Jaime F. Vazquez-Jimenez

Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort

OBJECTIVE Although AF-induced atrial contractile dysfunction has significant clinical implications the underlying intracellular mechanisms are poorly understood. METHODS From the right atrial appendages of 59 consecutive patients undergoing mitral valve surgery (31 in SR, 28 in chronic AF) thin muscle preparations (diameter<0.7 mm) were isolated. Isometric force of contraction was measured in the presence of different concentrations of Ca(2+) and isoprenaline. To assess the function of the sarcoplasmic reticulum, the force-frequency relationship and the post-rest potentiation were studied. The myocardial density of the ryanodine-sensitive calcium release channel (CRC) of the sarcoplasmic reticulum was determined by [3H]ryanodine binding. Myocardial content of SR-Ca(2+)-ATPase (SERCA), phospholamban (Plb), calsequestrin (Cals) and the Na(+)/Ca(2+)-exchanger (NCX) were analyzed by Western blot analysis. Adenylyl cyclase activity was measured with a radiolabeled bioassay using [32P]ATP as a tracer. RESULTS In 72 muscle preparations of SR patients contractile force was 10.9+/-1.8 mN/mm(2) compared to 3.3+/-0.9 mN/mm(2) (n=48, P<0.01) in AF patients. The positive inotropic effect of isoprenaline was diminished but the stimulatory effect on relaxation and the adenylyl cyclase were not altered in AF patients. The force-frequency relation and the post-rest potentiation were enhanced in atrial myocardium of AF patients. The protein levels of CRC, SERCA, Plb, and Cals were not different between the two groups. In contrast, the Na(+)/Ca(2+)-exchanger was upregulated by 67% in atria of AF patients. CONCLUSIONS AF-induced atrial contractile dysfunction is not due to beta-adrenergic desensitization or dysfunction of the sarcoplasmic reticulum and thus is based on different cellular mechanisms than a ventricular tachycardia-induced cardiomyopathy. Instead, downregulation or altered function of the L-type Ca(2+)-channel and an increased Ca(2+) extrusion via the Na(+)/Ca(2+)-exchanger seem to be responsible for the depressed contractility in remodeled atria.

Twenty years experience with pediatric pacing: epicardial and transvenous stimulation

OBJECTIVE Permanent cardiac pacing in children and adolescents is rare and often occurs by means of epicardial pacing. Based on two decades of experience, operative and postoperative data of patients with epicardial and transvenous pacing were analyzed retrospectively. METHODS Between October 1979 and December 1998, 71 patients (mean age, 5.3+/-4.2, range, 1 day-16.2 years; mean body weight, 18+/-12; range, 8-56 kg) underwent permanent pacemaker implantation. Indications were sinus node dysfunction and atrio-ventricular block following surgery for congenital heart disease (69%), or congenital atrioventricular block (31%). Pacing was purely atrial (1.4%), purely ventricular (73%), ventricular with atrial synchronization (5. 6%), or atrioventricular synchronized (20%). Epicardial pacing was established in 49 (69%), transvenous in 22 (31%) patients. Follow-up was 3.4+/-3.8 years (epicardial) and 3.0+/-4.0 years (transvenous). RESULTS Epicardial leads were implanted in younger patients (mean age: 4.5 vs. 7.0 years, P<0.05) and preferably after surgery induced atrioventricular block (78 vs. 46%, P<0.05). The youngest patient with transvenous pacing was 1.3 years old (weight, 8.5 kg). At implantation epicardial ventricular stimulation threshold at 1.0 ms was 1.07+/-0.46 vs. 0.53+/-0.31 V (transvenous) (P<0.05). The age-adjusted rate of lead-related reoperations was significantly higher in patients with epicardial leads (P<0.05), mainly due to increasing chronic stimulation thresholds resulting in early battery depletion. In three patients who received steroid-eluting epicardial leads initial low thresholds persisted after five month to one years. In two patients with recurrent epicardial threshold increase, steroid-eluting epicardial leads led to good acute and chronic thresholds after nine to 15 month. Two post-operative death (2.8%) were probably due to a dysfunction of the (epicardial) pacing system. CONCLUSIONS Transvenous pacing in the pediatric population is associated with a lower acute stimulation threshold and a lower rate of lead-related complications. If epicardial pacing is necessary (e. g. small body weight, special intracardiac anatomy (e.g. Fontan), impossible access to superior caval vein), steroid-eluting leads may be considered.

Cantrell's syndrome : a challenge to the surgeon

We present a case of partial Cantrells syndrome with ventricular septal defect, left ventricular diverticulum, dextrorotation of the heart, an anterior diaphragmatic defect, and a midline supraumbilical abdominal wall defect with omphalocele. At the age of 20 months, the patient underwent a successful cardiac surgical procedure. To detect risk factors and to define therapeutic strategies, we analyzed the spectrum and the frequency of malformations described in 153 patients with Cantrells syndrome. Despite modern surgical standards, Cantrells syndrome represents a challenge to the surgeon because of the wide spectrum of anomalies, the severity of the abdominal and cardiac malformations, and the high mortality.

Influence of temperature during cardiopulmonary bypass on leukocyte activation, cytokine balance, and post-operative organ damage

This study examined the hypothesis that core temperature (T(o)) during cardiopulmonary bypass (CPB) influences the perioperative systemic inflammatory response and post-operative organ damage. Twenty-four pigs were assigned to a T(o) regimen during CPB: normothermia (T(o) 37 degrees C; n = 8), moderate hypothermia (T(o) 28 degrees C; n = 8), or deep hypothermia (T(o) 20 degrees C; n = 8). Perioperative leukocyte activation, endotoxin release, and production of tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL10) were examined with regard to post-operative organ damage, which was scored at histological examination of tissue probes of heart, lungs, liver, kidney, and ileum, taken 6 h after CPB. Total blood leukocyte count and TNFalpha plasma levels during CPB were significantly lower and IL10 levels were significantly higher in the moderate hypothermic group than in both other groups. Elastase activity, leukotriene B4-, and endotoxin levels were not affected by T(o) regimen. Moderate hypothermia was associated with the lowest histological organ damage score and normothermia with the highest. In all animals organ damage score for heart, lungs, and kidneys correlated significantly with TNFalpha levels at the end of CPB. Our data demonstrate a clear relationship between TNFalpha production during cardiac operations and post-operative multiple-organ damage. Moderate hypothermia, by stimulating IL10 synthesis and suppressing TNFalpha production during CPB, might provide organ protection.

Thromboembolic complications after Fontan procedures: comparison of different therapeutic approaches.

BACKGROUND Although patients after Fontan procedure have a high incidence of thromboembolic complications, anticoagulant therapy is not handled uniformly. We analyzed the frequency and clinical relevance of thromboembolism after Fontan procedure and compared different therapeutic approaches. METHODS From 1986 to 1998, 101 patients (mean age, 7.3 +/- 8.1 years) underwent Fontan type procedure (modified Fontan, n = 40; total cavopulmonary connection, n = 61). In 85 of 87 survivors, transthoracic echocardiography was performed; and in 31 transesophageal echocardiography and/or angiography was performed. Mean follow-up was 5.7 +/- 3.5 years. Three groups with different anticoagulant regimen were compared: group I without medication (n = 45), group II with acetylsalicylic acid therapy (n = 14) and group III with Coumadin (n = 26). RESULTS Thromboembolic events occurred in 13 of 85 patients (15.3%; 3.3 events/100 patient-years). Type of operation as well as other known risk factors had no influence on the rate of thromboembolism. Within the first postoperative year, seven of 13 events occurred. A second peak developed beyond 10 years of follow-up. Patients benefit significantly from Coumadin compared with those who did not receive any medication, with similar results in the entire population and the subgroup of patients with total cavopulmonary connection (log-rank, p = 0.031 and p = 0.033, respectively). With 4.2 events/100 patient-years, the cumulative event rate was substantially higher in group I than with 1.6 in group II and with 1.1 in group III. No relevant bleeding complications occurred. CONCLUSIONS Thromboembolism is frequent after Fontan procedure with a peak during the first postoperative year and another peak beyond 10 years of follow-up. Coumadin is the most effective prophylactic therapy in preventing thromboembolism. Therefore, we suggest initial oral anticoagulation therapy in patients with Fontan type operation.

Moderate Hypothermia During Cardiopulmonary Bypass Reduces Myocardial Cell Damage and Myocardial Cell Death Related to Cardiac Surgery

OBJECTIVES The goal of this study was to test the hypothesis that moderate hypothermia during cardiopulmonary bypass (CPB) provides myocardial protection by enhancing intra-myocardial anti-inflammatory cytokine balance. BACKGROUND Moderate hypothermia during experimental CPB stimulates production of interleukin-10 (IL10) and blunts release of tumor necrosis factor-alpha (TNFalpha). METHODS Twelve young pigs were assigned to a temperature (T degrees ) regimen during CPB: moderate hypothermia (T degrees : 28 degrees C; n = 6) and normothermia (T degrees : 37 degrees C; n = 6). Intra-myocardial TNFalpha- and IL10-messenger RNA were detected by competitive reverse transcriptase polymerase chain reaction and quantification of cytokine synthesis by Western blot. Levels of cardiac troponin I (cTnI) in cardiac lymph and in arterial and coronary venous blood were examined during and after CPB. Myocardial cell damage was assessed by histologic and ultrastructural anomalies of tissue probes taken 6 h after CPB. RESULTS Synthesis of IL10 was significantly higher, while that of TNFalpha was significantly lower, in pigs that were in moderate hypothermia during surgery than in the others. In contrast with normothermia, moderate hypothermia was also associated with significantly lower cumulative cardiac lymphatic flow during and after CPB, significantly lower lymphatic cTnI concentrations after CPB, significantly lower percentages of myocardial cell necrosis and a significantly lower score of ultrastructural anomalies of myocardial cells. While the percentage of apoptotic cells was not different between groups, the apoptosis/necrosis ratio tended to be higher in animals that were in moderate hypothermia during surgery. In all animals, TNFalpha synthesis correlated positively while IL10 production correlated negatively with necrosis and total cell death, respectively. CONCLUSIONS Our results suggest that moderate hypothermia during CPB provides myocardial protection by enhancing intra-myocardial anti-inflammatory cytokine balance.

Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects

OBJECTIVES We sought to test the hypothesis that cytokines would be expressed in the myocardium of infants with congenital cardiac defects and to identify the signaling pathways involved. BACKGROUND Mechanical stress upregulates pro-inflammatory cytokines in the myocardium. METHODS Fifteen infants with tetralogy of Fallot (TOF) (n = 7) or with ventricular septal defects (VSDs) (n = 8) were investigated. Concentrations of pro- and anti-inflammatory cytokines and of the inducible nitric oxide synthase (iNOS) were measured by enzyme-linked immunosorbent assay and/or Western blotting in the right ventricular myocardium taken during cardiac surgery. Activation of the nuclear factor-kappa-B (NF-kappa-B) and p38 mitogen-activated protein kinase (MAPK) pathways was assessed by electrophoretic mobility shift assay with supershift and/or Western blotting, respectively. RESULTS The pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1-beta, and IL-6 and the anti-inflammatory cytokine IL-10 were detected in the myocardium of all patients. Concentrations of the pro-inflammatory cytokines and also of phosphorylated p38 MAPK were higher in patients with TOF than in those with VSD and correlated with the degree of pressure overload of the right ventricle. Levels of phosphorylated I-kappa-B-alpha, iNOS, and IL-10 were similar in patients with TOF and in those with VSD. CONCLUSIONS Our results show intramyocardial synthesis of pro-inflammatory cytokines in infants with congenital cardiac defects. This is associated with activation of both the NF-kappa-B and p38 MAPK pathways. The latter could be particularly important for the transduction of mechanical signals in the infants myocardium. Synthesis of IL-10 indicates an intramyocardial anti-inflammatory potential in this age group.

Aortopexy in severe tracheal instability: short-term and long-term outcome in 29 infants and children

BACKGROUND Tracheal instability is a hazardous situation after operation for esophageal atresia. In cases with life-threatening apneas, aortopexy is a therapeutic option. To assess efficacy, short-term and long-term outcome was analyzed retrospectively. METHODS Between 1985 and 2000, 29 patients (age, 1.5 months to 5.2 years) were operated on. A flaccid trachea after operation for esophageal atresia was the cause for life-threatening apneas in 27, and there was external vascular compression in 2 patients. The operative procedure consisted of ventropexy of the aortic arch to the sternum and ventral thoracic wall. RESULTS There was neither early nor late mortality. A reversible lesion of the phrenic nerve was observed in 2 patients, a pneumothorax in 3, and secondary wound healing in 1. In all but 1 patient symptoms improved markedly or disappeared within days or within the first 3 months postoperatively. An increased susceptibility to respiratory infections was observed in long-term follow-up. CONCLUSIONS Aortopexy can be performed with no mortality and low morbidity. Aortopexy is effective to prevent further life-threatening apneas, but does not prevent an increased susceptibility to respiratory infections.

Allergy to Pacemaker Silicone Compounds: Recognition and Surgical Management

Silicone is a widely used biomaterial. Contact allergy, particularly to silicone components of pacemaker coatings, is uncommon. We present a 12-year-old girl with a history of complex congenital heart disease and acquired complete heart block excluding transvenous lead placement. Contact allergy to silicone led to multiple surgical interventions until the etiology for recurrent pacemaker wound complications was discovered. The key to diagnosis was a specific manufacturers patch test. Complete removal of the former pacing system and placement of custom-made silicone free pacemaker components and epicardial use of silicone free transvenous leads were essential for successful therapy.

Intrahepatic synthesis of tumor necrosis factor-α related to cardiac surgery is inhibited by interleukin-10 via the Janus kinase (Jak)/signal transducers and activator of transcription (STAT) pathway

ObjectivesTo identify the signaling pathways involved in the anti-inflammatory shift of the cytokine balance due to hypothermia during cardiopulmonary bypass. DesignExperimental animal study. SettingDepartment of experimental surgery of a university hospital. SubjectsYoung pigs. InterventionsAnimals underwent normothermic (37°C) or hypothermic (28°C) cardiopulmonary bypass (n = 6 each). Samples of liver tissue were taken before and 6 hrs after cardiopulmonary bypass. Measurements and Main ResultsIntrahepatic expression of tumor necrosis factor-&agr;, interleukin-10, inducible nitric oxide synthase, and suppressor of cytokine signaling-3 was detected by reverse transcriptase polymerase chain reaction and/or Western blotting. Concentrations of the inhibitory protein of nuclear factor-&kgr;B, I&kgr;B, and of the signal transducer and activator of transcription (STAT)-3 were measured by Western blotting. The DNA-binding activity of nuclear factor-&kgr;B and STAT-3 was assessed by electrophoretic mobility shift and supershift assays. Liver cell necrosis and apoptosis were assessed by histology and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, respectively. Pigs operated on in hypothermia showed significantly higher intrahepatic concentrations of interleukin-10 and lower concentrations of tumor necrosis factor-&agr; than the others. They also showed a lower percentage of hepatic cell necrosis but not of apoptosis. This anti-inflammatory reaction observed in the hypothermic group was associated with a higher expression of suppressor of cytokine signaling-3 and with increased activation of STAT-3. Activation of nuclear factor-&kgr;B and expression of inducible nitric oxide synthase, however, were not significantly different between both groups. ConclusionOur results show that hypothermia during cardiopulmonary bypass up-regulates interleukin-10 via STAT-3 activation, which in turn leads to the attenuation of tumor necrosis factor-&agr; expression and to hepatic protection.