Recovery from hypoxic pulmonary hypertension in rats.

To characterize the time frame of changes in pulmonary arterial pressure, right ventricular hypertrophy and morphology of small pulmonary arteries male Wistar rats were exposed to isobaric hypoxia (3 weeks, F1O2 0.1) and then let to recover on air for 1 or 5 weeks. Normoxic animals (group N) served as controls. Mean pulmonary arterial pressure (PAP), ratio of the weight of the right heart ventricle to the sum of the weights of the left ventricle and septum (RV/LV+S) and percentage of double laminated pulmonary vessels ( % DL) were measured at the end of hypoxic exposure (group H), after 1 or 5 weeks of recovery (groups 1R and 5R), and in controls kept in air (group N). Three weeks in hypoxia resulted in increase in PAP, RV/LV+S and % DL. After 1 week of recovery RV/LV+S normalized, PAP decreased, while % DL did not change. After 5 weeks in air PAP returned to control values and % DL diminished significantly but did not normalize. Our results suggest that recovery depends on the degree of HPH and that knowledge of the time-frame of recovery is important for future studies in our rat model.

Prenatal ultrasound screening of congenital heart disease in an unselected national population: a 21-year experience.

OBJECTIVE: To determine the prevalence and spectrum of congenital heart disease (CHD) and the impact of a national prenatal ultrasound screening programme on outcome in a well-characterised population. DESIGN AND SETTING: A comprehensive registry was created of all paediatric and fetal patients with CHD over a 21-year period (1986-2006) in the Czech Republic. The centralised healthcare system enabled confirmation of prenatal and postnatal findings clinically and by post mortem. PATIENTS AND RESULTS: In the entire cohort of 9475 fetuses referred for detailed cardiac evaluation, 1604 (16.9%) had CHD, of which 501 (31.2%) had additional extracardiac anomalies. In the pregnancies which continued, 59 (8.6%) of 685 fetuses died in utero, and 626 (91.4%) babies were born alive. Prenatal detection rate was highest in double outlet right ventricle (77.3%) and hypoplastic left heart (50.6%). Detection rate increased significantly (p<0.001) for 12/17 lesions comparing 1986-1999 and 2000-2006. In recent years, detection of hypoplastic left heart reached 95.8% while transposition of the great arteries was diagnosed antenatally in only 25.6%. CONCLUSION: The nationwide prenatal ultrasound screening programme enabled detection of major cardiac abnormalities in 1/3 of patients born with any CHD and 80% of those with critical forms. Nevertheless, owing to the severity of lesions and associated extracardiac anomalies, the overall mortality of antenatally diagnosed CHD remains high. These findings are important for the understanding natural history of CHD for the establishing of screening programmes in Europe.

Prevention of mast cell degranulation by disodium cromoglycate attenuates the development of hypoxic pulmonary hypertension in rats exposed to chronic hypoxia.

BACKGROUND: Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. Vascular remodeling is associated with collagenolysis and activation of matrix metalloproteinases (MMPs). One of the possible sources of MMPs in hypoxic lung are mast cells. OBJECTIVE: The role of lung mast cell collagenolytic activity in hypoxic pulmonary hypertension was tested by the inhibitor of mast cell degranulation disodium cromoglycate (DSCG). METHODS: Rats were treated with DSCG in an early or later phase of isobaric hypoxia. Control groups were exposed to hypoxia only or to normoxia. Lung hemodynamics, muscularization and collagen metabolism in the walls of peripheral pulmonary vessels in the lungs were measured. RESULTS: DSCG applied at an early phase of exposure to hypoxia reduced the development of pulmonary hypertension, inhibited muscularization in peripheral pulmonary arteries and decreased the amount of collagen cleavage fragments in prealveolar vessels. CONCLUSIONS: Mast cell degranulation plays a role in the initiation of hypoxic pulmonary vascular remodeling.

N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia.

Exposure to chronic hypoxia results in hypoxic pulmonary hypertension (HPH). In rats HPH develops during the first two weeks of exposure to hypoxia, then it stabilizes and does not increase in severity. We hypothesize that free radical injury to pulmonary vascular wall is an important mechanism in the early days of the hypoxic exposure. Thus antioxidant treatment just before and at the beginning of hypoxia should be more effective in reducing HPH than antioxidant therapy of developed pulmonary hypertension. We studied adult male rats exposed for 4 weeks to isobaric hypoxia (F(iO2) = 0.1) and treated with the antioxidant, N-acetylcysteine (NAC, 20 g/l in drinking water). NAC was given "early" (7 days before and the first 7 days of hypoxia) or "late" (last two weeks of hypoxic exposure). These experimental groups were compared with normoxic controls and untreated hypoxic rats (3-4 weeks hypoxia). All animals kept in hypoxia had significantly higher mean pulmonary arterial blood pressure (PAP) than normoxic animals. PAP was significantly lower in hypoxic animals with early (27.1 +/- 0.9 mmHg) than late NAC treatment (30.5 +/- 1.0 mmHg, P < 0.05; hypoxic without NAC 32.6 +/- 1.2 mmHg, normoxic controls 14.9 +/- 0.7 mmHg). Early but not late NAC treatment inhibited hypoxia-induced increase in right ventricle weight and muscularization of distal pulmonary arteries assessed by quantitative histology. We conclude that release of free oxygen radicals in early phases of exposure to hypoxia induces injury to pulmonary vessels that contributes to their structural remodeling and development of HPH.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats.

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 +/- 3 mmHg in hypoxic controls, 24 +/- 1 mmHg in Batimastat-treated hypoxic rats, and 16 +/- 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

Gender differences in the long-term effects of perinatal hypoxia on pulmonary circulation in rats.

Some effects of perinatal hypoxia on pulmonary circulation are permanent. Since pulmonary vascular sensitivity to hypoxia in adults differs between sexes, we hypothesized that gender-based variability also exists in the long-term effects of perinatal hypoxia. Rats spent 1 wk before and 1 wk after birth in hypoxia (12% O2) and then lived in normoxia. When adult, females, but not males, with the perinatal experience of hypoxia had right ventricle hypertrophy. To assess the role of sex hormones, some rats were gonadectomized in ether anesthesia as newborns. Compared with intact, perinatally normoxic controls, muscularization of peripheral pulmonary vessels in adulthood was augmented in perinatally hypoxic, neonatally gonadectomized males (by 85%) and much more so in females (by 533%). Pulmonary artery pressure was elevated in perinatally hypoxic, neonatally gonadectomized females (24.4 +/- 1.7 mmHg) but not males (17.2 +/- 0.6 mmHg). Gonadectomy in adulthood had no effect. We conclude that female pulmonary circulation is more sensitive to late effects of perinatal hypoxia, and these effects are blunted by the presence of ovaries during maturation.