Pulmonary Hypertension

DR GAINE: Mrs JL is a 44-year-old businesswoman who has primary pulmonary hypertension (PPH). Mrs JL gives us an opportunity to explore the clinical presentation of patients with pulmonary hypertension and to discuss the current approach to evaluation and treatment. She first noticed that she had shortness of breath in 1997; however, it was 10 months later before the diagnosis of PPH was made. Mrs JL, can you tell us a little bit about what was going through your mind when you first noticed that you couldn't do the things you used to?

PATIENT: I had many different thoughts about it. I thought that I'd gained weight and was out of shape. I was going through menopause at the time and I thought that maybe the hormone replacement therapy was causing some of the problems. Then I thought that it was adult asthma or something like that. Just lots of different things.

DR GAINE: It is very common for patients with pulmonary hypertension to have this kind of presentation. It usually takes a considerable time for patients to come to terms with their slow steady decrease in exercise tolerance, increasing fatigue, and dyspnea on exertion. The initial symptoms of pulmonary hypertension are nonspecific, which can result in a significant delay in diagnosis.¹ Mrs JL was diagnosed with pulmonary hypertension in September 1998 following an echocardiogram, which revealed a right ventricular systolic pressure estimated at 75 to 85 mm Hg, with normal left heart function. Her condition continued to deteriorate until we saw her in November 1998.

How limited were you by the time we saw you and what could you do then?

PATIENT: Very little in terms of continuous activity. For instance, if I went to the grocery store, I would have to stop maybe 2 times between the car and the front door of the store, and walking up and down aisles in the grocery store was a problem. I was constantly stopping whether I needed to pick up a piece of merchandise or not. I noticed that sometimes after standing up quickly or bending over I'd be lightheaded. Working in the garden, all I could do was water the plants, and even that was an effort. Little things like that were very difficult.

DR GAINE: Patients with pulmonary hypertension will complain of progressive shortness of breath on exertion, which can be quantified in terms of the distance a patient can walk without stopping. In more advanced disease stages, they may experience exertional chest pain, secondary to right ventricular ischemia. Exertional dizziness or lightheadedness is also seen as the disease progresses. Overt syncope is a serious complication of pulmonary hypertension and portends a poor prognosis. Other symptoms to inquire about include Raynaud phenomenon, which occurs in 10% of patients with PPH, predominately women, but may also suggest an underlying connective tissue disease such as scleroderma. Cough and hemoptysis are uncommon with PPH, although hoarseness from compression of the left recurrent laryngeal nerve by an enlarged pulmonary artery can occur (Ortner syndrome).

On examination, when we saw Mrs JL in November, she was 5 ft 4 in (1.5 m 10 cm) and weighed 220 lb (99 kg). She had a blood pressure of 136/84 mm Hg, a heart rate of 70/min, and a resting room air oxygen saturation of 98%. Her jugular venous pressure was elevated at 9 cm. Her heart examination was notable for the presence of a right ventricular heave, a prominent P₂ and an S₄. Auscultation revealed her lungs were clear and her abdominal examination revealed no hepatomegaly or ascites. The results of musculoskeletal examination were normal. Her extremities had only trace edema, with no clubbing. There were no dermatological manifestations of connective tissue disease: she had no cutaneous telangiectasias or sclerodactyly to suggest the presence of scleroderma or malar rash indicative of lupus.

At the time of initial presentation, patients with pulmonary hypertension typically have a loud P₂, a reliable indicator of elevated pulmonary artery pressures. It is important to first compare the intensity of both aortic (A₂) and pulmonary components (P₂) to the second heart sound in the pulmonic area, which is the second left interspace at the sternal border. A P₂ that is louder than the A₂ in the pulmonic area, and if this difference in intensity is sustained as the stethoscope is moved down toward the apex, is a helpful bedside method for defining the presence of pulmonary hypertension.² The majority of patients will also have an audible right ventricular S₄. As the right ventricle dilates, patients may develop the murmur of tricuspid regurgitation, and on occasion, the pulmonary valve ring may also dilate, producing the Graham Steele murmur of pulmonary insufficiency. As right ventricular function worsens, a right ventricular S₃, which unfortunately portends a grave prognosis, may be heard. The findings of jugular venous distention, ascites, and edema are signs of advanced right heart failure. On occasion, there may be marked ascites as a manifestation of progressive right heart failure without significant peripheral edema.

Mrs JL underwent a right heart catheterization in November 1998, which revealed a pulmonary artery pressure of 110/40 mm Hg (mean, 72 mm Hg). (The normal mean [SD] pulmonary artery pressure for an adult in their 40s at rest is 14 [1] mm Hg.³ ) However, to make the diagnosis of pulmonary hypertension, the National Institutes of Health registry, formed to study PPH in the early 1980s, decided that the mean pulmonary artery pressure must be greater than 25 mm Hg at rest or greater than 30 mm Hg in response to exercise. While these arbitrary figures are significantly outside the normal range, they are low enough to include patients who may be identified in the early stages of the course of their disease. Mrs JL had a right atrial pressure of 15 mm Hg, which was consistent with significant right ventricular dysfunction. Her pulmonary capillary wedge pressure was less than 15 mm Hg while her cardiac output was 5 L/min. During the catheterization procedure, Mrs JL underwent a vasodilator trial with inhaled nitric oxide to determine whether she had any reversible vasoconstriction present. However, there was no change in either her pulmonary artery pressure or her cardiac output in response to the nitric oxide at 40 ppm for 10 minutes. This finding indicates that she had considerable pulmonary vascular intimal proliferation in addition to the smooth muscle hypertrophy that are seen in early stages of the disease.

Mrs JL also underwent a number of special studies that are necessary in the evaluation of pulmonary hypertension. These included a chest radiograph, which revealed the characteristic enlarged right and left pulmonary arteries with clear lung parenchyma. The result of a ventilation-perfusion scan was normal without evidence for thromboembolic disease. Subtle abnormalities at the periphery of the perfusion lung scans can occasionally be observed in PPH. Results of an echocardiogram confirmed the presence of pulmonary hypertension with normal left heart function and absence of defects in the septum to suggest congenital heart disease. The results of her pulmonary function tests had features characteristic of PPH with a mild reduction in her lung volumes and diffusing capacity without any evidence of airway obstruction. Results of a number of blood tests, including an antinuclear antibody, human immunodeficiency virus (HIV), and liver function and hepatitis serological tests, were also negative. Therefore, her extensive evaluation excluded secondary causes of pulmonary hypertension, including congenital heart disease, interstitial lung disease, and liver disease, and pointed to the diagnosis of PPH.

Primary pulmonary hypertension is a rare disease that occurs in 1 to 2 per million of the population with a female/male ratio range of 1.7:1 to 3.5:1.^{1 ,4} While the majority of cases are sporadic, the disease is familial in at least 6% of cases.⁵ The familial disease is inherited in an autosomal dominant manner with incomplete penetrance. The gene responsible was recently discovered on chromosome 2q33.^{6 - 7} Heterozygous germline mutations in the bone morphogenetic protein receptor II gene (BMPR2) encoding a transforming growth factor β receptor were described. The high frequency of apparently sporadic cases of PPH and the observed reduced penetrance of a dominant gene within families suggest that additional triggers may be necessary to precipitate dysregulated vascular growth. A number of risk factors or possible triggers for the development of PPH have been identified. Anorexigens have been determined to be associated with PPH in susceptible individuals.^{8 - 12} Mrs JL took anorexigens (fenfluramine and phentermine) intermittently between 1994 and 1996 prior to the development of symptoms. Sporadic case reports have described a relationship between PPH and pregnancy. While oral contraceptive use may exacerbate the symptoms of pulmonary hypertension, it does not appear to increase the risk of developing PPH.^{13 - 14} An association between PPH and substance abuse (eg, methamphetamines and cocaine) has also been reported.⁸

Since Mrs JL had New York Heart Association class III symptoms and had no response to inhaled nitric oxide at catheterization, we recommended that she begin continuous intravenous epoprostenol therapy. She began treatment in January 1999.

DR GAINE: Can you tell us a little about what you can do now with this treatment?

PATIENT: I can do much more. I only notice the shortness of breath if I am walking fast, if I am hurrying. Sometimes I do notice if I stand up real quickly I might have just a bit of lightheadedness, but I am much more back to a normal routine of life than I was.

DR GAINE: What problems have you had with your pump or catheter to date?

PATIENT: I am wearing it underneath my arm here. I am never without it. I spend maybe tops an hour a day mixing the medicine, changing the dressing and cleaning the catheter, changing the tubing and the pump. So far I have had few problems with either the pump or catheter. I have become much more comfortable over time with operation of the pump and I have not had any catheter infections.

DR GAINE: Catheter infections and problems with drug delivery are not uncommon in patients treated with continuous intravenous epoprostenol. Are you back at work?

PATIENT: Yes.

DR GAINE: Mrs JL has PPH. She does not appear to have the familial variety of this disease by history. Her history of exposure to diet suppressants supports a diagnosis of anorexigen-associated PPH in the absence of other conditions by history or by her extensive laboratory work-up to date. She is currently being treated with continuous intravenous epoprostenol. I would like now to discuss the current approach to the evaluation and treatment of pulmonary hypertension.

The World Health Organization (WHO) sponsored the first international symposium on PPH in 1973. The symposium reviewed the rather limited knowledge, at that time, about the disease and developed a consensus about future directions in evaluation and treatment.¹⁵ In 1998, on the occasion of the 25-year anniversary of that original meeting, the World Symposium on PPH, co-sponsored by the WHO, was held in Evian, France.¹⁶ The previous 25 years had seen a dramatic growth in knowledge about the pathology, pathobiology, and treatment options for the disease. One of the significant outcomes of this most recent symposium was to propose a new more clinically useful classification system for pulmonary hypertension. Traditionally, pulmonary hypertension has been classified as being either "primary" or "secondary." While PPH is relatively rare, secondary pulmonary hypertension is distinctly more common and includes a heterogeneous group of diseases, such as emphysema, scleroderma, congenital heart disease, pulmonary fibrosis, or mitral valve disease.¹⁷ A consensus was reached at the 1998 symposium to develop a more inclusive and clinically useful classification system.

The classification system proposed at the World Symposium on PPH divides the causes of pulmonary hypertension into 5 distinct categories (Table 1). Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia result in pulmonary hypertension as a result of either parenchymal destruction that should be readily appreciated on review of a chest radiograph or pulmonary function testing, or due to ventilation-perfusion mismatching and chronic alveolar hypoxia. An elevation in left atrial pressure would be expected to cause a similar rise in the upstream pulmonary artery pressure simply by backward transmission resulting in pulmonary venous hypertension. Pulmonary hypertension due to chronic thrombotic and/or embolic disease includes a variety of emboli, such as thromboemboli, tumor particles, or Schistosoma mansoni ova, that may lead to pulmonary vascular occlusion and the development of pulmonary hypertension. While the vast majority of patients who survive an acute pulmonary embolism will recover completely, chronic thromboembolic pulmonary hypertension occurs in a minority of patients (<1%) who do not effectively remove the vascular obstruction. In these patients, recanalized residua remain, narrowing or obstructing the pulmonary vascular bed, resulting in chronic pulmonary hypertension.²⁰ Disorders directly affecting the pulmonary vasculature, such as capillary hemangiomatosis, or inflammatory conditions, such as sarcoidosis, can also lead to pulmonary hypertension. The final category to be discussed, pulmonary arterial hypertension (PAH), produces characteristic (Figure 1) abnormalities in the wall of small distal pulmonary arteries (Table 1). Mrs JL falls into this category.

The diagnostic evaluation of a patient with suspected pulmonary hypertension that seeks to categorize patients into 1 of 5 distinct categories (Table 2). This is a treatment-based classification system; therefore, by identifying patients in this way, we can more clearly approach treatment of the underlying disease. A contrast echocardiogram provides an estimate of pulmonary artery pressure and reveals left ventricular dysfunction, mitral valve disease, or evidence of congenital heart disease as a cause for the pulmonary hypertension. A chest radiograph and a full set of pulmonary function tests (spirometry, lung volumes, and diffusing capacity) demonstrate parenchymal lung diseases, pulmonary fibrosis, emphysema, or thoracic cage abnormalities as a cause for the pulmonary hypertension (Figure 2). In patients who are overweight with a history of loud snoring and hypersomnolence, a sleep study is performed to rule out obstructive sleep apnea, a potentially reversible cause of pulmonary hypertension.²¹ All patients with pulmonary hypertension should have a ventilation perfusion (V/Q) scan to rule out thromboembolic disease. If the results of the V/Q scan are abnormal, a pulmonary angiogram and spiral chest computed tomography with contrast is performed to define the extent of the disease and to explore the feasibility of thromboendarterectomy surgery. A spiral chest computed tomographic scan with contrast alone is not adequate to rule out chronic thromboembolic disease. Lung biopsy is rarely necessary, generally poorly tolerated by patients with severe pulmonary hypertension, and reserved for cases in which the clinical diagnosis is unclear. A number of blood tests, including antinuclear antibody, rheumatoid factor, and HIV, are performed to look for causes of PAH. Human immunodeficiency virus infection is associated with the development of PAH with a frequency estimated at 0.5%^{22 - 23} that is clinically and pathologically indistinguishable from PPH. Portal hypertension is associated with the development of pulmonary hypertension, a condition called portopulmonary hypertension.²⁴ The presence of portal hypertension may be demonstrated on abdominal imaging using Doppler ultrasound or by obtaining hepatic wedge pressure at the time of catheterization.

The diagnostic evaluation for patients with suspected pulmonary hypertension (Table 2) allows for the categorization of patients based on the treatment-orientated classification (Table 1). Once classified, attention can be focused on treating the underlying disease in an effort to attenuate the pulmonary hypertension. In patients with a disorder of the respiratory system, such as emphysema, the underlying disease is treated with long-term oxygen therapy, steroids, and bronchodilator therapy when appropriate, to reduce the pulmonary artery pressure. Similarly, if a patient has pulmonary venous disease secondary to left ventricular dysfunction, afterload reduction and diuretics are administered in an effort to reduce left atrial pressure and thereby decrease the pulmonary artery pressure. Those patients with mitral valve disease are considered for valve repair or replacement to reduce the chronically elevated left atrial pressure. Chronic thromboembolic pulmonary hypertension requires life-long anticoagulation therapy, an inferior vena cava filter, and possibly a thromboendarterectomy to restore luminal patency and reduce pulmonary vascular resistance.²⁰ For the remainder of this article, we will focus on PAH.

Despite the heterogeneous nature of the various diseases or insults that result in PAH, the vascular lesion produced looks similar with 3 pathological characteristic findings (Figure 1 and Figure 3).²⁵ First, the majority of patients have in situ thrombosis. This in situ thrombosis is believed to occur in part as a result of endothelial dysfunction. Second, there is smooth muscle hypertrophy, secondary to chronic vasoconstriction. Finally, there is intimal and adventitial proliferation. The plexiform lesion (Figure 1 and Figure 3) is frequently seen in PAH and appears to represent a dysfunctional response to vascular injury. The approach to treatment of PAH focuses on these 3 pathological findings: patients undergo anticoagulation with warfarin to keep an international normalized ratio in the range of 1.7 to 2.2; the smooth muscle hypertrophy and vasoconstriction are treated with vasodilator therapy, when appropriate, using calcium channel blockers (CCBs); and the administration of continuous intravenous epoprostenol works not only as a vasodilator but also it is now believed to work on the proliferative disease seen in the intima and adventia.^{4 ,26}

It appears that PAH occurs in susceptible individuals following an insult to the pulmonary vascular bed, resulting in an injury that progresses to produce the characteristic pathological features outlined above (Figure 1). The nature of the insult can be as diverse as the use of certain anorexigenic agents or the increased pulmonary blood flow in individuals with congenital heart disease. However, the individual needs to be susceptible for the injury to progress and develop the characteristic chronic vascular lesion. While a lot of people, like Mrs JL, took diet pills, only a small fraction developed the full-blown pulmonary vascular disease.⁸ Between 1967 and 1970, 3 European countries showed a 20-fold increase in the incidence of PPH associated with the anorexigen aminorex fumarate.²⁷ The overall incidence of developing PPH in individuals who had used aminorex was 1% to 3%.^{9 - 12}

We know from immunohistochemical studies of lung tissue samples from patients with PPH that the endothelium does not stain for endothelial nitric oxide synthase, the constitutive enzyme responsible for the production of the vasodilating and antiproliferative molecule nitric oxide.²⁸ Furthermore, it also has been determined that the production of endogenous prostacyclin is impaired in PPH while thromboxane production is enhanced.²⁹ On the other hand, we know that the endothelium-derived vasoconstrictive and proproliferative peptide, endothelin 1, is increased in the lungs of these patients.³⁰

The vascular smooth muscle is also abnormal in PAH. Potassium channels on the surface of vascular smooth muscle cells regulate the concentration of calcium inside the cell and therefore the degree of muscle contraction. When vascular smooth muscle is depolarized the voltage on the cell surface changes, resulting in inhibition of voltage-gated potassium channels and thereby allowing an influx of calcium and an increase in smooth muscle tone. In PPH, a voltage-gated potassium channel (K_V1.5) has been shown to be dysfunctional.³¹ This hypoxia-sensitive potassium channel is turned off in PPH, resulting in an increase in intracellular calcium in the smooth muscle leading to vasoconstriction, hypertrophy, and perhaps migration and proliferation into the intimal and adventitial layers. It is of particular interest to note that the anorexigen fenfluramine also inhibits this channel in normal pulmonary artery smooth muscle cells, suggesting a possible mechanism for the anorexigen-associated pulmonary hypertension described in Mrs JL.³² An alternative hypothesis links the anorexigens to the development of PAH by their ability to increase the vasoconstrictor serotonin.³³ The recent discovery of an abnormal gene in familial PPH on chromosome 2q33 raises new questions about the development of PPH. The gene, BMPR2, is important in regulating cell growth and proliferation.^{6 - 7} It can be speculated that in a susceptible individual with an abnormal BMPR2 gene, exposure to an insult, such as an anorexigen, may result in uncontrolled vascular proliferation in the vascular bed with a resultant increase in pulmonary vascular resistance. It remains to be determined whether the other abnormalities in endothelial or smooth muscle function discussed above are primary or secondary phenomena.

Early on in the course of PAH the pathological features of the predominant lesion are smooth muscle hypertrophy and vasoconstriction. During this stage of the disease, there is room for oral vasodilator therapy to relax the vascular smooth muscle and reduce pulmonary vascular resistance.³⁴ Later in the disease, however, the proliferative features predominate leaving no room for conventional vasodilator therapy. Unfortunately, more than 75% of individuals with PAH are in this proliferative or irreversible stage at the time of presentation, just like Mrs JL.^{25 ,34} The right heart catheterization and vasodilator trial using a short-acting pulmonary vasodilator is used to determine into which treatment category patients should fall.

The right heart catheterization provides 3 very important pieces of information. First, it confirms the presence of elevated pressure and the absence of pulmonary venous hypertension by demonstrating a normal pulmonary capillary wedge pressure (≤15 mm Hg). Second, hemodynamic measurements can predict survival in patients with PPH.³⁵ For example, an individual with PPH and a right atrial pressure of greater than 20 mm Hg has a median survival of 4 weeks without treatment, according to the NIH registry. Similarly, if the cardiac index is less than 2 L/min, median life expectancy is about 1 year. Indeed, this information was used to derive a formula that predicts a patient's life expectancy by combining the right atrial pressure, cardiac index, and mean pulmonary artery pressure.³⁵ Finally, the right heart catheterization allows for the determinination of the most appropriate therapy when performed in conjunction with a vasodilator trial. The vasodilator trial should be performed using a safe, short-acting vasodilator. The most ideal vasodilator is inhaled nitric oxide. Nitric oxide is specific for the pulmonary vascular bed with no effect on the systemic circulation.³⁶ In the past, CCBs were used to determine the degree of reversibility in the elevated pulmonary vascular resistance. However, there is no longer any role for CCBs in the acute evaluation of patients with pulmonary hypertension. Newer agents, such as nitric oxide, intravenous epoprostenol, or adenosine, allow a safe look for reversibility without much systemic effect. The perils of longer-acting negatively inotropic systemic vasodilators in patients with pulmonary hypertension are important to emphasize. There is a very significant chance that, in the majority of patients (approximately 75%) with PAH, the pulmonary artery pressure will not respond to an acute vasodilator trial because of the advanced proliferative, irreversible pathological feature that is prevalent at presentation.^{25 ,34} On the other hand, it can be predicted with certainty that the systemic blood pressure will eventually drop in all patients given a sufficient dose of these systemic vasodilators. Right ventricular coronary perfusion will be compromised as the systemic blood pressure drops while pulmonary pressures remain elevated, thereby resulting in right ventricular ischemia. Moreover, in the confines of the pericardium, both ventricles are vying for dominance (Figure 4). The marked right ventricular dilation seen in severe pulmonary hypertension is in sharp contrast to the small underfilled and compressed left ventricle. Furthermore, the intraventricular septum moves paradoxically to the left during systole, and so it is imperative that a decrease in left ventricular afterload and reduction in systemic blood pressure be avoided. Therefore, an abrupt drop in left ventricular pressure by the empiric use of a CCB can be disastrous.

The right heart catheterization and vasodilator trial help determine whether a patient is an acute responder, with increased pulmonary vascular tone due to vasoconstriction, or a nonresponder with more fixed and irreversible disease. While there is some controversy about what constitutes a positive acute response, it is generally agreed that a drop in the mean pulmonary artery pressure by greater than 10 mm Hg with either no change or an increase in cardiac output suggests a significant degree of reversibility.¹⁶ A reduction in pulmonary vascular resistance (PVR) of more than 20% is also used as a measure of response to the vasodilator trial. However, the implications of an acute reduction in PVR resulting from an increased cardiac output without a decrease in pulmonary artery pressure is controversial. Therefore, defining a responder in terms of change in pressure rather than PVR is currently favored. For patients who demonstrate a positive response during the vasodilator trial, long-term oral vasodilator therapy with CCBs (ie, amlodipine, diltiazem, or nifedipine) may be carefully initiated (Figure 5).³⁴ Treatment is started with a low dose and cautiously advanced to higher doses as tolerated, often to very high doses, with close monitoring of patient symptoms and systemic blood pressure. The systemic blood pressure should remain stable in responders while the decrease in pulmonary vascular resistance improves left heart filling and restores the cardiac output. Once CCBs have been successfully initiated, abrupt discontinuation can result in syncope and death as a result of rebound pulmonary hypertension.

Patients with New York Heart Association class III or IV symptoms, such as Mrs JL, who are determined to be nonresponders during the acute vasodilator trial, are considered for continuous epoprostenol therapy. The paradox of epoprostenol therapy is that patients who do not respond to it during acute testing, can respond to it long-term resulting in improved survival and hemodynamics in PPH.³⁷ Epoprostenol slowly decreases the pulmonary vascular resistance in pulmonary arteries previously believed to be "irreversible" and stiff, secondary to proliferation.³⁸ A recent randomized trial confirmed the benefits of epoprostenol therapy in patients with pulmonary hypertension associated with the scleroderma spectrum of disease, although a beneficial effect on mortality was not demonstrated.³⁹ However, epoprostenol therapy is currently only approved by the Food and Drug Administration for use in patients diagnosed as having PPH and PAH associated with the scleroderma spectrum of diseases. Therefore, for patients with other forms of PAH that may respond equally well to epoprostenol, there can be difficulty getting financial coverage for therapy.

To administer epoprostenol, patients require a considerable degree of teaching and preparation. A pediatric 66F tunneled catheter is placed into the internal jugular or subscapular vein for continuous intravenous drug delivery. These lines are changed only when infected or displaced. However, problems with catheter infection and interrupted drug delivery remain important pitfalls of continuous intravenous epoprostenol therapy. Patients must learn to mix their own medicine each day, including a back-up supply in case of problems. The medicine is continuously infused via an infusion pump. Because of the drug's short shelf life after reconstitution, the infusion pump and medicine cassette are placed in a bag containing icepacks to keep the drug cool. Patients need to learn how to manage and administer the drug independently and safely before they can go home. The drug dose is titrated upward at regular intervals during the first year of therapy. Abrupt discontinuation of the drug, even if only for a few seconds, can lead to syncope and death. Common adverse effects include jaw pain, flushing, diarrhea, and chronic foot pain.

Epoprostenol therapy is not suitable for pulmonary hypertension due to causes other than those listed under the classification PAH (Table 1). Patients who have significant parenchymal lung disease may develop considerable shunting and increased oxygen requirements while receiving continuous epoprostenol therapy as blood flow is improved to poorly ventilated regions. Patients with pulmonary venous hypertension can develop acute pulmonary edema while receiving epoprostenol, and therefore, it is contraindicated when the pulmonary capillary wedge pressure is elevated (>15 mm Hg). So as a general rule, epoprostenol therapy is reserved for patients with PAH with normal lung parenchyma and left heart function.

While epoprostenol therapy was initially developed as a bridge to lung transplantation, it has been determined that many patients can derive long-term survival with the drug, deferring the need for transplantation, often indefinitely.⁴⁰ The longest a patient received continuous intravenous epoprostenol is about 10 years and increasing (S.G., unpublished data). Epoprostenol therapy is now perhaps more a bridge to new therapies rather than an inevitable transplantation. Nevertheless, epoprostenol is relatively expensive (approximately $50 000 per year), and serious adverse effects are associated with the cumbersome method of drug delivery.

A number of adjunctive therapies also are used in pulmonary hypertension. A retrospective analysis and a nonrandomized, prospective study suggest that anticoagulation increases survival in patients with PPH.^{41 - 42} Unless a contraindication exists, patients should undergo anticoagulation with warfarin in doses adjusted to achieve an international normalized ratio of approximately 2.0. Diuretics are important in the treatment of right ventricular dilation and failure. While acute right ventricular failure in the setting of a right-sided myocardial infarct requires aggressive volume resuscitation, the high pressure loaded right ventricle generally responds well to a cautious reduction in its volume. The dilated, pressure and volume loaded right ventricle compresses the intraventricular septum, resulting in a reduction in left ventricular volume (Figure 4). In general, the diuresis should be slow, 1 to 2 lb (0.5-1.0 kg) a day, with close attention being paid to renal function. Cardiac glycosides may produce a modest increase in cardiac output in patients with PPH and right ventricular failure as well as a significant reduction in circulating norepinephrine.⁴³ Attention should be paid to drug levels and renal function when diuretics are used concomitantly. In individuals with borderline systemic blood pressure, low-dose dopamine can serve to maintain systemic blood pressure while enhancing natriuresis and also may be administered long-term as a bridge to lung transplantation. The need for supplemental oxygen in patients with pulmonary hypertension may indicate the presence of occult parenchymal lung disease or a patent foramen ovale. Atrial septostomy is generally reserved for patients with recurrent syncope or ascites despite maximal medical management. Atrial septostomy allows decompression of the right side of the heart by creating a hole between the right and left atrium, thereby improving left ventricular filling and enhancing cardiac output.⁴⁴

It is important that in patients with pulmonary hypertension, great care must be exercised when adding concomitant medications. Vasoconstricting agents, such as nasal decongestants, should be avoided. Sedation, when required, should be administered with caution, avoiding any agents known to decrease systemic blood pressure. Transfusion with platelets or fresh-frozen plasma is frequently poorly tolerated because of the combination of a significant volume load and the presence of vasoactive compounds, such as thromboxane and serotonin in these products. Agents that interfere with warfarin or potentiate the degree of anticoagulation should be avoided. On account of the high mortality with pregnancy and pulmonary hypertension, patients should be counseled on the importance of effective contraception. Caution should be exercised before oral contraceptives are prescribed. Oral contraceptives and long-acting depo-preparations can exacerbate the symptoms of pulmonary hypertension in some patients and also may increase the risk of thrombosis.^{13 - 14}

Single or bilateral lung transplantation is performed for patients with pulmonary hypertension who have not responded to medical therapy. Right ventricular dysfunction improves significantly on restoration of normal pulmonary vascular resistance. Heart-lung transplantation is reserved for patients with significant heart disease on the left side or complicated structural abnormalities associated with congenital heart disease. Less complex congenital abnormalities associated with pulmonary hypertension, such as atrial septal defects, can be repaired at the time of transplantation, thereby avoiding the need for heart transplantation. The 5-year survival rate following lung transplantation is between 45% and 50%.⁴⁵

While continuous intravenous epoprostenol therapy is an effective tool in the treatment of severe PAH, the drug delivery system remains complex and cumbersome. As a result, attention recently has been focused on developing better drug delivery systems for epoprostenol or similar analogs. New epoprostenol analog drugs currently in clinical trials include an oral form, beraprost,⁴⁶ and an inhaled analog, illoprost.⁴⁷ Furthermore, a subcutaneous analog, UT-15 (Uniprost) is longer-acting than epoprostenol and is delivered by an insulin pump subcutaneously.⁴⁸ The results of a recent multicenter multinational trial that evaluated the safety and efficacy of UT-15 in PAH are awaited. In contrast to epoprostenol-based therapies, there are a number of endothelin antagonists currently undergoing development. The endothelin antagonist, bosentan, is currently undergoing trials for patients with PAH.⁴⁹ A recent study evaluating terbogrel, a dual-acting agent that antagonizes thromboxane and inhibits thromboxane synthase, was unsuccessful. Inhaled nitric oxide or oral nitric oxide donors remains a possible option in the future, particularly in the setting of parenchymal lung disease. Gene therapy directed at the pulmonary vascular bed, using nitric oxide synthase, prostacyclin synthase, or perhaps the BMPR2 receptor, is a possible alternative approach to therapy in the future.