Latent hypoparathyroidism in children with conotruncal cardiac defects.

BACKGROUND: DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell-mediated deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11. METHODS AND RESULTS: Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions. CONCLUSIONS: A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.

Partial median sternotomy for repair of heart defects: a cosmetic approach.

A modified median sternotomy incision that results in a cosmetically appealing scar is described. It includes the use of a low-lying short skin incision and partial transection of the sternum. The outcome in 182 infants and children indicates that this approach is safe, provides adequate exposure, and has excellent cosmetic results.

Choreoathetosis after deep hypothermia without circulatory arrest.

In 8 of 758 patients undergoing an intracardiac operation under cardiopulmonary bypass and hypothermia, choreoathetosis developed 3 to 7 days postoperatively. Before the onset of choreoathetosis, varying degrees of neurological dysfunction were noted. Electroencephalography and neuroimaging failed to detect any responsible functional or structural changes. Six patients are alive 1 to 3 years postoperatively, and their condition is improving. Two patients died of aspiration or sepsis. All patients were grouped based on factors identified as being possibly causative: depth of hypothermia, cooling time, flow rate, and repeated hypothermia. The incidence of choreoathetosis was significantly different in group A (rectal temperature greater than 25 degrees C) compared with group B (rectal temperature less than or equal to 25 degrees C) (0/295 versus 8/463; p = 0.02). Based on cooling time, the incidence of choreoathetosis was significantly different in group B1 (cooling time less than 1 hour) compared with group B2 (cooling time greater than or equal to 1 hour) (1/220 versus 7/243; p = 0.05). Based on flow rate during cooling, group B2 was further divided into the low-flow group (less than 1,500 mL.min-1.m-2) and the high-flow group (greater than or equal to 1,500 mL.min-1.m-2). Although not significant, the incidence of choreoathetosis was higher in the high-flow group (6/153 versus 1/90; p = 0.22). In group B patients having reoperation, the incidence of choreoathetosis was higher than in patients operated on for the first time (5/54 versus 3/409; p less than or equal to 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Repair of complete atrioventricular septal defect with tetralogy of Fallot.

Repair of complete atrioventricular canal with tetralogy of Fallot was performed in 9 patients. Ventricular septal defect was closed through the right atrium using a single polytetrafluoroethylene patch with ample anterior extension to avoid subaortic obstruction. The atrial septal defect was closed with a separate patch. Undivided atrioventricular valve leaflets were sandwiched between the two patches. Right ventricular outflow tract stenosis was relieved by pulmonary valvotomy and an infundibular patch in 7, a supravalvar patch (none transannular) in 6, and right ventricle-to-pulmonary artery conduit in 2. There was one hospital death (1/9, 11%) in a patient with persistent clinically significant postoperative pulmonary stenosis and low cardiac output requiring reoperation and right ventricle-to-pulmonary artery conduit insertion. There was no late mortality. All patients are asymptomatic 0.3 to 5.6 years after operation. Follow-up right ventricular outflow tract gradient ranged from 11 to 43 mm Hg and was 70 mm Hg in 1 patient who later had successful relief of obstruction. Three patients had mitral valve insufficiency; 1 needed reoperation. Aggressive relief of right ventricular outflow tract stenosis with maintenance of pulmonary valve competence and use of two separate patches for closure of the septal defects contribute to optimum immediate and long-term results after repair of this lesion.

Myosin heavy chain mRNA during the development and regression of myocardial hypertrophy.

RNA synthesis increases during the development and decreases during the regression of pressure-overload induced myocardial hypertrophy. Until now, we have been unable to determine whether these events actually reflected changes in the messenger RNAs for the myosin heavy chain mRNA in the total RNA extracted from rat heart during the development and regression of hypertrophy. We found that the amount of MHC mRNA increased in proportion to the overall increase in total RNA during the development of hypertrophy. However, upon relief of pressure-overload, MHC mRNA decreased to a much greater degree than did total RNA. This is probably related to a sudden cessation of synthesis and the rapid degradation of mRNA. We conclude that the development and regression of myocardial hypertrophy is a function of changes in the mRNA for contractile proteins.

Cation distributions in the hypertrophic myocardium (aortic constriction) of the rat.

Calcium, magnesium, sodium, potassium, and water distributions were determined in rat ventricular muscle during the development of myocardial hypertrophy. Hypertrophy was produced by constriction of the ascending aorta with a silver band. Sham-operated controls were treated similarly, except that the aorta was not constricted. Cation and water distributions were examined at intervals of 1 hour, 1 day, 1 week. Myocardial extracellular space was determined by distribution of [35S] sulphate. In separate experiments, extracellular space was determined in different regions of the normal rat ventricle using [3H] inulin as the extracellular marker. Although some changes were observed in tissue calcium content and the plasma concentrations of several cations, at no time were the cellular concentrations of any cation significantly altered. Myocardial water content and distribution remained nearly constant after constriction of the aorta. Results do not support hypotheses that the heart responds to increased afterload with an accumulation or loss of myocytic calcium sufficiently large to be detectable with standard quantitative methods.

Cardiac involvement in adolescent hypertension. Echocardiographic determination of myocardial hypertrophy.

We measured left ventricular chamber dimension and wall thickness using M-mode echocardiography in 61 adolescents with systolic or diastolic blood pressures above the 90th percentile for age and sex and in 49 normotensive adolescents. Left ventricular posterior wall and ventricular septal thickness indexed to body surface area were significantly greater (p less than 0.001) in the hypertensive group than in the normotensive controls. Left ventricular chamber diastolic and systolic dimensions were not different in the hypertensive group when compared to normotensive adolescents with comparable body size. Left ventricular diastolic and systolic volumes as well as left ventricular function did not differ between the hypertensive and control groups. Calculated parameters of left ventricular hypertrophy, namely, the radius-to-wall-thickness ratio, cross-sectional muscle area, and left ventricular mass, in the hypertensive adolescents were all significantly different (p less than 0.001) from those in the control groups. The finding of myocardial hypertrophy in young, mildly hypertensive subjects suggests early myocardial involvement in the hypertensive process.

Muscle and nonmuscle cell RNA polymerase activities in early myocardial hypertrophy.

RNA polymerase was solubilized from separated rat cardiac muscle and nonmuscle cells during the development of myocardial hypertrophy 1 or 3 days after sham operation or aortic constriction. Six fractions of enzymes designated IA, IB, IIA, IIB, IIIA, and IIIB were identified by DEAE-Sephadex chromatography in each cell population. Fractions designated IA and IB, IIA and IIB, and IIIA and IIIB were similar to RNA polymerase I, II, and III, respectively, found in other eukaryotes. Muscle cell enzyme activity from sham-operated and aortic-constricted rats did not significantly differ 1 day after intervention. By 3 days there was a significant increase in the activity of each enzyme fraction in muscle cells from aortic-constricted rats. There was a slight increase in IIA activity in nonmuscle cells from aortic-constricted rats at 1 day. By 3 days after aortic constriction RNA polymerase IIA, IIB, and IIIB activities increased in nonmuscle cells, but no change was noted in nonmuscle RNA polymerase IA, IB, and IIIA. Changes in RNA polymerase activities in cardiac muscle and nonmuscle cells occur during the development of myocardial hypertrophy but do not appear to correlate with reported changes in RNA synthesis. chromatin-template activity, however, did increase in cardiac muscle cells at both 1 and 3 days after aortic constriction. A similar increase was not seen in nonmuscle cell chromatin-template activity until 3 days. These data suggest that the initial increase in RNA synthesis during the development of myocardial hypertrophy is related to changes in chromatin-template activity in muscle cells. The activities of the RNA polymerase increase after a short delay and vary in their response.

Management of aortic arch interruption with prostaglandin E1 infusion and microporous expanded polytetrafluoroethylene grafts.

Prostaglandin E1 infusion and a microporous expanded polytetrafluoroethylene graft were used in the management of eight infants, all less than 4 days old, with interruption of the aortic arch. Five of the six infants receiving prostaglandin E1 responded dramatically to this therapy, with return of lower limb pulses and lessening of metabolic acidosis. There were no adverse effects attributable to the prostaglandin E1 infusion. Seven infants subsequently underwent aortic reconstruction with a polytetrafluoroethylene graft. There were no operative deaths, and in up to 3 years of follow-up of these patients, graft obstruction occurred in only one patient and this graft was successfully revised. The long-term mortality rate was high (62 percent); all deaths but one were attributable either to the palliation or to the total correction of the associated cardiac malformations.

Hemodynamic response to vascular expansion following immunosympathectomy in spontaneously hypertensive rats.

Spontaneously hypertensive male rats (SHR) or normotensive Kyoto-Wistar (WKY) male rats underwent either sham or nerve growth factor antiserum (NGFAS) treatment during the first week of life. The NGFAS treatment prevented the development of hypertension in SHR but did not prevent the development of left ventricular groups in vivo under general anesthesia. After the recording of resting parameters, homologous whole blood was transfused until the rise in cardiac output reached a plateau. At rest, LV systolic pressure of the NGFAS-treated SHR was significantly lower than that of the sham-treated SHR and not statistically different from that of the WKY rat. The LV end diastolic pressures did not differ among the four groups. Both SHR groups had significantly lower cardiac, stroke, and contractility indices than di the WKY groups. Following vascular expansion, LV filling pressure, stroke index, and stroke work index rose in all groups. The response in the SHR was greater than that in WKY groups. Interestingly, the systolic pressure of the NGFAS-treated SHR rose to the same level as in the sham-treated SHR. Heart rate and calculated systemic vascular resistance fell following transfusion. The SHR appears to exhibit an altered response to increased filling pressure and increased afterload. Our findings are consistent with the concept of an alteration in the compliance of the LV in the SHR.

Effect of a mild exercise program on myocardial function and the development of hypertrophy.

Cardiac function and the development of myocardial hypertrophy were studied in rats conditioned by an exercise program consisting of 8 wk of running on a treadmill. At the end of the training period a group of exercised and sedentary rats was subjected to hemodynamic evaluation under general anesthesia. Except for a slight elevation in the heart rates of the exercised animals there were no significant differences between the exercised and sedentary rats at rest. Following an increase in afterload or a period of hypoxia, the cardiac index of the exercised animals remained significantly higher than that of the sedentary controls. These differences were related to changes in stroke volume. Another group of exercised and sedentary animals underwent either constriction of the ascending aorta or a sham operation. Sedentary rats developed significant hypertrophy at 3 days but had no hypertrophy at 1 day after aortic constriction. Exercised rats, however, developed significant myocardial hypertrophy by 1 day after pressure overload. These data suggest that the heart from an exercised animal is better able to tolerate increases in afterload and hypoxia and can respond with compensatory myocardial hypertrophy more rapidly than the heart of a sedentary animal.

Changes in transcriptional activity during myocardial hypertrophy.

We have demonstrated alterations in the composition of certain groups of nuclear no-histone proteins which could account for the changes in template activity. Further identification of the individual proteins essential for this regulation will aid us in our understanding of the mechanism of myocardial cell growth during hypertrophy. We also have demonstrated the existence of several different RNA polymerase enzymes and have characterized them. The question of de novo synthesis or activation of preexisting enzyme remains unanswered. The delay in changes in activity which we found is also of great interest and may provide information as to the mechanism of increased RNA polymerase activity. The regulation of transcription can occur by changes either in the activity of the chromatin template or in the activities of the various RNA polymerase. Our studies thus far strongly suggest that during the development of hypertrophy both regulatory mechanisms are operative. Furthermore, this appears to be a bimodal function; initially there are changes only in the template and only later do changes in enzyme activity occur. To our knowledge this is the first demonstration of this form of regulation of RNA synthesis in myocardial tissue.

Surface cooling (20 degrees C) and circulatory arrest in infants undergoing cardiac surgery. Results in ventricular septal defect, complete atrioventricular canal, and total anomalous pulmonary venous connection.

During a six-year period, 46 severely symptomatic infants (average age, 5.1 months) underwent correction of ventricular septal defect (22 patients), total anomalous pulmonary venous connection (13 patients), and complete atrioventricular canal (11 patients), with the use of surface cooling to 20 degrees C. Cardiac repair was performed during circulatory arrest, and rewarming was performed with a pump oxygenator. Ten patients undergoing repair of ventricular septal defects were studied hemodynamically at 21 degrees C, before repair and at 37 degrees C after rewarming. Heart rate, left ventricular systolic pressure, maximum dp/dt, cardiac index, stroke work, and oxygen consumption were reduced substantially at 21 degrees C. Systemic vascualr resistance was increased at 21 degrees C. All changes were reversible with repair and rewarming. A protocol for hemodilution and crystalloid volume loading was devised to maintain urine output after early patients were noted to demonstrate renal dysfunction. With this protocol, survival rates were 89% for patients with ventricular septal defects, 67% for those with atrioventricular canal defects, and 85% for those with total anomalous pulmonary-venous connection.