PULMONARY HYPERTENSION Jigme Sethi, M.D. LEARNING OBJECTIVES 1. To be able to list the causes of pulmonary hypertension based on the underlying mechanism 2. To understand the changes in cardiac function produced by chronic pulmonary hypertension THE PULMONARY CIRCULATION IN HEALTH The pulmonary circulation is a low-resistance, low-impedance, highly compliant and therefore high-capacitance vascular bed. It is highly dependent upon the performance of the two ventricles it connects, and because the capillaries of the pulmonary circulation run within the walls of the alveoli, the resistance of the pulmonary vasculature depends upon airway (and pleural) pressures. It is poorly equipped for self-regulation, unlike the coronary or cerebral circulation. At any time, a given stroke volume ejected from the RV is proportioned into a pass-through component that returns to the LV, and a stored component that remains temporarily within the pulmonary vasculature. The capacitance of the pulmonary circulation is approximately 400-500 ml, or about a tenth of the circulating blood volume. The pulmonary capillary blood volume is about 100-200 ml, and circulation time is about 0.75 sec. The blood flow through the lungs is equal to the alveolar ventilation, and both occur in a phasic manner, but the rates are different (respiratory rate is much slower than heart rate). Therefore matching of blood flow to ventilation occurs on a regional basis by means of a system of hypoxic vasoconstriction, in that vessels in poorly ventilated, hypoxic areas of the lung are vasoconstricted so as not to waste blood flow to those poorly gas exchanging areas. This is fundamentally different from the systemic circulation where arterioles dilate in areas of hypoxemia and poor oxygenation. Pulmonary vascular resistance is defined by the equation: R= Ppa-Pla/ Q, where Ppa-Pla is the difference of mean pressures between the pulmonary artery and the left atrium respectively, and Q is the pulmonary blood flow in L/min. Normal R is 0.1mmHg/L/min (or 100 dynes/sec.cm5) Changes in PVR can be either active or passive. Active changes refer to changes in arterial tone mediated by the sympathetic nerves or hypoxic vasoconstriction (see below), whereas passive changes are alterations of caliber or pressure resulting from changes in lung volumes, gravitational effects and recruitment. Changes in the structure of the pulmonary vessels, or so-called remodeling, can also change PVR, and therefore, the pressure in the circulation. For example, the fetal vessels are thicker and more muscularized than adults and failure of this muscularization to regress in the neonatal period causes persistent pulmonary hypertension. Similarly, unlike the yak, which is native to high altitudes, humans living at high altitude have muscularized vessels and therefore higher PVR, and higher pulmonary arterial pressures for a given cardiac output. Thus at 4540m with an ambient P02 of 80 mmHg, the mean PA pressure is about 28 mmHg in healthy humans, twice that of persons at sea level (about 12 mmHg), with the same cardiac output. THE DEFINITION OF PULMONARY HYPERTENSION Pulmonary hypertension is defined as sustained elevations of pulmonary mean arterial pressures more than 25 mmHg at rest or 30 mmHg on exercise. Ordinarily, mean pulmonary artery pressures are around 10-12 mmHg in health. Aging is associated with a slight increase in mean pressures but less than the diagnostic criteria for the definition. These criteria apply to persons living at sea level. Pulmonary hypertension without a known underlying cause is termed primary pulmonary hypertension, and is a unique disorder affecting young women predominantly, with an incidence of approximately 1-2/million in the general population. Familial forms of the disease constitute about 6% of PPH cases, and are autosomal dominant with genetic anticipation. The majority of PPH patients have the clinically identical sporadic form. Secondary pulmonary hypertension occurs when an underlying cause can be demonstrated (see below). Although the manifestations of the pulmonary hypertension are mostly similar to the PPH variety, the underlying cause usually overshadows the more subtle abnormalities attributable to the pulmonary hypertension. Thus the manifestations of emphysema are prominent long before the symptoms of secondary pulmonary hypertension appear in the patient. Cor pulmonale exists when the right ventricle dilates and fails from exposure to high pulmonary artery pressures. PATHOPHYSIOLOGICAL TYPES OF PULMONARY HYPERTENSION The processes that give rise to pulmonary hypertension are a combination of increased vasoconstriction of the pulmonary arteries, structural changes that result in increased vascular resistance (remodeling), and various degrees of intra-vascular thrombosis causing further obstruction to pulmonary blood flow. 1. Passive Pulmonary Hypertension: Elevated left heart filling pressures (usually a PAWP above 20 mmHg) lead passively to pulmonary venous hypertension, followed thereafter by reactive vasoconstriction, and structural remodeling of the pulmonary arterial and venous beds, resulting in further pulmonary hypertension. Reactive vasoconstriction of the small pulmonary arteries can be attenuated, in experimental models, by alpha adrenergic blockers such as phentolamine or calcium channel blockers such as nifedipine. Dilatation and medial hypertrophy of the pulmonary veins, and eccentric intimal fibrosis of the arteries and veins are seen as a result of remodeling. Both the vasoconstriction and the remodeling reverse rapidly after alleviation of the downstream elevations in LV filling pressures (e.g. surgical correction of mitral stenosis) with reversal of pulmonary hypertension. 2. Hyperkinetic Pulmonary Hypertension: This entity is seen in conditions causing high flow through the pulmonary circulation in combination with pressure overload. Normal humans can increase blood flow through the pulmonary circulation by a factor of 4 without appreciably changing PA pressure, due to a combination of recruitment of hitherto collapsed vessels and vasodilatation leading to a lower PVR under such circumstances. However, in the presence of a high flow Left to Right Shunt, as in a VSD or PDA, the pulmonary circulation is exposed to a combination of pressure overload generated by the left ventricle and the increased flow, leading to reactive vasoconstriction and then remodeling. In the case of a shunt at the atrial level, usually the elevations of PA pressure are modest and reflect the absence of exposure to LV pressures. Additionally, in the neonate, the elevated flows and pressures resulting from a shunt from left to right, are superimposed upon the failure of involution of the thick arterial media, aggravating the pulmonary hypertension. The structural remodeling in hyperkinetic pulmonary hypertension is reversible if the changes are limited to medial hypertrophy, extension of muscular coats into non-muscular distal pulmonary arteries and intimal fibrosis, but become irreversible if plexiform lesions are present. Reversal of the direction of shunting to right to left due to the very high PA pressures is called Eisenmenger’s syndrome. 3. Obstructive Pulmonary Hypertension: This may be seen in situations where the pulmonary bed is obstructed by chronic thromboembolic disease, or in schistosomiasis where parasite eggs are deposited in the pulmonary vessels. Over time, remodeling takes place, and the obstructions become fixed, leading to pulmonary hypertension. Chronic thromboembolic disease must always be excluded in unexplained cases of pulmonary hypertension. 4. Obliterative Pulmonary Hypertension: This results from loss of the pulmonary vascular bed as a whole due, for example, to emphysema where alveolar surface area is lost from destruction of the walls of the alveoli, along with their component capillaries. Similar destruction of the pulmonary vasculature is seen in the extensive destruction resulting from pulmonary fibrosis. 5. Vasoconstrictive Pulmonary Hypertension: Unlike the systemic arteries which vasodilate in response to hypoxia or hypoxemia, the pulmonary arteries react by vasoconstriction. Thus, diseases of the lungs resulting in chronic hypoxia, e.g. severe COPD, pulmonary fibrosis, long-standing obstructive sleep apnea, or end stage sarcoidosis, or extensive right to left shunting through the myriad arteriovenous spiders of hereditary hemorrhagic telengiectasia can lead to vasoconstriction as the primary pathophysiological basis for the pulmonary hypertension that ensues. In other situations, the vasoconstriction can be idiopathic, or of unknown cause. Although Primary Pulmonary Hypertension or PPH is the classic example, other associations include HIV disease, anorexigen use, inhaled cocaine abuse, connective tissue disorders (SLE, RA, scleroderma, or mixed connective tissue disease) and liver disease (so-called portopulmonary hypertension).. This classification, though somewhat simplistic in pathophysiological terms, is extremely useful clinically, and the approach to establishing the etiology of the pulmonary hypertension in a given patient must proceed along the orderly schema outlined above. Thus, primary pulmonary hypertension is excluded if left ventricular failure exists with elevated pulmonary capillary wedge pressures, if an un-repaired VSD can be detected on echocardiogram, or if extensive pulmonary fibrosis or chronic thromboembolism can be established. PATHOLOGY OF PULMONARY HYPERTENSION 1. The earliest pathological change in pulmonary hypertension of any etiology is that of medial hypertrophy with thickening of the muscular media of pulmonary arteries and extension of muscular media into previously non-muscularized pulmonary vessels. While smooth muscle stretch and elevated pressures can stimulate proliferation of smooth muscle cells, elevated endothelin-1 levels can mediate smooth muscle proliferation. 2. While intimal proliferation leading to intimal fibrosis and concentric intimal hyperplasia is a later feature of pulmonary hypertension, two aspects of endothelial dysfunction bear special mention. First, endothelial dysfunction of a more subtle nature may well underlie the development of pulmonary hypertension. Thus loss of endogenous endothelial derived relaxing factor, or NO, may predispose to vasoconstriction, as may overproduction of the potent vasoconstrictor substance endothelin-1. Similarly, increases in the endothelial content of von willebrands factor as is seen in PPH or patients with high flow left to right shunts, may predispose to local thrombosis. Second, the hallmark lesion of pulmonary arterial hypertension, especially, (but not limited to) PPH, is the plexiform lesion, a complex branching system of endothelial channels within the lumen of the pulmonary arteries. This must be differentiated from recanalized thrombi obstructing the pulmonary vessels. In familial PPH, the endothelial cells forming the plexiform lesions are monoclonal in origin, and indeed the gene for familial hypertension has been localized to a short segment of chromosome, but remains to be exactly characterized. 3. Thrombosis occurring in situ is another characteristic abnormality in the smaller vessels of the hypertensive pulmonary circulation, and must be distinguished from the larger obstructing clots in the proximal vessels that characterize thromboembolic pulmonary hypertension. CONSEQUENCES OF CHRONICALLY HIGH PULMONARY ARTERY PRESSURES The right ventricle bears the brunt of the hemodynamic burden imposed by chronically elevated PA pressures. Although normally a thin walled chamber with a crescent-shaped cavity on cross section, after exposure to high PA pressures for a prolonged period, it dilates, initially developing a more ovoid cross sectional chamber pattern. Progressive thickening of the wall ensues and it can finally exceed LV thickness in the most advanced cases. In severe pulmonary hypertension, the combination of free wall thickening and dilatation imposed by incomplete emptying against high PA pressures leads to bowing of the septal wall into the LV cavity, encroaching upon LV size, filling, and therefore, stroke volume. These changes in the structure of the right ventricle are adaptive in nature— designed to preserve RV output in the face of increased pulmonary artery pressures and hence, afterload. The adaptive nature of the response can be best understood by reviewing the cardiac response to exercise as pulmonary hypertension progresses. The normal response to exercise consists of an increase in cardiac output, a consequent “hyperkinetic” increase in pulmonary artery pressure that is however blunted by recruitment and distension of pulmonary vasculature, and no change in pulmonary wedge pressure. All of this is accomplished without an increase in RV end-diastolic pressure, which is a negative marker of RV compliance and ejection efficiency. As pulmonary hypertension develops, baseline PA pressures and exercise-induced increments increase, but RV hypertrophy and dilatation allow appropriate increases in cardiac output, albeit at the cost of an increasing RVEDP. In the stage of RV failure however, the extremely high PA pressure overcomes the compensatory RV remodeling and cardiac output fails to rise appropriately with exercise. Since RV adaptation maintains CO in the face of high PA pressures, it follows that RV function may be a predictor of survival in patients with pulmonary hypertension. Genetic factors may also predict which patients will adapt appropriately in terms of RV remodeling, and hence determine outcome. In general, once RV failure develops, patients usually die in <1 year, in contrast to a 3.5-5.0 year survival in patients with preserved RV function. PRIMARY PULMONARY HYPERTENSION: SALIENT FEATURES This is a rare disease, with an incidence of 1-2 per million, affecting predominantly young to middle aged women. 6% of the incidence of PPH is accounted for on a familial, autosomal dominant basis. One important gene, PPH1, encoding for Bone Morphogenetic Protein Receptor Type II (BMPR II) has been identified, and there is growing evidence that dysfunction of the receptor leads to abnormal proliferation of vascular endothelial cells, such as is seen in the plexiform lesion. Subjects with the haplotype have elevated PA pressures during exercise even while they have normal PA pressures at rest—a potential screening test. The exact mechanism of the disease is not known. There is clearly an imbalance of vasodilator and vasocontrictor substances in the regional pulmonary circulation. Reduced expression of nitric oxide synthase and prostacyclin synthase in the pulmonary endothelium leads to decreased activity of nitric oxide and prostacyclin, both very potent vasodilators. On the other hand, endothelin, a potent vasoconstrictor and endothelial cell mitogen, is overexpressed in the lungs of PPH patients, and elevated plasma levels are correlated with disease severity and worsening prognosis. CLINICAL FEATURES OF PULMONARY HYPERTENSION The primary symptom experienced by patients with isolated primary pulmonary hypertension is dyspnea, and this is the chief complaint in up to 60% of patients. As the PA pressures rise with a resulting drop in RV ejection fraction leading to a reduction in cardiac output, fatigue and reduced exercise tolerance become more prominent symptoms. Since the cardiac output is fixed and reduced by the elevated PA pressures and does not rise appropriately with increased needs, these symptoms are initially pronounced during exercise. In addition, during exercise, due to systemic vasodilatation, blood pressure may fall and if the cardiac output cannot rise appropriately, patients may experience syncope or sudden death. Hemoptysis is a relatively uncommon symptom and is often due to bleeding from unrelated causes, such as bronchitis or endobronchial lesions. It may, however, also be precipitated by the high pulmonary artery pressures. 10% of patients with PPH, usually women, report Raynaud’s phenomenon. Other clues to the diagnosis can be categorized as follows: Evidence of elevated pulmonary arterial pressures: ejection systolic murmur over the pulmonic area, often with wide splitting of the S2 (i.e. delayed P2 component). P2 may be accentuated enough to be louder than A2, and may even be heard in the mitral area. Evidence of right ventricular pressure overload: Parasternal heave, raised JVP, often with the elevated CV waves of triscuspid regurgitation, and later in the course of the disease, hepatomegaly with nutmeg liver and congestive hepatopathy, and leg edema. Ascites and pleural effusions may also be seen in advanced pulmonary hypertension. Evidence of loss of the pulmonary vascular bed: elevated A-a gradient, hypoxemia, cyanosis, and decreased diffusion capacity for Carbon Monoxide. Other pulmonary function tests will reflect the underlying etiology for the pulmonary hypertension, e.g. severe obstruction in cor pulmonale from emphysema, or severe restriction in pulmonary fibrosis, or an increased shunt fraction in patients with Hereditary Hemorrhagic Telengiectasias. Evidence of reduced cardiac output: In the later stages, as right ventricular ejection fraction drops due to the high afterload of the right ventricle, cardiac output falls, and patients complain of severe fatigue in addition to shortness of breath, and may be orthostatic. The same situation can be seen if patients with pulmonary hypertension are over-diuresed in an effort to reduce the leg edema resulting from RV failure. Cardiac output drops, patients may be dizzy or orthostatic or syncopal, and complain more of fatigue than dyspnea. Evidence of pulmonary hypertension on the chest radiograph includes dilated pulmonary arteries (main right descending pulmonary artery width greater than 1.4 cm in a female or more than 1.6 cm in a male), dilated pulmonary outflow tract bulging out beyond the aortic knuckle on the left side of the cardiac silhouette, pruning of pulmonary vasculature (vessels cannot be traced out to within 2 cm of the edge of the lung as is normal), and dilatation of the RV with uplifting of the apex of the heart from the left hemidiaphragm. On the EKG, right ventricular hypertrophy is suggested by right axis deviation or a right bundle branch block pattern. On echocardiography, if tricuspid regurgitation is present, as it often is, the systolic PA pressures can be estimated by adding 4 x the square of the regurgitation jet velocity, to the CVP. The right ventricle may be hypertrophic or dilated, and occasionally clots can be seen in the proximal pulmonary arteries in patients with thromboembolic pulmonary hypertension. A VSD may be seen if that is the cause of the hypertension. 25% of normal adults have a patent foramen ovale, through which right to left shunting may take place if PA pressures are very high, further exacerbating the hypoxemia. Therefore, a bubble study should always be obtained—either direct shunt through the patent foramen ovale may be detected, or hypoxic pulmonary hypertension diagnosed if premature appearance of bubbles in the left side of the heart within 6 cycles suggests a right to left shunt through an unsuspected AV malformation in the lung or elsewhere. A V/Q scan should not be abnormal in pulmonary hypertension unless there is underlying chronic thromboembolic disease, or other parenchymal lung disease causing pulmonary hypertension. A spiral CT scan of the chest with radio-opaque contrast may well show the clots obstructing the lumen of the pulmonary arteries in those with thromboembolic disease, but a pulmonary angiogram which outlines only the lumen of the arteries may well miss these clots. Nevertheless the angiogram is very useful in detecting pulmonary artery malformations or macroscopic telengiectasias that may cause shunting with hypoxemia and ensuing hypoxic pulmonary hypertension, and sometimes in detecting pulmonary thromboembolic disease. It is not often required however. A right heart catheterization is diagnostic, allowing measurement of PA systolic, diastolic and mean pressures, calculation of pulmonary vascular resistance, determination of cardiac output, measurement of elevated left heart filling pressures (i.e., the PAWP) and occasionally, detection of step-ups in oxygen saturation in the right atrium or right ventricle resulting from left to right shunts at those levels. Finally, right heart catheterization allows observations of responses to some therapeutic interventions such as infusion of prostacyclin, inhaled nitric oxide, or orally-acting calcium channel blockers. The etiology of the pulmonary hypertension should suggest itself on the history or physical, by providing clues to the presence of the various diseases listed as causes in the various categories. If no obvious clinical cause is apparent, then serology for connective tissue disorders, testing for HIV or liver disease, especially cirrhosis, search for thromboembolic disease and procoagulant disorders, a sleep study to rule out sleep apnea, a history to exclude anorexigen or cocaine use or travel to areas endemic for schistosomiasis, and an echocardiogram to detect occult valvular disease such as mitral stenosis, mitral valve prolapse or diastolic disease, are appropriate. A high resolution CT scan may be used to screen for occult pulmonary parenchymal disorders where the chest x-ray is normal, as occurs in a proportion of patients with pulmonary fibrosis, or bronchiectasis for example. An arterial blood gas may show evidence of unsuspected alveolar hypoventilation, as in patients with obesity hypoventilation or Pickwickian syndrome, and unexplained hypoxemia should suggest a shunt if supplemental oxygen does not improve the hypoxemia. Finally, the diagnosis of PPH is one of exclusion, in all circumstances. It is important to note however, that the clinical stigmata of pulmonary hypertension, may be very subtle in the early stages of the disease, especially in young patients with the primary form, and one must not wait for evidence of right ventricular failure to develop before investigating for the disease. Every patient with dyspnea and hypoxemia or cyanosis, developing over months, with a clear chest X-ray and no evidence of cardiac abnormalities, especially if young, should be investigated for this disease. The mean length of time to diagnosis is about 2 years in 90% of patients with PPH. MANAGEMENT OF PULMONARY HYPERTENSION 1. Treat the underlying cause: For example, this could involve treating the left sided heart failure, resorting to a mitral valve commissurotomy for mitral stenosis, surgical correction of a shunt, treatment of sleep apnea, discontinuing any anorexigen use, optimal treatment of COPD, etc. 2. In particular, emphasis should be placed on correcting hypoxia, which predisposes to accelerated pulmonary hypertension in patients with COPD, sleep apnea, or advanced lung disease. Oxygen is an excellent pulmonary vasodilator! Screen for hypoxemia during exertion, and provide supplemental oxygen during exertion. Care must be taken to detect and eliminate occult nocturnal desaturations, which over time can exacerbate pulmonary hypertension. Look for and close if possible, any major shunting through a patent foramen ovale for example, and especially suspect a shunt if patients do not respond to supplemental oxygen with improved saturations or exercise tolerance. 3. Anticoagulate patients with advanced pulmonary hypertension: This has been shown to improve survival in a few studies, and since thrombosis is such a common finding in all forms of advanced pulmonary hypertension, it has a sound basis. Anticoagulation reduces in situ thrombosis, and the incidence of thromboembolism in patients predisposed to DVT due to leg edema and heart failure. 4. Warn against vigorous exertion—exercise may precipitate an acute drop in blood pressure, syncope, and even death. 5. Diurese gently, since in right ventricular failure, the pressure overloaded right ventricle may cause the septum to bulge into the left ventricle raising LVEDP and cause pulmonary edema. Diurese cautiously, since the RV relies on elevated preload to maintain ejection in the face of elevated afterload, so that overdiuresis can lead to a further, deleterious, and avoidable reduction in cardiac output. Digoxin has limited use, perhaps only in patients on the negatively inotropic calcium channel blockers. 6. Vasodilator therapy is useful in selected patients, i.e. those with PPH and pulmonary hypertension resulting from Scleroderma and perhaps other connective tissue diseases, or HIV. However there is increasing data that some of these agents are possibly useful in other forms of secondary pulmonary hypertension as well. The pharmacologic therapy of pulmonary vascular disease will be discussed in detail in a subsequent lecture. 7. Lung transplantation is often beneficial in patients with primary pulmonary hypertension, especially since this disease often afflicts younger patients. 5-year survival is about 50-70%, but since waiting times are about 2 years for double lung transplants, patients should be referred when still in NYHA class 1-2, i.e. symptoms only with moderate exertion. If referred when symptoms are present at rest, mean survival may only be on the order of 6 months. Complications such as post-operative mortality and bronchiolitis obliterans are more common in patients transplanted for PPH than for other causes. OUTCOME OF PATIENTS WITH PULMONARY HYPERTENSION The development of pulmonary hypertension and right heart failure, or cor pulmonale, from underlying hypoxic or pulmonary disease represents a late stage of the illness, and although patients rarely die from the pulmonary hypertension itself, mortality from advanced respiratory failure is about 90% at 3 years. Pulmonary hypertension from cardiac or congenital shunts may be either reversible or irreversible, depending on the duration and severity of shunted blood flow (e.g. a pulmonary to systemic blood flow through a left to right shunt of > 2:1 is usually associated with severe pulmonary hypertension, but may still be reversible after anatomic correction, whereas the development of Eisenmenger’s syndrome usually signifies an irreversible stage of pulmonary hypertension). Primary pulmonary hypertension is a deadly disease as patients on conventional therapy prior to the use of prostacyclin were almost uniformly dead in 5 years. Median survival was 2.5 years. Anticoagulants double the 3 yr survival rates, Current survival on continuous infusions of prostacyclin is in the order of 50% at 5 years, which compares very favorably with survival after lung transplantation for this disease. Survival may be even better as more patients are started on prostacyclin earlier, and indeed many patients have been removed from transplantation registries because of excellent response to this drug. Most patients succumb to right sided heart failure, but 7% may experience sudden death. In terminal stages dilatation of the right heart causes septal bulging and compromise of LV filling, with congestive heart failure. Balloon septostomy creates a low resistance shunt from right to left, decompressing the RV and allowing LV filling, but is seldom used. Pregnancy often accelerates pulmonary hypertension in patients with PPH, and is poorly tolerated. Oral contraceptives also exacerbate PPH and are contraindicated.
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