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The causes of pulmonary hypertension fall into four broad categories: (1) passive increases in pulmonary artery pressure secondary to increased left atrial pressure and left ventricular dysfunction, (2) veno-occlusive disorders, (3) conditions in which the blood flow through the pulmonary arteries is increased beyond the ability of the pulmonary circulation to compensate, and (4) conditions associated with vasospasm or occlusion, resulting in a diminished effective cross sectional area of the pulmonary vascular bed.1 ,2 In many cases several factors are present simultaneously. Regardless of the initiating cause, severe prolonged pulmonary hypertension appears to result in largely irreversible changes which involve vascular remodelling and often thrombosis.3-5
Because the signs and symptoms of pulmonary hypertension are often very non-specific, patients commonly present late and, until recently, invasive tests were required to establish the diagnosis. Consequently pulmonary hypertension was frequently an important but unrecognised component of other disease states, many of which will be the subject of this discussion.
The main importance of severe pulmonary hypertension is that it may cause right ventricular dysfunction and ultimately death from right heart failure. Pulmonary heart disease, usually associated with pulmonary hypertension, has been estimated to account for at least 10% of all cases of heart disease in the USA.6 The significance of milder pulmonary hypertension is less clear, but it is probably important. A study in Chicago of 1118 subjects who were undergoing coronary angiography for suspected heart disease showed that the finding of pulmonary hypertension, independent of left ventricular dysfunction, was the single most important predictor of the likelihood of death over the subsequent two years.7 Pulmonary hypertension also has important prognostic implications in critically ill surgical patients8 and in those with chronic obstructive pulmonary disease (COPD).9
The changes which take place in pulmonary arteries as a result of hypertension have been intensively studied, and numerous pro-inflammatory factors have been identified which can influence these changes.10 It is often difficult, if not impossible, to distinguish cause from effect. However some factors are frequently present. The aim of the present discussion is to examine the possible role of one such factor, serotonin. This may have added importance since a number of serotonin antagonists are available for oral use. For the purposes of this review pulmonary hypertension is defined as a pulmonary artery pressure of >25 mm Hg at rest.
Origin of serotonin and causes of elevated levels
Serotonin, also known as 5-hydroxytryptamine, is secreted from neuroendocrine cells in the gut, and tumours of these cells, called carcinoid tumours, are a source of increased production.11 ,12 Serotonin from the gastrointestinal tract is normally metabolised by the liver before it reaches the lungs, and it is also effectively removed by the lungs. Both these organs usually localise the effects of serotonin to the circulation of origin, except when abnormal channels of communication exist, as in portal hypertension, or when metabolic capacity is overwhelmed. Lack of removal of vasoactive substances by the liver could help to explain the association between pulmonary hypertension, portal hypertension, and liver diseases.13 ,14 The vascular adverse effects of serotonergic amines such as ergotamine are exacerbated in liver disease.15 The ability of the endothelial cells of the lungs to metabolise amines may also be reduced in disease states, probably because of impairment of amine oxidase enzymes.16 ,17 Such impairment results in raised circulating amine levels, which may provide early evidence of endothelial dysfunction in pulmonary hypertension before morphological changes are apparent.18 ,19
Pulmonary neuroendocrine cells secrete vasoactive substances in response to airway hypoxia and hypercapnia.20 ,21 For unknown reasons these cells commonly proliferate in patients with pulmonary hypertension, producing a variety of peptides in addition to large amounts of serotonin.22 In lung transplant recipients with end stage primary pulmonary hypertension the degree of hyperplasia of these cells was found to correlate with the extent of proliferation of myofibroblasts in the pulmonary arteries.23 In bronchopulmonary dysplasia, a condition strongly associated with pulmonary hypertension, a 34-fold increase in serotonin immunoreactive cells has been demonstrated.20Pulmonary neuroendocrine cells, rather than platelets, have been postulated to be the source of increased serotonin production causing acute postoperative pulmonary hypertension in children with congenital heart defects.24 ,25 The mast cell also contributes to increased levels of circulating serotonin in the pulmonary hypertension which occurs in rats following exposure to asbestos.26
Conditions associated with the destruction of platelets are likely to cause the release of serotonin and other contents which may cause pulmonary hypertension.27 Immune mediated acute thrombocytopenia is one such condition.28 The aggregation of platelets also releases serotonin, and when the process occurs in pulmonary arteries this causes vasospasm.29 Binding of platelets to arteries is mediated largely by von Willebrand factor and factor VIII.30 Increased aggregation of platelets and decreased platelet survival time are regularly observed in most forms of primary and secondary pulmonary hypertension.4 ,31Abnormalities of endothelial factor VIII have been observed in cases of pulmonary hypertension in both humans and sheep,32-34 and adherence of platelets to the pulmonary arteries in pulmonary hypertension is likely to be pathologically enhanced by the increases in endothelial von Willebrand factor which result from increased shear stress (fig 1).35 These changes may lead to pulmonary arteriosclerosis, which is usual in pulmonary hypertension.36
Stages in the interaction of platelets with the walls of pulmonary arteries following trauma. Stage 1: adhesion of platelets following endothelial injury mediated by von Willebrand factor (vWF). Stage 2: formation of the platelet plug with aggregation and degranulation (some of the most important vasoconstricting and vasodilating substances are listed, many of which are released from platelets). Stage 3: fibrin clot formation (mediated by fibrinogen). Modified from reference 186 with permission.
Circulating serotonin is taken up by endothelial cells, and even more so by platelets, where it is stored in dense (delta) granules.30 When the endothelial cells or platelets are unable to take up serotonin because of damage or as a result of congenital abnormalities, circulating serotonin levels are increased and pulmonary hypertension may result. The increases in serotonin levels in patients with these problems persist following normalisation of pulmonary artery pressures after lung transplantation, indicating that the platelet abnormality is not caused by pulmonary hypertension.37
Effects of serotonin
A number of biogenic and synthetic amines are capable of causing endothelial disruption and platelet stimulation. Serotonin is somewhat unique in that these changes occur at levels which are not much higher than the “resting levels” which are observed in mammalian blood.38 The opening of junctions between endothelial cells causes oedema.39 On a molar basis, serotonin is the most potent pulmonary vasoconstrictor identified to date in humans,40 but in the systemic vasculature it causes profound vasodilation.41 These differing effects on the two circulations are similar to those of hypoxaemia and the effects of serotonin are intensified under hypoxaemic conditions and by the administration of catecholamines.41 In conditions characterised by stimulation of the sympathetic nervous system, such as cardiopulmonary bypass, subthreshold doses of serotonin can have significant vasoconstrictor effects.42 The vasoconstrictor effects of serotonin have been found to be synergistic with other concomitant variables which are too numerous to list.43Serotonin is also a bronchoconstrictor.41 ,44
Serotonin is a mitogen, causing hyperplastic and hypertrophic changes in smooth muscles.45 The most readily identifiable clinical manifestation of this effect is valvular heart disease.46 These effects are mediated by a variety of cellular processes, including cyclic nucleotides and protein kinase C activation.47 ,48 A complex interplay exists at a systemic and local level between inflammation, thrombosis, fibrinolysis, vasospasm, and vascular remodelling. Many of the important mitogens implicated in remodelling have a vasoconstrictor and prothrombotic effect, and vasodilators such as nitric oxide inhibit platelet aggregation, thrombosis, and remodelling.49 The histological changes which occur during pulmonary vascular remodelling have been reviewed elsewhere.3-5 Remodelling has many features in common with the changes that occur in arteriosclerosis, except that arteriosclerosis generally involves larger vessels with a high elastin content.50 Endothelial proliferation may also be more exuberant in some varieties of pulmonary hypertension than in arteriosclerosis.32 Hypoxia and stretching of the pulmonary vessels are believed to be important stimuli for these processes which involve phenotypic changes in endothelial cells, myofibroblasts, and numerous types of inflammatory cells.51 ,52 The end result of these changes are structural and functional changes which result in an increased pulmonary vascular resistance. These changes were accelerated by the administration of serotonin to rats exposed to chronic hypoxia.53 ,54
Serotonin receptors
At least five classes of serotonin receptor have been identified, each with numerous subclasses, and different receptors have been implicated in the pathogenesis of a number of vascular disorders.55 S1 and S2 are the principal receptors relevant to the pulmonary arteries.56The vascular response to serotonin is determined by a large number of concomitant variables, and also varies between vasodilation and vasoconstriction in different segments of the same artery, which makes generalisation difficult.57 However, under most experimental conditions, stimulation of S1 pulmonary receptors causes vasodilation and S2 receptors often mediate vasospasm.56 Functional imbalance of this system may result in hypertension, as in pre-eclampsia.58 With arteriosclerosis, numbers of S2 receptors are increased, causing increased sensitivity to serotonin.59-61Arteriosclerosis also appears to predispose to vasospasm due to deficiencies of endothelial vasodilation.62
Serotonergic agents
Pulmonary hypertension can be caused in most mammalian species by numerous serotonergic drugs, many of which are sympathomimetic anorexients. These include aminorex63 and dexfenfluramine.64 In rabbits, aminorex and other anorexients cause release of serotonin from platelets.65In dogs, intravenous dexfenfluramine augments hypoxic pulmonary vasoconstriction and, with long term oral use, pulmonary vascular resistance is increased.66 In rats phentermine and phenmetrazine cause pulmonary vasoconstriction by prolonging the vasoconstrictive influence of serotonin.67 ,68 More recently three other anorexient agents were found to cause pulmonary vasoconstriction by inhibiting potassium current in pulmonary vascular smooth muscle, an action which mimicked the effect of hypoxia.69 Other drugs with direct or indirect serotonergic effects70 have been associated with pulmonary hypertension—namely, cocaine,71 dopamine,72doxapram,73 fluoexetine,74lithium,75 methamphetamine,76methysergide,77 pentazocine,78phenmetrazine,73 protamine,79sertaline,80 and tryptophan.81 Most of these reactions are infrequent, implying individual variations in susceptibility, and for several of these agents possible alternative mechanisms of toxicity exist, but the common feature of serotonergy suggests that these may often be synergistic. In the case of pentazocine, for example, there are numerous reports concerning the illicit intravenous use of tablets containing talc, which cause a granulomatous arteritis, frequently resulting in chronic pulmonary hypertension. Crushed pentazocine tablets injected into dogs also cause transient pulmonary hypertension.82 However, other more common illicit drugs which are used in a similar way appear to cause these problems less frequently,83 and acute pulmonary hypertension is also a well established effect of pure pentazocine.
The pulmonary vasodilator urapidil is primarily an alpha-1 adrenoreptor blocker, but may also act by stimulating S1receptors.84
Specific pulmonary hypertensive diseases which may involve serotonin
THE CARCINOID SYNDROME
Investigators have found that about 25% of patients with the carcinoid syndrome have pulmonary hypertension which is often relatively mild.85 This is probably because of liver metabolism, since liver dysfunction is a prerequisite for the production of cardiac lesions in the guinea pig model of this disease.86 In addition to valve disease, pulmonary hypertension may contribute to the commonly observed tricuspid regurgitation.87 More severe valvular disease is found in patients with higher serotonin levels.88 ,89 Similar valvular lesions have frequently been observed during the use of ergotamine and methysergide, both of which are partial serotonin agonists, and have recently been reported in association with diet pills which also have serotonergic properties.90 Carcinoid tumours secrete peptides which also characteristically provoke florid vascular fibroproliferative reactions.91 ,92 Ketanserin provides relief of many of the symptoms of the carcinoid syndrome and, when used during anaesthesia, consistently reverses systemic hypertension,43 but the effects on pulmonary hypertension have not been studied.
MONOCROTALINE INDUCED PULMONARY HYPERTENSION
The plant Crotalaria spectabilis (the source of monocrotaline) is often used to induce pulmonary hypertension in experimental animals, most commonly the rat, and also has this effect in man. Endothelial injury is the first change observed, followed by hypertrophy of arterial smooth muscle and right ventricular hypertrophy.93 ,94 Plasma serotonin levels are increased, coinciding with platelet accumulation in the lungs, the vasoconstrictor response to serotonin is enhanced, and both pulmonary artery pressure and the severity of histological changes are reduced by selective serotonin blockade and by inhibition of serotonin synthesis with chlorophenylalanine.53 ,95 ,96 The hypertensive effect of monocrotaline was reduced in rats made moderately thrombocytopenic with antiplatelet serum,97 and by the platelet modifying drug sulphinpyrazone.98 Prednisolone was also beneficial.99 However, the thromboxane inhibitor dazmegrel was ineffective, suggesting a less important role for thromboxane A2 in this disorder.100
PULMONARY EMBOLISM
The pulmonary hypertension associated with acute pulmonary embolism (PE) is sometimes disproportionate to the degree of physical vascular occlusion, and some of this has been attributed to the vasoconstrictive effects of platelet derived serotonin.101-103 Bronchoconstriction following PE may have the same cause.104 ,105 Platelets adhere to the thrombus which has lodged in the pulmonary arteries106 ,107 and this commonly results in depletion of circulating platelet levels.108 Experimental embolisation in animals with fresh thrombotic material containing large amounts of platelet derived serotonin generates a more profound pulmonary vasoconstrictor response than embolisation with barium, glass beads, and other objects which do not contain platelets or stimulate thrombin mediated platelet degranulation.41 ,109 The degree of vasoconstriction is also proportionate to the extent of endothelial damage caused by the embolus.110 If experimental animals are rendered thrombocytopenic prior to embolisation, the pulmonary hypertension is significantly attenuated and inhibition of the platelet release reaction with sulphinpyrazone or heparin has a similar effect.111 ,112 A significant average reduction of approximately 5 mm Hg in the pulmonary hypertension generated by PE was observed in humans after the administration of ketanserin.113 Ketanserin and other serotonin blockers also reduce post embolic pulmonary hypertension in dogs.112 ,114
RADIATION PNEUMONITIS AND ANTITUMOUR DRUGS
Irradiation of tissues causes release of serotonin as evidenced by direct measurement,115 and indirectly by the well established beneficial effects of S3 receptor antagonists in the treatment of radiation induced side effects.116 Endothelium is a rapidly dividing tissue which suffers the early effects of radiation,117 and pulmonary hypertension often results.118 ,119 Serotonin levels were also increased significantly following treatment with vinblastine and other antitumour drugs.120
ADULT RESPIRATORY DISTRESS SYNDROME AND SHOCK
Pulmonary hypertension is observed in almost all cases of adult respiratory distress syndrome (ARDS),40 and vascular remodelling is pronounced in patients who survive longer than 10 days.121 Progressive thrombocytopenia occurs in 50% of cases, and often parallels the course of worsening hypoxia.122 ,123 Platelet activation and intrapulmonary platelet aggregation are also common.124 ,125 Sibbaldet al observed a correlation between raised serotonin levels and pulmonary hypertension in patients with ARDS related to sepsis.126 Serotonin contributed to pulmonary hypertension in dogs during haemorrhagic shock, and this hypertension was prevented with serotonin antagonists.127Administration of ketanserin to patients with acute respiratory failure following circulatory shock also caused significant haemodynamic improvements.128
COLLAGEN DISORDERS
Pulmonary hypertension is a complication of most varieties of collagen disease, particularly systemic lupus erythematosus (SLE), a disease in which pulmonary artery pressures were raised in over 30% of consecutive cases in several series.129-131 Patients with SLE and Raynaud’s syndrome appear to be particularly susceptible.132 Intraplatelet and circulating serotonin levels were found to be significantly higher in patients with calcinosis, Raynaud’s phenomenon, and oesophageal dysmotility (the CREST variant) than in controls.133 ,134 Stachowet al found evidence of impaired monoamine oxidase activity in scleroderma, and the increased levels of serotonin observed were normalised by treatment with ketanserin.135In a multicentre trial oral ketanserin reduced the frequency of episodes of Raynaud’s symptoms from 34% to 18% among 222 patients43 and, in a study of 14 patients with systemic sclerosis and relatively severe pulmonary hypertension, Seiboldet al found that intravenous ketanserin decreased pulmonary artery pressure by 13–44% in five patients but caused a paradoxical increase in one, with no change in the other eight.136
PORTAL HYPERTENSION
Hadengue et al found that 2% of 507 patients with portal hypertension also had pulmonary hypertension and the portal hypertension usually preceded the pulmonary hypertension.137 These authors postulated that either microemboli or unspecified vasoactive substances were bypassing the liver to reach the lung by way of portosystemic shunts Thrombocytopenia was present in most cases of portal hypertension with plexogenic pulmonary arteriopathy.138
HYPOXIC DISORDERS
Because of the prevalence of chronic lung disease, hypoxia is probably the commonest of all causes of pulmonary hypertension apart from diseases caused by parasites.2 The mechanisms of hypoxic vasoconstriction have been reviewed elsewhere, but much remains unknown.139 Hypoxia complicates many of the other diseases which have already been discussed, and modifies the effects of many vasoactive substances.140 ,141 In healthy subjects hypoxia per se does not appear to increase circulating serotonin levels,142 but levels are increased in patients with several types of chronic lung disease and associated pulmonary hypertension.143 ,144 Patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension show evidence of greater activation of platelets in pulmonary vessels than those with normotensive COPD,145 ,146 and a reduced platelet survival time is also found.147 In animal models platelets release their contents into the lung during hypoxic vasoconstriction.148 The release of platelet contents and the progression of pulmonary hypertension in patients with COPD may be slowed with the use of the platelet-inhibiting drug dipyridamole.149 ,150 This agent also reduced pulmonary artery pressure and the thickness of pulmonary arteries in rats exposed to chronic hypoxia.151 ,152
Inherited and acquired platelet disorders
PLATELET STORAGE POOL DISEASES
As noted above, patients with a deficiency of dense granules in platelets are unable to take up serotonin from the blood, often resulting in increased circulating levels of the amine. One such case of “platelet storage pool disease” has been described in which the patient developed severe pulmonary hypertension long after the platelet disorder was diagnosed.153 Ketanserin alleviated the pulmonary hypertension in this case. An experimental model of platelet storage pool disease exists in the fawn hooded rat, an animal which is studied for its propensity to develop pulmonary hypertension.154 In this species pulmonary vascular smooth muscle proliferates more rapidly in response to epidermal growth factor than in normotensive rats,155 there is increased vasoconstrictor sensitivity to serotonin,156 and decreased biogenic amine removal by lung tissue.157 These rats also appear to have a genetic propensity to overproduce endothelin-1, another mitogen and vasoconstrictor.158
An acquired form of platelet storage pool disease, associated with disordered uptake of serotonin, occurs commonly in patients with myeloproliferative disorders.159 Portal hypertension is a well recognised complication of these disorders and, in one series, a 13% incidence of pulmonary hypertension was also observed.160 Platelets in patients with myeloproliferative disorders have also been found to have a selectively exaggerated serotonin release induced by immune complexes.161
PLATELET CELL MEMBRANE DISORDERS
In addition to myeloproliferative disorders, other diseases are characterised by platelet cell membrane abnormalities, thrombocytopenia, increased circulating serotonin levels, portal hypertension, and pulmonary hypertension. These include paroxysmal nocturnal haemoglobinuria162–164 and the antiphospholipid syndrome.
Antiphospholipid antibodies occur in about 10% of patients with chronic thromboembolic pulmonary hypertension.165 Other pulmonary manifestations include: (1) pulmonary emboli, (2) adult respiratory distress syndrome, (3) alveolar haemorrhage, (4) pulmonary capillaritis, and (5) primary thrombosis of the lung vessels.166 These antibodies are also commonly found in association with collagen diseases. They may interact with phospholipids and phosopholipid-bound proteins in blood vessel walls and platelets causing damage to vessel walls and platelet aggregation, resulting in thrombocytopenia.167 ,168
THROMBOCYTOPENIA IN PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN
Platelets have been also implicated in the pathophysiology of persistent pulmonary hypertension of the newborn. Segallet al identified 90 newborn infants with perinatal asphyxiation and found that only the 12 infants with thrombocytopenia had proven pulmonary hypertension.169These authors suspected that platelet derived thromboxane A2 may have caused the hypertension, but were unable to find a correlation between pulmonary artery pressures and prostaglandin metabolites. In another study it was determined prospectively that infants who developed persistent pulmonary hypertension as a result of meconium aspiration could be identified by the onset of thrombocytopenia prior to the hypertension.170
Serotonin antagonists
The S2 receptor antagonist ketanserin is the best studied agent of this type for reducing pulmonary hypertension or vascular resistance. Inhibition of platelet aggregation is another effect.43 Like most vasodilators this drug has varying efficacy, reflecting the complex pathophysiology of the disease. In the treatment of primary pulmonary hypertension, McGoonet al detected an average reduction of pulmonary vascular resistance of 18% with intravenous use in 10 patients.171 In a later study of 20 patients, eight of whom had not previously responded to other vasodilator therapy, the same authors found a small but significant decrease in pulmonary vascular resistance in the group as a whole, with a clinically significant response in three patients.172 In addition to conditions previously discussed, studies showing haemodynamic benefits with ketanserin have involved patients with protamine induced pulmonary hypertension,79 respiratory failure,128 and valve surgery.173 ,174 In comparison to nitroprusside, ketanserin usually improved gas exchange.175 However Hametet al could detect no change following administration of ketanserin in patients with hypoxic COPD.176 Animal studies involving different species have shown decreases in pulmonary artery pressure following pulmonary oedema after acid injury,177 serotonin induced pulmonary hypertension,178 and endotoxaemia.179 In the latter condition there is a phasic response. In several species serotonin was found to mediate the pulmonary hypertension occurring three hours after endotoxin injections, but not the more severe pulmonary hypertension which occurred earlier. Ketanserin had no effect in the first two hours, but was effective after three hours at a time when platelet counts ceased to fall.180-182 Droperidol has been observed to prevent serotonin-induced bronchospasm and pulmonary hypertension in humans and dogs.183 ,184
Numerous pulmonary vasodilators are available, but their influence on survival has not been adequately demonstrated. Ketanserin is seldom mentioned in reviews of these agents, although in the short term it appears to be as efficacious as many other agents that have been more extensively studied. The effects of ketanserin on pulmonary hypertension suggest that serotonergic mechanisms may be contributing to the problem.
General conclusions
The pathophysiology of pulmonary hypertension cannot be fully understood in terms of a traditional single cause and effect model. The concept of a balance of factors is probably more helpful. Under different circumstances three general, often interrelated, types of response are apparent: vasodilation/vasospasm, mitogenesis/cytostasis, and thrombosis/fibrinolysis. Although the vascular response to insult often appears relatively stereotyped, causes are invariably multifactorial. Genetic, environmental, nutritional, gender related factors and comorbidities are all likely to influence the final outcome. Serotonin is clearly an important and pervasive pro-inflammatory influence in these processes. Most authorities are now in agreement that serotonergic mechanisms are important in the pathogenesis of dietary pulmonary hypertension.63 ,64 ,80 ,185 The role of serotonin in other varieties of pulmonary hypertension has been unjustly neglected.
The evaluation of effective therapies for this serious disorder demands a much better understanding of the precise mechanisms involved in different clinical situations and in different stages of the disease. In many variants the patients are young, the prognosis is very poor, and the clinical management is difficult. Vasodilator therapy in isolation is frequently ineffective. A multifaceted approach to treatment including antiserotonin agents or platelet modifying drugs may prove to be more successful.