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Atrial septostomy is performed in patients with severe pulmonary arterial hypertension, and has been shown to improve symptoms, quality of life and survival. Despite recognized clinical benefits, the underlying pathophysiologic mechanisms are poorly understood. We aimed to assess the effects of right-to-left shunting on arterial delivery of oxygen, mixed venous content of oxygen, and systemic cardiac output in patients with pulmonary arterial hypertension and a fixed flow of blood to the lungs. We formulated equations defining the mandatory relationship between physiologic variables and delivery of oxygen in patients with right-to-left shunting. Using calculus and computer modelling, we considered the simultaneous effects of right-to-left shunting on physiologies with different pulmonary flows, total metabolic rates, and capacities for carrying oxygen. Our study indicates that, when the flow of blood to the lungs is fixed, increasing right-to-left shunting improves systemic cardiac output, arterial blood pressure, and arterial delivery of oxygen. In contrast, the mixed venous content of oxygen, which mirrors the average state of tissue oxygenation, remains unchanged. Our model suggests that increasing the volume of right-to-left shunting cannot compensate for right ventricular failure. Atrial septostomy in the setting of pulmonary arterial hypertension, therefore, increases the arterial delivery of oxygen, but the mixed systemic saturation of oxygen, arguably the most important index of tissue oxygenation, stays constant. Our data suggest that the clinically observed beneficial effects of atrial septostomy are the result of improved flow of blood rather than augmented tissue oxygenation, provided that right ventricular function is adequate.
Lung biopsies were taken from 30 children aged three months to 15 years (median, 11 months) who had pulmonary hypertensive congenital heart disease and were living at an altitude of 1750 meters. They had either a ventricular septal defect and/or patency of the arterial duct, atrioventricular septal defect or complete transposition with a ventricular septal defect. Biopsies were studied using quantitative morphometric light microscopic techniques. All patients with a ventricular septal defect with or without patency of the arterial duct showed a significant increase in mean percentage arterial medial thickness of both pre- and intraacinar pulmonary arteries compared with those of normal children of similar age living at sea level (p<0.001 for both pre- and intraacinar vessels) and with children with a ventricular septal defect living at sea level (p<0.001 for both pre- and intraacinar vessels). Extension of muscle to more peripheral pulmonary arteries was also greater. Intimal proliferation and fibrosis was seen in 10 patients, in three of whom it was severe. Intimal proliferation occurred more frequently than in children with a ventricular septal defect living at sea level. The findings were similar in patients with atrioventricular septal defect and complete transposition with ventricular septal defect. These findings suggest that patients with congenital heart disease who live at a relatively high altitude develop pulmonary vascular disease more rapidly than do those living at sea level.
Oral sildenafil has been demonstrated to be an effective treatment for pulmonary hypertension, and is increasingly used in children. We report an infant with pulmonary hypertension, stable on regular treatment with oral sildenafil, who presented in acute respiratory failure after aspiration, requiring ventilation and intensive care. The course of the stay in intensive care was difficult, with recurrent pulmonary hypertensive crises despite use of oral sildenafil, use of 100% oxygen, high frequency oscillatory ventilation, and inhaled nitric oxide. In view of his instability, and the presumed inability to absorb the sildenafil orally due to gastrointestinal malabsorption, sildenafil was administered as a continuous intravenous infusion. With this therapy, it proved possible to wean from oxygen, nitric oxide, and ventilatory support. Intravenous sildenafil, therefore, might be an effective alternative for children with pulmonary hypertension during episodes of acute deterioration and malabsorption, preventing life-threatening pulmonary hypertensive crises. Its pharmacokinetics, efficacy, and safety, nonetheless, need to be validated in randomized controlled trials.
The pulmonary arterial smooth muscle cell (SMC) cytoskeleton was studied in tissue from 36 piglets aged
from within 5 min of birth to 21 d of age, and in 8 adults. An additional 16 piglets were made pulmonary
hypertensive by exposure to hypobaric hypoxia (50.8 kPa) for 3 d. In conduit intrapulmonary elastic arteries
α, β and γ actin, the 204, 200 and 196 kDa myosin heavy chain (MHC) isoforms and vinculin were localised
by immunohistochemistry. The total actin content, the proportion of monomeric to filamentous α and γ
actin and changes in the proportions of the MHC isoforms were determined biochemically. Dividing SMCs
were localised and quantified using Ki-67. We found a transient reduction in immunohistochemical
expression of γ actin, 204 kDa MHC isoform and vinculin at 3 and 6 d in the inner media, associated with a
transient increase in Ki-67 labelling. The actin content also decreased at 3 and 6 d (P < 0.05), but there was
a postnatal, permanent increase in monomeric actin, first the α then the γ isoform. The relative proportions
of the MHC isoforms did not change between birth and adulthood in elastic pulmonary arteries but in
muscular arteries the 200 kDa isoform increased between 14 d and adulthood. Pulmonary hypertension
prevented both the immunohistochemical changes and the postnatal burst of SMC replication and prevented
the transient postnatal reduction in actin content. These findings suggest that rapid remodelling of the actin
cytoskeleton is an essential prerequisite of a normal postnatal fall in pulmonary vascular resistance.
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