Pulmonary atresia with ventricular septal defect: preoperative and postoperative responses to exercise.

Between April 1982 and June 1984, maximal exercise testing was performed 35 times in 34 consecutive patients with pulmonary atresia and ventricular septal defect (14 studies in patients without repair, 11 studies in patients with partial repair [insertion of a right ventricle to pulmonary artery conduit without ventricular septal defect closure] and 10 studies in patients with complete repair [insertion of a conduit with septal defect closure]). Total work performed, maximal power achieved, exercise time and maximal oxygen uptake were significantly greater in patients after partial or complete repair than in patients without repair. Systemic arterial blood oxygen saturations at rest and during exercise were directly related to the degree of repair. Although heart rate at rest in the three study groups was similar to that in a separate group of normal control subjects, patients in all three study groups had a blunted heart rate response to exercise. The ventilatory equivalent for oxygen was increased both at rest and during exercise for patients without conduit repair and those with a right ventricle to pulmonary artery conduit without ventricular septal defect closure but was similar to that of control subjects in the group with conduit insertion and septal defect closure. This study indicates that patients with pulmonary atresia and ventricular septal defect have decreased exercise tolerance both before and after corrective surgery. Exercise tolerance improves significantly after placement of a conduit from the right ventricle to the pulmonary artery with or without ventricular septal defect closure. Although no further improvement in exercise tolerance occurs with closure of the septal defect, ventilatory function and systemic arterial blood oxygen saturation are improved.

Functional single ventricle: cardiorespiratory response to exercise.

The cardiorespiratory response to exercise was measured in 27 children with functional single ventricle. All 27 patients had a significant reduction in exercise time, work performed, maximal exercise heart rate, maximal oxygen uptake and systemic arterial blood oxygen saturation. The reduction in exercise performance increased with increasing age of the patients. All patients ventilated excessively at rest and during exercise. This study documented the precise level of exercise intolerance in patients with functional single ventricle. The progressive deterioration in exercise performance with increasing patient age may lend credence to the concept that operation for physiologic correction of functional single ventricle should be considered during or before adolescence.

Exercise tolerance and cardiorespiratory response to exercise after the Fontan operation for tricuspid atresia or functional single ventricle.

To determine the impact of the Fontan operation on exercise tolerance and on the cardiorespiratory response to exercise, we compared the results of graded exercise to maximal effort of 81 patients with tricuspid atresia or single functional ventricle studied preoperatively with those of 29 patients studied postoperatively. Postoperatively, the values for total work performed, duration of exercise and maximal oxygen uptake increased significantly. Regardless of operative status, the maximal heart rate during exercise was reduced. The cardiac output and stroke volume response to exercise were subnormal after operation. Systemic arterial blood oxygen saturation was reduced markedly preoperatively both at rest and during exercise; postoperatively, it was significantly greater than the preoperative value but it remained slightly abnormal. The ventilatory response to exercise (respiratory rate, minute ventilation and ventilatory equivalent for oxygen) decreased toward normal after operation. Exercise tolerance and the cardiorespiratory responses to exercise improve after the Fontan operation. Formal exercise testing is essential to quantitate the degree of improvement.

Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation.

Cardiac toxicity is a potential complication of bone marrow transplantation because recipients frequently receive cardiotoxic chemotherapy and/or irradiation before transplantation. Most studies indicate that transient cardiac toxicity occurs within weeks of transplantation, but few studies have evaluated either cardiac status before or late after transplantation. Cardiac performance was assessed via cycle ergometry in 20 children and young adults before transplantation and 31 other children and young adults after transplantation. Mean survival time in the group post-transplantation was 3.9 years with a range of 11 months to 12.1 years. Left ventricular size and shortening fraction at rest were assessed via echocardiography. Data were compared to those of 70 healthy subjects from our laboratory. Patients before and after transplantation had normal oxygen consumptions and cardiac indices at rest. During exercise, however, patients treated for cancer both before and after bone marrow transplantation had reduced exercise times, reduced maximal oxygen consumptions, and reduced ventilatory anaerobic thresholds. Cardiac reserve, as judged by the response of the cardiac output during exercise, was reduced severely. There were no significant differences between the groups tested before and after transplantation. Patients who had been treated for aplastic anemia, who had received less intensive therapy before transplantation, performed significantly better than did patients treated for cancer. Despite these findings, only four patients had abnormalities by echocardiography. In conclusion, before transplantation patients with oncologic diagnoses had serious limitations in exercise performance, most likely as a result of the effects of the cardiotoxic therapy given as part of their conventional cancer therapy. Long-term survivors of bone marrow transplantation also had similar abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular response to exercise after the Mustard operation for simple and complex transposition of the great vessels.

After the Mustard operation, patients have reduced exercise tolerance, abnormal right and left ventricular responses to exercise and cardiac rhythm disturbances. The cardiovascular response to exercise was measured noninvasively in 19 patients from 4.5 to 20 years (mean 10.3) after operation. Mean work performed and maximal oxygen uptake for the group were substantially subnormal (42 +/- 23% and 59 +/- 18% [mean +/- 1 standard deviation] of the predicted values, respectively). Resting heart rate, blood pressure, systemic arterial blood oxygen saturation, cardiac index, stroke volume and systemic vascular resistance were not significantly different from control values. At maximal exercise, heart rate, systemic arterial blood oxygen saturation, cardiac index and stroke volume were significantly reduced in comparison with control values. After the Mustard operation, cardiovascular status at rest may be relatively normal, but during maximal exercise, marked abnormalities occur in nearly all indexes of cardiovascular function. Decreased cardiac output response to exercise is a result of decreased stroke volume response and, to a lesser extent, diminished heart rate. It is associated with abnormally increased total systemic vascular resistance.

Cardiorespiratory response to exercise in Ebstein's anomaly.

Fourteen patients with unrepaired Ebstein's anomaly underwent maximal exercise testing between October 1982 and April 1984. Compared with control subjects, these patients had significantly lower values for total work performed, exercise time, maximal oxygen uptake, blood oxygen saturation at rest and during exercise, and heart rate and systolic blood pressure during maximal exercise. They had a significant increase in heart rate at rest. The ventilatory equivalent for oxygen was increased significantly both at rest and during exercise. Thus, patients with Ebstein's anomaly have decreased exercise tolerance owing to both cardiac and respiratory limitations.

Cardiorespiratory function in asymptomatic survivors of neonatal respiratory distress syndrome.

We measured cardiopulmonary function at rest and during exercise in 15 healthy survivors of neonatal respiratory distress syndrome (RDS) and compared the results with those in 15 normal subjects. The mean birth weight of the RDS group was 1,771 g, and 12 of the 15 patients had required endotracheal intubation. The oxygen scores ranged from 79 to 3,322. Five of the 15 RDS patients had abnormal results of pulmonary function studies at rest. Peak expiratory flow was lower (P less than 0.05) in the RDS group (2.98 liters/min) than in the control group (3.57 liters/min). A negative correlation was noted between the forced expiratory flow between 25 and 75% of vital capacity and the oxygen score in these patients. Exercise tolerance was below normal in two of the RDS patients, both of whom also had abnormal pulmonary function at rest. One patient in the RDS group had systemic arterial hypertension at rest and during exercise. No significant differences in exercise tolerance or the cardiorespiratory response to exercise were observed between the two groups.

Cardiorespiratory response to exercise after repair of tetralogy of Fallot.

We studied 24 patients who had a graded exercise test 1 to 16 years after correction of tetralogy of Fallot. Maximal oxygen consumption was subnormal in 19 of the patients. We found no relationship between age at repair, postoperative right ventricular pressure, right ventricular-to-pulmonary artery pressure gradient, or ratio of right ventricular and left ventricular pressure and degree of exercise intolerance. The stroke volume response to exercise was normal in only three of eight patients. Twenty-five percent of patients had arrhythmia just prior to, during, or after exercise. The arrhythmias were independent of the factors of age at repair, age at exercise, previous operation, presence of an outflow tract patch, or residual right ventricular outflow tract obstruction. The ventilatory responses to exercise were normal. Persistent exercise intolerance may be due, in part, to abnormal ventricular function.

Afterload reduction therapy in patients following intraatrial baffle operation for transposition of the great arteries.

Patients with intraatrial baffle procedure for transposition of the great arteries (TGA) have diastolic dysfunction, decreased exercise capacity, stroke volume response and elevated systemic vascular resistance (SVR) during exercise. Angiotensin-converting enzyme (ACE) inhibitors improve exercise capacity in adults with congestive heart failure by improving diastolic function and decreasing SVR. We tested the hypothesis that ACE inhibitors decrease SVR and improve exercise capacity in patients after intraatrial baffle procedure for TGA. We studied the effects of enalapril in nine patients with TGA s/p intraatrial switch (mean age, 13.8 +/- 3 years) 7 to 21 years (mean, 12 +/- 4 years) after intraatrial baffle procedure. Enalapril (0.5 mg/kg/day, maximum dosage 20 mg bid) was administered for 12 months. Patients exercised using a cycle ergometer ramp protocol (0.25 W/kg/min) before enalapril (baseline), 1 month, 6 months, and 12 months after treatment initiation. Heart rate, blood pressure, cardiac output, respiratory rate, minute ventilation, oxygen consumption (VO2), total exercise time, work, and power were measured. SVR, cardiac index, and stroke volume index (SVI) were calculated. Two-tailed paired Student's t-test was used to compare data to those of normal control patients and the patients' baseline data. Patients had lower resting heart rate, cardiac index, maximum heart rate, cardiac index (CI), SVI, VO2, exercise time, work, and power and higher maximal SVR at baseline compared to normal control patients. There was no significant difference in total exercise time, work, power, VO2 (rest/peak), SVR, SVI, and CI after 12 months of therapy compared to patients' baseline values. We conclude that short-term (<1 year) use of enalapril does not improve exercise performance in patients with TGA in whom the intraatrial baffle procedure has been performed.

Impaired secretion of rat mannose-binding protein resulting from mutations in the collagen-like domain.

Serum mannose-binding protein (MBP) or mannose-binding lectin initiates the lectin branch of the innate immune response by binding to the surface of potentially pathogenic microorganisms and initiating complement fixation through an N-terminal collagen-like domain. Mutations in this region of human MBP are associated with immunodeficiency resulting from a reduction in the ability of the mutant MBPs to fix complement as well as from reduced serum concentrations. Inefficient secretion of the mutant proteins, which is one possible cause of the reduced serum levels, has been investigated using a mammalian expression system in which each of the naturally occurring human mutations has been recreated in rat serum MBP. The mutations Gly25-->Asp and Gly28-->Glu disrupt the disulfide-bonding arrangement of the protein and cause at least a 5-fold increase in the half-time of secretion of MBP compared with wild-type rat serum MBP. A similar phenotype, including a 3-fold increase in the half-time of secretion, disruption of the disulfide bonding arrangement, and inefficient complement fixation, is observed when nearby glucosylgalactosyl hydroxylysine residues at positions 27 and 30 are replaced with arginine residues. The results suggest that defective secretion resulting from structural changes in the collagen-like domain is likely to be a contributory factor for MBP immunodeficiency.

Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor.

The mannose receptor of macrophages and liver endothelium mediates clearance of pathogenic organisms and potentially harmful glycoconjugates. The extracellular portion of the receptor includes eight C-type carbohydrate recognition domains (CRDs), of which one, CRD-4, shows detectable binding to monosaccharide ligands. We have determined the crystal structure of CRD-4. Although the basic C-type lectin fold is preserved, a loop extends away from the core of the domain to form a domain-swapped dimer in the crystal. Of the two Ca(2+) sites, only the principal site known to mediate carbohydrate binding in other C-type lectins is occupied. This site is altered in a way that makes sugar binding impossible in the mode observed in other C-type lectins. The structure is likely to represent an endosomal form of the domain formed when Ca(2+) is lost from the auxiliary calcium site. The structure suggests a mechanism for endosomal ligand release in which the auxiliary calcium site serves as a pH sensor. Acid pH-induced removal of this Ca(2+) results in conformational rearrangements of the receptor, rendering it unable to bind carbohydrate ligands.