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1.  Blood transfusions Associate with Urinary Biomarkers of Kidney Injury in Cardiac Surgery 
Objective
Cardiac surgery is a major cause of acute kidney injury. In this setting receipt of blood transfusions appears to associate with a higher risk of AKI, as measured using serum creatinine values. We examined this association further, using urinary biomarkers of kidney injury.
Methods
1210 adults underwent cardiac surgery and were divided into three groups based on the receipt of intraoperative packed red blood cell units (PRBC): no blood (n=894), ≤ 2 PRBC (n=206) and > 2 PRBC (n=110). AKI was defined as: i) Doubling of serum creatinine from the pre-operative value; ii) first post-operative urinary interleukin-18 in the 5th quintile; iii) first postoperative urinary neutrophil gelatinase-associated lipocalin in the 5th quintile. We determined the relative risk for AKI outcome according to PRBC group after adjusting for 12 pre-operative and surgical variables. Using the Sobel test for mediation analysis, we also evaluated the role of biomarkers in causing AKI through alternative pathways.
Results
AKI was more common in those who received >2 PRBC. In patients receiving > 2 PRBC, the adjusted RRs were 2.3 (95% CI 1.2-4.4, p 0.01), 1.36 (95% CI 1.0-1.9, p 0.05), and 1.34 (95% CI 1.0-1.8, p 0.06) for doubling of serum creatinine, urinary IL-18 in the 5th quintile (>60 pg/ml), and urinary NGAL in the 5th quintile (>102 ng/ml), respectively. Furthermore, the effect of PRBC transfusion on AKI was partially mediated by IL-18.
Conclusions
Receipt of two or more PRBC during cardiac surgery is associated with a greater risk of AKI defined by serum creatinine and kidney injury biomarkers.
doi:10.1016/j.jtcvs.2013.09.080
PMCID: PMC4104243  PMID: 24820190
acute kidney injury; PRBC transfusion; cardiac surgery; kidney injury biomarkers
2.  Should Use of Transcatheter Aortic Valve Implantation Be Rationed? 
doi:10.1016/j.jtcvs.2012.02.003
PMCID: PMC4501023  PMID: 22424515
Ethics; Aortic valve replacement; Health policy; Professionalism
3.  Preoperative B-type natriuretic peptide levels are associated with outcome after total cavopulmonary connection (Fontan) 
Objective
To determine the association between preoperative B-type natriuretic peptide (BNP) levels and outcome following TCPC.
Background
Surgical palliation of univentricular cardiac defects requires a series of staged operations, ending in a TCPC. Although outcomes have improved, there remains an unpredictable risk of early TCPC takedown. The prediction of adverse postoperative outcomes is imprecise, despite an extensive preoperative evaluation.
Methods
We prospectively enrolled 50 patients undergoing TCPC. We collected preoperative clinical data, preoperative plasma BNP levels, and postoperative outcomes including the incidence of an adverse outcome within one year of surgery (defined as death, TCPC takedown or the need for cardiac transplantation).
Results
Mean ± SD age was 4.7 ± 2.1 years. Median (IQR) preoperative BNP levels were higher in patients who required TCPC takedown and early postoperative mechanical cardiac support (n=3; 55 (42, 121)) compared with a good outcome (n=47; 11 (5,17)) (p<0.05). In fact, a preoperative BNP ≥ 40 pg/mL was highly associated with the need for TCPC take down (sensitivity = 100%, specificity = 93%; p<0.05), yielding a PPV of 50% and an NPV of 100%. Higher preoperative BNP levels were also associated with longer ICU length of stay, longer hospital length of stay and increased incidence of low cardiac output syndrome (p<0.05).
Conclusions
Preoperative BNP blood levels are uniquely associated with the need for mechanical support early after TCPC and TCPC take down, and thus may provide important information in addition to the standard preoperative assessment.
doi:10.1016/j.jtcvs.2013.08.009
PMCID: PMC3968237  PMID: 24079880
4.  Non-Physiologic Blood Flow Triggers Endothelial and Arterial Remodeling In Vivo: Implications for Novel LVADs with a Peripheral Anastomosis 
Introduction
Less-invasive circulatory support devices have been developed that require anastomosis to a peripheral artery. The Symphony Heart Assist System is a volume displacement pump sewn to the subclavian artery to provide partial circulatory support. The surgical configuration produces non-physiologic blood pressure and bidirectional flow in the subclavian artery. Our objective was to identify effects of altered hemodynamics on arterial structure and function.
Methods
In calves (n=23, 80-100kg), the Symphony pump was sewn end-to-side to the carotid artery. Acutely, carotid blood pressure and flow were recorded to evaluate hemodynamic changes. After medium-term support (1-4 weeks), carotid artery cross sections were studied. Histology and molecular assays evaluated architectural changes. Quantitative real-time PCR evaluated gene expression of matrix metalloproteinase (MMP)-2 and MMP-9 and connective tissue growth factor (CTGF). In vitro carotid arterial-ring studies evaluated physiological responses.
Results
During Symphony support, carotid arterial pressure was 200/15mmHg. Antegrade flow increased significantly (p<0.05) from 1.40±0.32 to 4.29±0.33L/min. Flow during native cardiac diastole reversed completely from 0.25±0.05 to -4.15±0.38L/min in carotid artery proximal to the anastomosis. After medium-term support, the carotid artery was significantly dilated with significantly thinner tunica media and thicker tunica adventitia versus controls. MMP-9 gene expression decreased significantly, CTGF gene expression increased significantly, and collagen, elastin, and total extracellular matrix increased significantly. Endothelial cells were significantly hypertrophied and produced significantly more von Willebrand factor. Endothelial apoptosis increased significantly. Platelet-endothelial interactions decreased significantly. Endothelial-independent contraction decreased significantly, whereas endothelial-dependant relaxation increased modestly.
Conclusions
Assisted circulation with a left ventricular assist device (LVAD) triggered arterial remodeling that allowed a peripheral artery to accommodate the altered hemodynamics of a novel partial-support pump. Further delineation of remodeling pathways may be of significance for the emerging field of partial circulatory support.
doi:10.1016/j.jtcvs.2013.10.027
PMCID: PMC4048802  PMID: 24332190
LVAD; mechanical circulatory support; arterial remodeling; endothelial remodeling
6.  Preconditioning of skeletal myoblast-based engineered tissue constructs enables functional coupling to myocardium in vivo 
Objective
Skeletal myoblasts fuse to form functional syncytial myotubes as an integral part of the skeletal muscle. During this differentiation process, expression of proteins for mechanical and electrical integration is seized, which is a major drawback for the application of skeletal myoblasts in cardiac regenerative cell therapy, because global heart function depends on intercellular communication.
Methods
Mechanically preconditioned engineered tissue constructs containing neonatal mouse skeletal myoblasts were transplanted epicardially. A Y-chromosomal specific polymerase chain reaction (PCR) was undertaken up to 10 weeks after transplantation to confirm the presence of grafted cells. Histologic and electrophysiologic analyses were carried out 1 week after transplantation.
Results
Cells within the grafted construct expressed connexin 43 at the interface to the host myocardium, indicating electrical coupling, confirmed by sharp electrode recordings. Analyses of the maximum stimulation frequency (5.65 ± 0.37 Hz), conduction velocity (0.087 ± 0.011 m/s) and sensitivity for pharmacologic conduction block (0.736 ± 0.080 mM 1-heptanol) revealed effective electrophysiologic coupling between graft and host cells, although significantly less robust than in native myocardial tissue (maximum stimulation frequency, 11.616 ± 0.238 Hz, P<.001; conduction velocity, 0.300 ± 0.057 m/s, P<.01; conduction block, 1.983 ± 0.077 mM 1-heptanol, P<.001).
Conclusions
Although untreated skeletal myoblasts cannot couple to cardiomyocytes, we confirm that mechanical preconditioning enables transplanted skeletal myoblasts to functionally interact with cardio-myocytes in vivo and, thus, reinvigorate the concept of skeletal myoblast-based cardiac cell therapy.
doi:10.1016/j.jtcvs.2014.09.034
PMCID: PMC4476636  PMID: 25439779
8.  High Molecular Weight Polyethylene Glycol Inhibits Myocardial Ischemia-Reperfusion Injury In Vivo 
Objectives
Cardiac ischemia-reperfusion (I-R) injury remains a significant problem as there are no therapies available to minimize the cell death that can lead to impaired function and heart failure. We have shown that high-molecular-weight PEG (15–20kD) can protect cardiac myocytes in vitro from hypoxia-reoxygenation injury. In this study, we investigated the potential protective effects of PEG in vivo.
Methods
Adult rats underwent LAD occlusion for 60 minutes followed by 48 hrs or 4 weeks of reperfusion. One mL of 10% PEG solution or saline (PBS) control (n=10 per group) was administered intravenously (IV) immediately prior to reperfusion.
Results
Fluorescein-labeled PEG was robustly visualized in the myocardium 1 hr after IV delivery. The PEG group had significant recovery of LV ejection fraction at 4 wks vs. a 25% decline in the PBS group (p<0.01). There was 50% less LV fibrosis in the PEG group vs. PBS with smaller peri-infarct and remote territory fibrosis (p<0.01). Cell survival signaling was upregulated in the PEG group with increased Akt (3-fold, p<0.01) and ERK (4-fold, p<0.05) phosphorylation compared to PBS controls at 48 hrs. PEG also inhibited apoptosis as measured by TUNEL positive nuclei (56% decrease, p<0.02) and caspase-3 activity (55% decrease, p<0.05).
Conclusions
High-molecular-weight PEG appears to have a significant protective effect from I-R injury in the heart when administered IV immediately prior to reperfusion. This may have important clinical translation in the setting of acute coronary revascularization and myocardial protection in cardiac surgery.
doi:10.1016/j.jtcvs.2014.10.074
PMCID: PMC4459731  PMID: 25455467
9.  Risk Factors for Prolonged Length of Stay Following the Stage II Procedure in the Single Ventricle Reconstruction Trial 
Objectives
The Single Ventricle Reconstruction trial randomized patients with single right ventricle lesions to a modified Blalock-Taussig or right ventricle-to-pulmonary artery shunt at the Norwood. This analysis describes outcomes at the stage II procedure and factors associated with a longer hospital length of stay (LOS).
Methods
We examined the association of shunt type with stage II hospital outcomes. Cox regression and bootstrapping were used to evaluate risk factors for longer LOS. We also examined characteristics associated with in-hospital death.
Results
There were 393 subjects in the analytic cohort. Median stage II procedure hospital LOS (8 days, IQR (6,14)), hospital mortality (4.3%), transplantation (0.8%), median ventilator time (2 days, IQR (1,3)), median intensive care unit LOS (4 days (IQR (3,7)), number of additional cardiac procedures or complications and serious adverse events did not differ by shunt type. Longer LOS was associated (R2=0.26) with center, longer post-Norwood LOS (HR 1.93 per log day, P<0.001), non-elective timing of the stage II procedure (HR 1.78, P<0.001) and pulmonary artery (PA) stenosis (HR 1.56, P<0.001). By univariate analysis, non-elective stage II (65% vs. 32%, P=0.009), ≥ moderate atrioventricular valve (AVV) regurgitation (75% vs. 24%, P<0.001) and AVV repair (53% vs. 9%, P<0.001) were among the risk factors associated with in-hospital death.
Conclusions
Norwood LOS, PA stenoses and non-elective stage II procedure, but not shunt type, are independently associated with longer LOS. Non-elective stage II, >moderate AVV regurgitation and need for AVV repair are among the risk factors for death.
doi:10.1016/j.jtcvs.2013.07.063
PMCID: PMC3964142  PMID: 24075564
10.  Aprotinin, but not epsilon aminocaproic acid and tranexamic acid, exerts neuroprotection against excitotoxic injury in an in vitro neuronal cell culture model 
Objective
Lack of availability of aprotinin has resulted in increased clinical use of the alternative antifibrinolytic agents epsilon aminocaproic acid (EACA) and tranexamic acid (TXA) which are known to be associated with an increased risk of seizures. In contrast aprotinin has previously been demonstrated to be neuroprotective through suppression of excitotoxicity-mediated neuronal degeneration via the extracellular plasminogen/plasmin system. We compared the impact of antifibrinolytic agents on neuronal and mixed glial/neuronal cell cultures.
Methods
Mixed cortical cultures containing neuronal and glial cells were prepared from fetal mice and plated on a layer of confluent astrocytes from postnatal pups. Primary neuronal culture was obtained from the same gestational stage and plated in multiwall vessels. Slowly triggered excitotoxicity was induced by 24-hour exposure to 12.5 mM N-methyl-D-aspartate (NMDA). Apoptotic neuronal cell death was induced by exposure of primary neural cultures to 24 hours of serum deprivation.
Results
Compared to NMDA alone, no significant changes in cell death were observed for any dose of TXA or EACA in mixed cultures. Conversely, a clinical dose of aprotinin significantly reduced cell death by -31% on average. Aprotinin reduced apoptotic neuronal cell death from 75% to 37.3%, and 34.1% at concentrations of 100 and 200 KIU/mL, and significantly decreased neuronal nuclear damage. These concentrations of aprotinin significantly inhibited caspase 9 and 3/7 activations. 250 KIU/ml aprotinin exerted maximal protection on primary cortical neurons.
Conclusions
In contrast to aprotinin, EACA and TXA exert no protective effect against excitotoxic neuronal injury that can occur during cardiac surgery.
doi:10.1016/j.jtcvs.2013.09.054
PMCID: PMC4019727  PMID: 24237885
11.  Comparison of David V valve-sparing root replacement and bioprosthetic valve conduit for aortic root aneurysm 
Objective
Valve sparing root replacement (VSRR) is an attractive option for the management of aortic root aneurysms with a normal native aortic valve. Therefore, we reviewed our experience with a modification of the David V VSRR and compared it with stented pericardial bioprosthetic valve conduit (BVC) root replacement in an age-matched cohort of older patients.
Methods
A total of 48 VSRRs were performed at our institution, excluding those on bicuspid aortic valves. We compared these cases with 15 aortic root replacements performed using a BVC during the same period. Subgroup analysis was performed comparing 16 VSRR cases and 15 age-matched BVC cases.
Results
The greatest disparity between the VSRR and BVC groups was age (53 vs 69 years, respectively; P < .0005). The matched patients were similar in terms of baseline demographics and differed only in concomitant coronary artery bypass grafting (2 VSRR vs 7 BVC patients; P = .036). None of the VSRR and 3 of the BVC procedures were performed for associated dissection (P = .101). Postoperative aortic insufficiency grade was significantly different between the 2 groups (P = .004). The cardiopulmonary bypass, crossclamp, and circulatory arrest times were not different between the VSRR and BVC groups (174 vs 187 minutes, P = .205; 128 vs 133 minutes, P = .376; and 10 vs 13 minutes, respectively; P = .175). No differences were found between the 2 groups with respect to postoperative complications. One postoperative death occurred in the BVC group and none in the VSRR group. The postoperative length of stay and aortic valve gradients were less in the VSRR group (6 vs 8 days, P = .038; 6 vs 11.4 mm Hg, P = .001). The intensive care unit length of stay was significantly less in the VSRR group (54 vs 110 hours, P = .001).
Conclusions
VSRR is an effective alternative to the BVC for aortic root aneurysm.
doi:10.1016/j.jtcvs.2014.05.092
PMCID: PMC4433158  PMID: 25173127
12.  Younger gestational age is associated with worse neurodevelopmental outcomes after cardiac surgery in infancy 
Objective
Evaluate the impact of near-term delivery on neurodevelopmental (ND) outcomes in children with congenital heart disease (CHD).
Methods
Secondary analysis of data from a study of genetic polymorphisms and ND outcomes after cardiac surgery in infants. The effect of gestational age (GA) as a continuous variable on ND outcomes was evaluated using general linear regression models. GA was also evaluated as a categorical variable to seek a threshold for better outcomes. ND domains tested at 4 years of age included cognition, language skills, attention, impulsivity, memory, executive function, social competence, visual-motor, and fine-motor skills.
Results
ND outcomes and GA were available for 378 infants. Median GA was 39 weeks (range, 28–42 weeks) with 351 born at 36 weeks or more (near-term/term). In univariate analysis of the near-term/term subgroup, older GA predicted better performance for cognition, visual-motor, and fine-motor skills. After covariate adjustment, older GA predicted better performance for fine-motor skills (P = .018). Performance for cognition, language, executive function, social skills, visual-motor, and fine-motor skills was better for those born at 39 to 40 weeks of GA or more versus those born at less than 39 weeks (all P<.05).
Conclusions
These findings are consistent with the hypothesis that delivery before 39 to 40 weeks of GA is associated with worse outcomes in patients with CHD. Early delivery of a child with CHD is often indicated because of maternal or fetal health issues. In the absence of these concerns, these data suggest that elective (or spontaneous) delivery at 39 to 40 weeks of GA is associated with better ND outcomes.
doi:10.1016/j.jtcvs.2011.11.029
PMCID: PMC4423823  PMID: 22340027
13.  END-DIASTOLIC FLOW REVERSAL LIMITS THE EFFICACY OF PEDIATRIC INTRAAORTIC BALLOON PUMP COUNTERPULSATION 
OBJECTIVE
Counterpulsation with an intraaortic balloon pump (IABP) has not achieved the same successes or clinical use in pediatric patients as in adults. In a pediatric animal model, IABP efficacy was investigated to determine whether IABP timing with a high-fidelity blood pressure signal may improve counterpulsation therapy versus a low-fidelity signal.
METHODS
In Yorkshire piglets (n=19, 13.0±0.5 kg) with coronary ligation-induced acute ischemic left ventricular failure, pediatric IABPs (5 or 7cc) were placed in the descending thoracic aorta. Inflation and deflation were timed with traditional criteria from low-fidelity (fluid-filled) and high-fidelity (micromanometer) blood pressure signals during 1:1 support. Aortic, carotid, and coronary hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption was calculated from coronary sinus and arterial blood samples. Left ventricular myocardial blood flow and end-organ blood flow were measured with microspheres.
RESULTS
Despite significant suprasystolic diastolic augmentation and afterload reduction at heart rates of 105±3bmp, left ventricular myocardial blood flow, myocardial oxygen consumption, the myocardial oxygen supply/demand relationship, cardiac output, and end-organ blood flow did not change. Statistically significant end-diastolic coronary, carotid, and aortic flow reversal occurred with IABP deflation. Inflation and deflation timed with a high-fidelity versus low-fidelity signal did not attenuate systemic flow reversal or improve the myocardial oxygen supply/demand relationship.
CONCLUSIONS
Systemic end-diastolic flow reversal limited counterpulsation efficacy in a pediatric model of acute left ventricular failure. Adjustment of IABP inflation and deflation timing with traditional criteria and a high-fidelity blood pressure waveform did not improve IABP efficacy or attenuate flow reversal. End-diastolic flow reversal may limit the efficacy of IABP counterpulsation therapy in pediatric patients with traditional timing criteria. Investigation of alternative deflation timing strategies is warranted.
doi:10.1016/j.jtcvs.2013.08.044
PMCID: PMC3988268  PMID: 24139614
pediatric; heart failure; intraaortic balloon pump (IABP); counterpulsation; flow reversal; coronary steal
14.  Hypogammaglobulinemia After Cardiopulmonary Bypass in Infants 
Background
Hypogammaglobulinemia has been reported after cardiac surgery and may be associated with adverse outcomes. We sought to define baseline immunoglobulin (Ig) concentration in neonates and infants with congenital heart disease, determine its course following cardiopulmonary bypass (CPB), and determine if post-CPB hypogammaglobulinemia was associated with increased morbidity.
Methods
Single center, retrospective analysis of infants who underwent cardiac surgery with CPB between June 2010 and December 2011. Ig concentration obtained from banked plasma of 47 patients from a prior study (pre-CPB, immediately post-CPB, and 24- and 48-hours post-CPB). Additionally, any Ig levels drawn for clinical purposes after CPB were included. Ig levels were excluded if drawn after chylothorax diagnosis or intravenous immunoglobulin G administration.
Results
Median age was 7 days. Preoperative Ig concentration was similar to that described in healthy children. IgG level fell to less than 50% of preoperative concentration by 24-hr post-CPB and failed to recover by 7 days. 25/47 (53%) patients had low IgG after CPB (<248 mg/dl). Despite no difference in demographics or risk factors between patients with low and normal IgG, low IgG patients had more positive fluid balance at 24-hours, increased pro-inflammatory plasma cytokine levels, duration of mechanical ventilation, and CICU length of stay. Additionally, low IgG patients had increased incidence of post-operative infections (40% vs. 14%, p=0.056).
Conclusions
Hypogammaglobulinemia occurs in half of infants after CPB. Its association with fluid overload and increased inflammatory cytokines suggests it may result from capillary leak. Postoperative hypogammaglobulinemia is associated with increased morbidity, including more secondary infections.
doi:10.1016/j.jtcvs.2013.07.040
PMCID: PMC4260623  PMID: 24035378
cardiopulmonary bypass; infants; neonates; infection; intensive care unit
16.  Valve-sparing aortic root replacement: Too many cooks? 
doi:10.1016/j.jtcvs.2014.11.020
PMCID: PMC4410812  PMID: 25524682
17.  Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial 
Objectives
We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial.
Methods
Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality.
Results
Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30-day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations.
Conclusions
Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization.
doi:10.1016/j.jtcvs.2012.05.019
PMCID: PMC4385520  PMID: 22704284
18.  Risk Factors for Preoperative Periventricular Leukomalacia in Term Neonates with Hypoplastic Left Heart Syndrome are Patient Related 
BACKGROUND
Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury called periventricular leukomalacia (PVL) in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS).
METHODS
Neonates with HLHS or HLHS variants from three prospective MRI studies (2003–2010) were selected for this cohort. A preoperative brain MRI was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs. vaginal), time of diagnosis (prenatal vs. postnatal), HLHS subtypes, brain total maturation score (TMS), time to surgery, individual averaged daily preoperative blood gases and CBC values was used to determine significant associations.
RESULTS
A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks, 86% (49/57) had a prenatal diagnosis with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, (41/57, 71%). Preoperative PVL was identified in 19% (11/57). Male patients with aortic atresia (p=0.004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL (p=0.005).
CONCLUSIONS
In neonates with HLHS, non-modifiable patient related factors including male gender with aortic atresia (lack of antegrade blood flow) and lower total brain maturation score placed neonates at the greatest risk for preoperative white matter injury.
doi:10.1016/j.jtcvs.2013.06.021
PMCID: PMC3896504  PMID: 23879933
19.  Analysis of First Recurrence and Survival in Patients with Stage I Non-Small Cell Lung Cancer Treated with Surgical Resection or Stereotactic Radiation Therapy 
Objectives
Comparative studies of survival between stereotactic body radiation therapy (SBRT) and surgery have been limited by lack of comparisons of recurrence patterns between matched cohorts in non-small cell lung cancer (NSCLC).
Methods
All patients undergoing treatment with surgery or SBRT for clinical Stage I NSCLC between June 2004-December 2010 were reviewed. Age, tumor characteristics, comorbidity score, pulmonary function, overall (OS) and disease free survival (DFS) and recurrence data were collected and propensity matching performed..
Results
The mean age for surgery (N=458) was 65.8 ± 10.5 vs. 74.4 ± 9.4 for SBRT (N=151) (p<0.0001). For the entire surgical cohort 3-year OS and DFS were 78% and 72%, respectively. For the entire SBRT cohort 3-year OS and DFS were 47% and 42%, respectively. The overall local recurrence rate for surgery was 2.6%. The overall local recurrence rate for SBRT was 10.7%. A propensity matched comparison based on age, tumor size, ACE comorbidity score, FEV1%, and tumor location resulted in 56 matched pairs. The 3-year overall survival was 52% vs. 68% for SBRT and surgery, respectively (p=0.05) while disease-free survival was 47% vs. 65% (p=0.01). At 3 years, local recurrence free survival was 90% vs. 92% for SBRT and surgery, respectively (p=0.07)
Conclusions
While surgical resection seems to result in better overall and disease free survival vs. SBRT, matching these disparate cohorts of patients remains challenging. Participation in clinical trials is essential to define the indications and relative efficacy of surgery and radiation therapy in a high-risk population with Stage I NSCLC.
doi:10.1016/j.jtcvs.2013.11.057
PMCID: PMC4113038  PMID: 24507980
Stereotactic body radiation therapy; clinical stage I non-small cell lung cancer; ACE-27; propensity matching; lobectomy; sublobar resection
21.  Effect of Mechanical Assistance of the Systemic Ventricle in Single Ventricle Circulation with Cavopulmonary Connection 
Background
Previous attempts to support the single ventricle circulation mechanically have suggested that a custom-built assist device is needed to push rather than pull through the pulmonary circulation. We hypothesized that using a conventional ventricular assist device, with or without conversion of a total cavopulmonary connection to a bidirectional Glenn cavopulmonary connection would allow assistance by pulling blood through the circuit and improve cardiac index (CI).
Methods
Cavopulmonary connections were established in each of five Yorkshire pigs (25kg) using ePTFE conduits in a “Y” configuration with appropriate clamping of limbs of the Y to achieve: total cavopulmonary Fontan connection (TCPC), SVC cavopulmonary connection (SVC Glenn) and IVC cavopulmonary connection (IVC Glenn). A common atrium had been established previously by balloon septostomy. Mechanical circulatory assistance of the single systemic ventricle was achieved using a centrifugal pump with common atrial inflow and proximal ascending aortic outflow. CI was calculated using an ultrasonic flow meter placed on the distal ascending aorta and compared between assisted and non-assisted circulation for 3 conditions: TCPC, SVC Glenn and IVC Glenn. Mean pulmonary artery pressure (PAP), common atrial pressure (LAP), arterial oxygen saturation (SAT), partial pressure of arterial oxygen (PO2) and oxygen delivery (DO2) were calculated.
Results
Unassisted SVC Glenn CI tended to be higher than TCPC or IVC Glenn (Figure 1). Significant augmentation of total CI was achieved with mechanical assistance for SVC Glenn (109% ± 24%, P =.04) and also with TCPC (130% ± 109%, P = .01). Assisted CI achieved at least mean baseline biventricular CI for all 3-support modes. Oxygen delivery was highest for assisted SVC Glenn 1786 ± 1307 ml/l/min and lowest with TCPC 1146 ± 386 ml/l/min, with a trend toward lower common atrial pressure and lower pulmonary artery pressure for SVC Glenn.
Conclusions
SVC bidirectional Glenn circulation may allow optimal augmentation of cardiac index and oxygen delivery in a failing single ventricle using a conventional pediatric ventricular assist device. Our model also suggests that the Fontan circulation itself can be supported with systemic ventricular assistance of the single ventricle.
doi:10.1016/j.jtcvs.2013.12.018
PMCID: PMC4209246  PMID: 24530198
22.  Mitral valve hemodynamics after repair of acute posterior leaflet prolapse: Quadrangular resection versus triangular resection versus neochordoplasty 
Objective
Leaflet prolapse resulting from acute chordal rupture is one presentation of fibroelastic deficiency that is associated with minimal leaflet changes in the prolapsing segment. Minimizing resection and preserving leaflet tissue may be an optimal surgical strategy. We examined the importance of the leaflet preservation concept by comparing resective and nonresective surgical procedures in practice today.
Methods
Eight porcine mitral valves were evaluated in an in vitro heart simulator before surgical manipulation. Mitral regurgitation was created in these valves by transecting the posterior marginal chordae resulting in severe P2 prolapse. After confirmation of mitral regurgiation via regurgitant flow measurement (mL/beat), regurgitation was corrected by three repairs: neochordoplasty with polytetrafluoroethylene sutures (Gore-Tex; W. L. Gore & Associates, Inc, Flagstaff, Ariz), triangular resection, and quadrangular resection with annular compression. Post-repair valve hemodynamics were quantified under pulsatile conditions of 120 mm Hg peak transmitral pressure and 5 L/min cardiac output at 70 beats/min. Furthermore, hemodynamic, geometric, and echocardiographic indices were measured.
Results
Transecting the marginal chordae resulted in severe P2 prolapse and significant mitral regurgiation (19.3 ± 4.3 mL/beat). Regurgitant volume was significantly reduced after any of the three surgical approaches (quadrangular, 4.38 ± 1.6 mL/beat; triangular, 2.56 ± 1.0 mL/beat; neochordal, 2.86 ± 1.24 mL/beat). In comparison with the baseline normal valves, leaflet coaptation length and posterior leaflet mobility were significantly reduced in the quadrangular resection group, whereas they were partially restored in the triangular resection and fully preserved in the neochordoplasty group.
Conclusions
Although the three repair procedures are hemodynamically comparable, valve function and leaflet kinematics were significantly better after a nonresection or limited resective correction of leaflet prolapse in this experimental model of acute chordal rupture with otherwise normal leaflet geometry.
doi:10.1016/j.jtcvs.2009.01.031
PMCID: PMC4375960  PMID: 19619772
23.  Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants 
Objective
Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association.
Methods
The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores.
Results
Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058).
Conclusions
These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD. (J Thorac Cardiovasc Surg 2014;148:2560-8)
doi:10.1016/j.jtcvs.2014.07.052
PMCID: PMC4376113  PMID: 25282659
24.  Right atrial lesions do not improve the efficacy of a complete left atrial lesion set in the surgical treatment of atrial fibrillation, but they do increase procedural morbidity 
Objective
Some have suggested the superiority of biatrial versus left atrial lesions. We sought to analyze our experience.
Methods
We retrospectively reviewed 305 consecutive patients from 2007 to 2011. Rhythm success was defined as freedom from atrial fibrillation (AF) or flutter determined by 12-lead electrocardiograms at 3-month intervals. Lesions sets were pulmonary vein isolation (PVI), left-extended (PVI + mitral valve annulus [MV] lesion ± left atrial appendage lesion [LAA]) or biatrial-extended (right atrial ablation + PVI + MV ± LAA).
Results
The success rates of PVI, left-extended, and biatrial-extended lesions were as follows: at 3 months, 56.7%, 74.7%, and 79.4% (P = .003); at 6 months, 56.9%, 72.9%, and 74.6% (P = .02); at 9 months, 54.6%, 72.5%, and 83.3% (P < .001); and at 12 months, 52.6%, 76.1%, and 80.0% (P < .001). Biatrial lesions had a higher rate of pacemaker placement than did left atrial lesions (16.5% vs 7.5%; P = .02). When we grouped patients by left lesion (PVI, PVI + MV, PVI + MV + LAA) irrespective of right atrial ablation, success was as follows: 3 months, 57.9%, 71.1%, and 87.8% (P < .01); 6 months, 58.1%, 71.6%, and 77.6% (P = .03); 9 months, 55.9%, 71.3%, and 89.6% (P < .01); and 12 months, 54.1%, 74.7%, and 83.7% (P < .01).
Conclusions
PVI is associated with lower rhythm success than an extended left atrial lesion set. The addition of a right atrial lesion to an extended left atrial lesion set does not improve efficacy, but it does increase the rate of pacemaker placement for sinus dysfunction. Adding an LAA lesion may confer additional efficacy when added to a lesion set that includes PVI + MV.
doi:10.1016/j.jtcvs.2012.09.091
PMCID: PMC4369381  PMID: 23321126
25.  The impact of CHADS2 score on late stroke after the Cox maze procedure 
Objective
The Heart Rhythm Society, European Heart Rhythm Association, and European Cardiac Arrhythmia Society jointly recommend indefinite warfarin anticoagulation in patients with CHADS2 (congestive heart failure, hypertension, age, diabetes, and stroke) score of at least 2 who have undergone ablation for atrial fibrillation. This study determined the impact of CHADS2 score on risk of late stroke or transient ischemic attack after the performance of a surgical Cox maze procedure.
Methods
A retrospective review of 433 patients who underwent a Cox maze procedure at our institution was conducted. Three months after surgery, warfarin was discontinued regardless of CHADS2 score if the patient showed no evidence of atrial fibrillation, was off antiarrhythmic medications, and had no other indication for anticoagulation. A follow-up questionnaire was used to determine whether any neurologic event had occurred since surgery.
Results
Follow-up was obtained for 90% of the study group (389/433) at a mean of 6.6 ± 5.0 years. Among these patients, 32% (125/389) had a CHADS2 score of at least 2, of whom only 40% (51/125) remained on long-term warfarin after surgery. Six patients had late neurologic events (annualized risk of 0.2%). Neither CHADS2 score nor warfarin anticoagulation was significantly associated with the occurrence of late neurologic events. Among the individual CHADS2 criteria, both diabetes mellitus and previous stroke or transient ischemic attack were predictive of late neurologic events.
Conclusions
The risk of stroke or transient ischemic attack in patients after a surgical Cox maze procedure was low and not associated with CHADS2 score or warfarin use. Given the known risks of warfarin, we recommend discontinuation of anticoagulation 3 months after the procedure if the patient has no evidence of atrial fibrillation, has discontinued antiarrhythmic medications, and is without any other indication for systemic anticoagulation.
doi:10.1016/j.jtcvs.2012.03.087
PMCID: PMC4369384  PMID: 22818126

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