Quinidine interactions with human atrial potassium channels: developmental aspects.

Clinical studies have suggested that quinidine is less effective when used for the treatment of atrial arrhythmias in pediatric patients compared with its clinical effectiveness in the adult patient population. Age-related changes in the cardiac actions of quinidine on action potential duration and interaction with potassium channels in several mammalian species also have been reported. We investigated the effects of postnatal development on quinidine's interaction with major repolarizing currents (Ito, IKur, Ins, and IK1) in human atrial myocytes, using the whole-cell configuration of the voltage-clamp technique. Our results indicate that there are age-related changes in both the IC50 for quinidine blockade of Ito, as well as the mechanism of quinidine unblocking. In contrast, quinidine was found to inhibit both adult and pediatric IK1 and IKur in an age-independent manner, whereas the nonselective cation current (Ins), which contributes to the sustained outward current (Isus), was insensitive to quinidine. The results from this study help to clarify the electrophysiological mechanism by which quinidine elicits its antiarrhythmic effect in the pediatric and adult human population.

Age-related differences in response to neutrophil-mediated reperfusion injury in the neonatal piglet heart.

BACKGROUND: Neonatal hearts have altered adhesion molecule interactions in response to ischemia-reperfusion. How this affects myocardial function is unknown. METHODS: Isolated, buffer perfused 0- to 2-day (newborn) and 2-week piglet hearts were first subjected to 20-minute global, normothermic ischemia, followed by 45 minutes of reperfusion during which 150 x 10(6) newborn or 2-week neutrophils were infused. In some hearts, an antibody to SLe(x) (CSLEX-1) was infused with neutrophils during reperfusion. Hemodynamic variables, including left ventricular developed pressure (LVDP), were recorded at timed intervals. Neutrophil CD-18, L-selectin, and SLe(x) contents were measured by flow cytometry. RESULTS: Full recovery of LVDP was observed in newborn hearts receiving newborn or 2-week-old neutrophils. Recovery of LVDP was depressed (p < 0.01, ANOVA) in 2-week-old hearts receiving 2-week old, not newborn, neutrophils. Infusion of CSLEX-1 in 2-week-old hearts restored LVDP to baseline. Whereas flow cytometry showed higher (p < 0.01, Student's t test) CD-18 and L-selectin expression on newborn versus 2-week-old neutrophils, newborn neutrophils expressed lower (p < 0.01) SLe(x) levels. CONCLUSIONS: Initial "loose" neutrophil-endothelial selectin interactions are a necessary prelude to "firm" adhesion and reperfusion injury. Operations performed soon after birth may be better tolerated than when surgery is delayed; anti-SLe(x) preparations may prove beneficial when performing cardiac procedures on older infants.

Carnitine supplementation improves myocardial function in hearts from ischemic diabetic and euglycemic rats.

BACKGROUND: Nonischemic myocardial dysfunction in patients with diabetes mellitus appears to be attenuated with long-term L-carnitine therapy. The effect of acute L-carnitine supplementation on rat hearts from euglycemic and diabetic animals subjected to ischemia and reperfusion is investigated in this study. METHODS: Study rats had diabetes mellitus induced by streptozocin (65 mg/kg intraperitoneally), and control rats had injection of saline solution (n = 12 per group). About 1 month later, the hearts were suspended on a Langendorff apparatus and perfused with either standard buffered Krebs-Henseleit solution or this standard solution supplemented with L-carnitine (5 mmol/L). After stabilization, normothermic, zero-flow ischemia was instituted for 20 minutes followed by 60 minutes of reperfusion. There were four study groups (n = 6 per group): hearts that were from euglycemic rats and that were perfused with standard buffered Krebs-Henseleit solution (E-STD); hearts that were from diabetic animals and that were perfused with the same standard buffered solution (DM-STD); hearts taken from diabetic animals and perfused with L-carnitine-enriched solution (DM-CAR); and hearts taken from euglycemic rats and perfused with the enriched solution (E-CAR). RESULTS: At 60 minutes of reperfusion, left ventricular developed pressure was significantly better in hearts from both groups (diabetic and euglycemic) with carnitine supplementation (DM-CAR versus DM-STD and E-CAR versus E-STD, p < 0.01 for both, by analysis of variance). Left ventricular end-diastolic pressure was significantly lower in the DM-CAR group compared with all other groups (p < 0.01 by analysis of variance). CONCLUSIONS: These findings suggest that acute L-carnitine supplementation significantly improves the recovery of the ischemic myocardium in diabetic and euglycemic rats.

Adrenomedullin mediates coronary vasodilation through adenosine receptors and KATP channels.

The following experiments were conducted to determine whether, and the mechanisms through which, endogenous peptides alter coronary artery blood flow. Ultrasonic transit time probes were placed around the ascending aorta and left anterior descending coronary artery in groups of anesthetized, open-chest dogs. A Millar pressure catheter monitored left ventricular developed pressure. Intracoronary artery bolus injections of adenosine (a purinergic receptor activator), pinacidil (a KATP channel activator), calcitonin gene-related peptide (CGRP; which causes vascular smooth muscle relaxation by intracellular increases in cyclic-AMP), and adrenomedullin (mechanism unknown) each significantly (P < 0.05, Student's t test) increased coronary blood flow in a dose-dependent fashion, without altering systemic hemodynamic measurements. Intracoronary artery injection of U37883A (a KATP channel antagonist) significantly (P < 0.05) blocked the coronary vasodilator responses to adenosine, adrenomedullin, and pinacidil. Intracoronary xanthine amine congener (an adenosine receptor antagonist) blocked only the responses to adenosine and adrenomedullin, not pinacidil. Intracoronary CGRP8-37 (CGRP receptor antagonist) blocked only the vasodilator response to CGRP. These data suggest that the coronary vasodilator effect of adrenomedullin is initiated first by activation of adenosine receptors, and subsequently through KATP channels-not by activation of CGRP receptors. That there were no changes in left ventricular developed pressure or in systemic hemodynamics after intracoronary artery infusions of adrenomedullin indicates that this endogenous peptide may have clinical utility in facilitating myocardial protection or preconditioning.

Mild preischemia hypothermia adversely affects postischemic myocardial function in the neonatal piglet heart.

BACKGROUND: During cardiac surgery, operative hypothermia has been shown to be beneficial in certain situations, although in children perioperative hypothermia has been associated with several physiologic alterations that have proven detrimental to their postoperative function. Little attention has been given to the effects of mild (34.5 degrees C) perioperative hypothermia on postischemic myocardial function in the pediatric population. It was hypothesized that mild hypothermia would be detrimental to postischemic ventricular function in the neonatal heart. METHODS: Neonatal (0-2 days old) piglets were subjected to mild perioperative hypothermia without rewarming (HT-only, n = 6), hypothermia followed by rewarming (HT-RW, n = 6), or continuous normothermia (NT, n = 8). The hearts were rapidly excised, suspended on an isolated perfusion apparatus, and allowed to spontaneously beat while being perfused with an asanguinous solution. All hearts were subjected to 20 min global, normothermic, zero-flow ischemia followed by 45 min oxygenated crystallite buffer reperfusion (I-R). RESULTS: Compared to that of NT piglets, there were significant (P < 0.05) reductions in recovery of left ventricular (LV) diastolic and systolic function following ischemia and reperfusion in HT-RW animals. When the hearts were rendered ischemic without first rewarming, the degree of myocardial dysfunction was not as severe. In contrast to the NT piglets, HT-RW animals demonstrated significant (P < 0.05) reductions in the final recovery of LV developed pressure (71 +/- 6 vs 105 +/- 6 in NT), LV rate pressure product (52 +/- 4 vs 102 +/- 9 NT), and LV end diastolic pressure (32 +/- 7 vs 3 +/- 1 in NT) following I-R. When compared to the HT-RW group, HT-only piglets did not exhibit significant differences in systolic function, although diastolic function was minimally altered initially as evidenced by the slight elevation of LV end diastolic pressure at 5 min, with reperfusion in the HT-only group (P < 0.05). CONCLUSIONS: In this newborn piglet model, mild hypothermia significantly reduces recovery of systolic and diastolic left ventricular function when followed by an episode of global myocardial ischemia-reperfusion only when the animals are returned to normothermia prior to the ischemic insult. When hypothermia is immediately followed by the ischemic event, left ventricular function is unaffected.

L-type calcium current in pediatric and adult human atrial myocytes: evidence for developmental changes in channel inactivation.

Animal studies have documented the presence of marked, species-dependent, developmental changes in the properties of the L-type calcium current in cardiac myocytes. In an effort to understand the postnatal changes which occur in the calcium current in human heart, we characterized the calcium current in atrial myocytes isolated from 17 pediatric and older children (ages 3 d to 14 y) and 12 adult (ages 43-79 y) human hearts using the whole-cell patch clamp technique. In contrast to animal models, we found no evidence for age-related changes in calcium current density, steady-state inactivation, or kinetics of recovery from inactivation, suggesting that, in human atrium, calcium channels are in many aspects functionally mature at the time of birth. However, statistically significant differences were found in the kinetics of calcium current inactivation, with calcium current measured in cells isolated from pediatric human atria inactivating approximately 2-fold faster than cells isolated from adult hearts. These results suggest a possible role for age-related changes in calcium current inactivation in the shortened action potential duration observed in pediatric compared with adult human atrium.

Description of a nonselective cation current in human atrium.

Ion currents were examined in isolated human atrial myocytes by using the whole-cell patch-clamp technique. When currents were recorded with a K(+)-containing pipette solution, depolarizing voltage pulses elicited a rapidly activating outward current that decayed to an apparent steady state. Exposure of cells to 10 mmol/L 4-aminopyridine markedly reduced current amplitude; however, a rapidly activating current that was approximately 30% of the steady state current amplitude remained. When pipette K+ was replaced with Cs+, a similar rapidly activating current that reversed polarity at approximately 0 mV was recorded. This current was seen in 100% of the cells tested from 17 different hearts (n = 142), and its amplitude was approximately 40% of the amplitude of the steady state current recorded in the presence of pipette K+. The current amplitude was not significantly different in cells isolated from adult (6.31 +/- 1.35 pA/pF, n = 8) and pediatric (5.54 +/- 1.04 pA/pF, n = 9) hearts. Studies designed to determine the charge-carrying species indicated that changes in bath Cl- concentration had no effect on either the amplitude or the reversal potential of this current, whereas removal of pipette Cs+ and bath Na+ dramatically reduced this current. In addition, this current was not modulated by either isoproterenol (1 mumol/L, 22 degrees C) or cell swelling. This study provides the first description of a nonselective cation current in human atrial myocytes, which may play an important role in repolarization in human atria.

Comparison of Ito in young and adult human atrial myocytes: evidence for developmental changes.

In an effort to understand the ionic basis for the developmental changes that have been reported to occur in the configuration of the human atrial action potential, we characterized the transient outward current (Ito) and the inward rectifier current in atrial myocytes isolated from 20 young (ages 1 day-2.5 yr) and 8 adult (11-68 yr) human hearts using the whole cell patch-clamp technique. We found evidence for statistically significant (P < 0.05) age-related changes in the Ito, including 1) the presence of an Ito in only 67% of the cells isolated from young hearts vs. 100% of the cells isolated from adult hearts, 2) an almost twofold increase in the current density of Ito in adult cells vs. young cells, and 3) recovery kinetics that are approximately twofold slower in young myocytes relative to adult myocytes. In contrast, there were no age-related changes found in the current density of the inward rectifier current or the sustained current measured after the decay of Ito. These results suggest important current-dependent changes that occur with age in human atria.

Neonatal pneumonectomy for isolated unilateral pulmonary artery agenesis.

A 23-day-old female newborn was evaluated for acyanotic respiratory distress immediately after birth. Echocardiogram and cardiac catheterization revealed absence of the right pulmonary artery. Subsequent course was complicated by necrotizing bronchopneumonia. Despite antibiotic therapy and ventilator support she failed to improve; right pneumonectomy was performed to remove the source of sepsis. This case represents an example in which an infectious complication in a rare congenital pulmonary malformation served as an indication for neonatal pneumonectomy.

Effects of potassium cardioplegia on high-energy phosphate kinetics during circulatory arrest with deep hypothermia in the newborn piglet heart.

The protective effects of hypothermia and potassium-solution cardioplegia on high-energy phosphate levels and intracellular pH were evaluated in the newborn piglet heart by means of in vivo phosphorus nuclear magnetic resonance spectroscopy. All animals underwent cardiopulmonary bypass, cooling to 20 degrees C, 120 minutes of circulatory arrest, rewarming with cardiopulmonary bypass, and 1 hour off extracorporeal support with continuous hemodynamic and nuclear magnetic resonance spectroscopic evaluation. Group I (n = 5) was cooled to 20 degrees C; group II (n = 4) was given a single dose of 20 degrees C cardioplegic solution; group III (n = 7) was given a single dose of 4 degrees C cardioplegic solution; and group IV (n = 4) received 4 degrees C cardioplegic solution every 30 minutes. At end ischemia, adenosine triphosphate, expressed as a percent of control value, was lowest in group I 54% +/- 6.5% but only slightly greater in group II 66% +/- 7.0%. Use of 4 degrees C cardioplegic solution in groups III and IV resulted in a significant decrease in myocardial temperature, 9.9 degrees C versus 17 degrees to 20 degrees C, and significantly higher levels of adenosine triphosphate at end ischemia; with group III levels at 72% +/- 6.0% and group IV levels at 73% +/- 6.0%. Recovery of adenosine triphosphate with reperfusion was not related to the level of adenosine triphosphate at end ischemia and was best in groups I and II, with a recovery level of 95% +/- 4.0%. In group IV, no recovery of adenosine triphosphate occurred with reperfusion, resulting in a significantly lower level of adenosine triphosphate, 74% +/- 6.0%, than in groups I and II. Recovery of ventricular function was good for all groups but was best in hearts receiving a single dose of 4 degrees C cardioplegic solution. In this model, multiple doses of cardioplegic solution were not associated with either improved adenosine triphosphate retention during arrest or improved ventricular function after reperfusion, and in fact resulted in a significantly lower level of adenosine triphosphate with reperfusion. The complete recovery of adenosine triphosphate in groups I and II, despite a nearly 50% adenosine triphosphate loss during ischemia, may result from a decrease in the catabolism of the metabolites of adenosine triphosphate consumption in the newborn heart.

Prospective detection by Doppler color flow imaging of additional defects in infants with a large ventricular septal defect.

The use of Doppler color flow imaging and axial contrast angiography in the preoperative detection of additional ventricular septal defects (in the setting of a known large defect) were compared in a prospective fashion. One hundred seventy-nine infants with two ventricles (each of at least normal size) and a large, nonrestrictive ventricular septal defect underwent reparative surgery before 2 years of age. The reference standard for the presence of additional defects was intraoperative verification or (in cases in which the surgeon did not visualize any additional defect) subsequent identification at postoperative angiography, postoperative color Doppler examination or reoperation. Only six patients (3%) had additional ventricular septal defects confirmed at the time of repair; an additional five (3%) had defects found only postoperatively. The negative predictive value of Doppler color flow imaging and angiography was 0.95 (168 of 176) and 0.97 (168 of 174), respectively. The sensitivity was 0.27 (3 of 11) and 0.45 (5 of 11), respectively. For certain malformations with a very low prevalence of additional muscular defects (such as perimembranous ventricular septal defect with normally aligned great arteries), a clinical trial of reparative surgery without prior invasive study appears reasonable.

Pulmonary artery index. A nonpredictor of operative survival in patients undergoing modified Fontan repair.

The importance of pulmonary artery size and the value of a standardized pulmonary artery index (PAI) in predicting outcome after Fontan's repair have previously been reported and questioned. We retrospectively reviewed 29 patients undergoing modified Fontan repair at The Children's Hospital of Philadelphia to examine the relation between preoperative PAI (determined echocardiographically) and operative mortality. Twenty-four of these 29 patients underwent pulmonary artery augmentation at the time of Fontan repair. PAIs ranged from 48 to 541 mm2/m2. Operative mortality was 21%. PAI ranged from 68 to 233 mm2/m2 in nonsurvivors and from 48 to 541 mm2/m2 in survivors. There was no statistically significant difference in PAI between survivors and nonsurvivors; the lowest PAI associated with survival (48 mm2/m2) was one fourth of the lowest PAI value previously reported. There was a trend, not statistically significant, toward increased survival in those with larger PAIs. We conclude that patients should not be excluded from consideration for Fontan's repair solely on the basis of pulmonary artery size.

Pulmonary artery configuration after palliative operations for hypoplastic left heart syndrome.

Pulmonary artery architecture and symmetry after palliative operations for hypoplastic left heart syndrome may affect subsequent suitability for a modified Fontan operation. Two-dimensional echocardiography was used to measure pulmonary artery diameter and assess symmetry after two types of systemic-pulmonary artery shunts: modified right Blalock-Taussig shunt (14 patients) and central shunt (from underside of aortic arch gusset to pulmonary artery confluence) (14 patients). Age, weight, preoperative diameter of right and left pulmonary arteries (proximal, middle, and distal segments), and mean interval between preoperative and postoperative echocardiographic studies (20.2 +/- 4.4 days in the Blalock shunt group; 19.1 +/- 6.8 days in the central shunt group) were similar. Early postoperatively, patients with a Blalock shunt showed a significant decrease in the diameter of all pulmonary artery segments except the distal right pulmonary artery. The diameters tapered from distal right to distal left pulmonary artery in this group. Patients with the central shunt had a significant decrease in the diameter of all pulmonary artery segments. There were no significant differences when cross comparisons were made of the various pulmonary arterial segments in patients after a central shunt. Similar findings persisted in 19 patients from both groups who had a late postoperative echocardiogram (mean interval between studies = 271 days in the group of 10 patients with Blalock shunt and 167 days in the group of nine patients with a central shunt). In conclusion, the central shunt preserves pulmonary artery symmetry, which may be important in candidates for the Fontan operation in infancy.

Hypoplastic left heart syndrome: lack of correlation between preoperative demographic and laboratory findings and survival following palliative surgery.

To determine whether preoperative demographic and metabolic variables correlated with early or late survival following palliative surgery for hypoplastic left heart syndrome, we reviewed the charts of 89 patients operated upon from October 1984 to January 1987. The variables analyzed were age at operation, lowest preoperative pH and H2CO3, highest preoperative arterial oxygen saturation, the occurrence of a preoperative cardiorespiratory arrest, and location of birth relative to the surgical institution. The data were evaluated by chi-squared, multivariate, and life-table analyses to the end of the first postoperative year. None of the factors analyzed significantly correlated with either short-term (less than or equal to 30 days) or long-term (greater than 30 days) survival. Thus, neither demographic nor metabolic factors including prior cardiorespiratory arrest should be considered contraindications to surgical palliation for hypoplastic left heart syndrome.

The significance of tricuspid regurgitation in hypoplastic left-heart syndrome.

Palliation of hypoplastic left-heart syndrome involves use of the morphologic right ventricle as the systemic ventricle and the tricuspid valve (in cases of mitral atresia/stenosis) or the common atrioventricular valve (in cases of malaligned atrioventricular canal) as the systemic atrioventricular valve. To determine the relationship between tricuspid or common atrioventricular valve function and the ultimate outcome of palliative surgery, 100 patients with hypoplastic left-heart syndrome were evaluated preoperatively by Doppler echocardiography to determine the degree of tricuspid regurgitation. These patients were then followed serially to assess changes with time in the functional status of the tricuspid or common atrioventricular valve and to determine the correlation of tricuspid or common atrioventricular valve regurgitation with survival. We discovered that tricuspid or common atrioventricular valve regurgitation is common in hypoplastic left-heart syndrome. Thirty-seven percent of the patients had mild, 13% had moderate, and 3% had severe tricuspid or common atrioventricular valve regurgitation on their preoperative Doppler echocardiograms. Throughout the first 2 postoperative years most patients had no significant change in the degree of tricuspid or common atrioventricular valve regurgitation when findings were compared to those of the preoperative echocardiogram. Patients with moderate or severe tricuspid or common atrioventricular valve regurgitation preoperatively had a significant reduction in their survival when contrasted with patients with no or mild atrioventricular valve regurgitation. We therefore conclude that tricuspid or common atrioventricular valve competence is a significant factor in long-term survival after palliative surgery for hypoplastic left-heart syndrome. This function, however, appears to be unaffected by palliation and remains relatively constant over the first 2 postoperative years.

Fate of the pulmonic valve after proximal pulmonary artery-to-ascending aorta anastomosis for aortic outflow obstruction.

Transection of the main pulmonary artery and end-to-side anastomosis of the proximal pulmonary artery to the ascending aorta has been increasingly used in palliative surgery for cardiac malformations such as single ventricle with small outlet foramen (bulboventricular foramen) and hypoplastic left-heart syndrome. To evaluate pulmonary valve competence after this operation, we used color Doppler flow mapping to examine 45 survivors of pulmonary artery-to-ascending aorta anastomosis a median of 202 days postoperatively. Of 37 patients with hypoplastic left heart syndrome, mild regurgitation was detected in 9 (24%) and moderate regurgitation in 1 (3%). Of 8 with other lesions, mild regurgitation was observed in 2 and moderate regurgitation in 1. Seven of 11 patients imaged greater than or equal to 12 months postoperatively had regurgitation. In summary, one-fourth of survivors developed mild pulmonary regurgitation. Its presence should not be considered a contraindication to eventual application of Fontan's principle, although further follow-up appears warranted because the long-term fate of pulmonary valve function is not yet known.

Recent advances in congenital cardiac surgery.

Today, the natural history of virtually all congenital cardiac malformations can be significantly altered by reconstruction surgery. It now appears that repair is feasible in most, very early in life, with the potential for achieving the best long-term functional outcome and minimizing multiple operations.

Palliative reconstructive surgery for hypoplastic left heart syndrome.

From August, 1985, through August, 1987, 104 consecutive, nonselected neonates underwent palliation of hypoplastic left heart syndrome. The technique included pulmonary artery homograft augmentation of the diminutive ascending aorta and aortic arch, atrial septectomy, transection of the main pulmonary artery with patch closure of the distal main pulmonary artery, anastomosis of the proximal main pulmonary artery to the augmented ascending aorta, and a 4-mm, modified, right Blalock-Taussig (N = 21) or central (N = 83) shunt. There were 30 early and 11 late deaths. Early mortality was most commonly associated with hypoventilation. Complications included development of aortic arch obstruction (N = 11) and progressive hypoxemia (N = 11). Alterations in surgical techniques and perioperative management should permit continued improvement in early and long-term survival.