Biomechanical Analysis of Age-Dependent Changes in Fontan Power Loss.

The hemodynamics in Fontan patients with single ventricles rely on favorable flow and energetics, especially in the absence of a subpulmonary ventricle. Age-related changes in energetics for extracardiac and lateral tunnel Fontan procedures are not well understood. Vorticity (VOR) and viscous dissipation rate (VDR) are two descriptors that can provide insights into flow dynamics and dissipative areas in Fontan pathways, potentially contributing to power loss. This study examined power loss and its correlation with spatio-temporal flow descriptors (vorticity and VDR). Data from 414 Fontan patients were used to establish a relationship between the superior vena cava (SVC) to inferior vena cava (IVC) flow ratio and age. Computational flow modeling was conducted for both extracardiac conduits (ECC, n = 16) and lateral tunnels (LT, n = 25) at different caval inflow ratios of 2, 1, and 0.5 that corresponded with ages 3, 8, and 15+. In both cohorts, vorticity and VDR correlated well with PL, but ECC cohort exhibited a slightly stronger correlation for PL-VOR (>0.83) and PL-VDR (>0.89) than that for LT cohort (>0.76 and > 0.77, respectively) at all ages. Our data also suggested that absolute and indexed PL increase (p < 0.02) non-linearly as caval inflow changes with age and are highly patient-specific. Comparison of indexed power loss between our ECC and LT cohort showed that while ECC had a slightly higher median PL for all 3 caval inflow ratio examined (3.3, 8.3, 15.3) as opposed to (2.7, 7.6, 14.8), these differences were statistically non-significant. Lastly, there was a consistent rise in pressure gradient across the TCPC with age-related increase in IVC flows for both ECC and LT Fontan patient cohort. Our study provided hemodynamic insights into Fontan energetics and how they are impacted by age-dependent change in caval inflow. This workflow may help assess the long-term sustainability of the Fontan circulation and inform the design of more efficient Fontan conduits.

Impact of Age-related change in Caval Flow Ratio on Hepatic Flow Distribution in Fontan.

Background: The Fontan operation is a palliative technique for patients born with single ventricle heart disease. The superior vena cava (SVC), inferior vena cava (IVC), and hepatic veins are connected to the pulmonary arteries in a total cavopulmonary connection by an extracardiac (EC) conduit or a lateral tunnel (LT) connection. A balanced hepatic flow distribution (HFD) to both lungs is essential to prevent pulmonary arteriovenous malformations and cyanosis. HFD is highly dependent on the local hemodynamics. Objective: The effect of age-related changes in caval inflows on HFD was evaluated using cardiac MRI (CMR) data and patient-specific computational fluid dynamics (CFD) modeling. Methods: SVC and IVC flow from 414 Fontan patients were collected to establish a relationship between SVC:IVC flow ratio and age. CFD modeling was performed in 60 (30 EC and 30 LT) patient models to quantify the HFD that corresponded to patient ages of 3, 8, and 15 years, respectively. Results: SVC:IVC flow ratio inverted at ∼8 years of age, indicating a clear shift to lower body flow predominance. Our data showed that variation of HFD in response to age-related changes in caval inflows (SVC:IVC = 2,1, and 0.5 corresponded to ages 3, 8, and 15+ respectively) was not significant for EC but statistically significant for LT cohorts. For all three caval inflow ratios, a positive correlation existed between the IVC flow distribution to both the lungs and the HFD. However, as the SVC:IVC ratio changed from 2→0.5 (age 3→15+), the correlation's strength decreased from 0.87→0.64, due to potential flow perturbation as IVC flow momentum increased. Conclusion: Our analysis provided quantitative insights into the impact of the changing caval inflows on Fontan's long-term HFD, highlighting the importance of including SVC:IVC variations over time to understand Fontan's long-term hemodynamics. These findings broaden our understanding of Fontan hemodynamics and patient outcomes. Clinical Perspective: With improvement in standard of care and management of single ventricle patients with Fontan physiology, the population of adults with Fontan circulation is increasing. Consequently, there is a clinical need to comprehend the impact of patient growth on Fontan hemodynamics. Using CMR data, we were able to quantify the relationship between changing caval inflows and somatic growth. We then used patient-specific computational flow modeling to quantify how this relationship affected the distribution of long-term hepatic flow in extracardiac and lateral tunnel Fontan types. Our findings demonstrated the significance of including SVC:IVC changes over time in CFD modeling to learn more about the long-term hemodynamics of Fontan. Fontan surgical approaches are increasingly planned and optimized using computational flow modeling. For a patient undergoing a Fontan procedure, the workflow presented in this study that takes into account the variations in Caval inflows over time can aid in predicting the long-term hemodynamics in a planned Fontan pathway.

Prenatal diagnosis of transposition of the great arteries over a 20-year period: improved but imperfect.

OBJECTIVE: To evaluate temporal trends in the prenatal diagnosis of transposition of the great arteries with intact ventricular septum (TGA/IVS) and its impact on neonatal morbidity and mortality. METHODS: We included in this study cohort newborns with TGA/IVS who were referred for surgical management to our center over a 20-year period (1992-2011). The study period was divided into five 4-year periods and the primary outcome was rate of prenatal diagnosis. Secondary outcomes included neonatal preoperative status and perioperative survival. RESULTS: Of the 340 patients with TGA/IVS, 81 (23.8%) had a prenatal diagnosis. The rate of prenatal diagnosis increased over the study period, from 6% in 1992-1995 to 41% in 2008-2011 (P < 0.001). Compared to patients with a postnatal diagnosis, balloon atrial septostomy (BAS) was performed earlier in patients with a prenatal diagnosis (0 days after delivery vs 1 day after delivery, respectively; P < 0.001) and fewer prenatally diagnosed neonates required mechanical ventilation (55.6% vs 68.0%; P = 0.03). Between patients with a prenatal or postnatal diagnosis of TGA/IVS, there were no statistically significant differences in the incidence of preoperative acidosis (16.0% vs 25.5%; P = 0.1), need for preoperative extracorporeal membrane oxygenation (2.5% vs 2.7%; P = 1.0) or mortality (one preoperative and no postoperative deaths among prenatally diagnosed patients compared with four preoperative and six postoperative deaths among postnatally diagnosed patients). CONCLUSIONS: The prenatal detection rate of TGA/IVS has improved but still remains below 50%, suggesting the need for strategies to increase detection rates. The mortality rate was not statistically significantly different between prenatally and postnatally diagnosed patients, however, there were significant preoperative differences with regard to earlier BAS and fewer neonates that required mechanical ventilation. Ongoing work is required to ascertain whether prenatal diagnosis confers long-term benefits.

Biventricular repair in patients with heterotaxy syndrome.

OBJECTIVE: Complex intracardiac and extracardiac anatomy is often confronted during biventricular repair in patients with heterotaxy syndrome. We examined factors affecting surgical outcomes in these patients. METHODS: Between January 1990 and July 2007, 371 patients received a diagnosis of heterotaxy syndrome; 91 (91/371, 24.5%) underwent biventricular repair. Left atrial isomerism was present in 73% (66/91) and right atrial isomerism in 10% (9/91), with indeterminate atrial anatomy in 17% (16/91). Median age at biventricular repair was 6.8 months (5 days to 22.3 years). Systemic venous anomalies were present in 75 patients, pulmonary venous anomalies in 26, and endocardial cushion defects in 36. Transposition complexes were present in 15 patients with atrioventricular discordance in 10; 8 underwent double switch, 2 received a physiologic repair, 2 underwent arterial switch, and 3 underwent the Rastelli operation. Other conotruncal anomalies included double-outlet right ventricle in 10 patients, tetralogy of Fallot in 3, and hemitruncus in 2. Separation of systemic from pulmonary venous return included intra-atrial baffling in 48 patients and extracardiac grafting in 2. Combined lesions were common, occurring in 99% (90/91). Statistical analysis with Kaplan-Meier and Cox proportional hazards models were performed. RESULTS: Average follow-up was 44.9 +/- 57.5 months (3 days to 189.3 months). Kaplan-Meier estimated survival was 93.4% at 10 years; unbalanced complete atrioventricular canal was the only risk factor for mortality (P = .006). Subsequent procedures were common with a 10-year freedom from reoperation or reintervention of 38% +/- 7.5%. Arrhythmias occurred in 36 (39.6%) patients; bradyarrhythmia in 27 (29.7%) and tachyarrhythmia in 15 (16.5%). Freedom from any arrhythmia was 53.9% +/- 6.7% at 10 years. CONCLUSIONS: Excellent survival for patients with heterotaxy undergoing biventricular repair can be expected, even for multiple, complex lesions. Reintervention is common, and arrhythmia is a long-term concern. This experience shows that patients with heterotaxy syndrome and complex cardiac anatomy can be considered for biventricular repair. Patients with unbalanced complete atrioventricular canal are a high-risk group for which selection criteria are particularly important.

Ventricular size and function assessed by cardiac MRI predict major adverse clinical outcomes late after tetralogy of Fallot repair.

BACKGROUND: Factors associated with impaired clinical status in a cross-sectional study of patients with repaired tetralogy of Fallot (TOF) have been reported previously. OBJECTIVES: To determine independent predictors of major adverse clinical outcomes late after TOF repair in the same cohort during follow-up evaluated by cardiac magnetic resonance (CMR). METHODS: Clinical status at latest follow-up was ascertained in 88 patients (median time from TOF repair to baseline evaluation 20.7 years; median follow-up from baseline evaluation to most recent follow-up 4.2 years). Major adverse outcomes included (a) death; (b) sustained ventricular tachycardia; and (c) increase in NYHA class to grade III or IV. RESULTS: 22 major adverse outcomes occurred in 18 patients (20.5%): death in 4, sustained ventricular tachycardia in 8, and increase in NYHA class in 10. Multivariate analysis identified right ventricular (RV) end-diastolic volume Z >or=7 (odds ratio (OR) = 4.55, 95% confidence interval (CI) 1.10 to 18.8, p = 0.037) and left ventricular (LV) ejection fraction <55% (OR = 8.05, 95% CI 2.14 to 30.2, p = 0.002) as independent predictors of outcome with an area under the receiver operator characteristic curve of 0.850. LV ejection fraction could be replaced by RV ejection fraction <45% in the multivariate model. QRS duration >or=180 ms also predicted major adverse events but correlated with RV size. CONCLUSIONS: In this cohort, severe RV dilatation and either LV or RV dysfunction assessed by CMR predicted major adverse clinical events. This information may guide risk stratification and therapeutic interventions.

Vascular endothelial growth factor delays onset of failure in pressure-overload hypertrophy through matrix metalloproteinase activation and angiogenesis.

OBJECTIVE: Pressure-overload hypertrophy is associated with decreased capillary density in myocardium resulting in impaired substrate delivery. Treatment of hypertrophied hearts with vascular endothelial growth factor (VEGF) induces angiogenesis. Since angiogenesis is associated with extracellular matrix degradation, we sought to determine whether VEGF induced angiogenesis in hypertrophy required matrix metalloproteinases (MMP) activation. METHODS: Newborn rabbits underwent aortic banding. Progression of hypertrophy (mass-to-volume (M/V) ratio) and mid-wall contractility index was monitored by echocardiography. At 4 and 6 weeks, VEGF (2 microg/kg), vehicle or VEGF combined with GM6001 (5 mg/kg), a MMP inhibitor, was administered intrapericardially. CD-31 (indicator of angiogenesis), MMP-2, MT1-MMP and TIMPs (endogenous MMP inhibitors) expression were measured by immunoblotting. MMP-2 activity was determined by gelatin zymography. RESULTS: Untreated hypertrophied hearts progressed to ventricular dilatation at 7 wks (M/V ratio: 0.75 +/- 0.07), but compensatory hypertrophy was maintained with VEGF (0.91 +/- 0.07; p < 0.05). LV contractility declined in untreated hearts from -0.41 +/- 0.9 (5 wks) to -0.73 +/- 0.5 (7 wks; p < 0.05) but remained normal with VEGF (+1.61 +/- 0.6 vs. +0.47 +/- 0.2). MMP-2 expression and activity were significantly elevated in VEGF treated hypertrophied hearts (p < 0.05) and were blocked by concomitant administration of GM6001. VEGF induced neovascularization was inhibited by addition of GM6001. MT1-MMP showed a trend to higher levels in VEGF treated hearts. TIMPs were unchanged in all three groups. CONCLUSIONS: Exogenous VEGF and resultant MMP-2 activation leads to increased capillary formation in severe hypertrophy, preventing progression to ventricular dilation and dysfunction. VEGF and the associated MMP-2 activation play an important and potentially therapeutic role in vascular remodeling of hypertrophied hearts.

Protein kinase C and myocardial calcium handling during ischemia and reperfusion: lessons learned using Rhod-2 spectrofluorometry.

OBJECTIVE: We sought to assess myocardial Ca (2+) handling and excitation-contraction coupling in surgically relevant models of ischemia-reperfusion injury and to clarify the importance of protein kinase C (PKC) for cardioprotection. METHODS: Experimentally, surgical ischemia and reperfusion can only be mimicked in intact perfused heart models. We introduced the long-wavelength fluorescent Ca (2+) indicator Rhod-2 for real-time recording of cytosolic Ca (2+) transients in Langendorff-perfused rabbit, rat, and mouse hearts, and utilized it to study the impact of PKC on myocardial Ca (2+) handling during ischemia and reperfusion. RESULTS: We first established that the dissociation constant for Rhod-2 and Ca (2+) must be adjusted to account for changes in pH and temperature during ischemia and reperfusion. Based on this method, we determined the time-course and extent of cytosolic Ca (2+) accumulation during myocardial ischemia, which is associated with translocation of the PKC isoforms alpha and epsilon between the cytosolic and particulate compartments in cardiomyocytes. The PKC translocation is mediated by activation of phosphatidyl-inositol-specific phospholipase C (PI-PLC), and represents a cardioprotective mechanism. Finally, we studied the mechanism of action of PKC and found that it both limits the accumulation of cytosolic Ca (2+) during reperfusion and attenuates contractile protein Ca (2+) sensitivity via phosphorylation of troponin I. CONCLUSIONS: Rhod-2 spectrofluorometry is a valuable tool for assessment of cytosolic Ca (2+) in surgically relevant experimental models and can aid the development of more effective methods for myocardial protection.

Rapid endotoxin-induced alterations in myocardial calcium handling: obligatory role of cardiac TNF-alpha.

BACKGROUND: Bacterial endotoxin (lipopolysaccharide [LPS]) induces septic shock and depressed myocardial contractility. The mechanism of LPS-mediated cardiac dysfunction remains controversial. We hypothesized that LPS exerts significant effects on myocardial excitation-contraction coupling by rapid stimulation of tumor necrosis factor alpha (TNF-alpha) expression in the heart. METHODS: Isolated rat hearts were studied with and without recirculation of cell-free perfusate. The effects of LPS, exogenous TNF-alpha, anti-TNF-alpha antibody, and ceramidase inhibition were examined. Measurements included myocardial uptake of LPS, left ventricular contractility, myocardial oxygen consumption, intracellular calcium [Ca2+] cycling, and TNF-alpha concentrations in coronary perfusate and myocardium. RESULTS: Lipopolysaccharide was rapidly taken up by the perfused heart. With non-recirculating perfusion, LPS had no effect on contractility, oxygen consumption, coronary vascular resistance, or intracellular free calcium concentration ([Ca2+]i). However, with recirculating perfusion contractility was significantly impaired after 30 min of LPS, associated with lower [Ca2+]i levels and attenuated systolic rise in [Ca2+]i. Significant amounts of TNF-alpha accumulated in recirculating perfusate and myocardial tissue from LPS-perfused hearts. Ceramidase inhibition or neutralizing anti-TNF-alpha antibody inhibited the effects of LPS on contractility and [Ca2+]i. Recombinant rat TNF-alpha mimicked the LPS effects with faster onset. CONCLUSIONS: Lipopolysaccharide exerts rapid, negative inotropic effects on the isolated whole rat heart. The reduction in contractility is associated with depressed intracellular calcium cycling. In response to LPS, TNF-alpha is rapidly released from the heart and mediates the effects of LPS via the sphingomyelinase pathway. The present study for the first time directly links LPS-stimulated TNF-alpha production, abnormal calcium cycling, and decreased contractility in intact hearts.

Insulin-like growth factor-1 improves postischemic recovery in hypertrophied hearts.

BACKGROUND: Severe myocardial hypertrophy is associated with decreased tolerance to ischemia compared with normal hearts. We hypothesized that treatment with insulin-like growth factor-1 (IGF-1) improves postischemic myocardial recovery by increasing glucose uptake during ischemia and early reperfusion. METHODS: Banding of the thoracic aorta in 10-day-old rabbits created pressure-overload hypertrophy. At 5 weeks of age (severe hypertrophy), aortic banded and sham-operated isolated hearts underwent 30 minutes of normothermic ischemia with or without IGF-1 in the preischemic perfusate and cardioplegia followed by 30 minutes of reperfusion. RESULTS: 2-Deoxyglucose uptake (31P-NMR) and phosphatidylinositol-3-kinase (PI-3-kinase) activity were significantly lower in hypertrophied hearts. Insulin-like growth factor-1 restored glucose uptake and PI-3-kinase activity to control levels in the hypertrophied hearts and both effects were blocked by wortmannin (a PI-3-kinase inhibitor). Postischemic developed pressure was significantly improved in IGF-1-treated hearts compared with untreated or IGF-1+wortmannin-treated hypertrophied hearts. CONCLUSIONS: These data indicate that IGF-1 improves glucose uptake and tolerance to ischemia in hypertrophied hearts. Myocardial IGF-1 effects are likely mediated through a PI-3-kinase-dependent pathway.

Inhibition of tumor necrosis factor-alpha improves postischemic recovery of hypertrophied hearts.

BACKGROUND: Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of heart failure and ischemia-reperfusion injury. Effects of TNF-alpha are initiated by membrane receptors coupled to sphingomyelinase signaling and include altered metabolism and calcium cycling, contractile dysfunction, and cell death. We postulate that pressure-overload hypertrophy results in increased myocardial TNF-alpha expression and that it contributes to decreased contractility in hypertrophied infant hearts subjected to ischemia-reperfusion. METHODS AND RESULTS: Neonatal rabbits underwent aortic banding to induce LV hypertrophy. Myocardial TNF-alpha protein expression increased progressively with LV hypertrophy. Serum TNF-alpha was detected only after the onset of heart failure. Before onset of ventricular dilatation and heart failure (determined by serial echocardiograms), hearts from aortic banded and age-matched control rabbits were perfused in the Langendorff mode and subjected to 45 minutes of ischemia and 30 minutes of reperfusion. Postischemic recovery was impaired in hypertrophied hearts, but addition of neutralizing anti-rabbit TNF-alpha antibody to cardioplegia and perfusate solutions restored postischemic function. This effect was mimicked by treatment with the ceramidase inhibitor N-oleoyl ethanolamine. TNF-alpha inhibition also was associated with faster postischemic recovery of phosphocreatine, ATP, and pH as assessed by (31)P nuclear magnetic resonance spectroscopy. Intracellular calcium handling, measured by Rhod 2 spectrofluorometry, demonstrated lower diastolic calcium levels and higher systolic calcium transients in anti-TNF-alpha treated hearts. CONCLUSIONS: TNF-alpha is expressed in myocardium during compensated pressure-overload hypertrophy and contributes to postischemic myocardial dysfunction. Inhibition of TNF-alpha signaling significantly improves postischemic contractile function, myocardial energetics, and intracellular calcium handling.

Optimal surgical approach for repair of aortopulmonary window.

BACKGROUND: This is a review of the experience over 26 year in a single institution with surgical repair of aortopulmonary window. METHODS: Between July 1973 and March 1999, 38 patients underwent surgery for aortopulmonary window at a median age of 5 weeks, and with a median weight of 3.9 kg. Median follow-up was 6.6 years, with a range from 0.8 to 26 years. Additional defects were present in 25 (65%) patients, including interruption of the aortic arch in 7, tetralogy of Fallot in 7, ventricular septal defect in 5, functionally univentricular anatomy in 3, aortic coarctation in 2, and anomalous origin of a coronary artery in 1. We approached via an aortotomy in 45%, an incision through the defect in 31%, and using a pulmonary arteriotomy in 24% of patients. Closure was achieved using a single patch in 30 patients (79%). RESULTS: There were 3 (7.9%) in-hospital deaths. Actuarial patient survival was 88% at 10 years. Three patients required reinterventions for stenoses of the great arteries. Freedom from any reintervention was 70% at 10 years. By multivariate analysis, the approach through a pulmonary arteriotomy was shown to result in a higher need for reintervention (p = 0.01). CONCLUSIONS: Repair of aortopulmonary window can be done with excellent results. A pulmonary arteriotomy should be avoided.

Echocardiographic characteristics and outcome of straddling mitral valve.

OBJECTIVES: This study sought to characterize the echocardiographic features of straddling mitral valve (SMV) and to determine its surgical implications and midterm outcome in a large clinical cohort. BACKGROUND: Despite a relatively large body of literature on the postmortem anatomy of SMV, there is a paucity of information regarding its echocardiographic features, surgical implications and preoperative predictors of outcome. METHODS: A retrospective review identified 46 patients with SMV between 1982 and 1999 who underwent echocardiography and surgery and had follow-up data. A detailed review of the echocardiograms, surgical reports and all pertinent records was undertaken. RESULTS: Review of the echocardiograms revealed a widely varying anatomy among the study patients. However, four distinct groups with relatively uniform morphologic features could be distinguished on the basis of segmental analysis. Cardiac malposition associated with right ventricular hypoplasia, superior-inferior ventricles and criss-cross atrioventricular relations were common among patients with [S,D,L] (S = visceroatrial situs solitus, D = D-ventricular loop, L = L-malposition of the great arteries) (n = 6) and [S,L,D] (n = 5) segmental combinations but were rare among patients with [S,D,D] (n = 26) and [S,L,L] (n = 9) combinations. Surgical management consisted of a functional single-ventricle palliation in 38 patients (83%) and biventricular repair in 8 patients (17%). Overall mortality was 22%, but none of the seven patients who were operated on during the cohort's last five years (1994 to 1999) has died. By multivariate analysis, noncommitted ventricular septal defect was the strongest independent predictor of death (relative risk = 10.2), followed by multiple ventricular septal defects (relative risk = 4.7). CONCLUSIONS: This study demonstrates that echocardiography provides detailed noninvasive imaging of the complex anatomic features of SMV and its associated anomalies. Anatomic classification based on segmental analysis allows the distinction of four groups with more uniform morphologic features. Although a biventricular approach is feasible in selected patients, a functional univentricular palliation is indicated in those with major straddling and markedly hypoplastic ventricles.

Long-term results after early primary repair of tetralogy of Fallot.

OBJECTIVE: Early primary repair of tetralogy of Fallot has been routinely performed at Children's Hospital, Boston, since 1972. We evaluated the long-term outcome of this treatment strategy including the influence of a transannular patch. METHODS: Fifty-seven patients less than 24 months of age (median 8 months) underwent primary repair of tetralogy of Fallot between January 1972 and December 1977. Thirty-one patients had a transannular patch. Survival and freedom from reintervention were determined by the Kaplan-Meier method with 95% confidence intervals. RESULTS: There were 8 early deaths, and 1 patient died 24 years after initial repair. Recent follow-up was obtained for 45 of the 49 long-term survivors (92%). Median follow-up was 23.5 years. Ten patients underwent reintervention, 8 of whom underwent relief of right ventricular outflow tract obstruction. Right ventricular outflow tract obstruction occurred in 6 patients without a transannular patch and 2 with a transannular patch (33% vs 6%, P =.04). One pulmonary valve replacement was performed at another institution 20 years after the repair. Forty-one long-term survivors were in New York Heart Association class I and 4 were in class II. Actuarial survival was 86% at 20 years (95% confidence intervals = 80%-92%). Freedom from reintervention was 93% at 5 years (95% confidence intervals = 87%-99%) and 79% at 20 years (95% confidence intervals = 70%-86%). No significant differences were found between patients with and without a transannular patch (survival, P =.34; freedom from reintervention, P =.09, log-rank tests). CONCLUSIONS: Long-term survival is excellent and the freedom from reintervention is satisfactory after early primary repair of tetralogy of Fallot in the 1970s. Use of a transannular patch does not reduce late survival and is associated with a lower incidence of right ventricular outflow tract obstruction.

Situs inversus totalis and corrected transposition of the great arteries [I,D,D] in association with a previously unreported vascular ring.

A 3-month-old girl with "noisy breathing" was found to have situs inversus totalis, corrected transposition of the great arteries [I,D,D], and a vascular ring. The ring was composed of a left aortic arch with normal branching pattern and a right ligamentum arteriosum that extended from a diverticulum off the descending aorta and coursed retroesophageal and to the right to join the pulmonary artery. There was no circumflex component of the aorta or aberrant subclavian artery. The descending aorta was left sided. Compression of the esophagus and trachea was noted on contrast esophagram, magnetic resonance imaging (MRI), and at the time of surgery to divide the vascular ring. In association with her corrected transposition, the patient also was shown to have a mild Ebstein's deformity of the right-sided (systemic) atrioventricular valve and electrocardiographic evidence of Wolfe-Parkinson-White syndrome. The combination of situs inversus totalis, corrected transposition of the great arteries [I,D,D], and an aortic arch anomaly has not been previously reported. In addition, the aortic arch anomaly suggested by MRI imaging and confirmed at surgery has previously only been postulated to exist but to our knowledge never reported.

Post-ischemic PKC inhibition impairs myocardial calcium handling and increases contractile protein calcium sensitivity.

OBJECTIVE: Protein kinase C (PKC) activation impairs contractility in the normal heart but is protective during myocardial ischemia. We hypothesized that PKC remains activated post-ischemia and modulates myocardial excitation-contraction coupling during early reperfusion. METHODS: Langendorff-perfused rabbit hearts where subjected to 25 min unmodified ischemia and 30 min reperfusion. Total PKC activity was measured, and the intracellular translocation pattern of PKC-alpha, -delta, -epsilon, and -eta assessed by immunohistochemistry and fractionated Western immunoblotting. The PKC-inhibitors chelerythrine and GF109203X were added during reperfusion and also given to non-ischemic hearts. Measurements included left ventricular function, intracellular calcium handling measured by Rhod-2 spectrofluorometry, myofibrillar calcium responsiveness in beating and tetanized hearts, and metabolic parameters. RESULTS: Total PKC activity was increased at end-ischemia and remained elevated after 30 min of reperfusion. The translocation pattern indicated PKC-epsilon as the main active isoform during reperfusion. Post-ischemic PKC inhibition affected mainly diastolic relaxation, with lesser effect on contractility. Both PKC inhibitors increased the Ca(2+) responsiveness of the myofilaments as indicated by a leftward shift of the calcium-to-force relationship and increased maximum calcium activated tetanic pressure. Diastolic Ca(2+) removal was delayed and the post-ischemic [Ca(2+)](i) overload further exacerbated. Depressed systolic function was associated with a lower amplitude of [Ca(2+)](i) transients. CONCLUSION: PKC is activated during ischemia and remains activated during early reperfusion. Inhibition of PKC activity post-ischemia impairs functional recovery, delays diastolic [Ca(2+)](i) removal, and increases Ca(2+) sensitivity of the contractile apparatus, resulting in impaired diastolic relaxation. Thus, post-ischemic PKC activity may serve to restore post-ischemic Ca(2+) homeostasis and attenuate contractile protein calcium sensitivity during the period of post-ischemic [Ca(2+)](i) overload.

Surgery for coarctation of the aorta in infants weighing less than 2 kg.

BACKGROUND: Low- and very low-birth weight infants are now candidates for reparative cardiac surgery. Outcomes after coarctation repair have not been characterized in this patient population. METHODS: We performed a retrospective review of 18 consecutive neonates less than 2 kg who underwent repair of aortic coarctation between August 1990 and December 1999. RESULTS: Median weight was 1,330 g, and median gestational age was 31 weeks. A ventricular septal defect was present in 5 patients, and Shone's complex in 4. Sixteen patients had resection and end-to-end anastomosis, and 2 had resection and subclavian flap. Median clamp time was 15.5 minutes. One patient died during hospitalization. Two patients died late postoperatively (5-year estimated survival 80%). Mean follow-up was 28.5 months. Eight patients (44%) had a residual or recurrent coarctation, 5 underwent balloon dilation, and 3 underwent reoperation. Freedom from reintervention for recoarctation was 60% at 5 years. Shone's complex or a hypoplastic arch was an independent risk factor for decreased survival (p < 0.001). Very low birth weight was a multivariate predictor for increased risk of recoarctation (p = 0.01). CONCLUSIONS: Coarctation repair in less than 2-kg premature non-Shone's infants can be performed with a low mortality. The rate of recoarctation is higher in the very low-birth weight infants, but can be managed with low risk.

Lipopolysaccharide internalization activates endotoxin-dependent signal transduction in cardiomyocytes.

We tested the hypothesis that bacterial lipopolysaccharide (LPS) must be internalized to facilitate endotoxin-dependent signal activation in cardiac myocytes. Fluorescently labeled LPS was used to treat primary cardiomyocyte cultures, perfused heart preparations, and the RAW264.7 macrophage cell line. Using confocal microscopy and spectrofluorometry, we found that LPS was rapidly internalized in cardiomyocyte cultures and Langendorff-perfused hearts. Although LPS uptake was also observed in macrophages, only a fraction of these cells were found to internalize endotoxin to the extent seen in cardiomyocytes. Colocalization experiments with organelle or structure-specific fluorophores showed that LPS was concentrated in the Golgi apparatus, lysosomes, and sarcomeres. Similar intracellular localization was demonstrated in cardiomyocytes by transmission electron microscopy using gold-labeled LPS. The internalization of LPS was dependent on endosomal trafficking, because an inhibitor of microfilament reorganization prevented uptake in both cardiomyocytes and whole hearts. Inhibition of endocytosis specifically restricted early activation of extracellular signal-regulated kinase proteins and nuclear factor-kappaB as well as later tumor necrosis factor-alpha production and inducible nitric oxide synthase expression. In conclusion, we have demonstrated that bacterial endotoxin is internalized and transported to specific intracellular sites in heart cells and that these events are obligatory for activation of LPS-dependent signal transduction.

Minimal sternotomy approach for congenital heart operations.

BACKGROUND: In recent years, minimal access cardiac operations have increased in application in both the adult and pediatric population. As our experience has grown with these approaches to atrial septal defect closure, we have expanded the same approach to the repair of more complex congenital heart disease. METHODS: At the Children's Hospital in Boston, from August 1996 to November 1999, a minimal sternotomy approach was used to surgically correct 104 children with congenital heart defects other than atrial septal defect. The approach, in most patients, consisted of a skin incision based over the xiphisternum, 3.5 to 5 cm in length, with division of the xiphoid only and elevation of the sternum by fixed retractor. All patients underwent cannulation for cardiopulmonary bypass through the great vessels in the chest using this same incision. The lesions corrected included ventricular septal defect in 41 patients, tetralogy of Fallot in 27, common atrioventricular canal in 15, mitral valve operation in 3.5, and other defects in 18 patients. There were 53 male and 51 female patients. Mean age at operation was 1.4 years (range, 2 weeks to 11 years). RESULTS: There were no deaths. The mean cardiopulmonary bypass time was 71 minutes (standard deviation, 19 minutes), mean cross-clamp times 40.8 minutes (standard deviation, 13 minutes), and length of stay 4.5 days (standard deviation, 1.9 days). Complications included transient atrioventricular block in 2 patients, pleural effusion requiring drainage in 4, and pericardial effusion in 3 patients. When compared to similar lesions repaired using a full sternotomy approach there was no difference in operating times and length of stay tended to be shorter in the minimal sternotomy group. CONCLUSIONS: A minimal sternotomy approach can be used to repair congenital cardiac lesions other than atrial septal defects. It gives good exposure, particularly for transatrial repairs, does not prolong ischemic times, and may lead to shorter hospital stay.

Ischemic dysfunction in transgenic mice expressing troponin I lacking protein kinase C phosphorylation sites.

To determine the in vivo functional significance of troponin I (TnI) protein kinase C (PKC) phosphorylation sites, we created a transgenic mouse expressing mutant TnI, in which PKC phosphorylation sites at serines-43 and -45 were replaced by alanine. When we used high-perfusate calcium as a PKC activator, developed pressures in transgenic (TG) perfused hearts were similar to wild-type (WT) hearts (P = not significant, NS), though there was a 35% and 32% decrease in peak-systolic intracellular calcium (P < 0.01) and diastolic calcium (P < 0.005), respectively. The calcium transient duration was prolonged in the TG mice also (12-27%, ANOVA, P < 0.01). During global ischemia, TG hearts developed ischemic contracture to a greater extent than WT hearts (41 +/- 18 vs. 69 +/- 10 mmHg, perfusate calcium 3.5 mM, P < 0.01). In conclusion, expression of mutant TnI lacking PKC phosphorylation sites results in a marked alteration in the calcium-pressure relationship, and thus susceptibility to ischemic contracture. The reduced intracellular calcium and prolonged calcium transients suggests that a potent feedback mechanism exists between the myofilament and the processes controlling calcium homeostasis.

Congenital supravalvar aortic stenosis: a simple lesion?

The underlying cause of congenital supravalvular aortic stenosis (SVAS) has recently been identified as a loss-of function mutation of the elastin gene on chromosome 7q11.23, resulting in an obstructive arteriopathy of varying severity, which is most prominent at the aortic sinutubular junction. The generalized nature of the disease explains the frequent association with stenoses of systemic and pulmonary arteries. Furthermore, localization of the supravalvular stenosis at the level of the commissures of the aortic valve has important implications for both aortic valve function and coronary circulation. This review summarizes the recent advances with regard to the pathogenesis of SVAS and describes the multitude of clinically relevant pathologic features other that the mere 'supra-aortic' narrowing that have important implications for surgical therapy.