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Lung Disease Pulmonary Arterial Hypertension: An Update John Granton, MD, Assistant Professor of Medicine, University of Toronto; Pulmonary Arterial Hypertension Programme, University Health Network,Toronto, ON. Moiz Zafar, MD, Resident, Respiratory Medicine, McMaster University, Hamilton, ON; Pulmonary Arterial Hypertension Programme, University Health Network, Toronto, ON. Introduction On first glance, a review of pulmonary arterial hypertension (PAH) in a journal that focuses on the health of the elderly may seem out of place. PAH is typically envisioned as a progressively disabling disease in young females. However, PAH is not a disease restricted to the young. Indeed, 20% of the patients followed in our pulmonary hypertension clinic are over the age of 65. Although information regarding the natural course of PAH has been described in a report of the National Registry for Primary Pulmonary Hypertension, this information is not representative of the elderly population.1 In particular, given the greater prevalence of comorbid conditions in the elderly, one must be particularly vigilant in searching for an underlying secondary cause of PAH. Owing to a paucity of information in this population, most of our comments derive from our own observations of PAH in the elderly and from inferences made from their younger counterparts. Definition PAH is defined as an elevation in pulmonary arterial pressure greater than 25mmHg at rest or 30mmHg with exercise.2 In most instances, however, the diagnosis of PAH is first made echocardiographically (ECHO). It is important to emphasize that the ECHO definition of PAH is less reliable. Although the typical upper limit of normal for right ventricular systolic pressure (RVSP) is 40mmHg, one is commonly confronted with either an asymptomatic or mildly symptomatic patient with mild elevations in RVSP at rest. In general, the diagnosis of pul- monary hypertension should not rest solely on ECHO estimates of pulmonary arterial pressure; secondary ECHO features and additional confirmatory tests are required vide infra. PAH is typically classified as being either primary or secondary. The diagnosis of primary pulmonary hypertension (PPH) can be made only in the absence of an identifiable systemic disease process. Primary PAH is thought to arise as a consequence of biological and chemical mediators acting on the pulmonary vasculature in potentially genetically susceptible hosts. Secondary pulmonary hypertension (SPH) may be a consequence of a large number of cardiac and respiratory disorders or other systemic diseases. A recent reclassification of pulmonary arterial hypertension by the World Health Organization was developed to emphasize the similarities between idiopathic or primary PAH and secondary PAH (Table 1).2 Advances in the understanding of the mechanisms underlying the vascular changes in PAH have contributed to the development of successful therapeutic strategies. It appears that some of the medical therapies initially targeted for primary PAH also benefit patients with secondary PAH. In this regard, although there is diversity in the etiology of PAH, the therapeutic literature supports some uniformity of process. Epidemiology An estimated incidence of PPH in the general population is one to two persons affected per one million population. It is more prevalent in females than in males, with a ratio of 1.7:1. In a small case series of patients with PAH over age 65, this female predilection was also seen.3 However, reliable estimates of the incidence and prevalence of secondary PAH in the geriatric population are difficult to attain. Secondary PAH is likely under-diagnosed and may be obscured by the underlying medical condition. Pathogenesis The mechanisms underlying the development and progression of PAH are incompletely understood. A range of systemic and regional vascular defects has been implicated in the development of PAH (Table 2).4 However, it is often unclear whether the defect represents a cause or consequence of the disease. The extent to which these factors are causal remains an active area of investigation. Genetic susceptibility is recognized as an underlying factor and much knowledge has been gathered from genetic studies in kindreds with familial PPH. Recently, mutations in a gene on chromosome 2q encoding BMPR-2 (Bone Morphogenic Protein Receptor Type-2), a member of the TGF-b receptor superfamily, have been described in both familial and sporadic forms of PAH.5,6 At present, the relevance of the defect in the gene coding for BMPR-2 in the elderly patient has not been determined, and the precise functional consequences of this altered gene still need to be fully elucidated. The defect is currently thought to code for a dysfunctional protein that leads to unregulated smooth muscle and possibly endothelial cell growth.7 It is likely that a multistep process is required in genetically susceptible individuals before the genetic defect manifests clinically. Some environmental injury (hypoxia, anorexigens) or coexisting disease (scleroderma, lupus) may potentially incite a process leading to PAH by causing an initial vascular injury that in turn leads to dysfunctional growth and repair www.geriatricsandaging.ca 29 Pulmonary Arterial Hypertension and the characteristic structural and functional vascular changes in a susceptible individual. The histological appearances of primary and secondary PAH are indistinguishable. Several vascular lesions involving the arteries have been described. Although a single form of vascular lesion may predominate in an individual, it is more common that a range of these histological lesions are observed Table 1 Diagnostic Classification of Pulmonary Hypertension 2 Pulmonary Arterial Hypertension (PAH) Primary PAH – sporadic – familial PAH related to: – collagen vascular disease – congenital systemic to pulmonary shunts – portal hypertension – HIV infection – drugs/toxins (e.g., anorexogens) Pulmonary Venous Hypertension Left-sided atrial or ventricular disease Left-sided valvular heart disease Extrinsic compression of central pulmonary veins – fibrosing mediastinitis – adenopathy / tumour Pulmonary veno-occlusive disease Pulmonary Hypertension Associated with Disorders of the Respiratory System or Hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation syndromes Chronic exposure to high altitude Pulmonary Hypertension due to Chronic Embolism Thrombosis – proximal – distal Sickle cell disease Tumour/ova/parasites/foreign material (e.g., talc) Pulmonary Hypertension due to Disorders Directly Affecting the Pulmonary Vasculature Inflammatory – schistosomiasis – sarcoidosis Pulmonary Capillary Hemangiomatosis 30 GERIATRICS & AGING • November 2002 • Vol 5, Num 9 in a single patient. It is unclear if the prevalence of these lesions differs across age groups. It has been suggested that lesions which do predominate portend a worse prognosis and are less responsive to vasodilator therapy.8 Functional Consequences of Altered Vasculature The pulmonary circulation is normally a low-pressure circuit with high capacitance and remarkably low resistance. Normally, under exercise conditions large increases in cardiac output are accommodated with only slight increases in pulmonary arterial pressure. This is achieved through mechanisms of vascular recruitment and vascular distention. In PAH, there is effectively a reduction in the total cross-sectional area of pulmonary vasculature. The resultant increase in pulmonary vascular resistance leads to elevations in pulmonary arterial pressures initially under exercise conditions, but which later progress to sustained elevation at rest. Sustained elevation in pulmonary arterial resistance in turn leads to right ventricular dilatation and systolic dysfunction. Eventually, the right ventricle becomes unable to maintain cardiac output even at rest, and is manifested as right ventricular failure and worsening symptoms. It is important to emphasize the significance of the right ventricle and that PAH is a disease characterized by a low cardiac output (Figure 1). Clinical Presentation Due to the nonspecific nature of symptoms that patients with PAH describe, the length of time from the onset of symptoms to diagnosis may be prolonged. Consequently, many patients present with quite advanced disease. In a study by Rich et al., Table 2 Observed Defects Variably Implicated in Development of Pulmonary Arterial Hypertension Genetic Defect in BMPR-2 Deranged cellular growth Endothelium Altered angiogenesis Loss of barrier function Vasoconstriction ↑ Endothelin ↑ Prostacyclin ↑/↓ Nitric oxide synthase Abnormal K+ channels Smooth muscle cells Hypertrophy Matrix Growth factors (FGF, VEGF) Elastases Coagulation ↑ Thrombosis ↓ Platelet activating factor inhibitor Autoimmunity Positive ANA Pulmonary Arterial Hypertension Pulmonary Circulation Figure 1 Pulmonary artery Normal – pressure in pulmonary artery < 25mmHg at rest – low resistance in the capillaries Media Lumen Normal pulmonary arteriole Right ventricle Thickened pulmonary artery Pulmonary Arterial Hypertension – elevation in pulmonary pressure >25mmHg at rest – right ventricular dilatation – thickened pulmonary artery Lumen reduced Media thickened Dilated right ventricle Hypertension www.geriatricsandaging.ca 31 Pulmonary Arterial Hypertension the average time from onset of symptoms to diagnosis was two years.1 This delay in diagnosis may be particularly problematic for the elderly in whom it may be more difficult to distinguish progressive symptoms from co-existing medical conditions. Patients with both primary and secondary forms commonly present with symptoms and signs related to right ventricular dysfunction and reduced cardiac output (Table 3). Patients may also experience angina due to ischemia of the right ventricle in the setting of increased cardiac workload, even in the absence of significant coronary artery disease. Diagnostic Assessment A meticulous history and pertinent physical examination in conjunction with a high index of suspicion is essential in diagnosing PAH. The chest radiograph may show enlargement of the pulmonary arteries, and right-sided cardiac silhouette. Pleural effusions are not usually seen in even severe forms of PAH, and require further explanation. Although there are characteristic electrocardiographic changes (tall R wave in V1, and S1 - Q3 - T3) from PAH, these findings are insensitive. Echocardiography is the most useful imaging modality for both detecting PAH and evaluating the presence of underlying cardiac disease. However, as mentioned earlier, echocardiography can be misleading in patients with mild elevations in RVSP. These patients often have normal pulmonary arterial pressures during right heart catheterization and do not demonstrate an abnormal increase with exercise. In other patients, however, pulmonary arterial pressures do rise abnormally during exercise, suggesting a reduction in capacitance and compliance of the pulmonary vasculature—characteristics of PAH. When evaluating patients with suspected PAH, it is important to evaluate the right ventricle. Enlargement of the right atrium and ventricle, right ventricular hypokinesis, septal flattening and tricuspid insufficiency are characteristic of elevated right ventricular afterload. In addition, pericardial effusions (mild to moderate) are common. Absence of right ventricular dilation or dysfunction reduces the probability that the recorded RVSP is hemodynamically significant. It is also important to evaluate left ventricular systolic and diastolic function. Left atrial dilation raises the possibility that the observed increase in RVSP is due to primary left-sided cardiac abnormalities. Once the diagnosis of PAH is established, a thorough evaluation is required to exclude secondary causes. Secondary causes generally can be determined through a detailed history or clinical examination. In general, the approach to evaluating the causes of PAH follows from the various etiologies described in Table 1 and are listed in Table 4. It is important to emphasize that PAH singularly cannot account for significant arterial hypoxemia. In these patients, Table 4 Laboratory Evaluation of Patients with Pulmonary Arterial Hypertension Electrocardiogram Chest X-ray Surface and trans-esophageal echocardiography CT scan of the thorax (angiographic and/or high resolution protocols) Pulmonary function tests V/Q scan (if CT angiogram is not done) Assessment of exercise capacity—six minute walk distance Arterial blood gases Table 3 Symptoms and Signs in Patients with Pulmonary Arterial Hypertension Complete blood count Sickle cell screen* Fatigue Jugular venous distention (c-v wave) PTT (looking for anti-cardiolipin antibodies) Breathlessness Kussmaul’s sign Coagulation screen* Pre-syncope and syncope Loud pulmonic sound Electrolytes, urea, creatinine, urinalysis Chest pain Right sided S3/S4 HIV serology Forceful heart beat Tricuspid/pulmonic insufficiency Antinuclear antibodies Leg and abdominal swelling Peripheral edema Anti-histone antibodies (Ro, La, Scl-70, Jo)* Cough* Hepatomegaly Change in voice* Ascities Liver function tests * Possibly due to compression of recurrent laryngeal nerve from an enlarged pulmonary artery. 32 GERIATRICS & AGING • November 2002 • Vol 5, Num 9 Pulmonary angiography* Cardiac catheterization* Sleep study* * where indicated Pulmonary Arterial Hypertension a search for an intracardiac or pulmonary shunt must be performed. We find that computed tomographic scanning of the chest with high-resolution images is a critical tool. First, it is useful for evaluating the presence or burden of parenchymal lung disease. Second, it is helpful for evaluating the presence of less common forms of PAH, such as veno-occlusive disease, which respond poorly to therapy and may even worsen precipitously with the use of conventional vasodilator therapy. Finally, characteristic ventilation-perfusion scan findings generally exclude chronic thromboembolic disease. We commonly perform a right heart catheterization in our patients. We use the information to exclude secondary causes, such as left ventricular dysfunction, and evaluate the capacity of the pulmonary vasculature to vasodilate. Significant prognostic information including baseline cardiac output, mean right atrial pressure and mixed venous oxygen saturation can also be obtained. Again, findings related to poor right ventricular function, such as elevated right atrial pressure and low mixed venous saturation, portend a worse prognosis. Therapy Treatment of PAH has two main objectives: 1. In the setting of secondary PAH, therapy must be directed at the underlying disorder. 2. Therapy is directed at reducing the pulmonary arterial pressures, improving right ventricular pressure and preventing further vascular injury. Much of the literature regarding treatment comes from data obtained in patients with primary PAH or those with PAH associated with connective tissue disease. Although PAH remains a common reason for referral for lung transplantation, the surgery is not performed in patients with PAH who are over the age of 60.This is due to the higher perioperative mortality and morbidity of PAH patients compared with patients undergoing transplantation for other indications.9 Consequently, therapy for PAH in the elderly rests on medical strategies. Therapy for Primary Pulmonary Hypertension Vasodilators The rationale for therapy with vasodilators relates to the observed defects in vasoregulation. The typical (and likely becoming historic) class of vasodilators are calcium channel blockers. Unfortunately, these medications may have a significant effect on systemic blood pressure and negative inotropic effects. Only patients who demonstrate an acute “response” during right heart catheterization to inhaled or intravenous vasodilators are subsequently challenged acutely with calcium channel blockers. Characteristic changes that predict response to long-term oral calcium channel blocker therapy include a reduction in pulmonary artery pressure accompanied by an increase in cardiac output, with little change in systemic pressure or arterial oxygen saturation.10,11 However, the role of calcium channel blockers as sole therapy needs to be revisited. It is difficult to advocate the use of calcium channel blockers with the advent of newer oral therapies and in the face of the methodological quality of earlier studies of calcium channel blockers. Rationale for the use of prostacyclin stems from the observation of a relative reduction in prostanoids in patients with PAH as well as from its role as a short-acting vasodilator and inhibitor of platelet aggregation. Long-term treatment with continuous intravenous epoprostenol, a prostacyclin analog, has demonstrated long-term beneficial outcomes including improvement in hemodynamics, exercise tolerance and survival in patients with both PPH and SPH.12-14 Interestingly, the benefit of epoprostenol has been found even in patients who have no significant response to acute vasodilator challenge. This suggests that its mechanism of action is beyond simply decreasing vasomotor tone and is possibly due to other properties that mediate vascular remodeling. Epoprostenol must be administered continuously through a central venous catheter. It is chemically unstable and must be shielded from heat and light. The requirements of administration and the extensive side effects make it impractical for many elderly patients. Recently, a more stable analogue, UT-15 (Uniprost®, Remodulin™), has been developed.15 Uniprost is administered subcutaneously and does not require daily admixture. Despite demonstration of clinical benefit, significant pain at the injection site from UT-15 has become a severe limitation in its widespread use. Inhalation of a prostacyclin analogue called iloprost has recently been shown to improve hemodynamics and functional status in patients with PAH.16 Unfortunately, owing to the short halflife of this medication, it must be administered every four hours. In addition, it is not clear that the beneficial hemodynamic effects extend beyond the treatment intervals. For the ideal treatment of PAH, one should choose an agent that may be taken orally, is selective for the pulmonary circulation and is well tolerated. Endothelin receptor antagonists have shown recent promise for the long-term treatment of PAH. The rationale underlying their use is based on the observation of increased levels of endothelin in patients with PAH.17 Endothelin has been implicated in the pathogenesis of PAH as it is a potent vasoconstrictor, a mediator of smooth muscle cell growth and differentiation and found in high concentrations in the plexiform lesions that characterize PAH. Controlled studies have demonstrated hemodynamic improvement, increased exercise tolerance and improved survival over one year in class III/IV patients with PPH and SPH treated with the non-selective endothelial receptor antagonist, bosentan.18,19 Unfortunately, this medication is also extremely expensive, and liver toxicity (requiring dose adjustment or diswww.geriatricsandaging.ca 33 Pulmonary Arterial Hypertension continuation in 10% of patients) limits its use. In addition, the clinical experience with bosentan is limited to two short clinical trials (12 and 16 weeks, respectively). The long-term benefit of this agent remains to be established. Recent interest has focused on the use of phosphodiesterase inhibitors. As a class, these agents mediate vasodilation by decreasing the degradation of cyclic-guanosine monophosphate (cGMP). In particular, sildenafil (Viagra®) shows promise as a selective pulmonary vasodilator.20,21 A prospective study, however, is still required before one can embrace sildenafil as therapy for PAH. Inotropes The rationale for treatment with inotropic agents in PAH is to increase cardiac output. In patients with PPH and right ventricular failure, digoxin has been shown to have beneficial acute hemodynamic effects through an increase in cardiac output.22 The benefit to the patient and long-term consequences of digoxin are unknown. We currently reserve the use of digoxin for those patients who have moderate or worse right ventricular dysfunction. Anticoagulation The rationale for anticoagulant therapy in patients with PAH is based on the observations of in situ thrombosis, abnormalities in the coagulation cascade and endothelial dysfunction in PAH.23,24 There are also concerns that co-existing venous insufficiency and reduction in physical activity imposed by the disease may predispose to thromboembolism. Anticoagulant therapy with warfarin has been shown to improve survival in patients with PPH with added survival benefit when combined with a vasodilator.11 In general, the INR is maintained between 2 and 2.5. Other Supportive Measures The reduction of excessive preload in patients with right ventricular failure as a consequence of PAH can be achieved with diuretics and institution of a low-salt 34 GERIATRICS & AGING • November 2002 • Vol 5, Num 9 diet. Reduction in the degree of peripheral edema is often of symptomatic benefit to these patients. Oxygen, when required, should be administered to maintain saturation above 90%. In the absence of valvular or structural heart disease, patients do not require antibiotic prophylaxis for surgical procedures. We encourage an active lifestyle within limits of their symptoms. Deconditioning will only lead to further disability. Patients are cautioned to avoid sudden increases in activity, straining or environments that may lead to excessive peripheral vasodilation. Targeted Therapeutic Modalities in Secondary Pulmonary Hypertension Treatment of SPH is directed by management of the underlying disease. In patients with left ventricular dysfunction, treatment considerations include digoxin, diuretics and afterload reducing agents. The most important factor in PAH associated with chronic obstructive pulmonary disease is alveolar hypoxia. The approach to therapy is to optimize lung function and gas exchange with bronchodilators and steroids. If hypoxemia persists after one month of treatment, then long-term continuous home oxygen is indicated. It is clear that continuous use of oxygen in patients who have a PaO2 less than 60mmHg and PAH will experience an improvement in survival and pulmonary pressures. 25 The role of vasodilator therapy in patients with coexisting pulmonary parenchymal disease is unclear. Indeed, there is a significant concern that there is a potential for detriment owing to worsening of hypoxemia due to increased ventilation/perfusion mismatch. In patients with collagen vascular disease, a trial of corticosteroids or other immunosuppressive agents are occasionally prescribed to see if there is a reversible inflammatory component to the PAH. Surgery (pulmonary thromboendarterectomy) for accessible chronic thromboemboli is potentially curative. 26,27 Patients for this procedure must be carefully selected based not only on the location of the thrombosis but also on careful assessment of limiting comorbidities that may impact upon outcome. At present, only scattered specialized centres perform this procedure. Conclusion Advances in the understanding of the pathophysiology of PAH have led to the development of therapies that are capable of improving quality of life and life span in patients. Predictors of survival in PPH include severity of disease as measured by hemodynamic status, functional class, exercise tolerance, use of anticoagulant therapy and response to vasodilators. Patients who respond symptomatically and hemodynamically to directed therapy have the best prognosis.28 Although studies evaluating the pathogenesis of PAH and response to therapy in the elderly are lacking, with the advent of oral medications, the prospects for the elderly patient with PAH have improved. ◆ Dr. Granton has acted as a consultant and will be receiving funding for a clinical trial from Actelion, the maker of bosentan. Dr. Zafar has declared no competing financial interests. References 1. 2. 3. 4. 5. 6. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. 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Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2002;346:896903. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosental in patients with pulmonary hypertension: a randomized placebo controlled study. Lancet 2001;358:1119-23. Michelakis E, Tymchak W, Lien D, et al. 21. 22. 23. 24. 25. 26. 27. 28. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398-403. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000;343:1342. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787-92. Cella G, Bellotto F, Tona F, et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001;120:1226-30. Herve P, Humbert M, Sitbon O, et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med 2001;22:451-8. Lehrman S, Romano P, Frishman W, et al. Primary pulmonary hypertension and cor pulmonale. Cardiol Rev 2002;10:265-78. Jamieson SW, Nomura K. Indications for and the results of pulmonary thromboendarterectomy for thromboembolic pulmonary hypertension. Semin Vasc Surg 2000;13:236-44. Rubens F, Wells P, Bencze S, et al. Surgical treatment of chronic thromboembolic pulmonary hypertension. Can Respir J 2000;7:49-57. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780-8. www.geriatricsandaging.ca 35