Pulmonary Hypertension
François Haddad
Ramona L. Doyle
Juliana C. Liu
Roham T. Zamanian
BACKGROUND
Pulmonary hypertension (PH) refers to a state in which pulmonary artery pressure is elevated. By expert consensus, PH is defined as a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise as measured by right heart catheterization.1 Pulmonary arterial hypertension (PAH) refers to disease states that localize to small pulmonary muscular arterioles. It is characterized as PH in the presence of (a) a pulmonary capillary wedge pressure (PCWP) <15 mm Hg, (b) pulmonary vascular resistance (PVR) >240 dynes/s/cm5 (3 Wood units), and (c) a transpulmonary gradient >10 mm Hg (mPAP-PCWP).2
GRADING THE SEVERITY OF PH
The severity of PH may be described in terms of pulmonary arterial pressure (Table 10-1), pulmonary vascular resistance or impedance, or pulmonary pathological vascular changes (Heath-Edwards classification [Table 10-2]). When assessing the severity of PH using levels of pulmonary arterial pressure, it is important to always consider cardiac output (CO). In fact, lower pulmonary arterial pressure may reflect a failing right ventricle and more advanced pulmonary vascular disease. Pulmonary vascular resistance (PVR) takes into account pulmonary pressure and flow and is measured as the difference between mean PAP and wedge pressure divided by cardiac output (PVR = (mPAP-PCWP)/CO). PVR is considered a better marker of pulmonary vascular disease. A normal value of PVR is 1 Wood unit or 80 dynes/s/cm5 while PVR values higher than
10 Wood units in PAH or value of PVR higher than 6 Wood units in left heart failure are considered severe. Pulmonary vascular histological changes of the media and intima have also been associated with the severity and reversibility of pulmonary arterial hypertension (PAH) associated with congenital heart disease or idiopathic PAH (Table 10-3).3
10 Wood units in PAH or value of PVR higher than 6 Wood units in left heart failure are considered severe. Pulmonary vascular histological changes of the media and intima have also been associated with the severity and reversibility of pulmonary arterial hypertension (PAH) associated with congenital heart disease or idiopathic PAH (Table 10-3).3
DEFINING PULMONARY VASCULAR REACTIVITY
Pulmonary vascular reactivity refers to the decrease in PAP in response to vasodilators. Several agents are of value in assessing acute vasoreactivity including oxygen, inhaled nitric oxide (usually 20 ppm), epoprostenol (Flolan), adenosine, or nitroprusside (especially in pre-heart transplant evaluations). Pulmonary vascular reactivity studies provide useful prognostic information and guide the choice of therapy in PAH, help predict the reparability of complex congenital heart disease, and help stratify the risk of acute right failure after heart transplantation. A positive vasodilator response in PAH is defined as a reduction of mPAP by at least 10 mm Hg to a value of 40 mm Hg or less. Significant response is found in about 5% to 6% of PAH patients. These patients have a better response to calcium channel blockers.2 A significant response in advanced heart disease undergoing a pretransplantation evaluation is defined by a decrease in PVR to a value of 3 Wood units or less.
TABLE 10-1 Hemodynamic grading of PH | ||||||||||||||||
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TABLE 10-2 Heath-Edwards classification of PH3 | ||||||||||||||
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TABLE 10-3 Classification of pulmonary hypertension1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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WHO CLASSIFICATION OF PH
The World Health Organization (WHO) classifies patients with PH into five groups based on etiology and pathobiology. Pulmonary arterial hypertension (PAH) describes group 1 PAH; group 2 describes patients with pulmonary venous hypertension; group 3 refers to PH associated with lung disease and/or hypoxemia; group 4 describes PH associated with chronic thrombotic and/or embolic disease and group 5 refers to miscellaneous causes of PH.1 This revised classification provides a useful framework for the diagnosis and management of PH patients. Modifications to this classification have been made at the latest WHO meeting in 2008. Formal publication of the classifications is still pending.
PATHOPHYSIOLOGY OF PH
Multiple molecular pathways have been implicated in the pathogenesis of PAH. These include nitric oxide, prostacyclin, endothelin-1, and serotonin pathways.A dysfunction in these pathways can lead to an imbalance between vasodilatation and vasoconstriction,and between apoptosis and proliferation, which leads to progressive vascular disease. In patients with pulmonary venous hypertension, PH can be explained by left ventricular diastolic failure, left-sided valvular heart disease, or pulmonary vein stenosis. In patients with lung disease, PH can be explained by hypoxemic vasoconstriction and/or by the loss of pulmonary vascular bed. In chronic thromboembolic PH (CTEPH), in situ thrombosis and/or failure of resolution of thromboemboli contribute to disease progression. The development of pulmonary hypertensive arteriopathy in unobstructive lung regions as well as in vessels distal to partially occluded proximal pulmonary arteries also contributes to the pathophysiology of CTEPH.
One of the most important consequences of PH is right ventricular (RV) failure. Survival in PH is closely related to RV failure. RV adaptation to disease depends on the time of onset of PH (congenital or acquired), setting (acute versus chronic), and specific cause of PH. Hypoxemia can be seen in PH as a result of right-to-left shunting through a patent foramen ovale or congenital defect, ventilation-perfusion mismatches, or decreased diffusion capacity. Hemoptysis, although rare, can be associated with significant morbidity and mortality. Hemoptysis may originate from a rupture of a bronchial artery or pulmonary trunk.
CLINICAL PRESENTATIONS
Most patients initially experience exertional dyspnea and fatigue, which reflects low cardiac output during exercise (low exercise reserve). As the PH progresses and RV failure develops, peripheral edema, exertional syncope, exertional chest pain, and passive liver congestion may occur. Less common symptoms of PH include cough, hemoptysis, and hoarseness (Ortner
syndrome, which is due to compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery). Other symptoms may also reflect the specific underlying cause.
syndrome, which is due to compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery). Other symptoms may also reflect the specific underlying cause.
Signs of RV failure are commonly found in patients with advanced PH; these include elevated jugular veins, distended liver, peripheral edema, and occasionally ascites. An increased intensity of the pulmonic component of the second heart sound is an initial physical finding in PH. Other signs include a right-sided S3 gallop, a holosystolic parasternal murmur of tricuspid regurgitation, and in more severe disease, a diastolic pulmonic regurgitation murmur.The right-sided murmurs and gallops are augmented with inspiration.4
LAB EXAMS AND IMAGING
A comprehensive workup is necessary in order to confirm the presence of PH, assess its severity and identify its cause.1,2,5 Echocardiography is very helpful in estimating pulmonary artery pressure and assessing RV function. Signs of RV pressure overload may include D-shape left ventricle, tricuspid regurgitation, decreased systolic performance, and RV hypertrophy (>5 mm wall thickness). Right heart catheterization (RHC) is the most reliable method for measuring pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular reactivity. RHC is often obtained to confirm the diagnosis, assess pulmonary vascular reactivity, and evaluate the response to therapy. Electrocardiography may reveal signs of RV or right atrial dilatation, right bundle branch block, or arrhythmias. A comprehensive laboratory workup includes complete blood count, a comprehensive metabolic panel, B-type natriuretic peptide (BNP), troponins, collagen vascular disease workup, assessment for hypercoagulable states, hepatic serologies, and HIV screening. Functional studies such as 6-minute walk test or cardiopulmonary exercise test are important for the assessment of functional capacity and response to therapy. The diagnostic evaluation may also include a pulmonary function test, a sleep study, chest x-ray, ventilation-perfusion scanning, and/or CT-angiography. Magnetic resonance imaging is useful in studying RV function and in modeling pulmonary circulation.
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