- Email: [email protected]
Clinical Insights Into the Pathogenesis of Primary Pulmonary Hypertension
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 primary pulmonary hypertension has come from clinical experiences. The clinical response to vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the pathologic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunction, 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 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)
of primary pulmonary hypertenT hesionpathogenesis (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 hypotheses in the animal laboratory is problematic and forces speculation. Despite these obstacles, a wealth of information has been obtained from the clinical experience in diagnosing and treating patients with PPH that has provided insight into the underlying pathogenesis of the disease. Although the clinical experience tends to raise more questions than answers, 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
PPH represents a disease that is manifest by a pulmonary hypertensive vasculopathy that has multiple expressions. 1 One pathologic feature of PPH is medial hypertrophy of the pulmonary arterioles that appears to represent vasoconstriction. 2 Although it is usually seen in conjunction with other lesions, isolated medial hypertrophy has been described in several pathologic series of patients dying with PPH and seems to be more prevalent in children than *From the Section of Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago. Correspondence to: Stuart Rich, MD, Th e Rush Heart Institute, Center f or 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 constriction 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 short-acting vasodilator and measure the response. Observing a substantial fall in 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 causing smooth muscle cell relaxation. Consistent with this hypothesis, Sitbon and colleagues 7 have characterized patients with PPH as responders or nonresponders to nitric oxide based on acute reductions in mean pulmonary artery pressure following inhalation of the gas. However, Palevsky and colleagues8 compared the acute effects of several vasodilators with histology in patients with PPH and were unable to correlate the two. Obviously the mechanisms for pulmonary vasoconstriction and vasodilation are 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 hypertrophy of the pulmonary arterioles and pulmonary hypertension after approximately 4 weeks. However, close observation of the development of the medial CHEST I 114 I 3 I SEPTEMBER, 1998 SUPPLEMENT
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hypertrophy revealed that it is preceded by intense metabolic activity and proliferation of the pulmonary endothelial celllayer. 10 Studies such as these suggest that the development of medial hypertrophy is regulated by the endothelium, and that isolated medial hypertrophy represents an abnormality of endothelial cell control over pulmonary vascular smooth muscle. Nitric oxide has been identified as an endothelial-derived mediator that has important regulatory properties over vascular tone. 11 It is believed that nitric oxide, a powerful vasodilator, keeps the pulmonary vascular bed in a relatively relaxed state. One hypothesis is that the loss of normal endothelial cell production of nitric oxide could result in pulmonary arterial vasoconstriction and smooth muscle cell hypertrophy. Recently, reduced levels of nitric oxide synthase in the pulmonary vasculature of patients with PPH have been characterized, which implicates inadequate local nitric oxide production as part of this disease process.12 In addition, the more severe the pulmonary vascular changes, the lower the levels of 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 acetylcholine, with ones that are endothelial independent, such as nitroglycerine or nitric oxide, has been attempted with the hope of characte1izing the degree of endothelial cell dysfunction in a given patient. 13 The studies suggest a progressive loss of vasoreactivity in the pulmonary vascular bed that correlates with the severity of the disease. The response to any pulmonary vasodilator in PPH will likely be a graded one, and the characterization of an individual patient as being a responder or nonresponder an attempt to categorize them for selection of long-term therapy. One example is the common practice to categorize patients with PPH as being responders or nonresponders to calcium blockers. However, there is no accepted definition of a response to calcium block. ers, with investigators arbitrarily choosing an acute change in PVR that varies between 20% and 50%.1 4 •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 pulmonary artery pressure and PVR while receiving long-term therapy indefinitely. 16 As with nitric oxide, 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 answered. 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 unknown. It has also been shown that the vasodilatory response to calcium channel blockers does not represent 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 and PVR when a more potent vasodilator such as IV adenosine is added_l7 Another important question is how to interpret the more common acute hemodynamic response to calcium 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.1 9 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 pulmonary vascular smooth muscle cell hypertrophy appears to express marked reactivity early in the disease, and that it loses reactivity as endothelial cell injury progresses. It is possible that pulmonary vasoconstriction 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 characterized in patients with advanced PPH.l·3 •4 Wagenvoort and Wagenvoort3 have described this as a manifestation of advanced disease that follows medial hypertrophy and pulmonary vasoconstriction. However, severe endothelial proliferation in the absence of medial hypertrophy and demonstrable clinical vasoconstriction 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 endothelin receptors in the pulmonary vasculature that interact with G-proteins that regulate intracellular Pathogenesis of Primary Pulmonary Hypertension
calcium and reduce protein kinase C activity. 21 Patients 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 ofPPH. 23 Patients with primary and secondary forms of pulmonary hypertension have markedly elevated levels of endothelin-like activity in the pulmonary vascular endothelium, which raises the possibility that endothelin receptor blockers may be useful as a treatment of pulmonary hypertension. 24 Thromboxane, another growth factor that is primarily derived from platelets, has received particular attention in pulmonary hypertension.25 Besides its effects on platelet aggregation, it also causes vasoconstriction 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 anticoagulant 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 pulmonary artery pressure and PVR when prostacyclin (epoprostenol [Flolan]; Glaxo-Wellcome; Research Triangle Park, NC) is given to patients with PPH long term. 27-30 Prostacyclin is effective even in patients who show no acute vasodilatory response from it, suggesting that it works as an antiproliferative agent as wel1. 31 Angiotensin-converting enzyme (ACE) inhibitors have also been tested in patients with PPH. Shortterm studies have been disappointing, as the acute hemodynamic effects of these drugs seem to be minimal. 32 However, lessons learned from the effectiveness of ACE inhibitors in heart failure have taught us that they also work beyond vasodilation, as the effect of ACE inhibitors in reducing circulating neurohormones results in improved exercise tolerance and survival. 33 Recently, it has been described that patients with PPH have increased expression of ACE in the endothelium and media of the pulmonary vasculature. 34 Elevated neurohormonal profiles have also been demonstrated in these patients. 23 Thus, it might seem that ACE inhibition would be a logical treatment of PPH, not necessarily with the goal of causing acute pulmonary vasodilitation, but with the goal affecting the disease process by limiting vascular proliferation and by lessening the effects of neurohormonal activation on the pulmonary vasculature and myocardium. In summary, intimal proliferation of the pulmonary 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 chronicity of the disease. It is possible that the intimal proliferation is reversible, which suggests that we should also be evaluating drug therapy by looking at measures of the disease other than hemodynamics as an end point.
Thrombosis In Situ A third representation of PPH histologically is thrombosis in situ of the pulmonary arterioles.l,3,4 Vessels with eccentric intimal pads that are presumed 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 represent pulmonary microembolism, to our knowledge, a source of these microemboli in patients with PPH has never been demonstrated.4 The current thinking is that this represents local thrombosis of the pulmonary 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 hypothesis are the long-term effects of warfarin anticoagulation in improving survival as demonstrated in one retrospective study and one prospective 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 development of PPH. The National Institutes of Health Registry on Primary Pulmonary Hypertension reported that these thrombotic lesions seem to be equally prevalent between men and women, whereas plexiform lesions seem to be more commonly found in women. 4 It is quite possible that in some patients, thrombosis of the pulmonary arterioles may be the only pathologic manifestation of PPH. Warfarin therapy alone has been shown to improve survival and hemodynamics in some cases. 37 Another curiosity is the fact that some patients with PPH can develop extensive central thrombi that are nonocclusive in nature, suggesting that the local procoagulant state of the pulmonary vascular bed can be quite intense. 38 The basis for the in situ thrombosis of the pulmonary arteriolar bed in PPH is probably endothelial injury. It is likely that platelet activation and vasoactive substance release are occurring, and this may serve to 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 CHEST I 114 I 3 I SEPTEMBER, 1998 SUPPLEMENT
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SIGNALS
sheer stress
inflammatory mediators
SENSORS Pulmonary Vascular Endothelial Cell
MEDIATORS
Vasoactive Substances
Growth Factors
Pulmonary Vascu/ar Smooth Muscle Cell
FIGURE l. Based on clinical data, aparadigm can be proposed to explain pulmonary hypertension as a final common pathway. A variety of signals, acting on specific endothelial receptor sites, will 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 predisposition of the patient. In PPH, the signals remain unknown.
patients should benefit substantially from long-term anticoagulant therapy. However, because of the relatively ubiquitous nature of these thrombotic lesions in the lungs of patients with PPH, it is recommended that all patients be treated with anticoagulant therapy.39
ENDOTHELIAL INJURY- THE COMMON PATHWAY
So that one does not assume that PPH is three separate distinct diseases, it needs to be underscored 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 rapeseed oil. 42 It appears that the hypertensive vasculopathy that is seen in PPH represents a spectrum that includes medial hypertrophy, intimal proliferation 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 240S
triggers to the disease (such as HIV virus or anorexigens). Individual genetic susceptibility, combined with the intensity and duration of exposure to a trigger, probably influences the histologic manifestation of the disease, and hence its clinical expression (Fig 1). In the 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 forthcoming.
REFERENCES
1 Edwards WD, Edwards JE. Clinical primary pulmonary hypertension: three pathologic types. Circulation 1977; 56: 884-88 2 Wagenvoort CA. Vasoconstriction and medial hypertrophy in pulmonary hypertension. Circulation 1960; 22:535-46 3 Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-84 4 Pietra GG, Edwards WD, Kay JM , et a!. Histopathology of primary pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute Primary Pulmonary Hypertension Registly. Circulation 1989; 80:1198-1206 5 Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 20:557-70 6 Barst RJ. Pharmacologically-induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest 1986; 89:497-503 7 Sitbon 0 , Brenot F, Denjean A, et a!. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995; 151:384-89 8 Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension: vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation 1989; 80:1207-21 9 Wilson DW, Segall HJ, Pan LCW, et al. Progressive inflammatory and skeletal changes in the pulmonary vasculature of monocrotaline-treated rats. Microvasc Res 1989; 38:57-80 10 Rosenberg HC, Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am J Physiol 1988; 255:H1584-91 11 Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biologic activity of endothelium-derived relaxing factor. Nature 1987; 327:524-26 12 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Eng! J Med 1995; 333:214-21 13 Celermajer DS, Cullen S, Deanfield JE. Impairment of endothelium dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993; 87:440-46 14 Reeves JT, Groves BM, Turkevich D. The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134:342-46 15 Rich S, Brundage BH. High-dose calcium channel blocking therapy for primary pulmonary hypertension: evidence for Pathogenesis of Primary Pulmonary Hypertension
16 17 18
19
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21 22
23
24 25
26 27 28
long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 1997; 76:135-41 Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Eng! J Med 1992; 327:76-81 Schrader BJ, Inbar S, Kaufmann L, eta!. Comparison on the effects of adenosine and nifedipine in pulmonary hypertension. J Am Coli Cardiol 1992; 19:1060-64 Rich S, Kaufmann E. High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing. J Am Coli Cardiol 1991; 18:1323-27 Packer M, Medina N, Yushak M. Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative vascular disease. J Am Coli Cardiol 1984; 4:890-96 Voelkel NF, Tuder RM, Weir EK. Pathophysiology of primary pulmonary hypertension from physiology to molecular mechanisms. In: Rubin LJ, Rich S, eds. Primary pulmonary hypertension. New York: Marcel Dekker, 1997; 83-133 Filep JG. Endothelin peptides: biological actions and pathophysiological significance in the lung. Life Sci 1993; S2: 119-33 Yoshibayashi M, Nishioka K, Nakao K, et a!. Plasma endothelin concentration in patients with pulmonary hypertension associated with congenital heart defects: evidence for increased production of endothelin in the pulmonary circulation. Circulation 1991; 84:2280-85 Nootens M, Kaufmann E , Rector T, et a!. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamics and endothelin levels. JAm Coli Cardiol 1995; 26:1581-85 Giaid A, Yanagisawa M, Langleben D, et a!. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Eng! J Med 1993; 328:1732-39 Christman BW, McPherson CD, Newman JH, et a!. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Eng! J Med 1992; 327:70-75 Moncada S, Korbut R, Bunting S, et a!. Prostacyclin is a circulating hormone. Nature 1978; 273:767-68 Rubin LJ, Mendoza J, Hood M, et a!. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann Intern Med 1990; 112:485-91 Barst RJ, Rubin LJ, Long WA, et a!. A comparison of continuous intravenous prostacyclin versus conventional ther-
29
30
31
32 33
34
35
36 37
38 39 40 41 42
apy in primary pulmonary hypertension. N Eng! J Med 1996; 334:296-301 Shapiro SM, Oudiz RJ, Cao T, et a!. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coli Cardiol 1997; 30:343-49 Barst RJ, Rubin LJ, McGoon MD, et a!. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121:409-15 McLaughlin W, Genthner DE, Panella MM, eta!. Reduction in pulmonary vascular resistance with long-term prostacyclin therapy in primary pulmonary hypertension. N Eng! J Med 1998; 338:273-77 Leier CV, Bambach D, Nelson S, eta!. Captropril in primary pulmonary hypertension. Circulation 1983; 67:155-61 SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Eng! J Med 1991; 325:293-302 Schuster DP, Crouch EC, Parks WC, et a!. Angiotensin converting enzyme expression in primary pulmonary hypertension. Am J Respir Crit Care Med 1996; 154:1087-91 Eisenberg PR, Lucore C, Kaufmann E, et a!. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990; 82:841-47 Fuster V, Steele PM, Edwards WD, eta!. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70:580-87 Cohen M, Edwards WD, Fuster N. Regression in thromboembolic type of primary pulmonary hypertension during 2lh years of antithrombotic therapy. J Am Coil Cardiol 1986; 7:172-75 Moser KM, Fedullo PF, Finkbeiner WE, et a!. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation 1995; 91:741-45 Rubin LJ. ACCP Consensus Statement: primary pulmonary hypertension. Chest 1993; 104:236-50 Loyd JE, Atkinson JB, Pietra GG, et a!. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 1988; 138:952-57 Yamaki S, Horiuchi T, Miura M, et a!. Pulmonary vascular 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 a!. Pulmonary hypertension due to toxic oil syndrome: a clinicopathologic study. Chest 1989; 95:325-31
CHEST I 114 I 3 I SEPTEMBER, 1998 SUPPLEMENT
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Because of the lack of adequate animal models, much of our knowledge of the pathogenesis of primary pulmonary hypertension has come from clinical experiences. The clinical response to vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the pathologic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunction, 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 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)
of primary pulmonary hypertenT hesionpathogenesis (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 hypotheses in the animal laboratory is problematic and forces speculation. Despite these obstacles, a wealth of information has been obtained from the clinical experience in diagnosing and treating patients with PPH that has provided insight into the underlying pathogenesis of the disease. Although the clinical experience tends to raise more questions than answers, 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
PPH represents a disease that is manifest by a pulmonary hypertensive vasculopathy that has multiple expressions. 1 One pathologic feature of PPH is medial hypertrophy of the pulmonary arterioles that appears to represent vasoconstriction. 2 Although it is usually seen in conjunction with other lesions, isolated medial hypertrophy has been described in several pathologic series of patients dying with PPH and seems to be more prevalent in children than *From the Section of Cardiology, Rush-Presbyterian-St. Luke's Medical Center, Chicago. Correspondence to: Stuart Rich, MD, Th e Rush Heart Institute, Center f or 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 constriction 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 short-acting vasodilator and measure the response. Observing a substantial fall in 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 causing smooth muscle cell relaxation. Consistent with this hypothesis, Sitbon and colleagues 7 have characterized patients with PPH as responders or nonresponders to nitric oxide based on acute reductions in mean pulmonary artery pressure following inhalation of the gas. However, Palevsky and colleagues8 compared the acute effects of several vasodilators with histology in patients with PPH and were unable to correlate the two. Obviously the mechanisms for pulmonary vasoconstriction and vasodilation are 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 hypertrophy of the pulmonary arterioles and pulmonary hypertension after approximately 4 weeks. However, close observation of the development of the medial CHEST I 114 I 3 I SEPTEMBER, 1998 SUPPLEMENT
2378
hypertrophy revealed that it is preceded by intense metabolic activity and proliferation of the pulmonary endothelial celllayer. 10 Studies such as these suggest that the development of medial hypertrophy is regulated by the endothelium, and that isolated medial hypertrophy represents an abnormality of endothelial cell control over pulmonary vascular smooth muscle. Nitric oxide has been identified as an endothelial-derived mediator that has important regulatory properties over vascular tone. 11 It is believed that nitric oxide, a powerful vasodilator, keeps the pulmonary vascular bed in a relatively relaxed state. One hypothesis is that the loss of normal endothelial cell production of nitric oxide could result in pulmonary arterial vasoconstriction and smooth muscle cell hypertrophy. Recently, reduced levels of nitric oxide synthase in the pulmonary vasculature of patients with PPH have been characterized, which implicates inadequate local nitric oxide production as part of this disease process.12 In addition, the more severe the pulmonary vascular changes, the lower the levels of 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 acetylcholine, with ones that are endothelial independent, such as nitroglycerine or nitric oxide, has been attempted with the hope of characte1izing the degree of endothelial cell dysfunction in a given patient. 13 The studies suggest a progressive loss of vasoreactivity in the pulmonary vascular bed that correlates with the severity of the disease. The response to any pulmonary vasodilator in PPH will likely be a graded one, and the characterization of an individual patient as being a responder or nonresponder an attempt to categorize them for selection of long-term therapy. One example is the common practice to categorize patients with PPH as being responders or nonresponders to calcium blockers. However, there is no accepted definition of a response to calcium block. ers, with investigators arbitrarily choosing an acute change in PVR that varies between 20% and 50%.1 4 •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 pulmonary artery pressure and PVR while receiving long-term therapy indefinitely. 16 As with nitric oxide, 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 answered. 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 unknown. It has also been shown that the vasodilatory response to calcium channel blockers does not represent 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 and PVR when a more potent vasodilator such as IV adenosine is added_l7 Another important question is how to interpret the more common acute hemodynamic response to calcium 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.1 9 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 pulmonary vascular smooth muscle cell hypertrophy appears to express marked reactivity early in the disease, and that it loses reactivity as endothelial cell injury progresses. It is possible that pulmonary vasoconstriction 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 characterized in patients with advanced PPH.l·3 •4 Wagenvoort and Wagenvoort3 have described this as a manifestation of advanced disease that follows medial hypertrophy and pulmonary vasoconstriction. However, severe endothelial proliferation in the absence of medial hypertrophy and demonstrable clinical vasoconstriction 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 endothelin receptors in the pulmonary vasculature that interact with G-proteins that regulate intracellular Pathogenesis of Primary Pulmonary Hypertension
calcium and reduce protein kinase C activity. 21 Patients 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 ofPPH. 23 Patients with primary and secondary forms of pulmonary hypertension have markedly elevated levels of endothelin-like activity in the pulmonary vascular endothelium, which raises the possibility that endothelin receptor blockers may be useful as a treatment of pulmonary hypertension. 24 Thromboxane, another growth factor that is primarily derived from platelets, has received particular attention in pulmonary hypertension.25 Besides its effects on platelet aggregation, it also causes vasoconstriction 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 anticoagulant 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 pulmonary artery pressure and PVR when prostacyclin (epoprostenol [Flolan]; Glaxo-Wellcome; Research Triangle Park, NC) is given to patients with PPH long term. 27-30 Prostacyclin is effective even in patients who show no acute vasodilatory response from it, suggesting that it works as an antiproliferative agent as wel1. 31 Angiotensin-converting enzyme (ACE) inhibitors have also been tested in patients with PPH. Shortterm studies have been disappointing, as the acute hemodynamic effects of these drugs seem to be minimal. 32 However, lessons learned from the effectiveness of ACE inhibitors in heart failure have taught us that they also work beyond vasodilation, as the effect of ACE inhibitors in reducing circulating neurohormones results in improved exercise tolerance and survival. 33 Recently, it has been described that patients with PPH have increased expression of ACE in the endothelium and media of the pulmonary vasculature. 34 Elevated neurohormonal profiles have also been demonstrated in these patients. 23 Thus, it might seem that ACE inhibition would be a logical treatment of PPH, not necessarily with the goal of causing acute pulmonary vasodilitation, but with the goal affecting the disease process by limiting vascular proliferation and by lessening the effects of neurohormonal activation on the pulmonary vasculature and myocardium. In summary, intimal proliferation of the pulmonary 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 chronicity of the disease. It is possible that the intimal proliferation is reversible, which suggests that we should also be evaluating drug therapy by looking at measures of the disease other than hemodynamics as an end point.
Thrombosis In Situ A third representation of PPH histologically is thrombosis in situ of the pulmonary arterioles.l,3,4 Vessels with eccentric intimal pads that are presumed 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 represent pulmonary microembolism, to our knowledge, a source of these microemboli in patients with PPH has never been demonstrated.4 The current thinking is that this represents local thrombosis of the pulmonary 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 hypothesis are the long-term effects of warfarin anticoagulation in improving survival as demonstrated in one retrospective study and one prospective 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 development of PPH. The National Institutes of Health Registry on Primary Pulmonary Hypertension reported that these thrombotic lesions seem to be equally prevalent between men and women, whereas plexiform lesions seem to be more commonly found in women. 4 It is quite possible that in some patients, thrombosis of the pulmonary arterioles may be the only pathologic manifestation of PPH. Warfarin therapy alone has been shown to improve survival and hemodynamics in some cases. 37 Another curiosity is the fact that some patients with PPH can develop extensive central thrombi that are nonocclusive in nature, suggesting that the local procoagulant state of the pulmonary vascular bed can be quite intense. 38 The basis for the in situ thrombosis of the pulmonary arteriolar bed in PPH is probably endothelial injury. It is likely that platelet activation and vasoactive substance release are occurring, and this may serve to 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 CHEST I 114 I 3 I SEPTEMBER, 1998 SUPPLEMENT
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SIGNALS
sheer stress
inflammatory mediators
SENSORS Pulmonary Vascular Endothelial Cell
MEDIATORS
Vasoactive Substances
Growth Factors
Pulmonary Vascu/ar Smooth Muscle Cell
FIGURE l. Based on clinical data, aparadigm can be proposed to explain pulmonary hypertension as a final common pathway. A variety of signals, acting on specific endothelial receptor sites, will 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 predisposition of the patient. In PPH, the signals remain unknown.
patients should benefit substantially from long-term anticoagulant therapy. However, because of the relatively ubiquitous nature of these thrombotic lesions in the lungs of patients with PPH, it is recommended that all patients be treated with anticoagulant therapy.39
ENDOTHELIAL INJURY- THE COMMON PATHWAY
So that one does not assume that PPH is three separate distinct diseases, it needs to be underscored 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 rapeseed oil. 42 It appears that the hypertensive vasculopathy that is seen in PPH represents a spectrum that includes medial hypertrophy, intimal proliferation 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 240S
triggers to the disease (such as HIV virus or anorexigens). Individual genetic susceptibility, combined with the intensity and duration of exposure to a trigger, probably influences the histologic manifestation of the disease, and hence its clinical expression (Fig 1). In the 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 forthcoming.
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