Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients?

Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.

Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes.

In the first two-thirds of gestation, ovine fetal cardiomyocytes undergo mitosis to increase cardiac mass and accommodate fetal growth. Thereafter, some myocytes continue to proliferate while others mature and terminally differentiate into binucleated cells. At term (145 days gestational age; dGA) about 60% of cardiomyocytes become binucleated and exit the cell cycle under hormonal control. Rising thyroid hormone (T3) levels near term (135 dGA) inhibit proliferation and stimulate maturation. However, the degree to which intracellular signaling patterns change with age in response to T3 is unknown. We hypothesized that in vitro activation of ERK, Akt, and p70(S6K) by two regulators of cardiomyocyte cell cycle activity, T3 and insulin like growth factor-1 (IGF-1), would be similar in cardiomyocytes at gestational ages 100 and 135 dGA. IGF-1 and T3 each independently stimulated phosphorylation of ERK, Akt, and p70(S6K) in cells at both ages. In the younger mononucleated myocytes, the phosphorylation of ERK and Akt was reduced in the presence of IGF-1 and T3. However, the same hormone combination led to a dramatic twofold increase in the phosphorylation of these signaling proteins in the 135 dGA cardiomyocytes-even in cells that were not proliferating. In the older cells, both mono- and binucleated cells were affected. In conclusion, fetal ovine cardiomyocytes undergo profound maturation-related changes in signaling in response to T3 and IGF-1, but not to either factor alone. Differences in age-related response are likely to be related to milestones in fetal cardiac development as the myocardium prepares for ex utero life.

No detection of BK virus, JC virus, KI, WU and Merkel cell polyomaviruses in cerebrospinal fluid of patients with neurological complications after hematopoetic stem cell transplantation.

Neurological complications, often due to viral reactivation, after allogeneic hematopoetic stem cell transplantation (HSCT) are associated with increased mortality. Here, cerebrospinal fluid from 20 HSCT patients with neurological symptoms were analyzed and found to be negative by PCR for BK virus, JC virus, KI, WU and Merkel cell polyomavirus DNA.

Persistent changes in arterial blood gases in fetal sheep.

Two anaesthetic protocols were compared using pregnant sheep. In both groups of animals, anaesthesia was induced using an intravenous (i.v.) injection of diazepam and ketamine. The ewes were then intubated for positive pressure ventilation using 0.8 L/min of nitrous oxide and 2 L/min oxygen with 1.1-1.8% halothane. If the ewe showed any signs of awakening, one of two protocols was followed. First, the halothane concentration was increased to 2-3% until the ewe was completely anaesthetized. Second, the halothane concentration was not altered, but the ewe was given doses of i.v. diazepam (0.1 mg/kg) and ketamine (1 mg/kg) until again completely anaesthetized. At the completion of surgery, maternal recovery was rapid and similar between the two groups. However, five days after surgery, the fetal arterial Po(2) and oxygen content of the fetuses receiving additional halothane (1.9 +/- 0.2 kPa and 4.4 +/- 1.0 mL/100 mL) were statistically significantly depressed when compared with the fetuses receiving additional diazepam and ketamine (2.9 +/- 0.1 kPa and 7.0 +/- 0.5 mL/100 mL). These results led us to conclude that certain anaesthetic protocols, in spite of good maternal recovery, can lead to deleterious effects upon the fetus that persist for at least five days after surgery.

BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts.

The influence of conditioning regimen, donor background and HLA matching on development of BK virus (BKV)-associated haemorrhagic cystitis (HC) was examined in 175 allogeneic haematopoietic stem cell transplant (HSCT) patients, undergoing 179 HSCT events. Twenty-seven patients presented late-onset HC, and BK viruria was verified in 23/27 HC events. Seventy-one (40%) HSCTs were performed with myeloablative conditioning (MC), 108 (60%) were performed with reduced intensity conditioning (RIC), 66 (37%) were performed with a related donor (RD) grafts and 113 (63%) with an unrelated donor (URD) graft. BK viruria was more common during HC, than non-HC events, after MC as compared to RIC (both P<0.001), and with an HLA-mismatched donor (P<0.01). By multivariate logistical regression analysis, independent risk factors for HC were BKV (OR 6.7; 95% CI 2.0-21.7; P=0.001), MC (OR 6.0; 95% CI 2.1-17.3; P<0.001) and URD (OR 3.4; 95% CI 1.1-10.6; P=0.03). However, when analysing HSCT performed with URD or RD grafts separately, BKV (OR 8.5; 95% CI 1.8-19.3; P=0.004) and MC (OR 5.9; 95% CI 1.3-11.3; P=0.009) increased the risk for HC only with a URD, but not with an RD graft.

Thyroid hormone inhibits proliferation of fetal cardiac myocytes in vitro.

Thyroid hormone (T(3)) is a key regulator of fetal organ maturation. Premature elevations of thyroid hormone may lead to a 'mature' cardio-phenotype. Thyroid hormone will stimulate maturation of ovine fetal cardiomyocytes in culture by decreasing their proliferative capacity. Group 1 fetal cardiomyocytes (approximately 135 days gestation) were incubated with T3 (1.5, 3, 10, and 100 nM) and bromodeoxyuridine (BrdU; 10 microM) for 24 and 48 h. Group 2 cardiomyocytes were cultured with T3 alone for later protein analysis of cell cycle regulators. At all concentrations, T3 decreased BrdU uptake fourfold in serum media (P<0.001 versus serum, n=5). Following serum-free (SF) T3 treatment, BrdU uptake was inhibited when compared with serum (P<0.001 versus serum, n=5). p21 expression increased threefold (P<0.05 versus serum free, n=4) and cyclin D1 expression decreased twofold (P<0.05 versus serum, n=4) in T3-treated cardiomyocytes. (1) T3 inhibits fetal cardiomyocyte proliferation, while (2) p21 protein levels increase, and (3) cyclin D1 levels decrease. Thus, T3 may be a potent regulator of cardiomyocyte proliferation and maturation in the late gestation fetus.

Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation.

BK virus (BKV) load in urine alone or in combination with acute graft-versus-host disease (GVHD) was correlated to development of hemorrhagic cystitis (HC). BKV load in combination with acute GVHD discriminated the best, while BKV and viral load alone, but not GVHD, still showed predictive ability for HC.

Augmentation of coronary conductance in adult sheep made anaemic during fetal life.

Maximal coronary conductance with adenosine in anaemic fetal sheep is twice that of non-anaemic fetuses. To investigate whether this increase in conductance persists into adulthood we studied twin sheep as fetuses and again as adults. Nine anaemic fetuses (118 days gestation) underwent isovolaemic haemorrhage for 18.0 +/- 4.6 days (means +/- S.D.) during which time the haematocrit was reduced from 39.9 +/- 5.2 % to 16.3 +/- 3.4 % and oxygen content from 8.6 +/- 1.3 to 2.3 +/- 0.2 ml dl-1. At 138 days the anaemic fetuses were transfused; at delivery the haematocrit was 29.3 +/- 6.8 % compared to nine control fetuses in which the haematocrit was 38.5 +/- 4.3 %. The weight at delivery was 3.5 +/- 0.36 kg in the anaemic fetuses vs. 4.2 +/- 0.83 kg in controls. Twenty-eight weeks later, we placed an occluder on the descending thoracic aorta and inferior vena cava, a flow probe around the proximal left circumflex coronary artery, and catheters in the left atrial appendage, jugular and carotid vessels. Maximal coronary conductance was determined in the adults by recording coronary blood flow as driving pressure was altered by inflating the occluders while adenosine was infused into the left atrium. Right atrial, left atrial, systolic and mean arterial pressures, systemic vascular resistance and haematocrit were not different between 'in utero anaemic' and control adults. The adults that were anaemic in utero weighed less than the controls 39.4 +/- 4.6 kg vs. 45.0 +/- 5.6 kg. Maximal conductance was greater in the adults that were anaemic in utero: 11.2 +/- 4.0 ml min(-1) (100 g)(-1) mmHg-1 as compared to 6.1 +/- 1.8 ml min(-1) (100 g)(-1) mmHg(-1) in the controls. Vascular reactivity of the mesenteric arteries was not different. These data suggest that coronary conductance can be modified in utero by anaemia (high flow and hypoxaemia) and that the remodelled coronary tree persists to adulthood.

Increased coronary blood flow signals growth of coronary resistance vessels in near-term ovine fetuses.

We measured maximal coronary artery conductance in near-term fetal sheep before and after chronic infusion with adenosine to determine whether an increase in coronary flow without hypoxemia results in increased coronary vascular growth. Adenosine was infused into the circumflex coronary artery for 12 h each day for 4 days. Coronary flow was maintained at double the resting level by regulating the infusion of adenosine via a computerized servocontrol device signaled by a Doppler flow-velocity sensor. Total arterial hemoglobin, oxygen content, and hemodynamics were unchanged. Resting circumflex coronary blood flow increased from control of 250 +/- 111 to 530 +/- 216 ml x min(-1) x 100 g left ventricle(-1) with adenosine on day 1 and from 194 +/- 74 to 878 +/- 210 ml x min(-1) x 100 g left ventricle(-1) with adenosine on the last day (P < 0.01). Coronary conductance, determined during maximal vasodilation, increased from 14.0 +/- 5.0 to 26.9 +/- 3.9 ml x min(-1) x 100 g(-1) x mmHg(-1) over the 4 days (P < 0.001). Coronary flow reserve, the difference between resting and maximal myocardial blood flow interpolated at 40 mmHg, increased from 299 +/- 196 to 672 +/- 266 ml x min(-1) x 100 g(-1) (P < 0.001). Maximal coronary conductance was unchanged in control saline-infused fetuses (18.5 +/- 5.1 vs. 18.5 +/- 8.7 ml x min(-1) x 100 g(-1) x mmHg(-1)). We conclude that chronic intracoronary adenosine administration to the fetal myocardium modulates coronary vascular growth, even in the absence of tissue hypoxia.

Hemodynamic effects of S-nitrosocysteine, an intravenous regional vasodilator.

BACKGROUND: S-nitrosocysteine is a carrier form of nitric oxide that can be delivered intravenously. S-nitrosocysteine is rapidly metabolized by plasma (half-life = 2-3 seconds), forming nitric oxide and cysteine. With its short half-life and potent vasodilatory properties, S-nitrosocysteine may be useful as a pulmonary vasodilating agent in cases of postoperative and chronic pulmonary hypertension. OBJECTIVE: Our objective was to determine the hemodynamic properties of S-nitrosocysteine on the pulmonary and systemic circulations to assess its potential utility as a pulmonary vasodilatory agent. METHODS: Eleven adult swine were anesthetized. Thermodilution (Swan-Ganz; Baxter International, Inc, Deerfield, Ill) and arterial catheters were inserted. Flow probes were placed around the coronary, renal, superior mesenteric, and iliac arteries. Incremental infusion doses of S-nitrosocysteine (5-80 nmol. kg(-1). min(-1)) were delivered into the right atrium. Cardiac output, right and left heart pressures, heart rate, Pao(2), and iliac, renal, coronary, and mesenteric blood flow rates were recorded at baseline and at each infusion dose of S-nitrosocysteine. RESULTS: Low-dose S-nitrosocysteine infusion decreased mean pulmonary artery pressure (15%, P =.013) without a significant reduction in mean systemic artery pressure. Higher dose infusions produced further dose-dependent declines in pulmonary vascular resistance and measurable reductions in systemic vascular resistance (P =.01). At an S-nitrosocysteine dosage of 40 nmol. kg(-1). min(-1), there was a significant reduction in renal (P <.001) and mesenteric (P =.003) blood flow but no change in iliac (P >.2) or coronary (P >.2) blood flow. Cardiac output remained constant up to infusion rates of 40 nmol. kg(-1). min(-1) (P >.2). Doses higher than 5 nmol. kg(-1). min(-1) resulted in a substantial dose-dependent reduction in Pao(2) (P <.001), suggesting dilation of atelectatic areas of the lung. CONCLUSION: S-nitrosocysteine is a potent vasodilatory agent capable of overcoming the hypoxic vasoconstrictive response of the lung. Our results suggest it may prove useful as a pulmonary vasodilatory agent at low doses. Higher dose infusions reduce mean systemic pressure and lead to compensatory reductions in renal and mesenteric blood flow without a decrease in cardiac output.

Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher Disease: duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not. The Clinical European Network on Brain Dysmyelinating Disease.

Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of myelination affecting the central nervous system and segregating with the proteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic cases of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%). We analyzed the maternal status of 56 cases to determine the origin of both types of PLP mutation, since this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly (chi2=9. 20, P<.01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.3. Moreover, we observed the occurrence of de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimation of the k value (k=11). Again, a significant male mutation imbalance was observed only for the duplications. The mechanism responsible for this strong male bias in the duplications may involve an unequal sister chromatid exchange, since two deletion events, responsible for mild clinical manifestations, have been reported in PLP-related diseases.

Angiotensin type 1 receptor antagonism with irbesartan inhibits ventricular hypertrophy and improves diastolic function in the remodeling post-myocardial infarction ventricle.

To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.

The sequential effects of estrogen administration and hypertension on cardiac function in ewes.

OBJECTIVE: Our objective was to study the effect of estrogen administration and moderate hypertension on left ventricular size, pump function, and contractility in chronically instrumented ewes. STUDY DESIGN: Ewes were either given 0.06 mg/kg 17beta-estradiol intramuscularly (n = 8) or were made hypertensive (n = 6) by inflation of an occluder around the aorta and were studied weekly. After 3 weeks each ewe received the opposite treatment. RESULTS: Estrogen administration caused an increase in left ventricular chamber size at a given pressure, fractional shortening (21.9% +/- 2.9% to 28.5% +/- 3.7%), and stroke volume (1.4 +/- 0.3 mL/kg to 1.6 +/- 0.3 mL/kg). Subsequent hypertension further increased left ventricular size at a given pressure but decreased fractional shortening (20.0% +/- 4.4%) and stroke volume (1.3 +/- 0.3 mL/kg). With hypertension first, there was no left ventricular enlargement, even with subsequent estrogen administration, and there were no changes in left ventricular pump function. End-systolic pressure and stress-dimension relationships did not change with either treatment. The end-systolic wall stress-fractional shortening relationship was likewise unchanged, suggesting that neither treatment changed contractility. CONCLUSIONS: The left ventricle previously exposed to hypertension does not remodel when exposed to estrogen, and cardiac pump function decreases when the estrogen enlarged heart is faced with moderate, subacute hypertension.

Physical characteristics and gas composition of nasal air affect nasal nitric oxide release.

We studied modulation of release of nitric oxide (NO) into nasal passages by physical characteristics (airflow, temperature, humidity) or gases (oxygen, carbon dioxide) in nasal air of humans. Each characteristic or gas in nasal air was changed during voluntary soft palate elevation (to isolate nasal passages). Increasing airflow through the nose caused incremental increases in NO release from 211+/-23 nl/(min x m(-2)) at 1 L/min to 312+/-40 nl/(min x m(-2)) at 22 L/min (P<0.001, n = 6). Decreased humidity (dry airflow, 1-22 L/min) reduced NO release only at the highest airflow rate. Changing temperature (range 46 to 0 degrees C) had no effect on NO release. Hypoxia (below 4% O2) rapidly and reversibly decreased NO release (200+/-40 nl/(min x m(-2)) at 21% O2 versus 99+/-17 nl/(min x m(-2)) at 0% O2 for 3 min, (P<0.001, n = 5). Carbon dioxide (5%) reduced NO release slightly. We conclude that airflow, reduced humidity, carbon dioxide concentration, and oxygen concentration modulate NO release into nasal passages.

Alteration of ascending thoracic aorta compliance after treatment with menotropin.

OBJECTIVE: Our purpose was to determine whether aortic size and compliance are altered by an exogenously induced rise in estrogen. STUDY DESIGN: Magnetic resonance imaging was used to determine the aortic cross-sectional area/aortic pressure relationship in nine premenopausal women before and after menotropin therapy. Simultaneous electrocardiograms, carotid pulse tracings, phonocardiograms, and brachial artery pressures were obtained before each magnetic resonance imaging acquisition. Ascending thoracic aorta cross-sectional area was obtained every 32 msec and aligned with brachial artery pressures extrapolated from the carotid pulse tracing, allowing construction of the ascending thoracic aorta cross-sectional area/aortic pressure relationships. Aortic cross-sectional area was normalized to body surface area, and the shifts in the position for the ascending thoracic aorta cross-sectional area/aortic pressure relationship were determined with use of analysis of covariance. RESULTS: Heart rate and aortic pressure were unchanged before and after menotropin treatment. Initial estradiol levels were < 20 pg/ml. After menotropin treatment (7.4 +/- 1.0 days) estradiol levels rose to 905 +/- 371 pg/ml (p < 0.0001). Ascending thoracic aorta cross-sectional area/body surface area was not significantly increased, adjusted y mean of 389 +/- 7 mm2/m2 before and 403 +/- 7 mm2/m2 after menotropin treatment (p < 0.24). The slope of the ascending aorta cross-sectional area/aortic pressure relationship, an index of aortic compliance, increased from 1.4 +/- 0.6 mm2/m2/mm Hg before to 1.7 +/- 0.6 mm2/m2/mm Hg after menotropin treatment (p < 0.001). CONCLUSION: In premenopausal women a short-term rise in estrogen induced by menotropin treatment is associated with an increase in aortic compliance. Aorta size is not significantly increased within this time frame.

Decreased exhaled nitric oxide in subjects with HIV infection.

BACKGROUND: Nitric oxide (NO) may be an important component of the host defence against infections. Endogenously produced NO is present in exhaled air and may be representative of respiratory tract production of NO. Since subjects infected with HIV are prone to develop respiratory infections, it was postulated that exhaled NO might be reduced in such individuals. METHODS: The exhaled concentration of NO (nl/l) and minute ventilation (l/min) were measured and exhaled NO release (nl/min/m2) calculated in 36 subjects infected with HIV (20 non-smokers, 16 smokers) and 31 non-smoking subjects with no active medical conditions. RESULTS: Exhaled NO from HIV positive individuals was less than from control subjects of similar age, height, and weight. Cigarette smoking did not account for the decreased exhaled NO in HIV positive individuals as both smoking and non-smoking HIV positive subjects had decreased exhaled NO compared with control subjects. CONCLUSION: Exhaled NO is decreased in subjects infected with the HIV. Since NO functions in host defence against bacterial, viral, and fungal infections, reduced exhaled NO may indicate a mechanism of impaired host defence in HIV infection.

Effects of estrogen and progestin on aortic size and compliance in postmenopausal women.

OBJECTIVE: Our purpose was to determine whether sex steroids alter aortic size and compliance in postmenopausal women. STUDY DESIGN: Twenty-six postmenopausal women were randomized to receive either conjugated estrogens 0.625 mg per day (group 1) or conjugated estrogens 0.625 mg per day and medroxyprogesterone 2.5 mg per day (group 2). Aortic cross-sectional area was measured by magnetic resonance imaging before and after 3 months of hormone therapy. RESULTS: Estradiol levels increased in both group 1 and group 2 (p < 0.0001). Ascending aortic cross-sectional area increased from 439 +/- 7 mm2 to 466 +/- 7 mm2 in group 1 (p < 0.008) but was unchanged in group 2. Within the range of aortic pressures studied, no change in aortic compliance could be detected. CONCLUSION: Estrogen therapy in postmenopausal women was associated with an increase in aortic size; but this effect was not detectable with the addition of progestin. The potential antagonistic effect of progestin on estrogen-induced aortic enlargement suggests that the favorable cardiovascular effects of postmenopausal estrogen therapy cannot be automatically extended to the combination estrogen-progestin.

Effects of ductus arteriosus occlusion on pulmonary artery pressure during in utero ventilation in fetal sheep.

Seven fetal sheep were prepared to study the short-term effects of in utero ventilation and ductus arteriosus occlusion on pulmonary artery pressure and on fetal right ventricular function assessed using the right atrial pressure-right ventricular stroke volume relationship. Nine days post-surgery (140 days gestation), blood gas and haemodynamic values were obtained before and during in utero ventilation with 100% O2, and during ventilation with the ductus arteriosus occluded. Oxygen content increased significantly from 7.2 to 14.5 ml dl-1 with ventilation and remained elevated at 14.4 ml dl-1 with ventilation with the ductus arteriosus occluded. In utero ventilation produced a left to right atrial pressure gradient and depression of the right atrial pressure-right ventricular stroke volume relationship. Ductus arteriosus occlusion during in utero ventilation reduced the left to right atrial pressure gradient, and along with a decrease in pulmonary artery pressure, resulted in an upward shift of the right atrial pressure-right ventricular stroke volume relationship, but only to the preventilation level. This study indicates that the fetal right atrial pressure-right ventricular stroke volume relationship is significantly altered, both by changes in the left to right atrial pressure gradient and by changes in pulmonary artery pressure seen with in utero ventilation and subsequent ductus arteriosus occlusion.

Estrogen-induced left ventricular chamber enlargement in ewes.

We studied the chronic effect of administration of a single large intramuscular dose of 17 beta-estradiol on left ventricular chamber size and output in the ewe. Fourteen oophorectomized ewes were successfully instrumented and studied, with measurements made of left ventricular, aortic, right and left atrial pressures, left ventricular stroke volume, and left ventricular minor axis dimension. Unanesthetized ewes were studied before and 1, 2, and 3 wk after intramuscular administration of 0.6 mg/kg 17 beta-estradiol (7 ewes) or 1.5 ml sesame oil placebo (7 ewes). Left ventricular end-diastolic pressure-end-diastolic dimension (LVEDP-EDD) and left ventricular end-diastolic pressure-stroke volume (LVEDP-SV) relationships were quantified during graded inferior vena caval occlusion and volume infusion. Left ventricular end-diastolic diameter was larger after estrogen but not after placebo administration. The LVEDP-EDD relationship shifted progressively rightward, indicating left ventricular chamber enlargement in the estrogen group but was unchanged in the placebo group. The plateau limb of the LVEDP-SV relationship in the estrogen group shifted up from a mean stroke volume of 77.1-89.5 ml/beat and did not change in the placebo group. We conclude that administration of a single large intramuscular dose of 17 beta-estradiol resulted in left ventricular chamber enlargement and increased stroke volume in the ewe.

Maximal myocardial blood flow is enhanced by chronic hypoxemia in late gestation fetal sheep.

The measurement of maximal myocardial blood flow gives information about the total cross-sectional area of the coronary resistance vessels. During a continuous left atrial infusion of adenosine (60 micrograms.kg-1.min-1), maximal myocardial blood flow was measured in 4 fetuses hypoxemic for a minimum of 5-8 days (pH = 7.33 +/- 0.01, arterial PCO2 = 49.8 +/- 4.2 Torr, arterial PO2 = 16.1 +/- 1.3 Torr, and arterial concentration of O2 = 5.3 +/- 1.2 ml/dl). These data were compared with an identically instrumented group of normoxemic fetuses (n = 7) following the same study protocol (pH = 7.38 +/- 0.02, arterial PCO2 = 43.1 +/- 3.8 Torr, arterial PO2 = 19.8 +/- 2.0 Torr, and arterial concentration of O2 = 7.9 +/- 1.0 ml/dl) (P < 0.05). At comparable arterial pressures, the maximal myocardial flow (ml.min-1.100 g tissue-1) for hypoxemic vs. normoxemic fetuses was 974 +/- 273 and 630 +/- 181 for the total myocardium, 986 +/- 367 and 602 +/- 192 for the left ventricular free wall, 1,025 +/- 346 and 614 +/- 178 for the septum, and 1,231 +/- 274 and 757 +/- 269 for the right ventricular free wall, respectively (P < 0.01). These data suggest that hypoxemia in the fetus can significantly alter the coronary vascular bed, which, if confirmed, would represent an important adaptation in the developing fetus.