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Clinical Insights Into the Pathogenesis of Primary Pulmonary Hypertension* Stuart Rich, MD, FCCP Because of the lack of adequate animal models, much of our knowledge of the pathogenesis of from clinical experiences. The clinical response to primary pulmonary hypertension vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the patho¬ logic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunc¬ tion, as a primary abnormality in primary pulmonary hypertension, provides an explanation for the pathologic and clinical expression of the disease in its various forms. Other clinical features of the disease, such as age of onset and rapidity of progression, may be influenced by triggers of the disease process and underlying individual genetic susceptibility. As we have been able to has come correlate the spectrum of clinical observations with advances in vascular biology, newer, more focused and effective therapies should begin to emerge. (CHEST 1998; 114:237S-241S) HP he pathogenesis of primary pulmonary hyperten-*- sion (PPH) has been elusive. The disease is rare, which makes it difficult to study patients who present with PPH in its various stages. Because there is no comparable animal model, testing clinical hypothe¬ ses in the animal is problematic and forces laboratory these a wealth of speculation. Despite obstacles, information has been obtained from the clinical experience in diagnosing and treating patients with PPH that has provided insight into the underlying of the disease. Although the clinical pathogenesistends to raise more questions than an¬ experience swers, this review will focus on advances in our current understanding of the pathogenesis of this disease derived from clinical observations. Pulmonary Hypertensive Vasculopathy Medial Hypertrophy disease that is manifest by a that has mul¬ pulmonary hypertensive vasculopathy One feature of PPH is tiple expressions.1 pathologic medial hypertrophy of the pulmonary arterioles that appears to represent vasoconstriction.2 Although it is usually seen in conjunction with other lesions, iso¬ lated medial hypertrophy has been described in several pathologic series of patients dying with PPH and seems to be more prevalent in children than PPH represents a *From the Section of Cardiology, Medical Center, Chicago. Rush-Presbyterian-St. Luke's to: Stuart Rich, MD, The Rush Heart Institute, Correspondence Center for Pulmonary Heart Disease, Rush-Presbyterian-St. Luke's Medical Center, 1725 W Harrison St, Suite 020, Chicago, IL; email: [email protected] adults.1'3-4 The vessels are characterized by marked thickening of the media, with only modest amounts of intimal proliferation.4 It was originally postulated that this represented uncontrolled growth and con¬ striction of the smooth muscle cells of the pulmonary arterioles.2 Pulmonary vasoconstriction was believed to be the cause of pulmonary hypertension.5 Clinically, we test for the presence of pulmonary vasoconstriction by challenging the patient with a the response. short-acting vasodilator and measure in a substantial fall Observing pulmonary artery pressure and pulmonary vascular resistance (PVR) characterizes the patient as responsive, and thus implies reversible pulmonary vasoconstriction.6 The unresponsive patients, it is assumed, have advanced vascular changes that preclude the drug from caus¬ ing smooth muscle cell relaxation. Consistent with this hypothesis, Sitbon and colleagues7 have charac¬ terized patients with PPH as responders or nonre¬ sponders to nitric oxide based on acute reductions in mean pulmonary artery pressure following inhalation of the gas. However, Palevsky and colleagues8 com¬ several vasodilators with pared theinacute effects ofPPH with and were unable to histology patients correlate the two. Obviously the mechanisms for vasoconstriction and vasodilation are pulmonary more complex than initially thought. The monocrotaline rat model has been one of the most widely used animal models to study various aspects of PPH.9 In that model, monocrotaline is injected into the rat; this results in medial hypertro¬ phy of the pulmonary arterioles and pulmonary after approximately 4 weeks. However, hypertension close observation of the development of the medial CHEST / 114 / 3 / SEPTEMBER, 1998 SUPPLEMENT Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017 237S revealed that it is preceded by intense hypertrophy metabolic activity and proliferation of the pulmonary endothelial cell layer.10 Studies such as these suggest that the development of medial hypertrophy is reg¬ ulated by the endothelium, and that isolated medial hypertrophy represents an abnormality of endothe¬ lial cell control over pulmonary vascular smooth muscle. Nitric oxide has been identified as an endothelial-derived mediator that has important regula¬ tory properties over vascular tone.11 It is believed that nitric oxide, a powerful vasodilator, keeps the relaxed state. pulmonary vascular bed in a relatively One hypothesis is that the loss of normal endothelial cell production of nitric oxide could result in pulmo¬ nary arterial vasoconstriction and smooth muscle cell hypertrophy.reduced levels of nitric oxide synthase in Recently, the pulmonary vasculature of patients with PPH have been characterized, which implicates inade¬ quate local nitric oxide production as part of this disease process.12 In addition, the more severe the vascular changes, the lower the levels of pulmonary nitric oxide synthase observed. This may account for the clinical characterization of patients as being responsive or unresponsive to vasodilator challenge. Comparing the effects of vasodilators that are considered to be endothelial dependent, such as with ones that are endothelial inde¬ acetylcholine, such as nitroglycerine or nitric oxide, has pendent, been attempted with the hope of characterizing the endothelial cell dysfunction in a given degree ofThe studies suggest a progressive loss of patient.13 in vasoreactivity the pulmonary vascular bed that correlates with the severity of the disease. The response to any pulmonary vasodilator in PPH will and the characterization of an likely be a graded one, individual patient as being a responder or nonrean attempt to categorize them for selection sponder of long-term therapy. One example is the common practice to categorize patients with PPH as being responders or nonre¬ However, there is no sponders to calcium ofblockers. definition a response to calcium block¬ accepted ers, with investigators arbitrarily choosing an acute in PVR that varies between 20% and change 50%.14-15 In the calcium blocker experience, it is clear that there is a subset of patients who seem to be highly responsive, who maintain a sustained fall in while receiving pulmonary artery pressure and PVR As with nitric oxide, long-term therapy indefinitely.16 one would presume that the difference between these subgroups of patients relates to the severity of the pulmonary vascular disease. However, the experience with calcium channel blockers has raised more questions than it has an¬ swered. If one presumes that the calcium channel 238S blocker is opposing pulmonary vasoconstriction, which occurs as a result of endothelial injury, then one would expect that the long-term effectiveness of the calcium channel blockers would be limited by progressive endothelial dysfunction at some point in time. However, this does not appear to be the case, as we have patients with PPH receiving calcium channel blockers with sustained improvement for >10 years. Whether the calcium channel blockers affect endothelial cell proliferation or injury is un¬ known. It has also been shown that the vasodilatory response to calcium channel blockers does not rep¬ resent the maximal extent of pulmonary vasodilator reserve. For example, patients who are responsive to calcium channel blockers will have a further fall in pulmonary artery pressure IVand PVR when a more potent vasodilator such as adenosine is added.17 Another important question is how to interpret the more common acute hemodynamic response to cal¬ cium blockers in patients with PPH, namely a rise in cardiac output and thus a fall in PVR, without any fall in pulmonary artery pressure.18 The conditions of some patients will improve with long-term therapy, whereas others will deteriorate.19 Unfortunately, the widespread practice of using calcium blockers in PPH without documenting beneficial effects hemodynamically has probably led to worsening and death in many patients. From clinical observations, one can conclude that vascular smooth muscle cell hypertrophy pulmonaryto appears express marked reactivity early in the and disease, that it loses reactivity as endothelial cell injury progresses. It is possible that pulmonary vaso¬ constriction and smooth muscle cell hypertrophy are linked to endothelial cell regulation via nitric oxide. It remains unclear, however, what role the calcium channel plays in the regulation of pulmonary vascular tone in normal patients and patients with pulmonary hypertension. Intimal Proliferation and Fibrosis Endothelial proliferation leading to obliteration of the pulmonary vascular bed has also been character¬ ized in patients with advanced PPH.134 Wagenvoort and Wagenvoort3 have described this as a manifes¬ tation of advanced disease that follows medial hyper¬ trophy and pulmonary vasoconstriction. However, severe endothelial proliferation in the absence of medial hypertrophy and demonstrable clinical vaso¬ constriction has also been described.4 This suggests a causative role for growth factors, of which endothelin is a strong possibility, leading to intimal proliferation with or without vasoconstriction.20 There are endo¬ thelin receptors in the pulmonary vasculature that interact with G-proteins that regulate intracellular Pathogenesis of Primary Pulmonary Hypertension Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017 calcium and reduce protein kinase C activity.21 Pa¬ tients with PPH have elevated endothelin levels that appear to be liberated by the pulmonary vascular bed.22 A relationship between endothelin levels and severity of disease has been demonstrated, but it remains unclear whether endothelin is the cause or result of PPH.23 Patients with primary and secondary forms of pulmonary hypertension have markedly elevated levels of endothelin-like activity in the vascular endothelium, which raises the pulmonarythat endothelin receptor blockers may be possibility useful as a treatment of pulmonary hypertension.24 Thromboxane, another growth factor that is pri¬ marily derived from platelets, has received particular attention in pulmonary hypertension.25 Besides its effects on platelet aggregation, it also causes vaso¬ constriction and induces intimal proliferation. The action of thromboxane is opposed by prostacyclin, a compound that is produced by normal vascular endothelium and that has vasodilatory and anticoag¬ ulant properties.26 Patients with PPH have been characterized as having an imbalance in the ratio of thromboxane to prostacyclin production, suggesting that overproduction of one or underproduction of the other might be a factor in the disease.25 Clinical trials have now shown significant reductions in pul¬ monary artery pressure and PVR when prostacyclin Glaxo-Wellcome; Research (epoprostenol [Flolan]; Park, NC) is given to patients with PPH Triangle long term.27-30 Prostacyclin is effective even in pa¬ tients who show no acute vasodilatory response from it, suggesting that it works as an antiproliferative agent as well.31 Angiotensin-converting enzyme (ACE) inhibitors have also been tested in patients with PPH. Shortterm studies have been disappointing, as the acute to be hemodynamic effects of these drugsfromseem the effec¬ minimal.32 However, lessons learned tiveness of ACE inhibitors in heart failure have us that they also work beyond vasodilation, as taught the effect of ACE inhibitors in reducing circulating neurohormones results in improved exercise toler¬ ance and survival.33 Recently, it has been described that patients with PPH have increased expression of ACE in the endothelium and media of the pulmo¬ nary vasculature.34 Elevated neurohormonal profiles have also been demonstrated in these patients.23 Thus, it might seem that ACE inhibition would be a the logical treatment of PPH, not necessarily with but of causing acute pulmonary vasodilitation, goal with the goal affecting the disease process by limiting vascular proliferation and by lessening the effects of neurohormonal activation on the pulmonary vascu¬ lature and myocardium. In summary, intimal proliferation of the pulmo¬ nary arterioles appears to parallel increases in endo¬ thelin levels, implicating endothelin as important in the pathogenesis of the disease. The severity of the intimal proliferation seems to reflect the severity and of the disease. It is possible that the chronicity intimal proliferation is reversible, which suggests that we should also be evaluating drug therapy by of the disease other than hemo¬ looking at measures end as an point. dynamics Thrombosis In Situ A third representation of PPH histologically is thrombosis in situ of the pulmonary arterioles.1'3'4 Vessels with eccentric intimal pads that are pre¬ sumed to be caused by local thrombosis, as well as recanalized thrombi, are randomly scattered throughout the pulmonary vasculature of patients with PPH.4 Although once believed this could rep¬ microembolism, to our knowledge, pulmonary of these microemboli in patients with PPH been demonstrated.4 The current thinking has is that this represents local thrombosis of the pulmo¬ nary arteriolar bed. It has been shown that these patients have elevated levels of fibrinopeptide A, which reflects the procoagulant environment within the pulmonary vascular bed.35 Consistent with this long-term effects of warfarin hypothesis are the in improving survival as demon¬ anticoagulation strated in one retrospective study and one prospec¬ tive study.16'36 As platelet activation is likely part of thrombosis, it again brings into question the role of the platelet and its associated growth factors in the of PPH. The National Institutes of development Health Registry on Primary Pulmonary Hyperten¬ sion reported that these thrombotic lesions seem to be equally prevalent between men and women, whereas plexiform lesions seem to be more com¬ found in women.4 monly It is quite possible that in some patients, throm¬ bosis of the pulmonary arterioles may be the only manifestation of PPH. Warfarin therapy pathologic alone has been shown to improve survival and he¬ in some cases.37 Another curiosity is the modynamics fact that some patients with PPH can develop exten¬ sive central thrombi that are nonocclusive in nature, suggesting that the local procoagulant state of the vascular bed can be quite intense.38 pulmonary The basis for the in situ thrombosis of the pulmo¬ nary arteriolar bed in PPH is probably endothelial injury. It is likely that platelet activation and vasoac¬ and this tive substance release are resent a source never may occurring, either perpetuate or promote the disease process in many patients. In patients in whom in situ thrombosis is the predominant lesion, there may be no demonstration of pulmonary vasoreactivity (since pulmonary vasoconstriction is not underlying). These serve to CHEST/114/3/SEPTEMBER, 1998 SUPPLEMENT Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017 239S triggers to the disease (such as HIV virus or anorexi¬ gens). Individual genetic susceptibility, combined with the intensity and duration of exposure to a trigger, probably influences the histologic manifesta¬ tion of the disease, and hence its clinical expression SIGNALS SENSORS (FigIn 1). the MEDIATORS Vasoactive Growth Factors Substances Pulmonary Vascular Smooth Muscle Cell years to come, we will be looking to identify the triggers of endothelial injury in these patients and why some people seem to be predisposed whereas others are not. However, as we understand the nature of the vascular abnormality in these patients and the effects of drugs, more progress in drug treatment and improved survival will be forth¬ coming. Figure 1. Based on clinical data, a paradigm can be proposed to explain pulmonary hypertension as a final common pathway. A of signals, acting on specific endothelial receptor sites, will variety alter endothelial control of the arteriolar microenvironment. The variations in expression of a pulmonary arteriopathy are likely explained by the type and intensity of the signals affecting endothelial cell function, the mediators that are generated, and their effect on vascular tone, and the underlying genetic predis¬ position of the patient. In PPH, the signals remain unknown. References 1 Edwards WD, Edwards JE. Clinical primary hypertension: 884-88 2 3 three pathologic types. pulmonary Circulation 1977; 56: Wagenvoort CA. Vasoconstriction and medial hypertrophy in pulmonary hypertension. Circulation I960; 22:535-46 Wagenvoort CA, Wagenvoort N. Primary pulmonary hyper¬ a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84 Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension: a qualitative and quantita¬ tive study of pulmonary blood vessels from 58 patients in the tension: patients should benefit substantially from long-term However, because of the rel¬ anticoagulant therapy. nature of these thrombotic lesions atively ubiquitous in the lungs of patients with PPH, it is recommended that all patients be treated with anticoagulant the¬ rapy 39 Endothelial Injury.The Common Pathway one does not assume that PPH is three distinct diseases, it needs to be underscored separate that the three pathologic features of PPH that have been reviewed are typically seen throughout the lungs of most patients with PPH. This has been demonstrated in the National Institutes of Health Registry on PPH,4 in patients with familial PPH,40 in patients with pulmonary hypertension secondary to atrial septal defects,41 and from exposure to toxic that the hypertensive rapeseed oil.42thatItis appears in seen PPH vasculopathy represents a spec¬ trum that includes medial hypertrophy, intimal pro¬ liferation and fibrosis, and in situ thrombosis, all of which can be explained by injury to the pulmonary vascular endothelium. The clinical expression of PPH will be influenced by the underlying histologic changes so that patients with predominant medial hypertrophy should have more vasoreactivity than those whose predominant lesions are thrombotic in nature. The distribution of these lesions is likely influenced by the patient's age at onset, gender and other genetic factors, and 4 5 6 7 So that 240S 8 9 10 11 12 13 14 National Heart, Lung, and Blood Institute Primary Pulmo¬ nary Hypertension Registry. Circulation 1989; 80:1198-1206 Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 20:557-70 Barst RJ. Pharmacologically-induced pulmonary vasodilata¬ tion in children and young adults with primary pulmonary hypertension. Chest 1986; 89:497-503 Sitbon O, Brenot F, Denjean A, et al Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hyperten¬ sion: a dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151:384-89 Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension: vascular structure, morphometry, and respon¬ siveness to vasodilator agents. Circulation 1989; 80:1207-21 Wilson DW, Segall HJ, Pan LCW, et al. Progressive inflam¬ matory and skeletal changes in the pulmonary vasculature of monocrotaline-treated rats. Microvasc Res 1989; 38:57-80 Rosenberg HC, Rabinoviteh M. Endothelial injury and vas¬ cular reactivity in monocrotaline pulmonary hypertension. 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Chest 1993; 104:236-50 40 Loyd JE, Atkinson JB, Pietra GG, et al. Heterogeneity of pathologic lesions in familial primary pulmonary hyperten¬ sion. Am Rev Respir Dis 1988; 138:952-57 41 Yamaki S, Horiuchi T, Miura M, et al. Pulmonary vascular 42 disease in secundum atrial septal defect with pulmonary hypertension. Chest 1986; 89:694-98 Gomez-Sanchez MA, Mastre de Juan MJ, Gomez-Pajuelo C, et al. Pulmonary hypertension due to toxic oil syndrome: a chnicopathologic study. Chest 1989; 95:325-31 CHEST / 114 / 3 / SEPTEMBER, 1998 SUPPLEMENT Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21842/ on 05/02/2017 241S