Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment.

Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children. Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ET(A) and ET(B), respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n=7), following extended combined bosentan and epoprostenol therapy (n=5) and from normal subjects (n=5). Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ET(A) was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ET(A), ET(B) and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ET(A) and ET(B) were normal and eNOS increased. In smooth muscle, ET(A) expression was reduced in treated cases but ET(B) expression increased in all arteries of both treated and untreated cases. In summary, ET(A) is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.

Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children.

The aim of the present study was to evaluate a 5-yr experience of bosentan in children with pulmonary arterial hypertension (PAH). A retrospective, observational study was made of children in the UK Pulmonary Hypertension Service for Children (Great Ormond Street Hospital for Children, London, UK) who were given bosentan as monotherapy or in combination, from February 2002 to May 2008 and followed up for ≥ 6 months. Detailed studies were made of 101 children with idiopathic PAH (IPAH) (n = 42) and PAH associated with congenital heart disease (n = 59). Before treatment, World Health Organization (WHO) functional class, 6-min walk distance (6MWD), height, weight and haemodynamic data were determined. Evaluations were analysed after 6 months and annually to a maximum of 5 yrs. Median duration of treatment was 31.5 months. Initial improvement in WHO functional class and 6MWD was maintained for up to 3 yrs. Height and weight increased but the z-scores did not improve. After 3 yrs, bosentan was continued as monotherapy in only 21% of children with IPAH, but in 69% of repaired cases and 56% of those with Eisenmenger syndrome. The Kaplan-Meier survival estimates for the 101 patients were 96, 89, 83 and 60% at 1, 2, 3 and 5 yrs, respectively. A treatment regime that includes bosentan is safe and appears to be effective in slowing disease progression in children with PAH.

Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children.

Idiopathic pulmonary arterial hypertension (IPAH) is an incurable disease of multifactorial origin. Inflammation is frequently observed in IPAH, but its role in the pathobiology is unclear. In this study the distribution, nature and number of inflammatory cells in periarterial infiltrates in lungs of children with IPAH, pulmonary arterial hypertension associated with congenital heart disease (APAH) and in normal lung tissue were characterised and compared using immunohistochemistry The influence of treatment with combined prostacyclin and endothelin receptor blockers was also studied. In children with IPAH, both treated and untreated, but not in children with APAH or normal children, extensive periarterial infiltrates were present comprising macrophages and T lymphocytes with S100A4- and bone morphogenetic protein receptor type-2 (BMPR2)-positive cells. Although rarely co-expressing macrophage-specific antigens, BMPR2-positive cells were frequently closely associated with macrophages and lymphocytes. They were more abundant around peripheral arteries of children with IPAH than in APAH or normal lungs (15.1 (3.5), 2.3 (0.9) and 2.3 (0.9) cells/mm external elastic lamina, respectively; p<0.01 for IPAH vs APAH or normal lungs). Prostacyclin with endothelin receptor blockade resulted in a significant reduction in endothelial cell activation as indicated by human leucocyte antigen (HLA)-DR expression (treated 17% vs untreated 100%, p<0.002). This study shows that pulmonary inflammation is present in the lungs of children with IPAH. This may indicate a role for inflammation in the pathobiology of IPAH and provide the rationale for novel therapeutic intervention.

Early-life pulmonary arterial hypertension with subsequent development of diffuse pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia type 1.

The case history is presented of a male infant who was thought to have idiopathic pulmonary arterial hypertension (PAH) at 3 months of age. Subsequently the PAH decreased unexpectedly and diffuse pulmonary arteriovenous malformations (PAVMs) were seen at 6.9 years of age for the first time. Hereditary haemorrhagic telangiectasia type 1 (HHT1) related to an endoglin mutation was diagnosed. At 10.3 years of age a lung biopsy showed diffuse PAVMs as well as pulmonary arteriopathy with medial hypertrophy. This is the first case of HHT1 presenting with PAH at such a young age. The subsequent decrease in pulmonary arterial pressure (PAP) was probably caused by the development of PAVMs. In the presence of PAVMs, measurement of the PAP may underestimate the extent of PAH-related vasculopathy.

Vascular endothelium summary statement V: Pulmonary hypertension and acute lung injury: public health implications.

Although relatively rare, pulmonary hypertension can be devastating for those individuals who are affected and has significant societal implications. The 2003 WHO classification separates PAH (idiopathic, specific disease linked) from pulmonary hypertension related to lung disease, thromboembolic disease, and pulmonary venous hypertension. Another form of pulmonary hypertension, persistent pulmonary hypertension (PPHN), occurs in the newborn. In general, PPHN is thought to be responsible for approximately 10% of admissions to neonatal intensive care units and can be a complicating factor in 5 of 1000 live births. Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are complex disorders that pose a significant threat to critically ill patients. They are usually related to direct lung injury or indirect injury from sepsis, trauma, and other disorders. Although these pulmonary disorders reflect distinct pathophysiologic mechanisms, current evidence strongly suggests that a common denominator underlying many of the established molecular and cellular elements is endothelial cell activation and dysfunction. This summary statement briefly summarizes the state of the science and suggests future avenues of public health research.

Role of the endothelium in pulmonary arterial hypertension.

Pulmonary hypertension represents a significant disease burden in both the developed and developing worlds. Certain forms of pulmonary hypertension are more common in some countries than others but people of all races, all ages and both sexes are affected. Treatment options are limited and expensive. The development of new therapies will be determined by improved understanding of endothelial cell biology.

Lung biopsy findings in transposition of the great arteries with ventricular septal defect: potentially reversible pulmonary vascular disease is not always synonymous with operability.

Pulmonary vascular structure was analyzed in lung biopsy specimens taken from 28 children, aged 2 months to 15 years, with transposition of the great arteries and ventricular septal defect. Cellular intimal proliferation occurred in infants as young as 2 months, but it increased markedly between ages 7 to 9 and 10 to 12 months, and the increased obstruction was associated with a lower mean percent arterial medial thickness in patients older than 10 months than was found in younger patients. Early generalized arterial dilation appeared without the intimal fibrosis and dilation lesions characteristic of classical grade III and IV pulmonary vascular disease. Intimal abnormalities increased with age and pulmonary artery pressure, but mean percent arterial medial thickness was inversely related to mean pulmonary artery pressure (r = -0.5; p less than 0.0001). Nine patients survived intracardiac repair and six did not. Five of the patients who died were of similar age (12 months or less), had similar preoperative hemodynamic and pulmonary vascular abnormalities compared with the survivors and died after a clinical course compatible with pulmonary vascular disease. The findings emphasize that potential structural reversibility is not synonymous with "operability." Further studies are indicated on the function of the excessively muscularized pulmonary vascular bed of such infants.

Sildenafil in neonatal pulmonary hypertension due to impaired alveolarisation and plexiform pulmonary arteriopathy.

We report a case of severe pulmonary hypertension in a neonate associated with impaired alveolarisation and plexiform pulmonary arteriopathy. Treatment with oral sildenafil in addition to inhaled nitric oxide (NO) resulted in recovery from the pulmonary hypertensive crisis. Long term sildenafil therapy was associated with complete resolution of the pulmonary hypertension.

Effect of hypoxia on adaptation of the pulmonary circulation to extra-uterine life in the pig.

Pigs were exposed to hypoxia for 2 to 5 days, at ages ranging from bith to 2 weeks. The effect of hypoxia on structural adaptation of the pulmonary arterial circulation to extra-uterine life was studied by applying quantitative morphometric techniques to the injected autopsy lung specimens. In animals exposed to hypoxia from birth, the reduction in arterial muscularity, and increase in size and number which normally takes place after, began to occur, but the process was arrested by exposure to hypoxia which with increase in exposure time caused a secondary increase in muscularity. In animals allowed to adapt fully to extra-uterine life and first exposed at 14 days, increase in muscularity as shown by an increase in wall thickness and extension of muscle into smaller and more peripheral arteries than is normal, was secondary to the hypoxic insult and similar to that reported in adults of other species. Animals exposed a between 2 and 7 days of age showed an intermediate response, failure to adapt normally plus a secondary increase in muscularity. Right ventricular hypertrophy developed in all animals. The studies emphasise the vulnerability of the newborn pulmonary circulation to hypoxia and the rapidity with which structural change occurs.

Adaptation of the pulmonary circulation to extra-uterine life in the pig and its relevance to the human infant.

The normal structural and functional development of the pulmonary circulation has been studied in the pig, from fetal life to six months of age, with emphasis on the first 2 weeks. Pulmonary and systemic arterial pressures were measured in 50 animals, in 21 of which pulmonary vascular resistance was determined. After post mortem arterial injection, lung structure was analysed using quantitative morphometric techniques. Changes in the pulmonary circulation consisted of three overlapping phases: 1 Dilatation and recruitment of small arteries within the acinar region, beginning during the first 5 min and associated with a reduction in pulmonary arterial pressure. These changes continued during the first 24 h, associated with a loss of arterial muscle. 2 Between 24 h and 2 weeks, a significant reduction in the amount of arterial muscle was associated with a reduction in pulmonary: systemic vascular resistance ratio from 0.58 to 0.18. 3 Functionally, the pulmonary circulation appeared mature at rest by 2 weeks but growth and remodelling of the pulmonary arteries continued until an adult pattern was reached by 6 months of age.

Conducting pulmonary arteries: structural adaptation to extrauterine life in the pig.

A quantitative light microscopical and ultrastructural study of the elastic and large muscular pulmonary arteries of 30 Large White pigs aged from birth to 6 months yielded light microscopical measurements on 120 arteries and 62,560 ultrastructural assessments, which composed a computerised database. After birth mean arterial medial thickness and mean smooth muscle cell diameter decreased during the first 4 days (p less than 0.01). Mean interlamellar distance decreased, reaching its nadir at 1-3 weeks (p less than 0.01). All these features increased between 3 weeks and adulthood (p less than 0.01). In the smooth muscle cells synthetic rather than contractile organelles were dominant during the first 3 weeks. Between 3 weeks and adulthood, however, smooth muscle cell myofilament volume density increased (p less than 0.0001). At all ages the smooth muscle cells of the outer lamellar units of elastic arteries had a greater myofilament volume density than those of adluminal units (p less than 0.0001). The amount of connective tissue increased between 3 weeks and adulthood, collagen and basement membrane increasing preferentially (p less than 0.0001, p less than 0.05, respectively). Thus the conducting pulmonary arteries, like the peripheral resistance arteries, adapt structurally to extrauterine life. Remodelling occurred rapidly after birth, and then gradually during growth, as connective tissue was deposited and smooth muscle cells matured.

Changes in the distensibility of the intrapulmonary arteries in the normal newborn and growing pig.

The static elastic properties and structure of the intra-pulmonary arteries have been studied in pigs from fetal life to 4 months old, by radiographic and histological methods. During this period the average radius of the vessels examined varied from approximately equal to 0.9 mm at birth to 3.3 mm at the age of 4 months. The form of the pressure radius curves was similar to that observed in the systemic circulation and was characteristic of the gradual recruitment of collagen fibres with increasing pressure. In vessels near the hilum, wall thickness decreased from approximately equal to 180 microns to 100 microns during the first 2 weeks and thereafter increased to approximately equal to 250 microns. Throughout the lung and in all age groups there was a linear relationship between the logarithm of pressure strain elastic modulus (used as a measure of functional stiffness) and pressure. In contrast to the systemic arteries there was little change in functional stiffness towards the periphery, although the incremental elastic modulus (structural stiffness) did increase at sites further removed from the heart. During the first two weeks of life there was little change in functional stiffness (Ep approximately equal to 1.1 X 10(4) Nm2) although by 4 months Ep had increased by a factor of three. During this period despite fluctuations with age, an overall increase in structural stiffness was also observed (EINC approximately equal to 1 X 10(5) at 4 to 6 h to 2 X 10(5) Nm-2 at 4 months). The observations suggest that the changes in elasticity observed in early life are a consequence of the adaptation of the circulation to the lower pulmonary arterial pressure of extra-uterine life.

Maturation of the response to bradykinin in resistance and conduit pulmonary arteries.

OBJECTIVE: Immaturity of the endothelial-dependent relaxation is thought to be characteristic of the newborn pulmonary elastic arteries. In adulthood, the reactivity of different pulmonary arterial segments varies. Therefore, we investigated the presence of endothelial heterogeneity in perinatal porcine pulmonary arteries and compared it with the adult by studying the bradykinin-, substance P- and acetylcholine-induced relaxations in different arteries. METHODS: Three types of pulmonary arteries (large conduit elastic, distal branching and resistance-sized; in situ diameters 0.7-1.7, 0.3-0.5 and 0.1-0.2 mm, respectively) were isolated from lungs of adult (nine months), young (60-84 h), newborn (4 min) and near-term foetal pigs. They were mounted for isometric force recording, contracted first with K+ = 125 mmol/l (reference contraction). Cumulative concentration-response curves to acetylcholine, substance P or bradykinin were obtained from prostaglandin F2 alpha (30 mumol/l) precontracted vessels. The effects of captopril and O2(95 or 8%) were also determined. Experiments were terminated by adding 100 mumol/l papaverine, obtaining maximal relaxation, which was used for normalising relaxations. RESULTS: (i) Acetylcholine: In resistance arteries, relaxations were absent in the newborn and the adult. In conduit arteries, they were present from 60-84 h onward. (ii) Substance P: In resistance arteries, relaxations were only present in the adult. In the other two types of arteries, rudimentary relaxations were present from the mature foetal stage onward. (iii) Bradykinin: In resistance arteries, identical relaxations were present at all ages which, in the foetus and the adult, were insensitive to changes in O2 levels (95 to 8%). In conduit arteries, concentration-dependent relaxations were present from birth, increasing in amplitude with age and these were potentiated by captopril. Foetal conduit arteries relaxed to the single application of 0.1 mumol/l bradykinin, indicating age-dependent tachyphylaxis. CONCLUSIONS: (i) Bradykinin is unique among endothelium-dependent vasodilators in being able to relax all vascular segments, at all ages, subject to tachyphylaxis and bradykinin-breakdown but independent of the prevailing O2 concentration. (ii) Heterogeneity of the relaxations between conduit and resistance arteries is evident from the mature foetal stage onward. (iii) The type of agonist, the type of vessel and the age each independently determine the presence or absence of endothelial relaxations. Therefore, the perinatal pulmonary circulation is not immature with respect to endothelial-dependent relaxation; rather, the nature of this process changes within the perinatal period and between birth and adulthood.

Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently.

OBJECTIVE: As bradykinin (BYK) relaxes conduit (EPA) and resistance (RPA) pulmonary arteries from both perinatal and adult lungs, we investigated whether this vasodilator's relaxation-mechanisms were altered during perinatal development, differed between EPA and RPA and differed with other endothelium-dependent vasodilators, acetyicholine (ACH) and substance P (SP). METHODS: Arteries from mature foetal (5 days), neonatal (approximately 5 min), newborn (60-84 h) and adult pigs (> or =6 months) were isolated, mounted for in vitro isometric force recording, activated with PGF(2alpha) (30 micromol/l) and relaxed with BYK (10 pmol/l-1 micromol/l), SP (10 pmol/l-0.1 micromol/l) or ACH (1 nmol/l-1 mmol/l). RESULTS: (i) BYK: L-NAME (100 micromol/l) attenuated relaxations in foetal EPA ( approximately 55%) but nearly abolished them in the adult ( approximately 80%). In RPA, L-NAME nearly abolished ( approximately 90%) relaxations in the foetus and this effect diminished progressively with age to approximately 20% in the adult. Indomethacin (IND, micromol/l) attenuated relaxations in neonatal (approximately 25%), new-born and adult EPA (both approximately 45%). Together, L-NAME and IND abolished relaxations in all EPA and in neonatal RPA but not in older RPA. SKF525a (100 micromol/l) attenuated relaxations in foetal RPA ( approximately 4%), diminishing in the adult RPA to approximately 10%. Together, SKF52Sa and L-NAME largely abolished relaxations in postnatal RPA (approximately 80%). Activation with K(+)=125 mmol/l attenuated relaxations in adult EPA (approximately 80%), foetal RPA ( approximately 45%) and neonatal RPA (approximately 75%) and abolished relaxations in RPA from older ages. (ii) ACH: L-NAME abolished relaxations in new-born EPA and RPA. In adult EPA, combined L-NAME and IND moderately attenuated relaxations. (iii) SP: Combined application of L-NAME and IND attenuated relaxations to a similar degree in new-born and adult EPA and RPA. CONCLUSIONS: In postnatal EPA, BYK-relaxations depend completely on prostaglandin- and NO-synthesis whereas those to SP (at all ages) and ACH (in the adult) do not. In RPA, BYK-relaxations develop from being completely dependant on the sole release of NO (foetus) to being almost completely independent of it (adult), a situation mimicked partially by SP but not by ACH, which, in new-born RPA is completely dependent on NO. BYK-relaxations in postnatal RPA depend on the release of a hyperpolarising factor generated through an SKF525a-sensitive pathway in conjunction with NO. The mechanisms of endothelium-dependent BYK-relaxations in the pulmonary vascular bed undergo diverging alterations, depending on the stage of development and arterial size/function. These changes are specific for BYK as they differ from those obtained from ACH or SP.

Pulmonary vascular input impedance in the newborn and infant pig.

The input impedance of the main pulmonary artery in 26 pigs aged from 1 h to 2 weeks has been calculated from measurements of pressure and flow. From these data we have derived estimates of the hydraulic power output of the right heart. The impedance spectra were similar in form to those in many other studies and were consistent with the presence of a single reflection site within the lung. The frequency of the (single) minimum decreased steadily with increasing age as did the corresponding zero crossing point on the phase curve. From estimates of propagation velocity the position of this "reflection site" was found to coincide with the position of the lung periphery in each age group. An overall fall in characteristic impedance with increasing age was found to be due to the increasing diameter of the pulmonary artery rather than to changes in its elasticity. The total power output/body weight of the right heart fell from 10.4 to 4.8 mW X kg-1 from birth to 4 weeks of age. During this period the ratio of pulsatile to steady power fell from 0.5 to 0.31. We conclude that this fall is related to a reduction in the effective reflection of pressure and flow waves within the lung due to increasing attenuation and possibly to a reduction in the magnitude of the lumped reflection coefficient itself.

How the left lung is perfused after ligating the left pulmonary artery in the pig at birth: clinical implications for the hypoperfused lung.

The left pulmonary artery and ductus arteriosus were ligated in 14 pigs at birth. Animals were sacrificed at intervals from 2 to 24 weeks of age. In the right lung the pulmonary artery and in the left, either the distal pulmonary artery, bronchial arteries or both were injected. The fixed lung specimens were studied by arteriography, dissection and microscopic examination of serial and random sections of lung tissue. The bronchial arterial circulation to, and within the right lung appeared normal and was similar to that described in the human lung. In the left lung, the bronchial arterial circulation hypertrophied rapidly during the first 2 weeks, and large anastomoses between pulmonary and systemic circulations were found at the same sites as in the normal pig lung. The position and structural characteristics of the anastomosing arteries is described in the different types of broncho-pulmonary connection. In most animals aged 16 weeks or more, peripheral bronchial arteries immediately proximal to the anastomotic sites, developed intimal and medial proliferation. The left lung continued to grow although in all animals it was small. The axial pulmonary artery and its branches became smaller with age. These findings help explain how the lung is perfused and grows in children with congenital heart disease and an acquired collateral pulmonary arterial circulation.

Birth associated changes in pulmonary arterial connective tissue gene expression in the normal and hypertensive lung.

OBJECTIVES: To determine the temporal and spatial expression of the connective tissue precursors, procollagen and tropoelastin mRNA in normal and pulmonary hypertensive porcine pulmonary arteries from birth onwards. METHODS: Using in situ hybridisation, connective tissue gene expression for procollagen alpha1(I) and alpha1(III) and tropoelastin was studied in intrapulmonary arteries from normal piglets, 5 min-16 weeks, and from piglets made pulmonary hypertensive by exposure to hypobaric hypoxia for 3 days, from birth, 3 or 14 days of age. In addition, Type III pN-procollagen, tropoelastin and collagen I and III were studied by immunohistochemistry. Quantitative or semi-quantitative techniques were applied to both in situ and immunohistochemical studies. RESULTS: Procollagen alpha1(I) and alpha1(III) mRNA expression increased rapidly in the media and adventitia between birth and 3 days of age (P<0.05). The increase was transient and the number of cells expressing procollagen mRNA decreased to the low newborn number after 6 days of age. Type III pN-procollagen immunostaining was greatest in newborn elastic and muscular arteries and then decreased. Collagen I and III increased mainly after 6 days of age. In animals exposed to chronic hypobaric hypoxia from birth, the increase in procollagens I and III mRNA was prevented. Exposure to hypoxia from 3 or 14 days led to little change in either gene expression or in procollagen and mature collagen from the normal. Tropoelastin gene expression was high at birth in the endothelium and media for the first 6 days, and then decreased. Normally, tropoelastin decreased in the media and increased in the adventitia after 16 days of age. Hypoxia had no effect on the mRNA but led to increased tropoelastin. CONCLUSION: We demonstrated marked, rapid changes in temporal and cell specific connective tissue gene expression in normal pulmonary arteries immediately after birth as the vasculature remodels. Each gene appeared to have its own timetable of expression and responded differently to hypoxia-induced hypertension.

Four patterns of response to inhaled nitric oxide for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the clinical role of inhaled nitric oxide (iNO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: Prospective open observational clinical study. SETTING: A regional cardiac and pediatric intensive care unit. METHODS: Twenty-five consecutive near-term neonates (> 35 weeks gestation) with severe PPHN (oxygenation index [OI] > 25) were given a trial of iNO of 20 ppm for 20 minutes. Neonates who showed a greater than 20% improvement in PaO2 as well as a decrease in the OI to below 40 were defined as responders and continued on this therapy. RESULTS: Four patterns of response emerged to the iNO therapy: Pattern 1 neonates (n = 2) did not respond to the initial trial of iNO-one survived. Pattern 2 neonates (n = 9) responded to the initial trial of iNO, but failed to sustain this response over 36 hours, as defined by a rise in the OI to > 40. Six survived, five with extracorporeal membrane oxygenation. Pattern 3 neonates (n = 11) responded to the initial trial of iNO, sustained this response, and were successfully weaned from iNO within 5 days--all survived to discharge. Pattern 4 neonates (n = 3) responded to the initial trial of iNO, but developed a sustained dependence on iNO for 3 to 6 weeks. All three died and lung histology revealed severe pulmonary hypoplasia and dysplasia. These neonates (pattern 4) not only required iNO for a longer period of time than did the sustained responders (pattern 3), but they required significantly higher doses of iNO during their first 5 days of iNO therapy. CONCLUSIONS: Early responses to iNO may not be sustained. Neonates with pulmonary hypoplasia and dysplasia may have a decreased sensitivity and differing time course of response to iNO when compared with patients who have PPHN in fully developed lungs.

Pulmonary vascular bed in children with complete atrioventricular septal defect: relation between structural and hemodynamic abnormalities.

Pulmonary vascular structure was analyzed in lung tissue taken from 38 patients, aged 2 weeks to 9.1 years, with complete atrioventricular (AV) septal defect without important left AV valve regurgitation. Biopsy material was used in 27 patients (71%). Pulmonary artery (PA) pressure and resistance increased with age (r = 0.5, p less than 0.001 and r = 0.4, p less than 0.02, respectively). Intra-acinar mean PA arterial medial thickness decreased with age (r = -0.6, p less than 0.001), PA pressure (r = -0.6, p less than 0.001) and resistance (r = -0.4, p less than 0.05). Reduction in intra-acinar PA muscularity was associated with an increase in severity of obstructive intimal damage in pre-acinar PAs with age. A PA resistance of less than 6 units m2 was associated with age younger than 3 years (usually younger than 2 years), PA medial thickness of more than 19% (normal = 7.4%), and muscle extension with or without intimal proliferation. A higher resistance occurred in patients of all ages, but in those younger than 3 years structural abnormalities usually resembled those in patients with a lower resistance, whereas older patients had a normal or slightly increased PA medial thickness of 14% or less (normal = 7.4%), or classic grade III or IV disease. The 4 perioperative deaths attributed to pulmonary vascular disease occurred in patients who were similar in age and hemodynamic status to the survivors, but who had more severe pulmonary vascular abnormalities; either less muscularity with more severe intimal fibrosis or a much greater increase in muscularity, emphasizing that even potentially reversible abnormalities can prejudice intracardiac repair.

Pulmonary vascular disease in secundum atrial septal defect in childhood.

Pulmonary vascular structure was analyzed in the lungs of 10 patients with a secundum atrial septal defect (ASD) in whom pulmonary hypertension had developed. Four patients were aged 6 months or less, 5 were aged 2 to 9 years, and 1 was 21 years old. Pulmonary vascular structure was analyzed using lung biopsy tissue in 5 and autopsy material in the other 5. All the infants presented with heart failure and all had a marked increase in pulmonary arterial smooth muscle; only 1 infant survived surgery. Of the 5 older children, 1 presented with cyanosis, but in the rest the ASD was incidental to the presentation. Three patients had severe pulmonary vascular disease, similar to that seen in adults with a hypertensive ASD. Only 2 older children underwent successful surgery. In 1 child and in the 1 adult, the severity of the pulmonary vascular disease precluded surgery. The ASD was closed in 8 patients, but only 3 survived. Pulmonary hypertension develops rarely in secundum ASD in childhood.