Characterizing the Subcortical Structures in Youth with Congenital Heart Disease.

BACKGROUND AND PURPOSE: Congenital heart disease is a leading cause of neurocognitive impairment. Many subcortical structures are known to play a crucial role in higher-order cognitive processing. However, comprehensive anatomic characterization of these structures is currently lacking in the congenital heart disease population. Therefore, this study aimed to compare the morphometry and volume of the globus pallidus, striatum, and thalamus between youth born with congenital heart disease and healthy peers. MATERIALS AND METHODS: We recruited youth between 16 and 24 years of age born with congenital heart disease who underwent cardiopulmonary bypass surgery before 2 years of age (n = 48) and healthy controls of the same age (n = 48). All participants underwent a brain MR imaging to acquire high-resolution 3D T1-weighted images. RESULTS: Smaller surface area and inward bilateral displacement across the lateral surfaces of the globus pallidus were concentrated anteriorly in the congenital heart disease group compared with controls (q < 0.15). On the lateral surfaces of bilateral thalami, we found regions of both larger and smaller surface areas, as well as inward and outward displacement in the congenital heart disease group compared with controls (q < 0.15). We did not find any morphometric differences between groups for the striatum. For the volumetric analyses, only the right globus pallidus showed a significant volume reduction (q < 0.05) in the congenital heart disease group compared with controls. CONCLUSIONS: This study reports morphometric alterations in youth with congenital heart disease in the absence of volume reductions, suggesting that volume alone is not sufficient to detect and explain subtle neuroanatomic differences in this clinical population.

Hearing outcome of early postnatal exposure to hypoxia in Sprague-Dawley rats.

Objective: To determine the effect of experimentally induced hypoxia, in the first 10 days of life, on physiological hearing in a Sprague-Dawley rat model. Methods: A prospective, controlled animal study was carried out using 22 male rat pups. The rats in the hypoxic group (n = 12) were reared in hypoxia for the first 10 days of life, and subsequently reared in normoxia, while those in the control group (n = 10) were reared in normoxia for the duration of the experiment. Hearing was assessed using auditory brainstem response testing at approximately 72 days of age. Results: The hypoxia group had higher auditory brainstem response thresholds for all frequencies tested (more pronounced at 16 kHz), compared with controls. Wave I-V inter-peak latencies were more prolonged in the hypoxic rats, while both groups had similar wave I latencies. Conclusion: Chronic postnatal hypoxia induced permanent hearing loss in this Sprague-Dawley rat model. Prolonged wave I-V inter-peak latencies suggested functional abnormality in the central auditory pathway.

Maternal in utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate affects the blood pressure of adult male offspring.

Di-(2-ethylhexyl) phthalate (DEHP) is used industrially to add flexibility to polyvinyl chloride (PVC) polymers and is ubiquitously found in the environment, with evidence of prenatal, perinatal and early infant exposure in humans. In utero exposure to DEHP decreases circulating testosterone levels in the adult rat. In addition, DEHP reduces the expression of the angiotensin II receptors in the adrenal gland, resulting in decreased circulating aldosterone levels. The latter may have important effects on water and electrolyte balance as well as systemic arterial blood pressure. Therefore, we determined the effects of in utero exposure to DEHP on systemic arterial blood pressure in the young (2month-old) and older (6.5month-old) adult rats. Sprague-Dawley pregnant dams were exposed from gestational day 14 until birth to 300mg DEHP/kg/day. Blood pressure, heart rate, and activity data were collected using an intra-aortal transmitter in the male offspring at postnatal day (PND) 60 and PND200. A low (0.01%) and high-salt (8%) diet was used to challenge the animals at PND200. In utero exposure to DEHP resulted in reduced activity at PND60. At PND200, systolic and diastolic systemic arterial pressures as well as activity were reduced in response to DEHP exposure. This is the first evidence showing that in utero exposure to DEHP has cardiovascular and behavioral effects in the adult male offspring.

Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats.

Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 +/- 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/dtmax) and decrease (-dP/dtmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 +/- 6 vs. 51 +/- 35.3 mmHg (P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/dtmax 4,178 +/- 388 vs. 2,801 +/- 503 mmHg/s, LVP 115 +/- 11 vs. 83 +/- 14 mmHg, RPP 33,688 +/- 1,910 vs. 23,541 +/- 3,858 beats x min(-1) x mmHg(-1), -dP/dtmax -3,036 +/- 247 vs. -2,091 +/- 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.

Cardiovascular response to acute hypoxemia in adult rats hypoxemic neonatally.

OBJECTIVE: To determine the effects of chronic hypoxemia neonatally on the cardiovascular response to acute hypoxemia in adulthood. METHODS: Experiments were conducted on adult rats (82+/-2 days) which had been made chronically hypoxemic (hypobaric hypoxia equivalent to FiO(2)=0.14) during the first ten days of life but raised in room air (Neonatally Hypoxemia) as well as on adult rats never previously hypoxemic (Control). The animals were instrumented with catheters in the right common carotid artery and superior vena cava for measurements of mean systemic arterial pressure (MAP), central venous pressure, heart rate (HR), arterial blood gases, and arterial as well as mixed venous O(2) saturation. Oxygen consumption (VO(2)) was measured allowing calculation of cardiac index (CI), stroke volume index (SVI) and systemic vascular resistance index (SVRI). The rats were made acutely hypoxemic by exposure to FiO(2)=0.10 for 20 min. RESULTS: HR increased and MAP decreased to similar extents in both groups during acute hypoxemia. However, SVI and CI increased significantly (P<0.05) during acute hypoxemia in the Neonatally Hypoxemic group (24+/-6%, 41+/-8%) but respectively decreased and did not change in the Control animals (-13+/-6%, 2+/-6%). SVRI fell significantly more during hypoxemia in the Neonatally Hypoxemic animals than in the Control group (36+/-4% vs. 14+/-5%). CONCLUSIONS: Hypoxemia experienced in early life has long-term effects on the cardiovascular response to acute hypoxemia at maturity. This may have important implications for individuals hypoxemic in early life due to congenital cyanotic heart defects or pulmonary disease secondary to prematurity.

Natural history and surgical outcomes for isolated discrete subaortic stenosis in children.

OBJECTIVE: To document the natural history and surgical outcomes for discrete subaortic stenosis in children. DESIGN: Retrospective review. SETTING: Tertiary care paediatric cardiology centres. PATIENTS: 92 children diagnosed between 1985 and 1998. MAIN OUTCOME MEASURES: Echocardiographic left ventricular outflow gradient (echograd), and aortic insufficiency (AI). RESULTS: The mean (SEM) age at diagnosis was 5.3 (0.4) years; the mean echograd was 30 (2) mm Hg, with AI in 22% (19/87) of patients. The echograd and incidence of AI increased to 35 (3) mm Hg and 53% (36/68) (p < 0.05) 3.6 (0.3) years later. The echograd at diagnosis predicted echograd progression and appearance of AI. 42 patients underwent surgery 2.2 (0.4) years after diagnosis. Preoperatively echograd and AI incidence increased to 58 (6) mm Hg and 76% (19/25) (p < 0.05). The echograd was 26 (4) mm Hg 3.7 (0.4) years postoperatively, with AI in 82% (31/38) of patients. Surgical morbidities included complete heart block, need for prosthetic valves, and iatrogenic ventricular septal defects. Eight patients underwent reoperation for recurrent subaortic stenosis. The age at diagnosis of 44 patients followed medically and 42 patients operated on did not differ (5.5 (0.6) v 5. 0 (0.6) years, p < 0.05). However, the echograd at diagnosis in the former was less (21 (2) v 40 (5) mm Hg, p < 0.05) and did not increase (23 (2) mm Hg) despite longer follow up (4.1 (0.4) v 2.2 (0. 4) years, p < 0.05). The incidence of AI at diagnosis and at last medical follow up was also less (14% (6/44) v 34% (13/38); 40% (17/43) v 76% (19/25), p < 0.05). CONCLUSIONS: Many children with mild subaortic stenosis exhibit little progression of obstruction or AI and need not undergo immediate surgery. Others with more severe subaortic stenosis may progress precipitously and will benefit from early resection despite risks of surgical morbidity and recurrence.

Oxygen transport in conscious newborn dogs during hypoxic hypometabolism.

We questioned whether the decrease in O2 consumption (VO2) during hypoxia in newborns is a regulated response or reflects a limitation in O2 availability. Experiments were conducted on previously instrumented conscious newborn dogs. VO2 was measured at a warm ambient temperature (30 degrees C, n = 7) or in the cold (20 degrees C, n = 6), while the animals breathed air or were sequentially exposed to 15 min of fractional inspired O2 (FIO2): 21, 18, 15, 12, 10, 8, and 6%. In normoxia, VO2 averaged 15 +/- 1 (SE) and 25 +/- 1 ml . kg-1 . min-1 in warm and cold conditions, respectively. In the warm condition, hypometabolism (i.e., hypoxic VO2 < normoxic VO2) occurred at FIO2

Cardiovascular and respiratory consequences of body warming during hypoxia in conscious newborn cats.

Acute hypoxia in newborns of various species including humans is associated with decreased thermogenesis and a fall in body temperature. We have investigated the cardiorespiratory consequences of correcting the fall in colonic temperature (Tc) during acute hypoxia in newborn cats. Experiments were conducted on 21 unanesthetized kittens (12 +/- 1 d SEM, 244 +/- 8 g) instrumented with catheters in the left common carotid artery and superior vena cava for measurements of systemic arterial pressure, central venous pressure, heart rate, arterial blood gases, arterial O2 saturation (SaO2) and mixed venous O2 saturation. Oxygen consumption (VO2) and CO2 production (VCO2) were also measured. Alveolar ventilation (VA), cardiac index (CI), and systemic vascular resistance index (SVRI) were calculated. These determinations were made in 21% O2 at an ambient temperature (Tamb) of 25 degrees C, and after 80 min of exposure to Fio2 = 0.10. In one group Tamb was maintained at 25 degrees C (n = 8) during hypoxia and Tc fell by 2.7 +/- 0.4 degrees C whereas in a second group Tamb was increased to 35 degrees C for the second 40 min of hypoxia to raise Tc the prehypoxic level (n = 13). VO2, VCO2, VA, SaO2, and systemic arterial pressure during hypoxia did not differ between the animals which were warmed and those which were not. However, CI and heart rate were greater (452 +/- 23 versus 346 +/- 30 mL.min-1.kg-1 p < 0.05, 279 +/- 8 versus 228 +/- 12 beats.min-1 p < 0.05) and SVRI lower (0.115 +/- 0.022 versus 0.153 +/- 0.014 mm Hg.mL-1.min.kg, p < 0.05) during hypoxia in the warmed animals compared with the unwarmed group. Thus, artificially raising Tc during hypoxia resulted in peripheral vasodilation, whereas systemic arterial pressure was maintained by the increase in cardiac output. We conclude that, in the hypoxic kitten, raising Tc to normoxic values elicits a response that may reflect a condition of relative hyperthermia.

Observations on the hypoxic depression of sympathetic discharge in sinoaortic-denervated cats.

The effect of graded isocapnic hypoxia on the mass activity of the cervical sympathetic trunk and of the phrenic nerve was studied in sinoaortic-denervated, pentobarbital-anaesthetized cats. Under control conditions (normoxia, normocapnia) sympathetic discharge showed (i) a burst of action potentials synchronous with the phrenic nerve burst, which was selectively abolished by procedures suppressing inspiratory neuron activity (inspiration synchronous sympathetic activity, ISSA); and (ii) a lower level of sympathetic activity during expiration (tonic sympathetic activity, TSA). The effects of graded hypoxia on these two components of the sympathetic discharge were different. ISSA showed depression only, which began at inspired PO2 (Pinsp O2) of 58 +/- 10 (mean +/- SEM) mmHg (1 mmHg = 133.3 Pa), became progressively more marked as Pinsp O2 decreased further, and was paralleled by depression of phrenic nerve activity. Both ISSA and phrenic nerve activity were suppressed at Pinsp O2 of 46 +/- 9 mmHg. TSA increased progressively with the lowering of Pinsp O2, beginning at a Pinsp O2 significantly lower than that at which ISSA depression began (50 +/- 13 mmHg, p less than 0.01). In the range of Pinsp O2 values intermediate between the thresholds for ISSA depression and for TSA increase, some animals showed a depression of TSA that reversed to an increase as Pinsp O2 decreased further. During brief (duration 1.5 +/- 0.2 min) episodes of cerebral ischemia produced by occlusion of the brachiocephalic and left subclavian artery, the two components of sympathetic discharge showed responses similar to those observed in hypoxia, namely depression of ISSA as well as depression and enhancement of TSA.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural effects of systemic hypoxia and hypercapnia on hindlimb vascular resistance in acute spinal cats.

The effects of systemic hypoxia and hypercapnia on the neurogenic component of hindlimb vascular resistance were studied in 10 unanesthetized acute Cl spinal cats. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic and normocapnic blood from a donor cat. Ventilation with 5% CO2 and 10% CO2 in O2 caused increases in PP of 15 +/- 2 (mean +/- SE) mm Hg and 27 +/- 3 mm Hg from a control level of 106 +/- 6 mm Hg during ventilation with 100% O2. Changing the inspired gas mixture from 95% O2 plus 5% CO2 to 12.5%, 10%, 7.5%, or 5% O2 plus 5% CO2 in N2 caused increases in PP of 1.5 +/- 1, 14 +/- 2, 38 +/- 6, and 69 +/- 15 mm Hg respectively from a control level of 121 +/- 9 mm Hg. These vasoconstrictor effects were abolished by ganglionic blockade with hexamethonium (10 mg/kg iv). We conclude that in the acute Cl spinal cat a large part of the population of sympathetic preganglionic neurons in the lumbar spinal cord, controlling vascular smooth muscle of the hindlimb, is excited by systemic hypoxia or hypercapnia over a considerable range of PaO2 and PaCO2 values.

2-Deoxyglucose uptake in the central nervous system during systemic hypercapnia in the peripherally chemodenervated rat.

Changes in 2-deoxyglucose (2-DG) uptake in the central nervous system during systemic hypercapnia were determined by the [3H]2-DG autoradiographic method in peripherally chemodenervated rats. Autoradiographs were made from serial transverse sections of the brain and analyzed by a computer-based interactive image processing system for areas having increases or decreases in metabolic activity compared with control animals. The most pronounced change shown by autoradiographs of the hypercapnic animals was a generalized decrease in the metabolism of the gray matter throughout the central nervous system with respect to the normocapnic controls. However, several central structures showed evidence of either no change or an increased metabolism in the hypercapnic animals. In the brain stem these areas were localized to the ventrolateral region of the nucleus of the solitary tract rostral to the obex, around the region of the nucleus retroambiguus, in a region of the ventrolateral medullary reticular formation extending rostrally from the obex to the level of the intramedullary rootlets of the facial nerve, in the region of the ventral nucleus raphe pallidus, and in the region of the lateral parabrachial nucleus. In the diencephalon these regions included the supraoptic nucleus and the dorsal hypothalamic area, extending into the caudal portion of the paraventricular nucleus. The thoracolumbar cord showed activation of the lateral aspects of the dorsal horns, the region of lamina X and the region of the intermediolateral nucleus. These data may be interpreted as a functional map of the central structures activated in hypercapnia in the peripheral chemodenervated rat. It appears likely that these structures are involved in mediating the cardiorespiratory responses associated with the activation of central chemoreceptors by the increased carbon dioxide concentrations.

Neural effects of systemic hypoxia on hindlimb vascular resistance in sinoaortic-denervated cats.

The effects of systemic hypoxia on the neurogenic component of hindlimb vascular resistance were studied in six sinoaortic-denervated, anesthetized cats with intact central nervous system. Hindlimb perfusion pressure (PP) was measured under conditions of constant flow of normoxic blood from a donor cat. The neural component of the PP was estimated from the change in PP upon administration of hexamethonium (10 mg/kg i.v.). Ventilation of the recipient cat with 12.5% and 10% O2 was associated with an average 35 +/- 15% (SEM) and 13 +/- 10% decrease, respectively, of the estimated neural component of the PP. In contrast ventilation with 7.5% and 5% O2 produced increases of 27 +/- 7% and 58 +/- 10%, respectively, of the estimated neural component of the PP. Both the vasodilator and vasoconstrictor responses were abolished by hexamethonium (10 mg/kg i.v.). The vasodilator response appeared to be due to withdrawal of alpha-adrenergic tone since it was eliminated by constant infusion of phentolamine to the hindlimb (45 micrograms/ml blood/min). We conclude that, in addition to the already known sympatho-excitation seen in the sinoaortic-denervated cat during severe systemic hypoxia, there is also a sympatho-depressant effect which dominates at more moderate levels of systemic hypoxia.

Mediation of pressor responses to cerebral ischemia by superficial ventral medullary areas.

The effects on the pressor response to cerebral ischemia (CIR) of superfusion of the ventral medullary surface with artificial cerebrospinal fluid (CSF) containing local anesthetic was investigated in 10 sinoaortic-denervated, anesthetized cats. Prior to application of the local anesthetic, occlusion of the common carotid and vertebral arteries caused an increase in mean systemic arterial pressure (SAP) of 58 +/- 7 mmHg (+/- SE) from an initial level of 98 +/- 6 mmHg. Following 108 +/- 15 s of superfusion with artificial CSF containing 2% procaine, the CIR decreased to 19 +/- 3 mmHg. At this time phrenic nerve activity had been eliminated but basal SAP had only decreased by 14 +/- 2 mmHg, and significant neurogenic vasomotor tone remained. The residual CIR can be accounted for by the passive increase in systemic resistance due to occlusion of the cerebral vascular bed. The effects of procaine were reversible. On attenuation of the CIR, electrical stimulation of pressor points 2-4 mm from the ventral medullary surface was still effective. Autoradiographic analysis following application of 14C-labeled lidocaine showed that attenuation of the CIR occurred when estimated concentrations of the anesthetic sufficient to block nerve conduction extended 85 micron from the ventral medullary surface. These results indicate that the CIR is mediated by superficial structures in the ventral medulla that are not involved in the generation of a major fraction of basal vasomotor tone.

Aortic baroreceptor reflex pathway: a functional mapping using [3H]2-deoxyglucose autoradiography in the rat.

The organization of pathways within the central nervous system which are activated by aortic baroreceptor input was studied in the urethane anesthetized rat using the 2-deoxyglucose method. [3H]2-deoxyglucose was administered i.v. while either the aortic nerve was electrically stimulated or aortic baroreceptors were physiologically activated by pulse increases in arterial pressure in animals with bilateral denervation of the carotid sinus. Autoradiographs of transverse sections of the central nervous system were developed and analyzed for changes in metabolic activity in discrete regions compared to control animals, as indicated by the density of the photographic emulsion. Electrical stimulation of the aortic nerve resulted in all animals in an increase in the uptake of deoxyglucose in a number of sites throughout the central nervous system, primarily ipsilateral to the site of stimulation. In the brainstem, structures previously implicated in cardiovascular reflexes were labeled. These included the nucleus of the solitary tract, the solitary tract, the dorsal motor nucleus of the vagus, and the nucleus ambiguus. In addition, the inferior olivary nucleus, the parabrachial nuclei and the ventrolateral reticular formation showed increased labeling. In the hypothalamus, increased labeling was observed only in the paraventricular and supraoptic nuclei.

Hypoxic responses of sympathetic preganglionic neurons in sinoaortic-denervated cats.

The relation between arterial O2 tension (PaO2) and the firing rate of sympathetic preganglionic neurons (SPN) was studied in 16 strands of the cervical sympathetic trunk (CST) during graded isocapnic hypoxia in 11 sinoaortic-denervated central nervous system (CNS)-intact, anesthetized cats. SPN firing rate was independent of PaO2 from normoxia down to a PaO2 of 40 Torr. Below this PaO2 level three response patterns were observed, i.e., an excitatory response (n = 8), a depressant response (n = 3), and a mixed response consisting of a depression of firing at less severe hypoxic levels and an increase in firing rate at more extreme hypoxic levels (n = 5). Similar response patterns were also observed in four strands of the CST in three unanesthetized, sinoaortic-denervated, midcollicular decerebrate preparations. Systemic arterial pressure decreased in all cats as PaO2 decreased. Phrenic nerve activity also decreased in all cats with a course resembling that of the depression of sympathetic firing and disappeared at a PaO2 of 20 Torr. The data suggest that systemic hypoxia in the sinoaortic-denervated, CNS-intact or decerebrate animal activates both excitatory and depressant mechanisms acting on SPNs.

Responses of sympathetic preganglionic neurons to systemic hypercapnia in the acute spinal cat.

The relation between end-tidal (ET) pCO2 and firing rate of sympathetic preganglionic neurons (SPN) of the cervical sympathetic trunk was studied during hyperoxic hypercapnia in acute C1 or C4 spinal cats. The cats were under barbiturate anesthesia or anemically decerebrate. The firing rate of the majority of the tonically active strands (18/22) increased in hypercapnia and showed a continuous relation to ET pCO2 within the range studied. The firing rate of the remaining 4 strands was unaffected. The maximum increase in firing rate of the responsive strands was 3.7 times the control value on average (range 2.5-14.0). Recruitment of units which were silent in control conditions also occurred. These data demonstrate the existence of a spinal mechanism responsible for excitation of SPN during systemic hypercapnia.

Hypoxic responses of sympathetic preganglionic neurons in the acute spinal cat.

The relation between arterial O2 tension (PaO2) and the firing rate of sympathetic preganglionic neurons (SPN) of the cervical sympathetic trunk was studied during graded isocapnic hypoxia and hyperoxia in unanesthetized acute C-1 spinal cats. In the PaO2 range between 40 and 400 Torr there was no relation between the two variables. Below 40 Torr firing rate increased as PaO2 decreased, reaching an average peak value of ten times control at a PaO2 of 20 Torr. Mean arterial blood pressure (MABP) was also independent of PaO2 between 40 and 400 Torr and increased by an average of 25% at PaO2 values below 40 Torr. Intravenous administration of hexamethonium or phentolamine abolished the MABP response but not the SPN response to hypoxia. Pentobarbital (5-60 mg/kg iv) did not modify the SPN response to hypoxia, although normoxic SPN background firing was considerably depressed. The excitatory effect of hypoxia seems independent of excitatory afferent input and appears to be a general property of SPN.