 15% of patients with PH will not display TR jets, therefore making calculations impossible. In addition, small errors in TRV tracing can create significant changes in the reported results, so skill of the technician is paramount. In addition, severe TR with very high right atrial pressures may result in an underestimation of the dPAP. Reference: Stephen B, Dalal P, Berger M, et al. Noninvasive estimation of pulmonary artery diastolic pressure in patients with tricuspid regurgitation by Doppler echocardiography. Chest. 1999;116:73-77. Stephen B, et al. Chest. 1999;116:73-77.

Accuracy of PH Diagnosis by Echocardiography in Advanced Lung Disease
Cohort study of lung transplant patients (n=374) All patients Doppler echo 24 to 48 hours prior to RHC Prevalence of PH: 25% Echo frequently inaccurate leading to over diagnosis of pulmonary hypertension in patients with advanced lung disease Diagnosis of PH Overestimation Accurate Underestimation Studies (%) While echocardiography can discern right-heart morphology and provide an estimate of hemodynamics, it is not sensitive as a diagnostic tool. In this study of lung transplant patients, echocardiography frequently led to an inaccurate diagnosis of pulmonary hypertension in patients with advanced lung disease. Reference: Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med. 2003;167: No Pulmonary Hypertension Pulmonary Hypertension Arcasoy SM, et al. Am J Respir Crit Care Med. 2003;167:

Doppler Echo Overestimates PAH in Patients With Scleroderma-Related Lung Disease
Percent (%) Doppler echocardiography accurately assessed PAH in only 25% of patients with scleroderma-related lung disease, according to an evaluation of 13 patients being evaluated for participation in a Phase IV clinical trial. In this cohort, echocardiography overestimated pulmonary artery systolic pressure (PASP) in up to 60% of patients without PAH. The sensitivity, specificity, positive predictive value and negative predictive value for echocardiography was 62.5%, 40%, 62.5%, and 40%, respectively. Right heart catheterization should be performed in patients with scleroderma-related lung disease when pulmonary hypertension is suspected. Chan KM, Tishkowski E, Impens AJ, et al. Doppler echocardiography overestimates pulmonary hypertension in patients with scleroderma interstitial lung disease. Presented at: 2008 CHEST meeting; October 25-30, 2008; Philadelphia, PA. Session AP2217. N = 13. Chan KM. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

PAH Diagnostic Guidelines: Further Evaluation of Patients
Echocardiography Indicates PH Evaluate for Associated Causes PFTs Arterial Saturation V/Q scan If echocardiography indicates potential PAH, other tests may be considered to reveal secondary causes. Scleroderma and other connective tissue disorders are commonly associated with PAH. Other diseases may be potentially treatable, such as obstructive sleep apnea, leading to a marked improvement in PAH without PAH-specific therapy. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. HIV Infection, Scleroderma, SLE, Other CTD, Liver Disease, CHD, Drug-Associated Suspected Chronic Pulmonary Emboli Parenchymal Lung Disease, Hypoxemia, or Sleep Disorder McGoon M, et al. Chest. 2004;126:14S-34S.

Association Between Stimulant Use and IPAH
Patients Reporting Use (n=340) 28.9% Patients (%) Methamphetamine use may represent an additional risk factor for PAH. In this retrospective analysis of patients treated at a tertiary care center for PAH, almost 30% of patients diagnosed with idiopathic PAH reported stimulant usage, primarily methamphetamine. In addition (data not shown), 89% of patients with HIV disease and PAH reported stimulant use. Patients using methamphetamine were 7.73 times more likely to be diagnosed with PAH than patients with PAH based on other etiologies (age adjusted odds ratio; use of cocaine and amphetamine too infrequent to be reported separately), and times more likely to be diagnosed with PAH compared with thromboembolic PH. Reference: Chin KM, Channick RN, Rubin LJ. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest. 2006;130: 3.8% 4.3% Idiopathic PAH with Known Risk Factors Thromboembolic PH Retrospective analysis at single PH center of adults with PH. Chin KM, et al. Chest. 2006;130:

V/Q Scan for Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Normal V/Q scan makes CTEPH unlikely Sensitivity: 90% to 100% Specificity: 94% to 100% >1 segmental-sized or larger mismatched perfusion defects seen with CTEPH Spiral CT may underestimate degree of obstruction in chronic CTEPH ~7% false negative Ventilation-perfusion (V/Q) scans should be performed in all patients with pulmonary arterial hypertension identified by echocardiography, in order to distinguish between other causes of PAH and chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is a potentially curable condition, with appropriate surgical management. Normal V/Q scans have demonstrated a sensitivity of 90% - 100% with specificity of 94% to 100% in differentiating between idiopathic PAH and CTEPH. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Diagnosis
Pulmonary angiography remains gold standard Signs of CTEPH Stenoses, complete obstructions, partial recanalization, and intraluminal webs Pulmonary fiberoptic angioscopy can help define operability in selected patients Patients with suspected CTEPH based on V/Q scan results should undergo pulmonary angiography, which remains the gold standard for diagnosis. Patients with CTEPH may be candidates for curative pulmonary endarterectomy. Reference: Klepetko W, Mayer E, Sandoval J, et al. Interventional and surgical modalities of treatment for pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:73S-80S. Klepetko W, et al. J Am Coll Cardiol. 2004;43:73S-80S.

Pulmonary Function Testing for PAH Suspected by Doppler Echo
Lung volumes 60% to 80% of predicted Nocturnal hypoxemia occurs in >75% of patients with IPAH Desaturation may increase during exercise DLCO <55% of predicted associated with future development of PAH in limited systemic sclerosis Approximately 20% of patients with chronic pulmonary embolism have restrictive parameters (i.e., lung volumes 80% predicted) but may have near normal diffusing capacity for carbon monoxide (DLCO). The DLCO of 20% of patients with limited systemic sclerosis is below normal; a DLCO of 55% of predicted may be associated with future development of PAH. References: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S– 47S. McGoon M, et al. Chest. 2004;126:14S-34S. Barst RJ, et al. J Am Coll Cardiol. 2004;43:40S-47S.

PH in Patients With Obstructive Sleep Apnea
Tends to be milder than PH from other causes Prevalence range: 17% to 53% Spirometric abnormalities strongly associated with PH PH is strongly associated with other risk factors Left-sided heart disease Parenchymal lung disease Nocturnal desaturation Obesity Obstructive sleep disorders, such as peripheral or central sleep apnea, are associated with PH. However, in these patients the PH tends to be milder. Sleep apnea patients with lung function abnormalities on spirometry tend to have a higher risk of PH, and PH is also associated with other risk factors such as left heart disease, parenchymal lung disease, nocturnal desaturation, and obesity. Effective treatment of the sleep apnea usually helps ameliorate or resolve PH in this population. Reference: Atwood CW Jr, McCrory D, Garcia JGN, et al. Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:72S-77S. Atwood CW Jr, et al. Chest. 2004;126:72S-77S.

PAH Diagnostic Guidelines: Confirmation of PAH
Echocardiography Indicates PH Refer to PAH Specialty Center for Right Heart Catheterization Definitive diagnosis of PAH requires right heart catheterization, which ideally should be performed at a PAH specialty center. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. Adapted from McGoon M, et al. Chest. 2004;126:14S-34S.

Right Heart Catheterization
Required to confirm diagnosis, calculate resistance, and guide therapy for PAH Excludes other etiologies for PH Intracardiac or extracardiac shunts Left-heart disease Measures degree of right-heart dysfunction Right atrial pressure Cardiac output Right heart catheterization excludes other etiologies of PH, including undetected shunts or left-heart disease, as well as providing accurate measurements of right-heart dysfunction. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. McGoon M, et al. Chest. 2004;126:14S-34S.

Pulmonary Artery Wedge Pressure
Measurement is critical in PAH diagnosis PAH therapies increase cardiac output, therefore risk pulmonary edema and hypoxemia in patients with left ventricular diastolic dysfunction Interobserver variability in interpreting a pulmonary artery pressure waveform is extremely large Physicians consistently fail to make the determination of pulmonary wedge pressure only at end-expiration Direct measurement of left ventricular end-diastolic pressure may be necessary Determining a pulmonary artery wedge pressure is a critical component of establishing a PAH diagnosis. Unfortunately, interobserver variability in interpreting a PCWP waveform have been shown to be as large as 23 mm Hg. In addition, it has been shown that physicians consistently fail to make the determination of pulmonary wedge pressure only at end-expiration. Due to the potential for clinical worsening and pulmonary edema caused by the PAH therapies a direct measurement of the left ventricular end-diastolic pressure should be performed in patients for whom an adequate pulmonary capillary wedge pressure cannot be obtained or in whom its validity is in doubt. Ghofrani HA, Wilkins MW, Rich S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation. 2008;118: Ghofrani HA, et al. Circulation. 2008;118:

Hemodynamic Classification of PH (mean PAP >25 mmHg)
Post-Capillary PH VC RA RV PA PV LA LV Ao PC The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. Mixed PH High-Flow PH (O2 sat run) Pre-capillary PH

Post-Capillary PH PAWP>15 mmHg; PVR nl PV PVP LA LAP VC RA RV PA LV Ao PC The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. LVEDP

Post-Capillary PH PAWP>15 mmHg; PVR nl MR PV PVP LA LAP VC RA RV PA LV Ao PC The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. LVEDP Systemic HTN AoV Disease Myocardial Disease Dilated CMP-ischemic/non-ischemic Hypertrophic CMP Restrictive/infiltrative CMP Pericardial disease

Post-Capillary PH PAWP>15 mmHg; PVR nl Atrial Myxoma Cor Triatriatum PV PVP LA LAP VC RA RV PA LV Ao The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. PC MV Disease

Post-Capillary PH PAWP>15 mmHg; PVR nl PV PVP VC RA RV PA LA LV Ao PC The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. PV compression

PAH Lung Diseases +/- Hypoxemia CTEPH { PV LA LV Ao VC RA RV PA The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. { PC Pre-capillary PH PAWP < 15 mmHg; PVR > 3 Wu

PV PVP LA LAP VC RA RV PA LV Ao PC The hemodynamic derangements with LV dysfunction can result from systemic hypertension, AoV disease, MV disease predominantly MR presenting a volume overload to LV and myocardial diseases such as dilated CMP-of the ischemic or non-ischemic variety, hypertrophic cardiomyopathy, and restrictive/infiltrative CMP such amyloidosis, hemochromatosis, or sarcoidosis. LVEDP Mixed PH (“Reversible” vs. “Fixed”) PAWP >15 mmHg PVR > 3 Wu

Measuring Pulmonary Artery Wedge Pressure
Pulmonary Artery Pressure Decay Curve 160 140 120 100 80 60 40 20 Balloon Occlusion ARDS IPAH Pressure (mm Hg) Pulmonary artery occlusion is currently the most frequently used method for estimating pulmonary artery wedge pressure (PAWP) in a broad range of clinical conditions. This study tested the four commonly used algorithms to measure PCP in patients with IPAH and with adult respiratory distress syndrome (ARDS). The time constants of pulmonary artery emptying may differ according to the disease process. The authors concluded that the time constants may be useful for increasing the accuracy of PCP measurement using the arterial occlusion technique. Reference: Souza R, Amato M, Demarzo S, et al. Pulmonary capillary pressure in pulmonary hypertension. Crit Care. 2005;9:R132-R138. 2 4 6 8 10 12 Time (seconds) Time Steady State Is Longer in IPAH Than In ARDS ARDS: acute respiratory distress syndrome. Souza R, et al. Crit Care. 2005;9:R132-R138.

Correct and Incorrect Readings of PAWP
PA and RV Recordings in Patient With PAH PA Pressure Tracing Erroneously Labeled As PAWP Inaccurate pressure tracing may occur when the right-heart balloon flotation catheter is not in proper position, resulting in an incorrect interpretation of pulmonary artery wedge pressure. Inaccurate readings can lead to an inaccurate diagnosis of pulmonary venous hypertension, rather than PAH. Reference: Oudiz RJ, Langleben D. Cardiac catheterization in pulmonary arterial hypertension: an updated guide to proper use. Advances Pulmon Hypertens. 2005;4:15-25. Oudiz RJ, et al. Advances Pulm Hypertens. 2005;4:15-25.

Misclassification of PAH and PVH Through Use of PAWP Versus LVEDP
Percent (%) More than half of patients diagnosed as having PAH by right heart catheterization including a pulmonary artery wedge pressure were misclassified when results of left heart catheterization and left ventricular end diastolic pressure were measured. This was a single-center study of 4,666 patients over a 10-year period who underwent both LHC and RHC. 521 (11.1%) patients in this cohort met criteria for PAH using PCWP, but 50.2% of these would be classified as PVH if LVEDP were used instead. Among the 414 (8.9%) patients with PAH using LVEDP, 155 (37.4%) would have been classified as PVH using PAWP. Misclassification rates were 39.2% and 25.2% among patients with pulmonary vascular resistance ≥ 3 wood units. Reference: Halpern SD, Taichman DB. Misclassification of pulmonary arterial hypertension due to use of pulmonary capillary wedge pressure (PCWP) rather than left-ventricular end-diastolic pressure (LVEDP). Am J Respir Crit Care Med. 2008;177:A259. Misclassification of PAH by PAWP Misclassification of PVH by PAWP n=4,666, all patients undergoing LHC and RHC over 10 years at single center. Halpern SD, et al. Am J Respir Crit Care Med. 2008;177:A259.

PAH and the Right Ventricle
Pulmonary hypertension  Pressure overload Adaptive RV hypertrophy Decreased wall stress Maladaptive RV hypertrophy & fibrosis Diastolic dysfunction RV dilation & systolic failure RV ischemia:  Wall stress & heart rate  Coronary perfusion gradient Tricuspid regurgitation Preload-afterload mismatch Decreased LV compliance/preload: Inter-ventricular septal shift  Intrapericardial pressure Neurohormonal and other mediator activation  RV remodeling ] Compensated Phase Normal CO, normal RAP ] Decompensating Phase Higher RAP to maintain adequate CO Right ventricular failure is a predictor of poor prognosis in PAH. This diagram shows the progression of right ventricular dysfunction with untreated PAH. In early stages of PAH, there is a compensated phase with adaptive right ventricular hypertrophy and decreased wall stress. In the decompensating phase, there is maladaptive right ventricular hypertrophy and fibrosis, as well as increasing diastolic dysfunction. Higher right atrial pressures are required to maintain cardiac output. In the final decompensated phase, a wide range of defects are seen, including right ventricle dilation and systolic failure, right ventricular ischemia, tricuspid valve regurgitation, preload-afterload mismatch, and decreased left ventricular compliance. Reference: DeMarco T, McGlothin D. Managing right ventricular failure in PAH: an algorithmic approach. Advances Pulm Hypertens. 2005;4:16-26. Decompensated Phase  CO,  RAP  AV-DO2 Hypoxemia, acidosis, life-threatening dysrhythmias DeMarco T, et al. Adv Pulm Hypertens. 2005;4:16-26.

Measuring Diastolic Dysfunction
Normal Diastolic Function Mild Diastolic Dysfunction Moderate Diastolic Dysfunction Severe Diastolic Dysfunction DT>140 ms 0.75<E/A<2 E/A≤0.75 DT>140 ms 0.75<E/A<2 DT<140 ms E/A>2 2.0 E Mitral Inflow Velocity (m/s) A Distinguishing between diastolic heart failure with secondary pulmonary hypertension and IPAH with secondary diastolic dysfunction can be challenging. Diastolic heart failure may be an under-recognized cause of pulmonary hypertension. Clinicians should consider diastolic heart failure in addition to IPAH in patients with otherwise unexplained dyspnea and pulmonary hypertension, particularly among elderly patients with a normal ejection fraction and normal valves. References: Image from: Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic heart failure in the community. JAMA. 2006;296: Notes from: Shapiro BP, Nishimura RA, McGoon MD, et al. Diagnostic dilemmas: diastolic heart failure causing pulmonary hypertension and pulmonary hypertension causing diastolic dysfunction. Advance Pulm Hypertens. 2006;5:13-20. E/e’<10 E/e’<10 E/e’≥10 E/e’≥10 Doppler Tissue Imaging of Mitral Annular Motion Velocity (m/s) 1.5 a1 e1 E: early peak mitral inflow velocity. A: late peak mitral inflow velocity. DT: deceleration time of the E-wave. e’: velocity of annulus early diastolic motion. Bursi F, et al. JAMA. 2006;296:

PAH Diagnostic Workup Right Heart Catheterization Confirms PAH
6-Minute Walk Borg Score Functional Class Once patients have received a tentative diagnosis of PAH by echocardiography, their treatment and prognostic course is guided by additional assessments. In addition, patients must undergo right heart catheterization to confirm the diagnosis. Reference: McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126:14S-34S. Establish Baseline, Prognosis, and Document Progression/Response to Treatment With Serial Re-Assessment McGoon M, et al. Chest. 2004;126:14S-34S.

Blood Tests for Evaluation of PAH
Antinuclear antibody (ANA) Up to 40% of patients with IPAH have positive but low (>1:80 dilutions) ANA titers Antiphospholipid antibodies Lupus anticoagulant, anticardiolipin antibodies HIV serology CBC with platelets Liver function Thyroid function Hemoglobin electrophoresis, if indicated Blood tests for patients being screened for PAH should include ANA and antiphospholipid antibodies to detect connective tissue disorders, and HIV serology, as well as CBC and liver function tests. Reference: Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43:40S– 47S. Barst RJ, et al. J Am Coll Cardiol. 2004;43:40S-47S.

NT-proBNP Elevations Correlate With Right Ventricular Dysfunction in PH
4127 NT-proBNP (ng/L) B-type natriuretic peptide (BNP) and N-terminal-proBNP (NTproBNP) are released from both cardiac ventricles in response to raised heart chamber pressure or volume overload. Blyth KG, Groenning BA, Mark PB, et al. NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension. Eur Respir J. 2007;29:737–744. 354 With RVSD Without RVSD N = 25. Threshold value RVD detection: 1,685 ng/L. Sensitivity for RVD 100%; specificity 94%. Blyth KG, et al. Eur Respir J. 2007;29:

BNP Predictive Value For Adverse Outcomes
Death Cardiogenic shock Inpatient heart failure Outpatient heart failure Ventricular dysfunction WHO Class IV WHO Class III WHO Class II WHO Class I Control The predictive value of brain natriuretic peptide (BNP) for adverse cardiovascular events in PAH patients continues to be explored. Eighty-five patients with PAH were evaluated for the relationship between BNP and right ventricular dysfunction, heart failure, cardiogenic shock and death, compared with a control group of 33 patients. Simple regression analysis identified BNP as an independent variable for adverse cardiac events (p<0.001). The authors noted that BNP could improve the risk stratification and identify at-risk patients for poor outcomes. Garcia Badillo EV, Sanchez CJ, Ramirez Rivera A, et al. Predictive value of the brain natriuretic peptide in pulmonary arterial hypertension. Presented at: 2008 CHEST meeting; October 25-30, 2008; Philadelphia, PA. Session AP2217. N=85. Garcia-Badillo EV. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217.

6-Minute Walk Distance Correlates With IPAH Disease Severity
* Distance Walked in 6 Minutes (m) *† Many prognostic tests have been proposed for patients with IPAH. However, one of the simplest and most effective is the 6-minute walk test. Patients are asked to walk on a level treadmill for as far as they can for 6 minutes. The distance achieved is highly correlated with NYHA/WHO functional classification. Reference: 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. 2000;161: *†‡ Control NYHA II NYHA III NYHA IV *P<0.05 versus control. †P<0.05 versus NYHA Class II. ‡P<0.05 vs NYHA Class III. Miyamoto S, et al. Am J Respir Crit Care Med. 2000;161:

Impact of Baseline 6-Minute Walk Distance on Survival
Epoprostenol Versus Placebo 100 6-Minute Walk Distance Survivors (n=73) Deaths (n=8) 80 60 Percent Survival While 6MWD has been criticized as an incomplete marker of disease severity and risk of disease progression, it’s utility was noted early in the course of the search for effective therapies. In the initial trials of epoprostenol, baseline 6MWD was the only independent variable that predicted death in this population. 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;334: 40 6-minute walk distance at baseline was the only independent predictor of survival (P<0.003) Epoprostenol (n=41) 20 Conventional Therapy (n=40) 2 4 6 8 10 12 Week Barst RJ, et al. N Engl J Med. 1996;334:

Assessment of PH Severity: WHO Functional Classification (NYHA Modification for PH)
WHO Class Description I No limitation of usual activities II Mild limitation of usual activities No discomfort at rest Normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope III Marked limitation of physical activity Less than ordinary activity causes increased dyspnea, fatigue, IV Patient unable to perform any physical activity at rest and may have signs of right ventricular failure Dyspnea and/or fatigue and/or syncope/near-syncope may be present at rest, and symptoms are increased by almost any physical activity The severity of PAH is defined by functional limitations associated with severity of disease. Early in the course of PAH, patients may be largely unaffected in their usual activities. By the time patients reach Class IV, they are unable to perform any physical activities, and may have dyspnea and fatigue at rest, with an increase in symptoms in reaction to almost any physical activity. Reference: Rich S. Primary pulmonary hypertension: Executive summary. Evian, France: World Health Organization, 1998. Rich S. World Health Organization

Prognostic Factors for Risk of PAH Disease Progression
Lower Risk Higher Risk Evidence of RV failure No Yes Progression Gradual Rapid WHO Class II, III IV 6-minute walk distance >380 m <325 m Brain natriuretic peptide <180 pg/mL >180 pg/mL Echo findings Minimal RV dysfunction Pericardial effusion; significant RV dysfunction Hemodynamics Normal/near normal RAP and CI High RAP, Low CI Disease progression in PAH is variable. Factors associated with higher risk of disease progression are noted here, including evidence of right ventricular failure, a rapidly advancing symptomology, being diagnosed at WHO class IV, and not being able to walk 325 meters in 6 minutes. BNP (>180 pg/mL) is elevated in right ventricular pressure overload and correlates with severity of right ventricular dysfunction and mortality in PAH. Other factors associated with poorer prognosis include evidence of pericardial effusion and significant RV dysfunction on echocardiography, and high RAP and low CI on catheterization. Patients in this higher risk group should be referred to specialty centers of excellence in PAH for evaluation and initial management. Reference: McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114: McLaughlin VV, et al. Circulation. 2006;114:

Clinical and Hemodynamic Predictors of Survival in PAH
Concordance Index (C statistic) 0.8 0.7 0.6 0.5 P<0.005 P<0.001 NS Other Clinical Factors RHC Age, Sex, WHO Class ECHO & PFTs Monitoring of hemodynamics by echocardiography but not right heart catheterization significantly improved a predictive model of survival, according to a retrospective chart review of 657 PAH patients. Mortality predictions were made first according to noninvasive measures, followed by addition of hemodynamics measured by Doppler echocardiography and right heart catheterization (RHC). Multivariate analysis showed that right ventricular enlargement, pericardial effusion, and % DLCO were significant predictors of mortality, adjusted for age, functional class and baseline 6-minute walk test. The inclusion of echocardiographic hemodynamic variables significantly improved the prediction of a model that already included age, sex and functional class. Kane GC, Slusser JP, Scott CG, et al. Clinical and hemodynamic predictors of survival: a single center study of 657 patients with pulmonary arterial hypertension. Presented at: 2008 CHEST meeting; October 25-30, 2008; Philadelphia, PA. Session AP2217. N = 657. Kane GC. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AP2217. 67

Role of the Internist or Pediatrician in Diagnosis and Management of PH
Recognize possible PH in patient with unexplained dyspnea on exertion Initiate screening Facilitate referral Provide regular local follow-up Assess volume status, vital signs, and oxygenation Monitor laboratory tests Manage anticoagulation with warfarin, if indicated Provide local emergency care PH is complex with multiple etiologies and poor outcomes. The role of nonspecialist internists in managing PH includes recognizing the potential for PH in patients with unexplained dyspnea. Following initial evaluation, patients should be referred to a specialty center for diagnostic workups and initial management. Patients require long-term follow-up and monitoring, which can be done in local communities. Reference: Rubin LJ, Badesch DB. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med. 2005;143: Rubin LJ, et al. Ann Intern Med. 2005;143:

Summary: PAH Epidemiology and Diagnosis
PAH is rare, serious, and progressive PAH/PH has a wide range of etiologies Symptoms of PAH are nonspecific Screening for suspected PH can be done in local communities Consider referral to specialty centers for PAH confirmation by right heart catheterization and initiation of PAH specific therapy

Screening, Referral and Diagnosis of Pulmonary Arterial Hypertension

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Screening, Referral and Diagnosis of Pulmonary Arterial Hypertension

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