Developmental changes in mRNA encoding cardiac Na+/H+ exchanger (NHE-1) in rabbit.

The faster recovery of cardiac contractility in newborn rabbit hearts during acute acidosis compared to adult hearts correlates with greater cellular activity of the Na+/H+ exchanger. We quantified mRNA encoding Na+/H+ exchanger-1 (NHE-1) in rabbit ventricles of fetal (27 days gestation), newborn (2-5 days), and adult (> 6 months) New Zealand white rabbits using reverse transcription-polymerase chain reaction (RT-PCR) and RNase protection assay, with GAPD mRNA as standard. Both RT-PCR and RNase protection assay revealed similar (p > 0.05) cardiac levels of NHE-1 mRNA in fetal and newborn hearts, while NHE-1 mRNA in these hearts was 1.7x and 1.6x greater than in adult hearts by both RT-PCR and RNase protection assay. These developmental changes in NHE-1 mRNA correlate with the developmental changes in Na+/H+ activity in sarcolemmal vesicles purified from rabbit heart.

Effect of late postoperative atrial septal defect closure on hemodynamic function in patients with a Lateral tunnel Fontan procedure.

OBJECTIVES: The aim of this study was to evaluate prospectively the effect of late atrial septal defect closure on cardiac output and oxygen delivery in patients who have undergone the Fontan procedure. BACKGROUND: An adjustable atrial septal defect is incorporated in patients undergoing the Fontan procedure who have increased pulmonary vascular resistance or poor ventricular function, or both. After the Fontan procedure, the atrial septal defect is test occluded. Patients with mean right atrial and pulmonary artery pressures > 15 mm Hg are discharged with the atrial septal defect open. METHODS: Twelve patients (20 months to 12 years old) underwent evaluation and closure of the atrial septal defect at a mean interval of 3.8 months (range 1 to 18) after the Fontan procedure. Each patient underwent full right and left heart catheterization. Cardiac output was obtained using the cine-volume method. The study included six patients with a high transpulmonary gradient or poor ventricular function preoperatively, or both (high risk group) and six who had only borderline increased pulmonary vascular resistance (low risk group). Patients in both groups had a mean right atrial pressure > 15 mm Hg when the atrial defect was test occluded in the first week after the Fontan procedure. RESULTS: All results are given as mean value +/- SD. Ventricular end-diastolic pressure was significantly lower (p = 0.03) with the atrial septal defect open in low risk patients (6 +/- 3 mm Hg) than in high risk patients (10 +/- 3 mm Hg). With the atrial septal defect open, low risk patients had a significantly higher (p = 0.04) cardiac index (4.87 +/- 0.81 liters/min per m2) than the high risk patients (3.96 +/- 0.47 liters/min per m2). There was no significant difference (p = 0.14) in cardiac index between the two groups with occlusion of the atrial septal defect. Oxygen delivery was also significantly higher (p < 0.05) with the atrial septal defect open in low risk patients (836 +/- 99 ml/min per m2) than in high risk patients (704 +/- 106 ml/min per m2). There was no significant difference (p = 0.89) in oxygen delivery between the two groups with occlusion of the atrial septal defect. With the atrial septal defect open, the interatrial gradient was not significantly different in low risk patients (4 +/- 1 mm Hg) from that in high risk patients (4 +/- 1 mm Hg). CONCLUSIONS: These data show that an interatrial communication results in increased postoperative systemic perfusion and oxygen delivery in patients with good diastolic ventricular function after the Fontan procedure.

Factors influencing survival in patients undergoing the bidirectional Glenn anastomosis.

The bidirectional Glenn anastomosis (BGA) has long been used as a surgical intervention for patients with single ventricle physiology. Initially, this procedure was the final stage in palliation and was performed in older children. Eventually, as the Fontan procedure came to be used as a method to separate circulations, the Glenn procedure was performed as an intermediate step. Over time, the BGA was performed as an alternative for patients who were considered to be at high risk with the Fontan procedure. Between January 1, 1988, and January 1, 1994, 129 patients underwent BGA at the University of California-Los Angeles. These patients were reviewed retrospectively, including clinic visits, catheterization, and echocardiographic information. The overall survival rate was 87% (112 of 129 patients). The average length of follow-up was 27 months. This information was then analyzed by univariate and multivariate analysis. Several factors were related to failure in patients who underwent BGA including pulmonary artery pressure, systemic right ventricle, and presence of anomolous pulmonary venous drainage and heterotaxy syndrome.

Acute hemodynamic effects of adjustable atrial septal defect closure in the lateral tunnel Fontan procedure.

OBJECTIVES: This study evaluated the acute hemodynamic changes with atrial septal defect closure in the postoperative period in patients undergoing the Fontan procedure. BACKGROUND: The adjustable atrial septal defect is a modification of the Fontan procedure designed to improve cardiac output and reduce systemic venous hypertension during the postoperative period. Limited information is available on the effects of inter-atrial shunting on the physiology of direct cavopulmonary connection. METHODS: In 11 patients (aged 9 months to 14.5 years), the atrial septal defect was closed 8 h to 4.6 days (mean 1.7 days) postoperatively. Indications for closure included mean right atrial pressure < 15 mm Hg or arterial oxygen saturation < 80%, or both. RESULTS: Data presented are mean values +/- 1 SD. Mean right atrial pressure was 13.4 +/- 3.0 mm Hg on admission to the intensive care unit, 10.0 +/- 2.0 mm Hg (p = 0.02) immediately before closure and 11.4 +/- 2.8 mm Hg (p = 0.02) after closure. There was a significant decrease in cardiac output, as calculated from arteriovenous oxygen saturation difference (26 +/- 9%, p = 0.003), Doppler aortic flow (19 +/- 9%, p = 0.0002) and ventricular volumes by two-dimensional echocardiography (20 +/- 8%, p = 0.0001). Arterial oxygen saturation increased from 82 +/- 5% to 94 +/- 4% (p = 0.0001), and arteriovenous oxygen saturation difference increased from 25 +/- 8% to 33 +/- 9% (p = 0.0001). Systemic oxygen delivery decreased from 727 +/- 354 to 655 +/- 325 ml/min per m2 (p = 0.02). One patient required reopening of the atrial septal defect. CONCLUSIONS: These data demonstrate that a controlled right to left atrial shunt improves cardiac output and systemic oxygen delivery and facilitates the postoperative management of patients after the Fontan procedure. Atrial septal defect closure increases systemic saturation to normal values and prevents potential systemic embolization but significantly decreases oxygen delivery and might limit exercise tolerance.

Damus-Stansel-Kaye procedure: current indications and results.

Between October 1983 and August 1991, 29 consecutive Damus-Stansel-Kaye procedures were performed. Indications for operation included restrictive bulboventricular foramen or subaortic stenosis associated with complex univentricular congenital heart disease (25) and Taussig-Bing heart, subaortic stenosis, or both associated with complex biventricular congenital heart disease (4). Twelve patients underwent concurrent Fontan procedures. Average age at operation was 39.8 months (range, 1 to 132 months). Average outflow tract gradient was 28 mm Hg (range, dynamic to 80 mm Hg). Of the 29 patients, 23 were male and 6 were female. There were three early deaths (10%), two in patients who had a concurrent Fontan procedure. Although there was a trend toward lower age and higher outflow tract gradients in nonsurvivors, these and other factors were not statistically significant predictors of death. Actuarial freedom from cardiac-related death was 88% at 5 years (n = 7). In a mean follow-up of 3.5 years (range, 0.1 to 7.7 years), 3 patients have required reoperation (10%), 2 for aortic valve insufficiency (5 days and 2.75 years) and 1 for a gradient across the anastomosis (5.75 years). Actuarial freedom from reoperation related to a failed Damus-Stansel-Kaye procedure was 90% at 4 years and 75% at 6 years (n = 7).

Selective anterograde coronary arteriography in neonates with d-transposition of the great arteries: accuracy and safety.

OBJECTIVES: This study was designed to evaluate the accuracy and safety of selective anterograde coronary arteriography for the identification of the origin and branching pattern of the three main coronary arteries in neonates with d-transposition of the great arteries. BACKGROUND: Definition of coronary artery anatomy is important in neonates with d-transposition of the great arteries who are considered for the arterial switch operation. Balloon occlusion aortography defines coronary artery anatomy in most but not all cases. We have described a technique for selective anterograde coronary arteriography. METHODS: Between March 1987 and May 1991, 17 neonates underwent selective anterograde coronary arteriography and 29 patients had balloon occlusion aortography. After venous access was gained, a mesenteric catheter was used to engage the coronary ostia for contrast injection. All angiograms were reviewed by three independent observers and the coronary artery diagnoses were compared with operative findings. Complications with the catheterization procedure were also recorded. RESULTS: The accuracy of defining coronary artery anatomy with selective anterograde coronary arteriography (98 +/- 2%) was significantly (p < 0.05) greater than that achieved with balloon occlusion aortography (69 +/- 6%). There were no deaths with catheterization in either study group. Morbidity was similar in the groups with balloon occlusion aortography (7%) and selective anterograde coronary arteriography (6%) (p > 0.05) and was related to transient bradycardia induced by catheter manipulation in the right ventricle. No patient in either study group experienced cardiac ischemia. CONCLUSIONS: Selective anterograde coronary arteriography is an accurate and safe technique for the definition of coronary artery pattern in neonates with d-transposition of the great arteries.

Partial Fontan: advantages of an adjustable interatrial communication.

Systemic venous hypertension after the Fontan procedure is a major cause of mortality and morbidity, accounting for 11 of 16 deaths in our series of 228 Fontan procedures. A partial Fontan with a residual atrial septal defect (ASD) would allow controlled right-to-left shunting to reduce venous pressure and improve cardiac output while maintaining a reduced but acceptable arterial oxygen saturation. This allows complete or graded closure of the ASD after the discontinuation of cardiopulmonary bypass in the operating room or at any time in the postoperative period by exposing the snare under local anesthesia. From 1987 to 1990, 36 patients undergoing the modified Fontan procedure had placement of an adjustable interatrial communication. Indications for placement of an adjustable ASD included increased pulmonary artery pressures, increased pulmonary vascular resistance, reactive airway disease, previously increased or unknown pulmonary vascular resistance, small pulmonary arteries, and borderline ventricular function. Fourteen patients had the adjustable ASD closed at the time of operation, 8 patients underwent narrowing, and 12 underwent closure of the ASD in the postoperative period. Eight patients were discharged with the ASD partially open, and 2 patients underwent delayed closure. The partial Fontan with an adjustable ASD may increase the safety of the Fontan procedure for high-risk groups such as those with increased pulmonary vascular resistance, pulmonary hypertension, and impaired left ventricular function and for infants, who tolerate venous hypertension poorly. The ability to adjust the ASD in stages depending on the hemodynamic response increases flexibility and safety.

Developmental changes of sarcolemmal Na+-H+ exchange.

We previously demonstrated that the effect of respiratory acidosis on cardiac contractility in the newborn was less than in the adult rabbit, and these data suggested a higher [Na+]i and [Na+]i-[Ca2+]o exchange in the newborn as compared to the adult. In this study, we investigated developmental changes of Na+-H+ exchange in isolated sarcolemmal vesicles. Sarcolemmal purification for Na+-K ATPase was 61.9 and 67.1 fold in the newborn and the adult rabbit heart, respectively. In the presence of an outwardly directed proton gradient across the vesicular membrane, sarcolemmal 22Na uptake rate in the newborn (0.22 +/- 0.01 nmol Na+/mg prot/s) was significantly higher than than in the adult (0.16 +/- 0.01 nmol Na+/mg prot/s). 1.0 mM amiloride inhibited 22Na uptake by 75% and 80% in the newborn and the adult, respectively. In the absence of a pH gradient, vesicular 22Na uptake in the newborn and the adult were not significantly different. In conclusion, the higher Na+-H+ exchange in the newborn may lead to a higher [Na+]i and subsequent calcium influx via Na+-Ca2+ exchange as compared with the adult during acidosis. This may explain the greater recovery of mechanical function in the newborn heart as compared to the adult heart during acidosis.

Description of a venous technique for selective coronary arteriography in newborns with d-transposition of the great arteries.

An accurate description of the coronary anatomy is desired before anatomic correction of d-transposition of the great arteries. Two-dimensional echocardiography and aortic root angiography are occasionally unable to delineate the coronary arteries. In neonates, the arterial approach for selective coronary arteriography is difficult and may compromise visceral and lower limb perfusion. A venous technique was used in two newborns to define selectively the coronary origins and their distribution. The venous approach for selective coronary arteriography may be effective in the evaluation of newborns with d-transposition of the great arteries when echocardiography inadequately defines the coronary circulation.

Effect of respiratory acidosis on hypoxic newborn myocardium.

We studied the effect of respiratory acidosis (pH = 6.8) on mechanical function, tissue adenosine triphosphate (ATP), and effluent creatine kinase (CK) in isolated arterially perfused hypoxic newborn and adult rabbit hearts. In the oxygenated muscle, acidosis reduced tension (T) and maximal tension first derivative [+ dT/dt (max)] in the adult more than in the newborn. In the adult hypoxic and reoxygenated hearts, acidosis during hypoxia (not reoxygenation) improved the recovery of T, + dT/dt (max) and tissue adenosine triphosphate (ATP) and reduced CK release and the rise in the resting tension. In the newborn heart, respiratory acidosis during hypoxia had no beneficial effects on recovery of mechanical function, tissue ATP and CK release. The buffering capacity and sarcolemmal H-Na exchange rate are both higher in the newborn heart than in the adult heart. This suggests that acidosis reduces the rise in intracellular Na and Ca, that is observed during hypoxia and reoxygenation, in the adult more than in the newborn and this may explain the beneficial effect of acidosis in the adult and not in the newborn.

Effect of ischemia on sarcolemmal Na+-Ca2+ exchange in neonatal hearts.

We studied the effect of cardiac ischemia on sarcolemmal enzymes, Na+-Ca2+ exchange, Ca2+ binding, and Ca2+ efflux in the newborn and adult rabbit. Rabbit ventricle was made ischemic by incubation in hypoxic, glucose-free Tyrode solution at 37 degrees C for 60-120 min. Ischemia inhibited Na+-K+-ATPase and K+-p-nitrophenylphosphatase (PNPPase) activity in the adult myocardium more than in the newborn. In the oxygenated (control) hearts, Na+-Ca2+-exchange activity in the newborn sarcolemma [Michaelis constant (Km) 18 microM; maximum velocity (Vmax) 33] was similar to that in the adult (Km = 16 microM, Vmax = 32). After 60 min ischemia, however, Na+-Ca2+ exchange in the newborn (Km = 16 microM, Vmax = 18) was inhibited less than in the adult (Km = 25 microM, Vmax = 18). In the two age groups, Ca2+ binding and efflux rate were not increased after ischemia, which suggested that Ca2+ permeability did not increase during ischemia. In conclusion, ischemia inhibited sarcolemmal enzymes and Na+-Ca2+ exchange in the newborn less than in the adult, and this lesser inhibition might contribute to or be caused by the greater tolerance of the newborn heart to ischemia.

Sarcolemmal calcium kinetics in the neonatal heart.

We characterized sarcolemmal enzymes, Na+-Ca2+ exchange, Ca2+ efflux, and Ca2+ binding in the neonatal rabbit heart. Sarcolemmal vesicles were isolated by differential and sucrose gradient centrifugation. The sarcolemmal purification factor for K+-p-nitro-phenylphosphatase (pNPPase) was 38.8 and 34.5 in the newborn and the adult, respectively. Contamination by mitochondria and sarcoplasmic reticulum was minimal. Specific activities of Na+-K+ ATPase and K+-pNPPase in the newborn were significantly lower than those in the adult. In the newborn, maximal Na+-Ca2+ exchange was 24.6 +/- 1.1 nmol Ca2+/mg/1.5 s, passive Ca2+ efflux rate was 14.6 +/- 2.2 nmol Ca2+/mg/min and Ca2+ binding was 69.4 +/- 3.3 nmol Ca2+/mg/4 min. These values were not significantly different from the adult values. At pH 6.0, Na+-Ca2+ exchange and Ca2+ binding were approximately 60% of control values (pH = 7.4) in two age groups. These values were stimulated at pH 8.0 and 9.0. In conclusion, Na+-Ca2+ exchange, Ca2+ efflux, passive Ca2+ binding and the effect of pH on Na+-Ca2+ exchange and Ca2+ binding in the newborn were similar to those in the adult.

The effect of glutamate on hypoxic newborn rabbit heart.

Effects of glutamate on myocardial mechanical function and energy metabolism during 120 min of hypoxia and subsequent reoxygenation were studied in the isolated arterially perfused newborn and adult rabbit hearts. The muscle was perfused with a Krebs-Henseleit (KH) solution or KH solution which contained 1 mM glutamate. Glutamate attenuated the effects of hypoxia on mechanical function and tissue ATP concentration, and enhanced the recovery of mechanical function and tissue ATP during reoxygenation. During hypoxia, glutamate increased tissue succinate and GTP with no change in total lactate and pyruvate production. Trace studies using 14C-glutamate and the tissue homogenate showed that hypoxia increased tissue succinate and inhibited TCA cycle. Additional glutamate produced more CO2 and TCA intermediates in both oxygenated and hypoxic mediums. These data indicate that glutamate increased the rate of ATP production in the hypoxic and reoxygenated heart. This study shows that the improvement of mechanical function and ATP formation in the hypoxic myocardium by glutamate was due to an increase in both oxidative phosphorylation and substrate level phosphorylation. The effect of glutamate on the ATP and GTP production in the newborn heart was not different from the adult.

Effect of Ca2+ antagonists on mechanical function in the neonatal heart.

The effect of verapamil and diltiazem on mechanical function was studied in the isolated arterially perfused neonatal and adult rabbit heart. The negative inotropic effect of these drugs in the newborn was significantly greater than in the adult. At concentrations 10(-7) M of verapamil and 10(-6) M of diltiazem, resting tension was significantly increased in the newborn, but not in the adult. In both age groups, verapamil and diltiazem inhibited the positive inotropy of staircase, but did not alter the inotropic effect of hyperosmolarity (116 mM mannitol). The positive inotropy of paired electrical stimulation was eliminated by these drugs in the newborn, but not in the adult. These data suggest that the neonatal heart as compared with the adult heart is more dependent on transsarcolemmal calcium influx for contraction and transsarcolemmal calcium efflux for relaxation.

Developmental change in the function of sarcoplasmic reticulum.

This study investigates the developmental changes of sarcoplasmic reticulum function in rabbit heart. We used ryanodine to evaluate sarcoplasmic reticulum function in the isolated arterially perfused fetus, newborn and adult rabbit heart muscles. The magnitude of the negative inotropic effect of ryanodine was similar in the fetus and the 3-day-old newborn, and it was less than in the 7-day-old while the effect in the 7-day-old newborn was significantly less than in the adult. In the adult, and not in the newborn, ryanodine (10(-6) M) caused prolongation of half relaxation time and time to peak tension, and an increase in resting tension. In addition, ryanodine (10(-1) M was more effective in the adult, compared to the 3-day-old newborn, in the attenuation of the positive inotropism of staircase, hyperosmolarity and paired electrical stimulation. These data suggest that sarcoplasmic reticulum function dramatically changes during the perinatal period, and furthermore, suggests that the adult hearts are most likely dependent on Ca2+ release and uptake from sarcoplasmic reticulum, while the perinatal hearts are more dependent on transsarcolemmal Ca2+ influx than on sarcoplasmic reticulum Ca2+ release in excitation-contraction coupling.

Calcium paradox in the neonatal heart.

The age-dependent effect of a calcium-free medium on myocardial mechanical function, high energy phosphates (HEP), as well as HEP and creatine phosphokinase (CPK) release was studied in the arterially perfused rabbit heart. The effect in the newborn was significantly less than in the adult with the transition occurring between two and five weeks of age. Thirty minutes of Ca2+ depletion had no significant effect on tissue high energy phosphate, creatine phosphokinase (CPK) release and creatine release. During Ca2+ repletion, the recovery in developed tension (DT) and +dT/dt (max) in the newborn was significantly greater than in the adult. The increase in resting tension in the newborn was significantly less in the newborn than in the adult. A significant decrease in tissue adenosine triphosphate (ATP) and CP was observed after Ca repletion following 5 minute Ca depletion in the adult and only after 30 minutes depletion in the newborn. Significant increases in CPK, creatine, and adenine nucleotide release were observed during Ca2+ repletion and the amounts released in the adult were significantly greater than in the newborn. There was a significant correlation between the percent recovery of +dT/dt (max) and tissue ATP content in both age groups. In addition, there was an inverse correlation between the recovery of +dT/dt (max) and log CPK release. These data indicate that the Ca2+ paradox effect is minimal in the newborn rabbit and becomes similar to that of the adult at five weeks of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxygen consumption and tissue Ca2+ uptake during reoxygenation after hypoxia in the rabbit.

The relationship between tissue Ca uptake and myocardial oxygen consumption during reoxygenation after 20, 40, and 60 min hypoxia was studied in the isolated arterially perfused rabbit septum. During reoxygenation after 40 and 60 min of hypoxia, tissue 47Ca2+ uptake increased significantly, and myocardial oxygen consumption (MVO2) (approximately 125% of control) was significantly greater than the prehypoxic value. Recovery of myocardial ATP content and mechanical function after 40 and 60 min of hypoxia was minimal, and it was inversely related to net increases in tissue Ca2+ uptake. In muscles perfused with Tris buffer, tissue Ca2+ gain during reoxygenation was significantly less and recovery of tissue ATP was significantly greater than in muscles perfused with Krebs-Henseleit buffer. MVO2 was not enhanced during reoxygenation after 40 min of hypoxia in muscles perfused with Tris buffer. These data suggest that tissue Ca2+ gain during reoxygenation utilizes energy from mitochondrial electron transport or from ATP hydrolysis causing increased MVO2 and depression in total adenine nucleotides and mechanical function.

Low sodium attenuation of the Ca2+ paradox in the newborn rabbit myocardium.

The effect of low sodium (Na 24 mM) perfusate during Ca2+ depletion on mechanical function, tissue high-energy phosphate, creatine kinase (CK) release, and tissue potassium was studied in the arterially perfused newborn and adult rabbit heart. During Ca2+ depletion, the time for DT and +dT/dtmax to decline to half-maximal value in newborn muscles perfused with low Na (46 +/- 3 S) was significantly (P less than 0.05) longer than the value obtained with normal Na (14 +/- 1 S). Similar values were obtained in the adult. During Ca2+ repletion, the increase in resting tension and CK release was attenuated in the low Na groups, and the values in the newborn were significantly less than in the adult. The recovery of +dT/dtmax and tissue high-energy phosphates in the low Na groups were significantly greater than in the normal Na groups, and the values in the newborn were significantly greater than in the adult. These data suggest that low Na during the Ca2+-free period delays both cellular Ca2+ depletion during the Ca2+-free period and Ca2+ influx during Ca2+ repletion. This effect in the newborn is greater than in the adult and might be explained by Na+-Ca2+ exchange.