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Students learn more effectively when they know what they do not know. Gaining insight into students’ metacognitive awareness is needed as misalignment between actual and self-perceived knowledge impedes their learning process. The optimal method of measuring self-perceived knowledge is still under debate. In this study, we evaluate the use of psychology-derived post-decision wagering for mapping students self-perceived knowledge. Students (n= 71) performed a pre-test on medical physiology, followed by a teacher-moderated discussion and a post-test with isomorph questions. Half of the students rated their self-perceived knowledge on each question using post-decision wagering, i. e. betting 1–5 points on the correctness of their answer, whereas the other half used a 5-point Likert scale to rate their confidence. Self-perceived knowledge scores were higher for post-decision wagering (pre: 3.75 ± 0.14, post: 4.60 ± 0.07) compared with Likert scales (pre: 3.13 ± 0.08, post: 3.92 ± 0.08) despite similar actual knowledge scores. Furthermore, Likert ratings showed a near-normal distribution, whereas wagers were placed preferentially using the outer ends of the scale. Correlations between mean actual and self-perceived knowledge scores were low in both groups. On average, 8.5% of responses were classified as misconceptions, defined as highly confident incorrect answers. Despite the presumed reliability of post-decision wagering, our findings suggest that we should adhere to the use of Likert scales as a balanced measure for self-perceived knowledge in medical education. Moreover, the prevalence of misconceptions did not alter after instruction, indicating a need for instructional designs that enhance students’ conceptual understanding in basic sciences.

The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF.

The role, interplay, and relative importance of the multifactorial hemodynamic and myocardial mechanisms causing dysfunction of the Fontan circulation remain incompletely understood.

Objective Endoventricular circular patch plasty is a method used to reconstruct the ventricular cavity in patients with (post) ischemic left ventricular aneurysm or global dilatation. However, late redilatation with mitral regurgitation has been reported, in which postoperative apex shape seems to play an important role. We studied the feasibility of ventricular volume downsizing with a variably shaped patch in porcine hearts.Methods In five in vitro and two acute animal experiments, a dyskinetic aneurysm was simulated with a pericardial insert. Reducing patch surface by changing patch shape diminished end-diastolic volume. In vitro, static end-diastolic volume was determined for each patch shape using volumetry and echocardiography. In the acute animal experiments, preliminary observations of patch behavior in live material were made, and pressure/time relationship, dPdTmax, was registered.Results In vitro, bringing the convex patch into a flat plane reduced LV volume from 66 ± 7 mL (aneurysm) to 49 ± 5 mL. Four of 5 patch shapes further reduced volume to a mean of 38 ± 7 mL (P = 0.03). The in vitro echocardiographic measurements correlated with volumetry findings (r = 0.81). In the acute animal experiments, dPdTmax varied with patch shape, independent of volume changes.Conclusions In this pilot study, in vitro shape configuration of the resizable ventricular patch resulted in a calibrated end-diastolic volume reduction. The data of the two in vivo pilot experiments clearly indicate that change in patch configuration in the situation of more or less unchanged end-diastolic volume had impact on cardiac performance. Future studies must substantiate the results of this observation.

Objective Endoventricular circular patch plasty is a method used to reconstruct the ventricular cavity in patients with (post) ischemic left ventricular aneurysm or global dilatation. However, late redilatation with mitral regurgitation has been reported, in which postoperative apex shape seems to play an important role. We studied the feasibility of ventricular volume downsizing with a variably shaped patch in porcine hearts.Methods In five in vitro and two acute animal experiments, a dyskinetic aneurysm was simulated with a pericardial insert. Reducing patch surface by changing patch shape diminished end-diastolic volume. In vitro, static end-diastolic volume was determined for each patch shape using volumetry and echocardiography. In the acute animal experiments, preliminary observations of patch behavior in live material were made, and pressure/time relationship, dPdTmax, was registered.Results In vitro, bringing the convex patch into a flat plane reduced LV volume from 66 ± 7 mL (aneurysm) to 49 ± 5 mL. Four of 5 patch shapes further reduced volume to a mean of 38 ± 7 mL (P = 0.03). The in vitro echocardiographic measurements correlated with volumetry findings (r = 0.81). In the acute animal experiments, dPdTmax varied with patch shape, independent of volume changes.Conclusions In this pilot study, in vitro shape configuration of the resizable ventricular patch resulted in a calibrated end-diastolic volume reduction. The data of the two in vivo pilot experiments clearly indicate that change in patch configuration in the situation of more or less unchanged end-diastolic volume had impact on cardiac performance. Future studies must substantiate the results of this observation.

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered.

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered.

Left ventricular dyssynchrony can lead to adverse cardiac effects, particularly if left untreated. Dyssynchrony can be improved by cardiac resynchronization therapy, but accurate diagnosis of the disorder is essential to obtain good results. Here, Bleekeret al. present an overview of the causes, diagnostic techniques and management in heart failure patients.

The human heart has a limited capacity for self-repair because, unlike most other cells, cardiomyocytes do not regenerate. Therefore, if a substantial number of myocytes is lost after a myocardial infarction, the performance of the heart may become severely limited, leading to a condition of heart failure. Recently, cell transplantation has emerged as a potential therapy for patients with end-stage heart failure. Of the various cell types being investigated for this purpose, skeletal myoblasts are an attractive option, because they are readily available from muscle biopsies and, if autologous cells are used, immunosuppression is not required and ethical issues are avoided. Several studies have shown that the cells can survive and differentiate after transplantation, and promising clinical results have been reported. However, effects of this therapy on left ventricular function remain largely unknown. In the present study, we investigated the long-term hemodynamic effects of intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Our findings indicate hemodynamic improvement after follow-up for up to 1 year, which is especially promising in view of the expected decline in left ventricular function in these patients.

Abstract: Hearts of normotensive angiotensin II type 2 receptor (AT2)-deficient mice do not develop fibrosis after angiotensin II-induced chronic hypertension. Thus, the goal of our study was to clarify whether AT2 knockouts (KOs) are also characterized by altered left ventricular (LV) function and modified remodeling of the extracellular matrix (ECM) after induction of myocardial infarction (MI). MI was induced in 5-mo-old female AT2-deficient mice and controls by occlusion of the left coronary artery. Time-matched sham-operated animals served as controls. After 48 h, the first sets of mice were hemodynamically characterized using a pressure-tip catheter (n=8/group). We also obtained pressure volume loops using a microconductance catheter in additional sets of animals 3 wk after induction of MI (n=7/group). Finally, the collagen index was illustrated by Sirius red staining and quantified by digital analysis. Whereas the LV function of sham-operated animals did not differ between both genotypes, the collagen index was 44% lower in KO animals. Forty-eight hours and 3 wk post-MI, systolic and diastolic LV function were impaired in both AT2-deficient and wild-type (WT) animals to the same extent by approx 45%. No differences were found between the two genotypes with respect to LV hypertrophy and the fibrosis index in the infarcted and noninfarcted areas 3 wk post-MI. While AT2-KO mice had less cardiac collagen content under basal conditions, the receptor deficiency had no significant influence on LV function at the two investigated time points after induction of MI or on the remodeling of ECM at the latter time point. Thus, hypetension-induced fibrosis is probably triggered by other control mechanisms than fibrosis induced by MI.

Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n = 12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 µg/g) of life. Control pups (n = 10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasone-treated rats had a reduced ventricular weight (270 ± 40 versus 371 ± 23 mg, p < 0.001) and reduced systolic function (end-systolic elastance: 1.24 ± 0.43 versus 2.50 ± 1.39 mm Hg/µL, p = 0.028). Cardiac output was maintained and end-diastolic volume was increased (84 ± 23 versus 59 ± 19 µL, p = 0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention.

Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 g/g) of life. Control pups (n10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasone-treated rats had a reduced ventricular weight (270 ± 40 versus371 ± 23 mg, p< 0.001) and reduced systolic function (end-systolic elastance: 1.24 ± 0.43 versus2.50 ± 1.39 mm Hg/L, p0.028). Cardiac output was maintained and end-diastolic volume was increased (84 ± 23 versus59 ± 19 L, p0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention.

Cardiac pressure-volume relations enable quantification of intrinsic ventricular diastolic and systolic properties independent of loading conditions. The use of pressure-volume loop analysis in early stages of development could contribute to a better understanding of the relationship between hemodynamics and cardiac morphogenesis. The venous clip model is an intervention model for the chick embryo in which permanent obstruction of the right lateral vitelline vein temporarily reduces the mechanical load on the embryonic myocardium and induces a spectrum of outflow tract anomalies. We used pressure-volume loop analysis of the embryonic chick heart at stage 21 (3.5 d of incubation) to investigate whether the development of ventricular function is affected by venous clipping at stage 17, compared with normal control embryos. Steady state hemodynamic parameters demonstrated no significant differences between the venous clipped and control embryos. However, analysis of pressure-volume relations showed a significantly lower end-systolic elastance in the clipped embryos (slope of the end-systolic pressure-volume relation: 5.68 ± 0.85 versus 11.76 ± 2.70 mm Hg/µL, p < 0.05), indicating reduced contractility. Diastolic stiffness tended to be increased in the clipped embryos (slope of end-diastolic pressure-volume relation: 2.74 ± 0.56 versus 1.67 ± 0.21, p = 0.103), but the difference did not reach statistical significance. The results of the pressure-volume loop analysis show that 1 d after venous obstruction, development of ventricular function is affected, with reduced contractility. Pressure-volume analysis may be applied in the chick embryo and is a sensitive technique to detect subtle alterations in ventricular function.

Cardiac pressure-volume relations enable quantification of intrinsic ventricular diastolic and systolic properties independent of loading conditions. The use of pressure-volume loop analysis in early stages of development could contribute to a better understanding of the relationship between hemodynamics and cardiac morphogenesis. The venous clip model is an intervention model for the chick embryo in which permanent obstruction of the right lateral vitelline vein temporarily reduces the mechanical load on the embryonic myocardium and induces a spectrum of outflow tract anomalies. We used pressure-volume loop analysis of the embryonic chick heart at stage 21 (3.5 d of incubation) to investigate whether the development of ventricular function is affected by venous clipping at stage 17, compared with normal control embryos. Steady state hemodynamic parameters demonstrated no significant differences between the venous clipped and control embryos. However, analysis of pressure-volume relations showed a significantly lower end-systolic elastance in the clipped embryos (slope of the end-systolic pressure-volume relation: 5.68 ± 0.85 versus11.76 ± 2.70 mm Hg/L, p< 0.05), indicating reduced contractility. Diastolic stiffness tended to be increased in the clipped embryos (slope of end-diastolic pressure-volume relation: 2.74 ± 0.56 versus1.67 ± 0.21, p0.103), but the difference did not reach statistical significance. The results of the pressure-volume loop analysis show that 1 d after venous obstruction, development of ventricular function is affected, with reduced contractility. Pressure-volume analysis may be applied in the chick embryo and is a sensitive technique to detect subtle alterations in ventricular function.

In the present study, we sought to investigate the effects of differing inotropic conditions on regional myocardial function in ischaemic segments. In an experimental pig model (n=11), the regional deformation parameters peak systolic strain rate [SRSYS (peak velocity of thickening)], systolic strain [εSYS (systolic wall thickening)] and post-systolic strain [εPST (ongoing wall thickening after end of systole)] were measured during normal perfusion and regional ischaemia of the posterior wall. These parameters were compared with global contractility [EES (end-systolic elastance)] measured by a conductance catheter. Ischaemia was induced by an active coronary hypoperfusion in the circumflex coronary artery. Measurements were done at baseline, during dobutamine and during esmolol infusion. In normal perfused hearts, SRSYS (4.8±0.2 s-1 at baseline) increased during dobutamine infusion, decreased during esmolol infusion and correlated significantly with global EES. In addition, εSYS averaged 93±3% at baseline and there was almost no εPST (4±1%) in normal myocardium. In ischaemic myocardium, SRSYS and εSYS were significantly reduced compared with normal myocardium at baseline (SRSYS=2.8±0.3 s-1, and εSYS=43±6%; P<0.001 compared with normal perfused hearts), whereas global EES was unchanged. In contrast, εPST was significantly increased in regional ischaemic segments compared with the non-ischaemic myocardium (15±2%; P<0.001). During the dobutamine infusion, SRSYS remained unchanged. In contrast, εSYS decreased (25±5%; P<0.001) and εPST increased (25±4%; P<0.05) significantly during dobutamine infusion in ischaemic myocardium. In ischaemic segments, an inotropic stimulation with dobutamine resulted in a shift of strain from systole (εSYS) to post-systole (εPST). Thus dobutamine induced ineffective myocardial work in ischaemic segments.

Objective:Right ventricular pressure overload occurs in several types of (congenital) heart disease, as well as in pulmonary disease. Clinical outcome in some of these patient groups might in part be related to left ventricular loading conditions. The effects of left ventricular unloading on the function of the hypertrophic right ventricle have not been studied. We aimed to study the effects of left ventricular unloading on right ventricular hemodynamics and contractility in an animal model of chronic right ventricular pressure overload. Methods:In lambs the pulmonary artery was chronically banded to increase right ventricular pressure to systemic levels. After 8 weeks, right ventricular contractility and hemodynamic function were assessed in these lambs, as well as in age-matched control animals, by using a combined pressure-conductance catheter in the right ventricle during baseline conditions and during complete bypass of the left ventricle. Results:In both groups acute left ventricular unloading significantly decreased left ventricular pressure to low levels while aortic pressure was maintained. In the right ventricle of the control group, both end-systolic and end-diastolic volumes increased with left ventricular unloading (P<.01) while end-systolic pressure was maintained. Cardiac output was unchanged despite decreased right ventricular contractility. In the banding group acute left ventricular unloading also decreased right ventricular contractility but increased cardiac output. During acute left ventricular unloading, diastolic stiffness was unchanged in the control group, whereas it was significantly decreased in the banding group. Conclusions:Both in normal hearts and in hearts subject to chronic right ventricular pressure overload, acute left ventricular unloading decreases right ventricular contractility. Although no effects on cardiac output are encountered in normal hearts during left ventricular bypass, cardiac output is improved in right ventricular pressure-overloaded hearts, most likely related to improved right ventricular diastolic compliance.

Objective:Banding of the pulmonary artery might be required to prevent pulmonary vascular damage in patients with increased pulmonary artery flow and to retrain the left ventricle in preparation for an arterial switch operation in patients with congenitally corrected transposition of the great arteries. Readjustment of the pulmonary artery band might be required in the postoperative period. In this study we aimed to test the feasibility of a novel device for bidirectionally adjustable pulmonary artery constriction. Methods:A hydraulic main pulmonary artery occluder was implanted in lambs and gradually inflated to create right ventricular pressure overload at a systemic (aortic) level. During the following period (up to 12 weeks), this pressure overload was monitored by measuring aortic and right ventricular pressures by means of implanted subcutaneous reservoirs. If required to maintain the right ventricular pressure overload at a systemic level in the growing animals, the occluder was deflated through a third subcutaneous reservoir. Results:After the banding period (average of 64 ± 8 days), the main pulmonary artery cuff could still be adjusted, and the animals showed no clinical signs of heart failure. Histologic analysis of the pulmonary artery showed extensive fibrosis, a giant cell response around the device, and small areas of tissue necrosis; complete transmural necrosis was not detected. Conclusions:This device allows adjustment of the pulmonary artery cuff in a precise manner over a prolonged period of time without surgical reintervention. Potentially, the device might have applications for clinical use in children with congenital heart disease.

OBJECTIVES

Reoxygenation and reperfusion after severe hypoxia and ischemia (HI) contribute substantially to birth asphyxia-related brain injury. Excess production of free radicals via metabolization of arachidonic acid, xanthine oxidase, and non-protein-bound iron play an important role. Cerebral reperfusion injury is characterized by a decrease in perfusion, oxygen consumption, and electrical activity of the brain. Reduction of free radical production may attenuate these features. We therefore induced severe HI in 35 newborn lambs, and upon reperfusion the lambs received a placebo [control(CONT), n = 7], the cyclooxygenase inhibitor indomethacin (INDO, 0.3 mg/kg/i.v., n = 7), the xanthine oxidase inhibitor allopurinol(ALLO, 20 mg/kg/i.v., n = 7), the iron chelator deferoxamine (DFO, 2.5 mg/kg/i.v., n = 7), or a combination of these drugs (COMB,n = 7). In each group changes (%) from pre-HI values were investigated for brain perfusion [measured by carotid artery flow(Qcar, mL/min)], (relative) cerebral O2metabolism(CMRO2), and electrocortical brain activity (ECBA, µV) at 15, 60, 120, and 180 min post-HI. Qcardecreased significantly at 120 and 180 min post-HI in CONT (p < 0.05), but not in INDO, ALLO, DFO, and COMB groups. CMRO2decreased significantly in CONT at 60 min post-HI (p < 0.05), remained stable in DFO and INDO, and was significantly higher in ALLO and COMB (p < 0.05) at 120 and 180 min post-HI. ECBA was significantly lower in CONT during the whole post-HI period (p < 0.05), ECBA in INDO and COMB were significantly decreased at 60 and 120 min post-HI (p < 0.05), but recovered afterward, whereas DFO and ALLO remained stable during the post-HI period. In conclusion preservation of Qcarand CMRO2, and recovery of ECBA occurred after treatment with INDO, ALLO, and DFO; combination of these drugs did not have an additional positive effect.

ABSTRACT: Prevention of hyperperfusion of the brain in the perinatal period has been thought to be an important mechanism by which indomethacin reduces the risk for severe periventricular-intraventricular hemorrhage. The present study investigated whether an indomethacin-induced enhancement of the upper limit of cerebral vascular autoregulatory ability in the neonate contributed to this reduction in cerebral blood flow. In seven anesthetized newborn lambs, we measured temporal blood flow velocity (TMFV) in the carotid artery over a wide range of mean aortic blood pressures (MABP) before and 30 min after an i.v. dose of 1 mg/kg indomethacin. TMFV in the carotid artery was used as an estimate for changes in cerebral blood flow. Stepwise changes in MABP of approximately 10 mm Hg were achieved by progressive balloon occlusion of the thoracic aorta or by progressive bleeding. Multiple linear regression analysis of TMFV versus MABP, indomethacin, and the possible interactive effects confirmed that, at MABP values up to 86 mm Hg, indomethacin lowered TMFV of the carotid artery. Above 86 mm Hg, indomethacin reduced the slope of the TMFV-MABP relationship, indicating an improvement of the autoregulatory ability of the cerebral vascular bed. There was a significant interanimal variability. Thus, indomethacin may reduce the risk for PIVH by limiting cerebral blood flow, especially during increased cerebral perfusion pressures, which often occur after birth asphyxia.

We investigated the influence of quantitative changes in myocardial contractile state, reflected by changes in the end-systolic pressure-volume relationship (its slope and volume intercept) and by changes in the slope of the relationship between change in pressure per unit time and end-diastolic volume induced by ß-adrenergic stimulation or inhibition, on the Doppler derived blood flow velocity wave form of the carotid artery, using a newborn lamb model. Acceleration time of the velocity wave form was investigated during control state I, during 4 and 8 µg/kg/min dobutamine infusion, during control state II, and during 0.5 mg/kg propranolol infusion, respectively. Using multiple linear regression analysis with dummy variables, confounding effects such as interanimal variability were removed. Acceleration time showed a strong relationship to both the slope and the volume intercept of the end-systolic pressure-volume relationship and to the change in pressure per unit time-end-diastolic volume relationship. The relations appeared to be independent of aortic pressure and relative resistance in the vascular bed of the carotid artery. These results indicate that acceleration of cerebral blood velocity may prove to be useful in assessing changes in myocardial contractile state of the newborn.

It has been shown that in the intact canine heart the left-ventricular end-systolic pressure/volume relation (ESPVR) depends on loading conditions: an increase in arterial vascular resistance causes a leftwards shift and a steeper slope of the ESPVR, suggesting an increased inotropic state. Our purpose was to investigate the possible contribution of the sympathetic nervous system to this load sensitivity of the ESPVR, using intact, but denervated, hearts with normal coronary perfusion and afterload. We used two types of loading intervention: venous volume infusion and gradual occlusion of the descending aorta. ESPVRs were obtained in six anaesthetized open-chest dogs, both before and after bilateral ablation of the stellate ganglia. To exclude the influence of heart rate changes, bilateral vagotomy was performed and the heart was paced. The absence of (unpaced) heart rate changes in response to pressure alterations was used to confirm total denervation. Left ventricular pressure was measured with a micromanometer and volume with a conductance catheter. ESPVRs were essentially linear and characterized by their slope (Ees) and volume intercept at 12 kPa (V12). We found that Ees (P<0.0001) and V12 (P<0.05) were both significantly different during pressure and volume interventions (0.67±0.29 and 0.41±0.18 kPa/ml for Ees and 16.2±8.2 and 18.2±8.4ml for V12 respectively). Denervation did not significantly affect the parameters of the ESPVR obtained by either volume infusion or aortic occlusion. Two-way analysis of variance revealed no significant interactive effect between denervation and intervention, indicating that the sympathetic nervous system does not influence the load dependency of the ESPVR. The dP/dtmax: EDV relationship behaved similarly. These results suggest that load dependency is an intrinsic property of the myocardium.

In thirteen preterm infants receiving surfactant (Curosurf) replacement therapy, changes in cerebral hemodynamics and oxygenation were investigated by near infrared spectroscopy. Surfactant instillation led to an instantaneous increase in cerebral blood volume (CBV) in all infants, which was primarily due to an increase in deoxygenated hemoglobin. Five infants received a low dose (100 mg/kg =1.25 ml/kg) of surfactant and 8 a high dose (200 mg/kg = 2.50 ml/kg). A significantly larger increase in CBV was observed in the infants receiving a high dose compared to those receiving a low dose of surfactant. We conclude that cerebral perfusion is affected more after the instillation of a high dose compared to a low dose of surfactant.

Objectives. In this study we quantified the effects of a critical coronary stenosis on global systolic function using pressure-volume relations at baseline and during incremental dobutamine stress.

Post-hypoxic-ischemic (HI) reperfusion induces endothelium and neurons to produce excessive amounts of nitric oxide and superoxide, leading to peroxynitrite formation, release of protein-bound metal ions (i.e.iron), and cytotoxic oxidants. We produced severe HI in 18 newborn lambs and serially determined plasma prooxidants (non-protein-bound iron), lipid peroxidation (malondialdehyde), and antioxidative capacity [ratio of ascorbic acid/dehydroascorbic acid (AA/DHA), α-tocopherol, sulfhydryl groups, allantoin/uric acid ratio, and vitamin A] in blood effluent from the brain before and at 15, 60, 120, and 180 min after HI. The lambs were divided in three groups: six received a placebo (CONT), six received low dose (10 mg/kg/i.v.) Nω-nitro-L-arginine (NLA-10) to block nitric oxide production, and six received high dose NLA (40 mg/kg/iv; NLA-40), immediately after completion of HI. Non-protein-bound iron increased in all groups after HI but was significantly lower in both NLA groups at 180 min post-HI (p< 0.05), the AA/DHA ratio showed a consistent decrease in CONT (at 60 min post-HI, p< 0.05), but remained stable in NLA lambs. α-Tocopherol decreased steadily in the CONT, but not in the NLA lambs [180 post-H: 1.9 ± 0.9 versus4.2 ± 0.7 μM(NLA-40), p< 0.05). Malondialdehyde was significantly higher in CONT lambs 120 min post-H compared with NLA groups [0.61 ± 017versus0.44 ± 0.05 μM (NLA-40), p< 0.05]. Vitamin A and sulfhydryl groups did not differ among groups. We conclude that post-H inhibition of nitric oxide synthesis diminishes non-protein-bound iron increment and preserves antioxidant capacity.

Reoxygenation and reperfusion after severe hypoxia and ischemia (HI) contribute substantially to birth asphyxia-related brain injury. Excess production of free radicals via metabolization of arachidonic acid, xanthine oxidase, and non-protein-bound iron play an important role. Cerebral reperfusion injury is characterized by a decrease in perfusion, oxygen consumption, and electrical activity of the brain. Reduction of free radical production may attenuate these features. We therefore induced severe HI in 35 newborn lambs, and upon reperfusion the lambs received a placebo [control(CONT), n= 7], the cyclooxygenase inhibitor indomethacin (INDO, 0.3 mg/kg/i.v., n= 7), the xanthine oxidase inhibitor allopurinol(ALLO, 20 mg/kg/i.v., n= 7), the iron chelator deferoxamine (DFO, 2.5 mg/kg/i.v., n= 7), or a combination of these drugs (COMB,n= 7). In each group changes (%) from pre-HI values were investigated for brain perfusion [measured by carotid artery flow(Qcar, mL/min)], (relative) cerebral O2metabolism(CMRO2), and electrocortical brain activity (ECBA, µV) at 15, 60, 120, and 180 min post-HI. Qcardecreased significantly at 120 and 180 min post-HI in CONT (p< 0.05), but not in INDO, ALLO, DFO, and COMB groups. CMRO2decreased significantly in CONT at 60 min post-HI (p< 0.05), remained stable in DFO and INDO, and was significantly higher in ALLO and COMB (p< 0.05) at 120 and 180 min post-HI. ECBA was significantly lower in CONT during the whole post-HI period (p< 0.05), ECBA in INDO and COMB were significantly decreased at 60 and 120 min post-HI (p< 0.05), but recovered afterward, whereas DFO and ALLO remained stable during the post-HI period. In conclusion preservation ofQcarand CMRO2, and recovery of ECBA occurred after treatment with INDO, ALLO, and DFO; combination of these drugs did not have an additional positive effect.

Prevention of hyperperfusion of the brain in the perinatal period has been thought to be an important mechanism by which indomethacin reduces the risk for severe periventricular-intraventricular hemorrhage. The present study investigated whether an indomethacin-induced enhancement of the upper limit of cerebral vascular autoregulatory ability in the neonate contributed to this reduction in cerebral blood flow. In seven anesthetized newborn lambs, we measured temporal blood flow velocity (TMFV) in the carotid artery over a wide range of mean aortic blood pressures (MABP) before and 30 min after an i.v. dose of 1 mg/kg indomethacin. TMFV in the carotid artery was used as an estimate for changes in cerebral blood flow. Stepwise changes in MABP of approximately 10 mm Hg were achieved by progressive balloon occlusion of the thoracic aorta or by progressive bleeding. Multiple linear regression analysis of TMFV versus MABP, indomethacin, and the possible interactive effects confirmed that, at MABP values up to 86 mm Hg, indomethacin lowered TMFV of the carotid artery. Above 86 mm Hg, indomethacin reduced the slope of the TMFV-MABP relationship, indicating an improvement of the autoregulatory ability of the cerebral vascular bed. There was a significant interanimal variability. Thus, indomethacin may reduce the risk for PIVH by limiting cerebral blood flow, especially during increased cerebral perfusion pressures, which often occur after birth asphyxia. (Pediatr Res 34: 178–181, 1993)

We undertook the present study to determine whether afterload and contractility interact in the hearts of newborn lambs. We specifically investigated whether stepwise increases in afterload increase contractility.

Since an excessive production of nitric oxide upon reperfusion/reoxygenation may play an important role in post-hypoxic-ischemic (HI) brain injury, we investigated whether immediate post-HI blockade of nitric oxide synthesis by N-ω-nitro-L-arginine (NLA) may reduce this injury. In 18 newborn lambs, subjected to severe HI, changes from pre-HI values were measured for carotid blood flow (Qcar [ml/min]) as a measure of changes in brain blood flow, (relative) cerebral metabolic rate of oxygen (CMRO2), and electrocortical brain activity (ECBA) at 15, 60, 120 and 180 min after HI. Upon completion of HI, at the onset of reperfusion and reoxygenation, 6 lambs received a placebo (control group), 6 low-dose NLA (10 mg/kg i.v., NLA-10 group), and 6 high-dose NLA (40 mg/kg i.v., NLA-40 group). Histological damage to cerebellar Purkinje cells was assessed after termination of the experiment. Only the control group showed a distinct initial post-HI cerebral hyperperfusion. From 60 min after HI onward Qcar was decreased to about 75% of pre-HI Qcar in all 3 groups, although none of these changes in Qcar reached statistical significance. Despite the decreased Qcar in all 3 groups, only the control group showed a significantly decreased CMRO2 ECBA and its bandwidth decreased in all groups, but only recovered in the NLA-10 group 180 min after HI. The brain to body mass ratio (%) and percentage necrotic Purkinje cells were, respectively: 15.3 ± 0.8 and 56 ± 10 (control group); 12.5 ± 1.2 and 36 ± 9(NLA-10 group), and 11.3 ± 1.0 (p < 0.05 vs. the control group) and 35 ± 14 (NLA-40 group). Since post-HI reperfusion injury of the brain has been characterized by a decreased CMRO2 and electrical brain activity, we conclude that preservation of CMRO2 in both NLA groups, but a recovery of ECBA and its bandwidth only in the NLA-10 group, suggests that NLA, and especially low-dose NLA, may reduce post-HI brain injury.

Inhibition of nitric oxide (NO) production may reduce post-hypoxic-ischemic (HI) neonatal brain damage, but may also induce pulmonary hypertension by inhibiting endogenous NO production in the pulmonary vascular bed. The aim of this study was to evaluate the effect of nitric oxide inhibition on pulmonary artery pressure and oxygen need after hypoxic ischemia. Severe HI was produced in 18 newborn lambs. After completion of HI the lambs were divided into three groups of 6 animals receiving either placebo (Cont), low dose Nω-nitro-L-arginine (10mg/kg i.v., NLA-10) or high dose (40mg/kg i.v., NLA-40) to block NO production. Pulmonary artery pressure (Pap), aortic pressure, blood gases, inspiratory oxygen concentration and ventilator settings were recorded before and 15, 60, 120 and 180 min after HI. Mean Pap rose initially significantly as compared to baseline in all groups at 15 min post-HI, decreased to normal in Cont but not in treated animals; 180 min post-HI mean Pap was significantly higher in both treated groups as compared to control (NLA-10: 32 mm Hg, NLA-40: 34 mm Hg, Cont: 25 mm Hg, p < 0.05 for NLA-10 and NLA-40 vs. Cont). Moreover, in both NLA-treated groups the oxygenation index was significantly elevated 120 and 180 min post-HI as compared to those of the Cont group. NO synthase inhibition after HI causes a prolonged increase in pulmonary artery pressure leading to a higher oxygen need.

Post-hypoxic-ischemic (HI) reperfusion induces endothelium and neurons to produce excessive amounts of nitric oxide and superoxide, leading to peroxynitrite formation, release of protein-bound metal ions (i.e. iron), and cytotoxic oxidants. We produced severe HI in 18 newborn lambs and serially determined plasma prooxidants (non-protein-bound iron), lipid peroxidation (malondialdehyde), and antioxidative capacity [ratio of ascorbic acid/dehydroascorbic acid (AA/DHA), a-tocopherol, sulfhydryl groups, allantoin/uric acid ratio, and vitamin A] in blood effluent from the brain before and at 15, 60, 120, and 180 min after HI. The lambs were divided in three groups: six received a placebo (CONT), six received low dose (10 mg/kg/i.v.) N?-nitro-L-arginine (NLA-10) to block nitric oxide production, and six received high dose NLA (40 mg/kg/iv; NLA-40), immediately after completion of HI. Non-protein-bound iron increased in all groups after HI but was significantly lower in both NLA groups at 180 min post-HI (p < 0.05), the AA/DHA ratio showed a consistent decrease in CONT (at 60 min post-HI, p < 0.05), but remained stable in NLA lambs. a-Tocopherol decreased steadily in the CONT, but not in the NLA lambs [180 post-H: 1.9 ± 0.9 versus 4.2 ± 0.7 µM(NLA-40), p < 0.05). Malondialdehyde was significantly higher in CONT lambs 120 min post-H compared with NLA groups [0.61 ± 017versus 0.44 ± 0.05 µM (NLA-40), p < 0.05]. Vitamin A and sulfhydryl groups did not differ among groups. We conclude that post-H inhibition of nitric oxide synthesis diminishes non-protein-bound iron increment and preserves antioxidant capacity.