Role In Pulmonary Hypertension Research Articles

Vasoactive intestinal polypeptide in the respiratory tract: physiology and pathophysiology

Peptidergic neuromediators have gained importance in the field of respiratory physiology and pathophysiology due to the characterisation of numerous pulmonary effects in the past years. With regard to the multitude of mediators, the neuropeptide vasoactive intestinale polypeptide (VIP) plays a special role as it exerts potent anti-inflammatory and immunomodulatory effects. Neurophysiologically the peptide has been attributed to the family of the inhibitory non-adrenergic non-cholinergic (i-NANC) neuromediators of the pulmonary innervation. VIP-containing nerve fibres are localized in the airway and vascular smooth muscle layers of trachea and bronchi in the human respiratory tract. Apart from strong vasodilatory effects, the peptide also shows a high bronchodilatory potency. In a large number of respiratory diseases VIP may play a pathophysiological role. In this respect, increased levels of VIP have been demonstrated for inflammatory diseases of the upper and lower airways and the peptide may also play a role in pulmonary hypertension. Due to its fast enzymatic cleavage, VIP-based therapies have not been used in routine therapy so far. Also, the use of synthetic VIP-agonists did not lead to an improved outcome in patients with bronchial asthma if compared to classical drugs. However, recent data from animal experiments indicate potent immunomodulatory effects which suggest a future use of this mediator and its agonists in the therapy of immune diseases.

Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances

Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances

Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor–1α (HIF-1α), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2α is a homologue of HIF-1α and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2α–deficient (Hif2α+/–) mice after exposure to 10% O2 for 4 weeks. In contrast to WT mice, Hif2α+/– mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2α in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2α+/– mice after hypoxia, suggesting that HIF-2α–mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia.

Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2alpha is a homologue of HIF-1alpha and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2alpha-deficient (Hif2alpha(+/-)) mice after exposure to 10% O(2) for 4 weeks. In contrast to WT mice, Hif2alpha(+/-) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2alpha in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2alpha(+/-) mice after hypoxia, suggesting that HIF-2alpha-mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Synergistic effect of urotensin II with serotonin on vascular smooth muscle cell proliferation.

Urotensin II (U-II), the most potent vasoconstrictor, and serotonin (5-HT) are known to play an important role in pulmonary hypertension. However, little is known about the effect of U-II and its interaction with 5-HT on vascular smooth muscle cell (VSMC) proliferation. We assessed the interaction between U-II and 5-HT in inducing VSMC proliferation. Growth-arrested rabbit VSMCs were incubated in serum-free medium with different concentrations of U-II and 5-HT. VSMC proliferation was examined by the increase in [3H]thymidine incorporation into DNA and cell number. U-II or 5-HT induced [3H]thymidine incorporation in a dose-dependent manner with a maximal effect at a concentration of 50 nmol/l (161%) or 50 micromol/l (205%), respectively. When added together, low concentrations of U-II (50 nmol/l) and 5-HT (1 micromol/l) interacted synergistically in inducing [3H]thymidine incorporation (382%). These effects on [3H]thymidine incorporation were paralleled by an increase in cell number. The G-protein inactivator GDP-beta-S (100 micromol/l), protein kinase C (PKC) inhibitor Ro31-8220 (0.1 micromol/l), Src family tyrosine kinase inhibitor PP2 (1 micromol/l), and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 micromol/l) inhibited the mitogenic effects of U-II and 5-HT and also their interaction in inducing [3H]thymidine incorporation. Our results suggest that U-II and 5-HT may induce the synergistic interaction in inducing VSMC proliferation via a G-protein-coupled receptor/PKC/Src tyrosine kinase/MAPK pathway, thus contributing to the relatively rapid development of atherosclerosis in hypertensive vascular disease.

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebocontrolled study

Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Is antiphospholipid antibody determination clinically relevant to the vasculitides?

The arbitrary division between antiphospholipid antibody syndrome and secondary antiphospholipid antibody syndrome has not proven useful. Antiphospholipid antibodies in the absence of antiphospholipid antibody syndrome often occur as epiphenomena in many autoimmune diseases. They are very common in systemic lupus erythematosus. Antiphospholipid antibody syndrome is a significant comorbidity in lupus but is uncommon in Sjögren's syndrome, rheumatoid arthritis, scleroderma, and systemic vasculitis. Evidence is growing that antiphospholipid antibodies may have a pathogenic role in pulmonary hypertension and accelerated atherosclerosis of autoimmune diseases.

Effect of SB 217242 on Hypoxia-Induced Cardiopulmonary Changes in the High Altitude-Sensitive Rat

The effects of SB 217242, a non-peptide endothelin (ET) receptor antagonist, were investigated against hypoxia-induced cardiopulmonary changes in high altitude-sensitive rats. In isolated pulmonary artery rings, SB 217242 (30 nm) antagonized ET-1-induced contractions with apKBof 8.0. There was no difference in the sensitivity to ET-1 or the potency of SB 217242 in pulmonary artery from normoxic rats vs. rats exposed to hypoxia (9% O2) for 14 days. However, there was a marked reduction in the maximum response to ET-1, but not to KCl or phenylephrine, in pulmonary artery from hypoxic rats; this phenomenon was inhibited by treatment of animals with SB 217242 (10.8 mg/day, ip by osmotic pump) for the 14-day hypoxic period. Furthermore, there was a significant reduction in carbachol-induced, endothelium-dependent relaxation of precontracted pulmonary artery from hypoxic animals; SB 217242 treatment during the hypoxic period did not influence this difference. Vehicle-treated rats exposed to 14-day hypoxia had 173% higher pulmonary artery pressures and 75% higher right/left+septum ventricular mass ratios compared to normoxic animals. SB 217242 (3.6 or 10.8 mg/day, ip) markedly reduced (80 and 95%, respectively) hypoxia-induced increases in pulmonary artery pressure. Right ventricular hypertrophy was inhibited by 40% at the 10.8 mg/day dose. Marked medial thickening and luminal stenosis of small and medium-sized pulmonary arteries was observed in hypoxic rats. The SB 217242-treated, hypoxia-exposed rats had comparable small and medium-sized arteries to normoxic rats. Rats treated with SB 217242 (10.8 mg/day) for the last 14 days of a 28-day hypoxic exposure had significantly lower pulmonary artery pressures than those of vehicle-treated rats. In addition, the effects of the selective ETAreceptor antagonist, SB 247083, and the selective ETBreceptor antagonist, A-192621 (3.6 or 10.8 mg/day, ip), were compared against hypoxia-induced increases in pulmonary artery pressure and plasma ET concentrations. SB 247083, but not A-192621, inhibited hypoxia-induced pulmonary hypertension, whereas A-192621, but not SB 247083, significantly exacerbated hypoxia-induced increases in ET concentrations, suggesting that hypoxia-induced pulmonary pressor responses are mediated via ETAreceptor activation, while ETBreceptor blockade may alter clearance of hypoxia-induced elevated plasma ET. The inhibitory effects of SB 217242 on the functional and remodeling changes induced by hypoxia provide further evidence that ET may play a central role in pulmonary hypertension and that ET receptor antagonists may have a utility in the treatment of this disease.

Endothelin as a regulator of cardiovascular function in health and disease.

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.

Endogenous Production of Nitric Oxide in Neonatal Endotoxemia 1683

Pulmonary production of NO increases in adult animals exposed to endotoxin. Neonatal endotoxemia is usually accompanied by pulmonary hypertension. The existence of pulmonary hypertension in the presence of increased NO production is inconsistent with NO's role as a vasodilator. We examined pulmonary NO production in neonatal endotoxemia by measuring exhaled NO and by comparing plasma NO metabolite concentration in paired pulmonary artery and pulmonary vein samples. Ten to fourteen day old piglets were anesthetized, tracheostomized and instrumented with pulmonary artery and systemic arterial catheters. Each piglet received 20 mcg/kg E. Coli lipopolysaccharide infused over 30 minutes. PVR, SVR, exhaled NO and paired PA and PV plasma NO metabolites were measured at 60 minute intervals. One hundred twenty minutes after endotoxin infusion was completed, the piglets were randomized to receive either a nitric oxide synthase inhibitor (L-NAME or aminoguanidine), the substrate for NO production (L-Arginine) or saline control. PVR increased significantly from baseline and was sustained throughout the 240 minute experimental period with no difference among groups after randomization. There was no change in peak exhaled NO over time in the control group or in those receiving L-NAME or aminoguanidine. Exhaled NO increased significantly in the two hours following administration of L-Arginine (4.41 ± 2.6 to 8.1± 3.8 ppb, p < 0.01). There was no difference in plasma NO metabolites over time within groups or between groups. We conclude that neonatal endotoxemia does not acutely increase pulmonary production of NO. We speculate that an inability to increase NO production may play a role in pulmonary hypertension associated with neonatal sepsis.

The somatostatin analog angiopeptin does not reduce chronic hypoxic pulmonary hypertension in rats.

Angiopeptin is an analog of somatostatin-14, which has been found to inhibit cellular proliferation in several models of systemic vascular injury. As proliferation plays a major role in pulmonary hypertension, we examined the hypothesis that angiopeptin would inhibit the development of chronic hypoxic pulmonary hypertension in the rat. Angiopeptin was infused intravenously (90-100 microg/kg/day) by minipumps in 10 rats during a 3-week exposure to hypobaric hypoxia and in six normoxic rats. Normal saline was infused in six hypoxic control rats and in seven normoxic control rats. Angiopeptin produced no significant difference in mean pulmonary arterial pressure and resistance, right ventricular weight, or medial thickness of small pulmonary vessels. Vasoconstrictor responses of isolated lungs to acute hypoxia were not affected by angiopeptin. We conclude that angiopeptin, at the high intravenous dose used, does not significantly reduce the development of chronic hypoxic pulmonary hypertension in rats.

Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung.

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3 (500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose to 1.9 +/- 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.

Effects of thromboxane A2 on chronic hypoxic pulmonary hypertension in the rat

Chronic hypoxia (10% O2 for 2-3 weeks) causes pulmonary hypertension and vascular remodeling in the rat. To study the role of thromboxase A2 in chronic hypoxic pulmonary hypertension, the hemodynamic effects of intravenous administration of a thromboxane analogue (STA2) were measured in chronic hypoxic (H) and normoxic (N) Sprague-Dawley rats. During anesthesia baseline pulmonary arterial pressure (PAP) was higher in H rats (34.6 +/- 1.0 mmHg) than in N rats (18.4 +/- 1.2 mmHg). Intravenous STA2 (0.3 microgram) acutely increased pulmonary artery pressure by 74% +/- 11% (25 +/- 4 mmHg) in H rats and by 47% +/- 2% (9 +/- 1 mmHg) in N rats, which indicates that both the absolute and relative acute pulmonary vasoconstriction caused by STA2 were greater in H rats. The changes in systemic arterial pressure caused by STA2 were smaller than the changes in pulmonary arterial pressure both in H rats (11% +/- 3%) and in N rats (17% +/- 3%). Lungs were isolated and perfused with saline, and the vasoconstrictive response to 0.05 microgram of STA2 in lungs (14.5 +/- 2.4 mmHg) from H rats was greater than the response to 0.1 microgram of STA2 (5.6 +/- 1.3 mmHg) in lungs from N rats. To examine whether blockade of calcium channels could suppress the vasoconstrictor response to STA2, the effects of the calcium channel blocker nicardipine hydrochloride on vasoconstriction caused by STA2 were measured in H and N rats. In vivo, the blockade of calcium channels suppressed the increase in pulmonary artery pressure caused by STA2. This suppression was greater in H rats (56% +/- 11%) than in N rats (25% +/- 4%). Similar results were obtained with isolated perfused lungs. Blockade of calcium channels suppressed the vasoconstriction caused by STA2 and this suppression was greater in H rats than in N rats. The finding that thromboxane A2 induced greater vasoconstriction in H rats than in N rats indicates that thromboxane A2 may play an important role in pulmonary hypertension, and suggests that blockade thromboxane A2 may benefit some patients with primary and secondary pulmonary hypertension. Furthermore, the finding that suppression of thromboxane-induced vasoconstriction by blockade of calcium channels was greater in H rats than in N rats indicates that such treatment may also benefit some patients.

Heparin-Protamine Complexes Cause Pulmonary Hypertension in Goats

Protamine reversal of heparin-induced anticoagulation causes thromboxane release followed by pulmonary vasoconstriction in sheep and pigs. The aim of this study was to determine whether heparin-protamine (H-P) complexes are causative agents of thromboxane release followed by pulmonary hypertension associated with protamine reversal of heparin. We separated H-P complexes and non-heparin-protamine (non-H-P) complexes from heparinized defibrinated human plasma neutralized with protamine by chromatography and studied the changes in hemodynamics, airway pressure, and thromboxane B2 concentration after injection of H-P complexes or non-H-P complexes into seven goats. In addition, we studied whether these pulmonary responses were blocked in goats pretreated with cyclooxgenase inhibitor (Indomethacin, n = 5) or thromboxane synthetase inhibitor (OKY-046, n = 5). A very small dose of H-P complexes increased pulmonary arterial and peak airway pressures and was followed by thromboxane B2 release (from 12 [5.5-23] to 28 [16-44] mmHg, from 9.0 [7.5-15] to 12 [8-19] cmH2O, and from 0.85 [0.34-3.2] to 16.4 [1.4-39.3] ng.ml-1, respectively). On the other hand, animals that received non-H-P complexes showed no significant changes. Indomethacin totally blocked and OKY-046 partially blocked the increases in pulmonary arterial pressure and thromboxane B2 concentration. H-P complexes play a major role in pulmonary hypertension after protamine reversal of heparin, and thromboxane A2 is a main mediator of the pulmonary hypertensive response to H-P complexes in goats.

Plasma endothelin levels and surgically correctable pulmonary hypertension

To know the changes in plasma endothelin of patients with pulmonary hypertension, we studied 32 patients with valvular heart disease. Among them, 22 patients had pulmonary hypertension (group I) and 10 had pulmonary arterial pressures in the normal range (group II). Plasma endothelin-1 concentrations of the patients in group I were significantly greater than those of the patients in group II ( p < 0.05). No significant difference in plasma endothelin-3 concentrations existed between the two groups. Cardiac output and pulmonary capillary wedge pressure had a linear correlation with plasma endothelin-1 levels. There was also a significant correlation between plasma endothelin-1 levels and hemodynamic indicators of severity of pulmonary hypertension, such as mean pulmonary arterial pressure and pulmonary vascular resistance ( p < 0.05). All patients in this study underwent surgical procedures for the correction of valvular lesions. All patients in group I showed a decrease in pulmonary arterial pressures, and their plasma endothelin-1 levels decreased from 3.84 ± 0.20 pg/mL to 1.66 ± 0.07 pg/mL ( p < 0.05), whereas the plasma endothelin-3 levels had only slight variation from 0.64 ± 0.11 pg/mL to 0.75 ± 0.06 pg/mL ( p > 0.05) between the preoperative and the postoperative stages. The results demonstrated that plasma endothelin-1 rather than endothelin-3 had a role in pulmonary hypertension. Several pieces of evidence pointed out that endothelin-1 functioned as a reactive mediator during vasoconstriction in the case of pulmonary hypertension rather than as a triggering factor of pulmonary hypertension.

The role of pulmonary hypertension in the pathogenesis of bronchial asthma

In patients with bronchial asthma, when blood pressure in the pulmonary artery is measured, very often hypertension is registered. This pulmonary hypertension is not secondary to hypoventilation, as in patients with chronic bronchitis or pulmonary emphysema, since patients with bronchial asthma are hyperventilating. The pulmonary hypertension in them must be therefore classified as primary. It is probable that its origin is in an allergic vasoconstriction of the pulmonary artery, occurring simultaneously with the well known bronchoconstriction.

Dissecting aneurysm of the pulmonary artery in a case of unoperated patent ductus arteriosus

A 54-year-old woman with unoperated patent ductus arteriosus developed fatal cardiac tamponade due to a dissecting aneurysm of the pulmonary artery causing haemopericardium. Histology of the pulmonary artery showed the presence of cystic medial necrosis. Previous reports of this condition are reviewed and the role of pulmonary hypertension causing secondary cystic medial necrosis is discussed.

Atherosclerotic lesions from the reduction of pulmonary

Seventy-five intimal arterial thickenings (from 58 subjects) related to pulmonary emboli were examined. Many showed residua derived from the emboli (fibrin, platelets, haemosiderin) and proliferation of elastica and smooth muscle cells. Features resembling those of atherosclerosis were the frequent presence of extracellular lipid and apolipoprotein-B containing lipoproteins (LpB) which corresponded closely in distribution; and (in about 40% of the thickenings) collections of fat-filled (foam) cells. Platelet antigens were often detected within foam cells in some cases, in company with LpB. The results indicate that at least some intimal thickenings originating from pulmonary emboli undergo transformation to atherosclerotic plaques. The role of pulmonary hypertension in the process was investigated. Mechanisms relevant to this transformation and to theories of atherogenesis are discussed.

Pulmonary hypertension in children born and living at high altitudes

1. 1. Thirty-two healthy children aged 1 to 14 years, born and living at high altitudes were studied by means of right heart catheterization. They lived in Morococha and Cerro de Pasco, the former at an altitude of 14,900 feet, the latter at 14,200. 2. 2. Mild pulmonary hypertension and an increased pulmonary vascular resistance have been found in children born and living in high altitudes. Values of cardiac output and pulmonary wedge pressure were similar to those reported at sea level. The increased pulmonary vascular resistance is ascribed to structural changes reported by other investigators in the small pulmonary arteries and arterioles. 3. 3. Pulmonary hypertension is greater in children than in adults of high altitudes, and it is greater in children under 5 years of age than in those 6 to 14. In the younger group pulmonary pressures are similar to those obtained in newborns at sea level. This signifies that at high altitudes there is a delay in the evolution of the pulmonary pressures with aging, in contrast to what occurs at sea level. This slow evolution agrees with the slow regression of right ventricular hypertrophy at high altitudes as demonstrated by anatomic, electrocardiographic and vectorcardiographic studies. 4. 4. The pulmonary hypertension found at high altitudes could be considered to a certain extent as a form of primary pulmonary hypertension; however, basic differences are pointed out between both conditions. The role of pulmonary hypertension in the high incidence of patent ductus arteriosus at high altitudes is discussed.

The role of pulmonary hypertension and thromboembolism in the production of pulmonary arteriosclerosis.

Thromboembolism and pulmonary hypertension have been assessed as factors in the production of pulmonary arteriosclerosis. A study was made of autopsy records and tissue sections from 59 cases of congenital heart disease with anomalies permitting shunting of blood from the systemic to the pulmonary circulation and 31 cases of pulmonary stenosis with septal defect. Pulmonary arteriosclerosis was found to be common and of equal frequency in the two groups of cases, indicating that hypertension is not a necessary factor. There was a close correlation between the presence of pulmonary arterial thrombi and pulmonary arteriosclerosis.