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Primary Pulmonary Hypertension Manish J. Patel MD Internal Medicine Resident Grand Rounds February 17, 1998 HPI: 30 y.o. black female who has had chronic respiratory complaints for over five years. Originally had been diagnosed with restrictive lung disease of unknown etiology. From December 1993 to June 1996 the patient underwent extensive work-up including, rheumatologic studies, sleep studies, pulmonary function tests, right heart catheterization, ventilation- perfusion scan, and pulmonary arteriogram, which yielded a diagnosis of primary pulmonary hypertension. In June of 1996, the patient had an inhaled nitric oxide test with Swan-Ganz catheter monitoring and was found to be responsive to vasodilator therapy. She was subsequently started on Diltiazem and Coumadin. The patient presented to my clinic in March 1997 for Depo-Provera injection. The patient’s weight in Dec. 1993 was 222 lbs., but at the time of presentation to my clinic her weight was 300 lbs. On physical exam, the patient was extremely obese, had 1+ pitting edema of both lower extremities, and had a 2/6 tricuspid regurgitation murmur. She was otherwise unremarkable. In the following year, the patient has became more obese (gaining ~70 lbs.), more dyspneic with walking very short distances and spends a majority of her time in a wheelchair. She is still requesting Depo-Provera injection when she comes to my clinic. Definition Primary pulmonary hypertension (PPH) is a disease of unknown etiology in which patients have persistent elevation of pulmonary artery pressures that ultimately lead to right ventricular failure and death. In order to better define the pathophysiology, epidemiology, natural history, and optimal treatment, the National Institutes of Health initiated the Patients Registry for the Characterization of PPH in 1981. The registry consists of 194 patients collected from 32 medical centers over four years. The criteria used by the NIH in its registry include: 1) a mean pulmonary-artery pressure that is greater than 25 mm Hg at rest or more than 30 mm Hg with exertion, with 2) the exclusion of myocardial disease, congenital heart disease, left-sided cardiac valvular disease, and any clinically important respiratory, chronic thromboembolic, or connective tissue diseases. 1 Epidemiology The NIH registry reports the mean age at entry for both men and women as 36.4 years, although nine percent of cases were diagnosed at age 60 or later. In the Japanese registry the mean age was 31. The registry also showed a female-to-male ratio of 1.7:1 for all ages, which has been supported by most series. This is lower than had previously been published and may, in part, be due to a reluctance of physicians to make a diagnosis of PPH in men. In blacks, the female-to-male ratio was 4.3:1 but the distribution by race was similar to that of the general population (12.3% black and 2.3% hispanic). In women, the highest incidence was in the third decade and in men, the fourth. Women tended to have more severe symptoms: 74 percent of women were in the New York Heart Association Class III-IV compared to 64 percent of men. 2 Six percent of cases in the registry had a family history of PPH with histopathological and clinical features identical to the sporadic form of the disease. As expected, these patients tended to have the diagnosis made earlier in the course of the disease. The pattern of transmission appears to be autosomal dominant with variable expression. 7 Pathophysiology The vascular resistance seen in PPH is the result of three pathogenic mechanisms: vasoconstriction, vascular endothelial dysfunction, and thrombosis in situ. The mechanism of vasoconstriction was first recognized by Dr. Paul Wood, who noted that patients with pulmonary hypertension would vasodilate in response to an infusion of acetylcholine. Wagenvoort and Wagenvoort demonstrated that the earliest pathologic feature of PPH was medial hypertrophy, indicating a stimulus for vasoconstriction and the proliferation of smooth muscle.8 Vascular endothelial dysfunction may also play an important role in the pathogenesis of PPH. Christman et al.4 demonstrated that there was an imbalance in the ratio of metabolites of prostacycline to metabolites of thromboxane in some patients with pulmonary hypertension. Thromboxane A2 is a potent pulmonary vasoconstrictor and a procoagulant whereas prostacycline has opposing effects. They measured the urinary metabolites of both chemical mediators in 20 patients with PPH, 14 with secondary pulmonary hypertension, 9 patients with severe COPD but no clinical evidence of pulmonary hypertension, and 23 normal controls. They found that metabolites of Thromboxane A2 were increased in patients with pulmonary hypertension compared to normal controls and patients with COPD without evidence of pulmonary hypertension. They also found that the metabolites of prostacycline were depressed in these patients. Giaid and Saleh5 demonstrated a substantial reduction in the expression of endothelial nitric oxide synthase in the endothelium of pulmonary vessels of patients with arteriopathy from pulmonary hypertension, compared to normal lungs. Giaid et. al.6 also showed that patients with pulmonary hypertension have increased circulating and local levels of endothelin-1, a promoter of smooth muscle cell proliferation and a potent vasoconstrictor. Whether these abnormalities are a cause or the result of the disease remains uncertain. Immunocytochemical staining has shown progesterone, but not estrogen, receptors in the nuclei of the myofibroblasts that form the obstructive pulmonary lesions in a patient with PPH. Estrogen is known to have a vasodilatory effect and may play a role in the release of endothelium-derived relaxant factor.15 Patients with pulmonary vascular disease, regardless of cause, appear to develop in situ thrombosis within the pulmonary microcirculation as a secondary consequence of diminished or sluggish blood flow, and injury to the endothelium from high intravascular pressures. Pathology The most common pathologic finding is a plexogenic arteriopathy. Early disease is associated with smooth muscle hypertrophy and neo-intimal proliferation. With progression of the disease, there is gradual obstruction with concentric intimal fibrosis, fibrinoid necrosis, medial hypertrophy and the formation of plexiform lesions.9 Plexiform lesions are thin-walled, multi-channeled vascular lesions which are thought to develop in a sequence of vascular wall necrosis, aneurysmal dilatation, local thrombosis, recanalization and cellular proliferation.10 These features can also be seen in patients with congenital heart disease, portal hypertension associated with pulmonary hypertension, and toxin-induced pulmonary hypertension. Etiology The etiology of PPH is not well understood, however, it has been associated with a number of exposures, and conditions: An appetite suppressant called aminorex (5-amino-5-phneyloxazoline), which is an analog of amphetamine, caused an 20-fold increase in pulmonary hypertension in Switzerland, Austria and Germany between 1965 and 1968. The pulmonary lesions were identical to the plexogenic arteriopathy seen in PPH. The incidence of pulmonary hypertension declined to its previous level with the withdrawal of the drug from the market.11 An epidemic of pulmonary hypertension also occurred in Spain in the early 1980s with the use of rapeseed (canola) oil in cooking, that was contaminated with aniline and acetanilide dyes. In this toxic oil syndrome, most patients died from ARDS. Some, however, developed pulmonary hypertension with histologic findings of plexogenic arteriopathy.12 Plant products from crotalaria species, containing pyrolizidine alkaloids, produce lesions analogous to those of primary pulmonary hypertension when fed to small animals. “Bush tea”, made from another crotalaria indigenous to the Caribbean, causes veno-occlusive disease of the liver and a third species has been suspected of inducing primary pulmonary hypertension, based on scattered case reports.13 Patients with eosinophilia-myalgia syndrome from ingestion of contaminated L- tryptophan showed similar pathologic findings. Hormonal influences may play a role as well. This is demonstrated by the prevalence of PPH in young females, the fact that it sometimes presents or accelerates with pregnancy 16, and its association with oral contraceptives.14 A report of six cases of pulmonary hypertension with associated oral contraceptive use, was published in 1976. In this report, three women had no discernable predisposition to pulmonary hypertension, one woman had a patent ductus arteriosus that had been corrected surgically at the age of nine and had mild baseline hypertension, one had lupus, and the third had a family history of pulmonary hypertension and clubbing, and was a smoker. Pulmonary hypertension has also shown some association with portal hypertension 17, fenfluramine (4 reported cases)18 , crack cocaine use (4 cases reported), HIV, and autoimmune disorders. Symptoms The early diagnosis of PPH is difficult due to the nonspecific nature of the symptoms. According to the NIH registry, the mean length of time from onset of symptoms to diagnosis is about two years. Ten percent went undiagnosed for over three years. At the time of Symptom Initial complaint % enrollment in the registry % Dyspnea 60 98 Fatigue 19 73 Chest Pain 7 47 Near syncope 5 41 Syncope 8 36 Leg edema 3 37 Palpitations 5 33 Adapted from DR Dantzker 2 Raynaud’s phenomenon, almost exclusively seen in women, was reported in approximately 10% of patients. Hemoptysis has also been reported, and is thought to be due to rupture of microvascular aneurysms under high pulmonary artery pressures. Hoarseness, due to pressure on a laryngeal nerve by an enlarging pulmonary artery has also been reported. Some authors maintain that chest pain may be related to distension of the pulmonary artery as well, because its afferents enter the nervous system along the same pathways as afferents from the heart. Others believe that the chest pain in PPH is due to variant angina in patients who have generalized vasospastic disease.9 Signs The physical findings in patients in the NIH registry, was typical of patients with significant pulmonary hypertension. 93% of patients had a loud pulmonic component of the second heart sound; 23% had a right-sided S3; 38% had a right-sided S4; 40% had tricuspid regurgitation and was associated with high right-atrial pressure and low cardiac output; and 13% had pulmonic insufficiency and was associated with higher pulmonary artery pressures.2 Additional findings include a prominent a wave, which is exaggerated by compression of the liver (Hepato-jugular reflux), cold hands and feet, right ventricular lift at the left sternal border that is sustained throughout systole, and Graham Steel’s murmur, which occurs in diastole and is attributed to vibration of the aortic valve leaflet. Cyanosis is present in 20% of patients, and is usually a late phenomenon. Interestingly, clubbing is not associated with PPH, and its presence should prompt a search for other causes of pulmonary vascular disease.9 Atrial arrhythmias are uncommon and may reflect the patient’s need for an atrial kick to maintain cardiac output. The occurance of atrial arrhythmias, especially atrial fibrillation, may precipitate sudden death. Diagnosis The differential diagnosis of PPH can be broad and secondary causes of pulmonary hypertension must be ruled out. The generally accepted work-up includes: Echocardiography to rule out congenital, valvular and myocardial disease. It may also give an estimate of pulmonary-artery systolic pressure. In the NIH registry, 75% of patients showed right ventricular enlargement and 59% showed paradoxical motion of the septum. A small end-diastolic left ventricular size was common and was inversely correlated with pulmonary vascular resistance. Electrocardiogram revealed right axis deviation and RV strain in >75% of patients in the registry. Chest x-ray demonstrated an enlarged main pulmonary artery in 90%, enlarged hilar arteries in 80%, and decreased peripheral vessels in 51% of patients in the registry. Interestingly, 6% of patients had a normal CXR, EKG, and ECHO. Blood studies can help rule out collagen vascular diseases (although 29% of PPH patients have a positive ANA), as well as liver abnormalities seen in portal hypertension (which may be associated with pulmonary hypertension).19 Arterial blood gases usually show mild hypoxemia, out of proportion to pulmonary function abnormalities as well as a chronic respiratory alkalosis in patients with PPH.2 Pulmonary function tests should reveal normal expiratory flow rates, with normal or mildly reduced lung volumes. Typically DLCO is often reduced is thought to be due to the obliteration of the small pulmonary arteries.2 Ventilation-perfusion scans help rule-out thromboembolic disease. In the NIH registry 42% of patients have a normal scan and 77% had scans that were described as having diffuse patchy distribution of tracer, compared to larger perfusion defects seen in thromboembolic pulmonary hypertension.3 Pulmonary arteriography is useful when V/Q scans are inconclusive and typically shows the characteristic “pruning” of peripheral vessels. Cardiac catheterization in patients with PPH, typically reveals increased pulmonary-artery pressures to levels three or more times normal, elevated right atrial pressure, a reduction in cardiac index and a normal pulmonary capillary wedge pressure.2 The normal wedge pressure is due to the patency of the larger pulmonary veins and the patchy nature of the disease in the veins.3 Patients who were more symptomatic had similar pulmonary-artery pressures but had higher right atrial pressures and lower cardiac indices. There was no difference in degree of pulmonary hypertension between the sexes and there was no significant difference in pulmonary pressures as a function of duration of symptoms.2 Therapy Therapeutic strategies in the treatment of PPH include vasodilators such as calcium channel blockers and prostacycline, anticoagulation, transplantation, and treatment of right heart failure. Other strategies include counseling on smoking cessation, oxygen therapy in hypoxemic patients, and avoiding circumstances that may increase pulmonary artery pressure and decrease cardiac output. The alveolar hypoxia of high-altitude, such as flying in commercial aircraft or travel to mountainous regions can exacerbate pulmonary hypertension. The physician should also avoid using prostaglandin synthase inhibitors such as indomethacin and sympathomimetic drugs, both of which can cause vasoconstriction. Drugs that depress cardiac output should also be avoided. PPH is an absolute contraindication to pregnancy and female patients should practice birth control, preferably, without oral contraceptives as they may accelerate pulmonary hypertension. If a patient does become pregnant, termination of the pregnancy should be considered but abortifacients such as prostaglandin F2, which can increase pulmonary artery pressure, should not be used.9 In treating right heart failure all the standard medications may be useful. Digoxin has been shown to improve right ventricular function only when both right and left heart failure were present in patients with cor pulmonale secondary to COPD. 20 Digoxin has also been found to directly increase pulmonary vascular resistance. This effect, in conjunction with the high incidence of digoxin toxicity has led to a tendency to avoid its use in PPH. Rich and Brundage, proponents of high-dose calcium-channel blockers in patients with PPH, have advocated using digoxin in order to offset the negative inotropic effects of calcium channel blockers. Diuretics are very helpful in patients with right heart failure due to PPH, but care must be taken to avoid generating a contraction alkalosis which can, in turn, depress ventilation.19 Anticoagulation is recommended in all patients with PPH. Anticoagulants are believed to reduce or halt in situ thrombosis, thereby slowing progression of the disease. In a prospective non-randomized study of 64 patients, a significant improvement was observed in patients treated with coumadin (P=0.025). The most marked improvement, occurred in patients who were categorized as nonresponders to vasodilator therapy. Survival at 1, 3 and 5 years was 91%, 62% and 47% respectively in the treatment group, compared to 52%, 31%, and 31% in the untreated group.22 Vasodilators have been the mainstay of treatment for PPH, based on the observation that vasoconstriction is a prominent feature of the disease. Unfortunately, there is no way of predicting which patients will respond to vasodilator therapy without the use of invasive monitoring. Because of the potential for adverse consequences such as systemic hypotension, which can lead to myocardial ischemia due to decreased coronary perfusion, the most suitable drugs for testing acute response are potent, short- acting and titratable vasodilators such as nitric oxide, epoprostenol (prostacyclin), and adenosine. Rich and coworkers have shown that patients who respond to vasodilator therapy (defined as > 20% reduction of pulmonary vascular resistance and pulmonary artery pressure to the acute administration of vasodilator agents) clearly demonstrate improved survival. In this trial, 17 of 64 patients (26%) had a favorable response to either nifedipine or diltiazem. At 5 years, 94% of responders were alive compared to 55% of non-responders. Responders also had fewer symptoms, better exercise tolerance, and regression of right ventricular hypertrophy. The most widely used and studied drugs for long-term therapy are nifedipine and diltiazem. Doses as high as 240 mg of nifedipine and 720 mg of diltiazem may be required to produce benefit in PPH. Verapamil has not been used due to its negative inotropic effects24 and ACE-inhibitors have also not shown much benefit in PPH.25 Monitoring of oral vasodilator therapy can be done with echocardiography and can be adjusted based on symptoms and physical exam. The side effects of long-term vasodilator therapy include systemic hypotension, edema, and hypoxemia. Hypoxemia may be caused by a worsening ventilation-perfusion ratio due to increased perfusion of poorly ventilated portions of the lung, depression of cardiac output, and shunting of blood through a patent foramen ovale, if systemic vasodilation is present.3 Epoprostenol (trade name Flolan), or prostacyclin, has been shown to produce vasodilation more consistently than calcium-channel blockers. It is a potent vasodilator of both pulmonary and systemic arteries and has antithrombotic properties due to its effects on platelets. It had originally been introduced as a bridge to lung transplantation, but its use has been limited by its short half-life (3-5 minutes), necessitating a continuous infusion, and tachyphylaxis, requiring increasing doses to sustain hemodynamic benefit. In a 12-week prospective, randomized controlled trial of 81 patients, comparing continuous infusion of epoprostenol plus conventional therapy to conventional therapy alone, Barst and colleagues, demonstrated significant improvement in survival, symptoms and hemodynamics in the group receiving the infusion. Exercise tolerance improved in the 41 patients receiving the infusion and decreased in the conventional therapy group (P<0.002). Mean changes in pulmonary-artery pressure for the epoprostenol and control groups were – 8% and + 3%, respectively (P<0.002), mean changes in pulmonary vascular resistance were – 21% and + 9%, respectively (P<0.001). Eight patients died during the study, all of whom were in the control group (P=0.003). Complications from the epoprostenol group included four episodes of catheter-related sepsis and one episode of thrombosis. Side effects of epoprostenol include headache, cutaneous flushing, jaw pain and diarrhea. Two patients from the study group were withdrawn. The authors also noted long-term benefits in patients who did not show acute response to vasodilator infusion. They had noted this in previous studies as well.26 In a more recent study, Mclaughlin et al. evaluated the effects of long-term (16.7 + 5.2 months) epoprostenol infusion in patients with advanced PPH. The dose was titrated to maximum tolerated, a more aggressive approach than has previously been used. 27 patients were evaluated, 19 women and 8 men with a mean age of 39.8 years. At the time of initial evaluation, patients had severe symptoms; 63% were in NYHA functional class III and 37% were in NYHA functional class IV. At the time of follow- up, 22% were in NYHA functional class I, 74% in class II, and 4% in class III (P<0.001). The duration of exercise on treadmill increased by 142% (P<0.001) which did not correlate with decrease in pulmonary vascular resistance. Patient’s arterial oxygen saturation was unchanged. At the time of follow-up, cardiac catheterization revealed a decrease in the mean pulmonary arterial pressure by 22% (P<0.001), an increase in cardiac output by 67% (P<0.001), and a mean reduction in pulmonary vascular resistance of 53% (P<0.001).27 26 of the 27 patients had greater than 20% long-term reduction in pulmonary vascular resistance. Interestingly, the change in pulmonary vascular resistance after long- term epoprostenol was not related to pulmonary vascular resistance at base line. Eleven of the patients received epoprostenol and calcium-channel blockers concurrently and showed similar results to patients receiving only epoprostenol.27 This study is the first instance in which a substance produced by normal vascular endothelium has been used as a treatment for vasculopathy. Their results show that long- term therapy is not only associated with vasodilation, but also a significant reduction in pulmonary vascular resistance out of proportion to immediate vasodilation. Experimental data in animal studies with epoprostanol have shown a potential to reverse vascular lesions. As pulmonary vascular resistance returns towards normal with long-term use, patients waiting for transplantation may no longer need it. The use of this therapy must take into account the complexity and expense of the delivery system and the potential for complications. In this series of patients, 10 had a total of 17 local infections at the exit site of the Hickman catheter and three of these 10 also had positive blood cultures. All were successfully treated with antibiotics. The rate of local infection was 0.49 per patient-year and blood-borne rate of infection was 0.09 per patient-year. Lung transplantation (single- or double-lung transplant) and combined heart-lung transplant have been performed for PPH with similar survival rates. Single- and double- lung transplant is advocated only in patients that fail to respond to pharmacologic agents, but the timing of transplant is very difficult. Patients must be ill enough to require surgery, but well enough to survive it. In a review of 109 heart-lung transplants done at Stanford, survival rates were 68%, 43%, and 23% at one, five, and 10 years, respectively.28 Mortality rates after transplant are significantly higher among patients with PPH than patients who had transplant for other indications. Obliterative brochiolitis, the major long-term complication of transplantation, also occurs more frequently in patients who received transplant for PPH. PPH is not known to recur in transplant recipients.3 Contraindications to lung transplantation include, ventilator dependence (30-fold increased risk for poor outcome), current or recent presence of malignancy, significant life-threatening illness, extrapulmonary active infection, marked obesity (weight/height ratio > 120%) or cachexia (weight/height ratio < 80%), substance abuse, and significant psychological illness. Relative contraindications include previous thoracic surgery or pleurodesis and use of corticosteroids prior to transplant. Age is a relative contraindication with specific cutoffs based on surgical procedure. These cutoffs can vary from center to center.37 Survival The estimated median survival of patients in the NIH registry was 2.8 years. Estimated single-year survival rates were 68% at one year, 48% at three years, and 34% at five years. Survival from time of admission to the registry was related to the New York Heart Association (NYHA) functional class. Patients in functional classes I and II had a median survival of 58.6 months, 31.5 months for class III, and six months for class IV. Of the hemodynamic variables recorded at baseline, very high correlations with mortality were seen in elevated mean right atrial pressure, elevated mean pulmonary artery pressure, and decreased cardiac index. Presence of Raynaud’s phenomenon was associated with reduced survival as was decreased diffusing capacity for carbon monoxide (DLCO).29 PPH continues to have a poor prognosis, however, treatment strategies such as calcium channel blockers, anticoagulation and now, long-term prostacyclin infusion are making surgical options less necessary. Current work in prostacyclin analogs that can be given orally, transdermally, or by inhalation, may make the continuous infusion system obsolete, while preserving the benefits. Bibliography 1. Rich S, Dantzker DR, Ayres S, et al. Primary pulmonary hypertension, a national prospective study. 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The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 1997; 112:714-21. 34. Weir EK, Rubin LJ, Ayres SM, et al. The acute administration of vasodilators in primary pulmonary hypertension. Am Rev Respir Dis 1989; 140:1623-30. 35. Loscalzo J. Endothelial dysfunction in pulmonary hypertension (editorial). N Engl J Med 1992; 327:117-9. 36. Channick RN, Newhart JW, Johnson FW, et al. Pulsed Delivery of inhaled nitric oxide to patients with primary pulmonary hypertension. Chest 1996; 109:1545-49. 37. Smith CM. Patient selection, evaluation, and preoperative management for lung transplant candidates. Clinics in Chest Medicine 1997; vol 18:183-97.
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