The CorCap Cardiac Support Device (Acorn Cardiovascular, Inc.) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow up). This report summarizes results of extended follow up to 5 years.
107 patients were enrolled in the No-Mitral Valve Repair/Replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year until completing 5 years of follow up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status and echocardiograms, which were read at a core laboratory.
Overall survival rates were similar between the treatment and control groups demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end diastolic volume (p = 0.029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least one NYHA functional class (p= 0.0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end diastolic dimension, there was a significant reduction in the Kaplan Meier estimate of the freedom from the composite endpoint of death and major cardiac procedures (p= 0.04).
These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long term safety and efficacy of the CorCap Cardiac Support Device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.
In the Single Ventricle Reconstruction Trial, infants undergoing the Norwood procedure were randomized to a right ventricle-to-pulmonary-artery shunt or modified Blalock-Taussig shunt. Apart from shunt type, subjects received local standard of care. We evaluated variation in peri-operative care during the Norwood hospitalization across 14 trial sites.
Data on pre-operative, operative, and post-operative variables were collected prospectively on standardized case report forms, and variation across centers described for 546 enrolled subjects who underwent the Norwood procedure.
Subjects' gestational age, birth weight, and proportion with hypoplastic left heart syndrome were similar across sites. In contrast, all recorded variables related to pre-operative care varied across centers, including fetal diagnosis (range 55–85%), preoperative intubation (range 29–91%), and enteral feeding. Perioperative/operative factors were also variable across sites including median total support time (range 74–189 minutes) and other perfusion variables, arch reconstruction technique, intraoperative medication use, and use of modified ultrafiltration (range 48–100%). Additional variation across centers was seen in variables related to postoperative care, including proportion with an open sternum (range 35–100%), median intensive care unit length of stay (range 9–44 days), type of feeding at discharge, and enrollment in a home monitoring program (range 1–100%; 5 sites did not have a program). Overall inhospital death/transplant occurred in 18% (range across sites 7–39%).
Perioperative care during the Norwood hospitalization varies across centers. Further analysis evaluating the underlying causes and relationship of this variation to outcome is needed to inform future studies and quality improvement efforts.
Linear repair of left ventricular aneurysm has been performed with mixed clinical results. By using finite element analysis, this study evaluated the effect of this procedure on end-systolic stress.
Nine sheep underwent myocardial infarction and aneurysm repair with a linear repair (13.4 ± 2.3 weeks postmyocardial infarction). Satisfactory magnetic resonance imaging examinations were obtained in 6 sheep (6.6 ± 0.5 weeks postrepair). Finite element models were constructed from in vivo magnetic resonance imaging-based cardiac geometry and postmortem measurement of myofiber helix angles using diffusion tensor magnetic resonance imaging. Material properties were iteratively determined by comparing the finite element model output with systolic tagged magnetic resonance imaging strain measurements.
At the mid-wall, fiber stress in the border zone decreased by 39% (sham = 32.5 ± 2.5 kPa, repair = 19.7 ± 3.6 kPa, P = .001) to the level of remote regions after repair. In the septum, however, border zone fiber stress remained high (sham = 31.3 ± 5.4 kPa, repair = 23.8 ± 5.8 kPa, P = .29). Cross-fiber stress at the mid-wall decreased by 41% (sham = 13.0 ± 1.5 kPa, repair = 7.7 ± 2.1 kPa, P = .01), but cross-fiber stress in the un-excluded septal infarct was 75% higher in the border zone than remote regions (remote = 5.9 ± 1.9 kPa, border zone = 10.3 ± 3.6 kPa, P < .01). However, end-diastolic fiber and cross-fiber stress were not reduced in the remote myocardium after plication.
With the exception of the retained septal infarct, end-systolic stress is reduced in all areas of the left ventricle after infarct plication. Consequently, we expect the primary positive effect of infarct plication to be in the infarct border zone. However, the amount of stress reduction necessary to halt or reverse nonischemic infarct extension in the infarct border zone and eccentric hypertrophy in the remote myocardium is unknown.
Transection of the secondary chordae on the anterior leaflet of the mitral valve to relieve leaflet tethering and reduce regurgitation is an experimentally proven procedure to correct functional mitral regurgitation. In this study, we sought to investigate if transecting the secondary chordae has an impact on the marginal chordal force on the same leaflet.
Adult porcine mitral valves (N =8) were studied in a pulsatile heart simulator, in which the papillary muscle positions can be precisely positioned. The anterior marginal chordae were instrumented with miniature transducers to measure the chordal forces. Each valve was studied under baseline conditions, three different tethering conditions [apical, apical-lateral, apical-lateral-posterior], and following chordal cutting in the three tethering conditions. The temporal changes, the peak and average marginal chordal forces under each condition are reported.
Apical tethering increased marginal chordal force by an average 96% but remained unchanged after chordal cutting. With apical-lateral tethering, marginal chordal force increased by 210% from baseline, and further increased to 350% of baseline after chordal cutting. After apical-lateral-posterior tethering, the marginal chordal force increased to 335% of baseline before transection and by 548% after the transection.
Increase in marginal chordal force after secondary chordal cutting depends on the location of the papillary muscles and the extent of leaflet tethering. While, chordal cutting may not alter the valve mechanics under minimal leaflet tethering, it significantly impacts the mechanics when the leaflet tethering is more pronounced, which is typically seen in patients with functional mitral regurgitation.
Mitral valve; Chordae Tendineae; Ischemic Mitral Regurgitation; Chordal Cutting; Valve Mechanics
Average two-year survival following cardiac transplantation is approximately 80%. The evolution and subsequent approval of larger pulsatile and, more recently, continuous flow mechanical circulatory support (MCS) technology for destination therapy (DT) offers the potential for triage of some patients awaiting cardiac transplantation to DT.
The National Heart, Lung and Blood Institute Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is a national multi-institutional study of chronic mechanical circulatory support. Between June 2006 and December 2011, 127 pulsatile and 1160 continuous flow pumps (24% of total primary LVADs) carried an initial strategy of DT therapy.
By multivariable analysis, risk factors (p<0.05) for mortality following DT included older age, larger body mass index, history of cancer, history of cardiac surgery, INTERMACS level I (cardiogenic shock), dialysis, increased BUN, use of a pulsatile flow device and use of a RVAD. Among continuous flow LVAD patients who were not in cardiogenic shock, a particularly favorable survival was associated with no cancer, patients not in cardiogenic shock, and BUN < 50, resulting in one and two year survival of 88 and 80%.
1) Evolution from pulsatile to continuous flow technology has dramatically improved one and two year survival; 2) Destination Therapy is not appropriate for patients with rapid hemodynamic deterioration; or severe right ventricular failure 4) Important subsets of continuous flow DT patients now enjoy survival which is competitive with heart transplantation out to about two years.
Optimizing flow and diminishing power loss in the Fontan circuit can improve hemodynamic efficiency potentially improving long-term outcomes. Computerized modeling has predicted improved energetics with a Y-graft Fontan.
From August to December, 2010, six consecutive children had a completion Fontan (n=3) or a Fontan revision (n=3) using a bifurcated polytetrafluoroethylene Y-graft (18×9×9 mm in 2, 20×10×10 mm in 4) connecting the inferior vena cava (IVC) to the right and left pulmonary arteries (PAs) with separate graft limbs. Patents were imaged by magnetic resonance imaging (MRI; n-5) or computerized tomography (n=1). Computational fluid dynamics (CFD) assessed Fontan hemodynamics, power loss, and IVC flow splits to the branch PAs. Clinical parameters were compared with 12 patients immediately preceding this series who had a lateral Fontan procedure.
Despite longer crossclamp and bypass times (not statistically significant), the Y-graft Fontan patients had postoperative courses similar to the conventional Fontan patients. Other than two early readmissions for pleural effusions managed with diuretics, on 6–12 months follow-up (mean 8 months), all six patients have done well. Postoperative flow modeling demonstrated balanced distribution of IVC flow to both PAs with minimal flow disturbance. Improvements in hemodynamics and efficiency were noted when the Y-graft branches were anastomosed distally and aligned tangentially with the branch PAs.
This preliminary surgical experience demonstrates clinical feasibility of the bifurcated Y-graft Fontan. CFD shows acceptable hemodynamics with low calculated power losses and balanced distribution of IVC flow to the PAs as long as the branch grafts are anastomosed distally.
Myocardial infarction (MI) can lead to irreversible adverse left ventricular remodeling resulting in subsequent severe dysfunction. The objective of this study was to investigate the potential for biodegradable, elastomeric patch implantation to positively alter the remodeling process after MI in a porcine model.
Yorkshire pigs underwent a 60-minute catheter balloon occlusion of the left circumflex artery. Two weeks after MI animals underwent epicardial placement of a biodegradable, porous polyurethane (poly(ester urethane)urea; PEUU) patch (MI+PEUU, n = 7) or sham surgery (MI+sham, n = 8). Echocardiography before surgery and at 4 and 8 weeks after surgery measured the end-diastolic area (EDA) and fractional area change (% FAC). All animals were humanely killed 8 weeks after surgery and hearts were histologically assessed.
At 8 weeks, echocardiography revealed greater EDA values in the MI+sham group (23.6 ± 6.6 cm2 , mean ± standard deviaation) than in the MI+PEUU group (15.9 ± 2.5 cm2) (P < .05) and a lower %FAC in the MI+sham group (24.8 ± 7.6) than in the MI+PEUU group (35.9 ± 7.8) (P < .05). The infarcted ventricular wall was thicker in the MI+PEUU group (1.56 ± 0.5 cm) than in the MI+sham group (0.91 ± 0.24 cm) (P < .01).
Biodegradable elastomeric PEUU patch implantation onto the porcine heart 2 weeks post-MI attenuated left ventricular adverse remodeling and functional deterioration and was accompanied by increased neovascularization. These findings, although limited to a 2-month follow-up, may suggest an attractive clinical option to moderate post-MI cardiac failure.
Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis in high-risk older adults in Europe and has begun to do so in the United States. Recent Food and Drug Administration approval of the Edwards Lifesciences SAPIEN Transcatheter Heart Valve (Irvine, Calif) in inoperable and high-risk patients led to enthusiasm for widespread implementation of this technology. Experts have highlighted the central role of the multidisciplinary heart team in implementing a successful TAVR program.1 Other experts, such as Joseph Bavaria, have suggested that access to TAVR should be restricted to high-volume surgical aortic valve replacement centers. In our opinion, access to TAVR should not be limited to high-volume surgical centers for the following reasons. First, high surgical volume does not ensure good outcomes in complex interventional procedures. Second, centers with low or no surgical volume can have excellent interventional results. Third, new multidisciplinary heart teams have achieved excellent results in part because of the transmission of accumulated knowledge from experienced centers. Finally, in the absence of evidence suggesting that high-volume surgical centers produce superior TAVR results, therapeutic options for patients should not be limited.
Cardiac catheterization shortly before coronary artery bypass grafting or valve surgery has been associated with increased postoperative acute kidney injury. The relationship between catheterization timing and acute kidney injury following proximal aortic surgery remains unknown.
Between August 2005 and February 2011, 285 consecutive patients underwent cardiac catheterization prior to elective proximal aortic surgery with cardiopulmonary bypass at a single institution. The association between timing of catheterization and postoperative acute kidney injury (defined as postoperative increase in serum creatinine ≥ 50% of baseline) was assessed using logistic regression analysis.
Of 285 patients, 152 (53%) underwent catheterization on preoperative days 1-3 and 133 (47%) underwent catheterization on preoperative day 4 or before. Acute kidney injury occurred in 88 (31%) patients, three (1.1%) requiring dialysis. Acute kidney injury occurred in 37 (24%) patients catheterized on preoperative days 1-3, and 51 (38%) patients catheterized on preoperative day 4 or before. Catheterization on preoperative day 1-3 was not associated with an increased risk of acute kidney injury relative to catheterization on preoperative day 4 or before (unadjusted odds ratio 0.52, 95% confidence interval 0.31–0.86, P = 0.01; adjusted odds ratio 0.35, 95% confidence interval 0.17–0.73, P = 0.005).
Cardiac catheterization within one to three days of elective proximal aortic surgery appears safe and should be considered acceptable practice for patients at low-risk of acute kidney injury.
Inhibition of adenosine deaminase, with EHNA (erythro-9 (2-hydroxy-3-nonyl)-adenine), and the es-ENT1 transporter, with NBMPR (p-nitro- benzylthioinosine), entraps myocardial intracellular adenosine during on pump warm cross clamping (ACC) leading to a complete recovery of cardiac function and ATP during reperfusion. The differential role of entrapped intracellular and circulating adenosine in EHNA/NBMPR-mediated protection is unknown. Selective, DPCPX [8-cyclopentyl-1,3-dipropyl-xanthine], or non-selective, [8-(p-sulfophenyltheophyline], A1-receptor antagonists were used to block adenosine A1-receptor contribution in EHNA/NBMPR-mediated cardiac recovery.
Anesthetized dogs (n= 45), instrumented to measure heart performance using sonomicrometry, were subjected to 30 minutes of warm ACC and 60 minutes of reperfusion. Three boluses of the vehicle (Series A) or 100μM EHNA and 25μM NBMPR (Series B) were infused into the pump at baseline, before ischemia and before reperfusion. DPCPX (10 μM) or 8-SPT (100μM) was intra-aortically infused immediately after ACC distal to the clamp in Series (A) and Series (B). ATP pool and NAD+ was determined using HPLC.
Ischemia depleted ATP in all groups by 50%. The ratios between adenosine to inosine were >10 fold higher in Series (B) than in Series (A) (p<0.001). ATP and function recovered in the EHNA/NBMPR-treated group (p<0.05 vs. control group). DPCPX or 8-SPT partially reduced cardiac function in Series (A) and (B) to the same degree but did not abolish EHNA/NBMPR-mediated protection in Series (B).
In addition to cardioprotection mediated by activation of adenosine receptors by extracellular adenosine, EHNA/NBMPR-entrapment of intracellular adenosine provides a significant component of myocardial protection despite of A1-R blockade.
Cardiac surgery; Cardiopulmonary bypass; Ischemia and reperfusion; Myocardial protection; Nucleosides and Nucleotides; DPCPX; EHNA; NBMPR; 8-SPT
To determine the role of the es-ENT1 nucleoside transporter in post-MI reperfusion injury-mediated ventricular fibrillation (VFib) and regional dysfunction. We used erythro-9 (2-hydroxy-3-nonyl)-adenine (EHNA) and p-nitrobenzylthioinosine (NBMPR) to inhibit both adenosine deamination and transport in a canine model of off pump acute MI.
Anesthetized adult dogs (n= 37), instrumented to monitor systolic segmental shortening (SS %) and wall thickening (WT %) using sonomicrometry, underwent 90 minutes of LAD coronary artery occlusion and 120 minutes reperfusion. Myocardial coronary blood flow, ATP pool, infarct size and the incidents of ventricular fibrillation and cardioversions were also measured. Animals received an intravenous infusion of the vehicle (Control) or 100μM of EHNA and 25 μM NBMPR before ischemia (preconditioning, PreC group) or just before reperfusion (postconditioning, PostC group).
In the control group, ATP depletion was associated with accumulation of more inosine than adenosine during ischemia and washed out during reperfusion. Myocardial adenosine and inosine were the major nucleosides in the PreC- and Post-C groups during ischemia and remained detectable during reperfusion, respectively. In both groups, recovery of systolic SS% and WT%, and reduction in the incidence of VFib (p<0.05 vs. Control group) coincided with retention of myocardial nucleosides. Infarct sizes in the three groups were not significantly different, independent of myocardial blood flow during ischemia.
PreC-or PostC with EHNA/NBMPR significantly reduced the incidence of ventricular fibrillation and cardioversions and attenuated regional contractile dysfunction mediated by post-MI reperfusion injury and that es-ENT1 plays a major role in these events.
Acute Myocardial Infarction; Reperfusion Injury; fibrillation; es-ENT1; NBMPR; EHNA; Adenosine; Inosine
We sought to identify factors associated with death and cardiac transplantation in infants undergoing the Norwood procedure and to determine differences in associations that might favor either the modified Blalock-Taussig shunt (MBTS) or a right ventricle-to-pulmonary artery shunt (RVPAS).
We used competing risks methodology to analyze death without transplantation, cardiac transplantation, and survival without transplantation. Parametric time-to-event modeling and bootstrapping were used to identify independent predictors.
Data from 549 subjects (follow-up, 2.7±0.9 years) were analyzed. Mortality risk was characterized by early and constant phases; transplant was characterized by only a constant phase. Early phase factors associated with death included lower socioeconomic status (SES; P=.01), obstructed pulmonary venous return (P<.001), smaller ascending aorta (P=.02), and anatomic subtype. Constant phase factors associated with death included genetic syndrome (P<.001) and lower gestational age (GA, P<.001). The RVPAS had better survival in the 51% who were full term with aortic atresia (P<.001). The MBTS was better among the 4% who were preterm with a patent aortic valve (P =.003). Lower pre-Norwood right ventricular fractional area change, pre-Norwood surgery, and anatomy other than hypoplastic left heart syndrome were independently associated with transplantation (all P<.03); but shunt type was not (P=.43).
Independent risk factors for intermediate-term mortality include lower SES, anatomy, genetic syndrome, and lower GA. Term infants with aortic atresia benefited from a RVPAS and preterm infants with a patent aortic valve benefited from a MBTS. Right ventricular function and anatomy, but not shunt type, were associated with transplantation.
A 55-year-old man with critical aortic coarctation, aortic root aneurysm, and aortic insufficiency underwent median sternotomy for ascending–descending aortic bypass and aortic root replacement. The patient was found to have a salvageable trileaflet aortic valve, allowing for valve-sparing root replacement (VSRR). Aortic bypass with VSRR has not previously been reported and may be the ideal operation for repair of coarctation with concomitant aortic root aneurysm.
Thoracic endovascular aortic repair for chronic type B aortic dissection with associated descending thoracic aneurysm remains controversial. Concerns include potential ischemic complications due to branch vessel origin from the chronic false lumen and continued retrograde false lumen/aneurysm sac pressurization via fenestrations distal to implanted endografts. The present study examines midterm results with thoracic endovascular aortic repair for chronic (>2 weeks) type B aortic dissection with associated aneurysm to better understand the potential role of thoracic endovascular aortic repair for this condition.
Between March 2005 and December 2009, 51 thoracic endovascular aortic repair procedures were performed at a single institution for management of chronic type B dissection. The indication for thoracic endovascular aortic repair was aneurysm in all cases. A subset of 7 patients (14%) underwent placement of the EndoSure wireless pressure measurement system (CardioMEMS, Inc, Atlanta, Ga) in the false lumen adjacent to the primary tear for monitoring aneurysm sac/false lumen pulse pressure after thoracic endovascular aortic repair.
Mean patient age was 57 ± 12 years (range, 30–82 years); 14 patients (28%) were female. Mean aortic diameter was 6.2 ± 1.4 cm. There were no in-hospital/30-day deaths, strokes, or permanent paraplegia/paresis. There were no complications related to compromise of downstream branch vessels arising from the false lumen. Two patients (3.9%) who had preexisting ascending aortic dilation had retrograde acute type A aortic dissection; both were repaired successfully. Median postoperative length of stay was 4 days. Mean follow-up is 27.0 ± 16.5 months (range, 2–60 months). Actuarial overall survival is 77.7%at 60 months with an actuarial aorta-specific survival of 98%over this same time period. Actuarial freedom from reintervention is 77.3%at 60 months. All patients with the EndoSure wireless pressure measurement system exhibited a decrease in aneurysm sac/false lumen pulse pressure indicating a depressurized false lumen. The aneurysm sac/false lumen pulse pressure ratio decreased from 52% ± 27% at the predischarge measurement to 14% ± 5% at the latest follow-up reading (P = .029).
Thoracic endovascular aortic repair for chronic type B dissection with associated aneurysm is safe and effective at midterm follow-up. Aneurysm sac/false lumen pulse pressure measurements demonstrate a significant reduction in false lumen endotension, thus ruling out clinically significant persistent retrograde false lumen perfusion and provide proof of concept for a thoracic endovascular aortic repair-based approach. Longer-term follow-up is needed to determine the durability of thoracic endovascular aortic repair for this aortic pathology.
Massive perioperative blood product transfusion may be required with thoracic aortic operations and is associated with poor outcomes. Our objective was to determine the independent predictors of massive transfusion in thoracic aortic surgery patients undergoing deep hypothermic circulatory arrest (DHCA).
The study consisted of 168 consecutive patients undergoing open thoracic aortic procedure utilizing DHCA between July 2005 and August 2008. We identified 26 preoperative and procedural variables as being potentially related to blood product usage. We tested the variables for association with total blood products transfused using a multivariate linear regression model and then constructed a logistic regression model for massive transfusion, defined as requiring 5 or more units of transfused packed red blood cells between incision and 48 hours postoperatively.
Multivariate linear regression determined six significant variables as accounting for 42% of the variation in total blood products transfused: age (P=0.008), preoperative hemoglobin (P=0.04), weight (P=0.02), cardiopulmonary bypass time (P<0.0001), emergent status (P<0.0001), and re-do median sternotomy (P<0.0001). A final predictive logistic regression model associated every 1 g/dL increase in preoperative hemoglobin OR=0.54 [0.43, 0.69], P<0.0001; every 10 minute increase in CPB time, OR=1.15 [1.05, 1.26], P=0.0026; and emergent status OR=4.02 [1.53, 10.55], P=0.0047 with massive transfusion.
Our model described CPB time, emergent status, and preoperative hemoglobin as independent predictors of massive transfusion. These variables, along with weight, age, and re-do median sternotomy are associated with total blood product usage in thoracic aortic operations involving DHCA.
Magnetic Resonance Imaging (MRI) has defined neurologic abnormalities in infants with congenital heart disease (CHD) including pre-operative injury and delayed brain maturation. This study utilized qualitative scoring, cerebral biometry, and diffusion imaging to characterize pre-operative brain abnormalities in infants with CHD, including the identification of regions of greater vulnerability.
Sixty-seven infants with CHD had pre-operative MRI with analysis for brain injury by qualitative scoring and brain development by qualitative scoring, metrics and diffusion imaging.
Qualitative abnormalities were common, with 42% of infants having pre-operative focal white matter lesions. Infants with CHD had smaller brain measures in the frontal lobe, parietal lobe, cerebellum and brainstem (p<.001); with the frontal lobe and brainstem displaying the greatest alterations (p<.001). Smaller brain size in the frontal and parietal lobes correlated with delayed white matter microstructure reflected by diffusion imaging.
Infants with CHD commonly display brain injury and delayed brain development. Regional alterations in brain size are present, with the frontal lobe and brainstem demonstrating the greatest alterations, which may reflect a combination of developmental vulnerability and regional differences in cerebral circulation.
To investigated the effect of Granulocyte-colony stimulating factor (G-CSF) on expression of proteins that regulate apoptosis in newborn piglet brain following cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA).
The newborn piglets were assigned to three groups: 1/DHCA (30 min of DHCA, 1hr of low-flow CPB), 2/DHCA with prior injection of G-CSF (17µg/kg 2hrs before CPB) and 3/sham-operated. After 2hrs of post-bypass recovery the frontal cortex, striatum and hippocampus were dissected. The expression of proteins was measured by gel electrophoresis or protein arrays. Data are presented in arbitrary units. Statistical analysis was performed using one way ANOVA. p<0.05 was considered significant.
In the frontal cortex, only Fas-L expression was significantly lower in G-CSF group when compared with DHCA group. In the hippocampus, G-CSF increased Bcl-2 (54.3±6.4 vs. 32.3±2.2, p=0.001) and pAkt (141.4±19 vs. 95.9±21.1, p=0.047) when compared to DHCA group. Caspase-3, Bax, Fas, Fas-L, DR6 and pJAK2 levels were unchanged. The Bcl-2/Bax ratio was 0.33 for DHCA and 0.93 for G-CSF groups (p=0.02). In the striatum, when compared to DHCA group, G-CSF group had higher levels of Bcl-2 (50.3±7.4 vs. 31.8±3.8, p=0.01), pAkt (132.7±12.3 vs. 14±1.34, p=2.3×106), pJAK2 (126±17.4 vs.77.9±13.6, p=0.011), and lower Caspase-3 (12.8±5.0 vs. 32.2±11.5, p=0.033), Fas (390±31 vs. 581±74, p=0.038), Fas-L (20.5±11.5 vs. 57.8±15.6, p=0.04) and DR6 (57.4± 4.4 vs. 108.8±13.4, p=0.007). The Bcl-2/Bax ratio was 0.25 for DHCA and 0.44 for G-CSF groups (p=0.046).
In the piglet model of hypoxic brain injury, G-CSF decreases pro-apoptotic signaling, particularly in the striatum.
G-CSF; DHCA; apoptosis; newborn brain
Genetic modulation of heart function is a novel therapeutic strategy. We investigated the effect of molecular cardiac surgery with recirculating delivery (MCARD)–mediated carboxyl-terminus of the β-adrenergic receptor kinase (βARKct) gene transfer on cardiac mechanoenergetics and β-adrenoreceptor (βAR) signaling.
After baseline measurements, sheep underwent MCARD-mediated delivery of 1014 genome copies of self-complimentary adeno-associated virus (scAAV6)-βARKct. Four and 8 weeks after MCARD, mechanoenergetic studies using magnetic resonance imaging were performed. Tissues were analyzed with real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. βAR density, cyclic adenosine monophosphate levels, and physiologic parameters were evaluated.
There was a significant increase in dP/dtmax at 4 weeks: 1384 ± 76 versus 1772 ± 182 mm Hg/s; and the increase persisted at 8 weeks in response to isoproterenol (P <.05). Similarly, the magnitude of dP/dtmin increased at both 4 weeks and 8 weeks with isoproterenol stimulation (P <.05). At 8 weeks, potential energy was conserved, whereas in controls there was a decrease in potential energy (P <.05) in response to isoproterenol. RT-qPCR confirmed robustness of βARKct expression throughout the left ventricle and undetectable expression in extracardiac tissues. Quantitative Western blot data confirmed higher expression of βARKct in the left ventricle: 0.46 ± 0.05 versus 0.00 in lung and liver (P <.05). Survival was 100%and laboratory parameters of major organ function were within normal limits.
MCARD-mediated βARKct delivery is safe, results in robust cardiac-specific gene expression, enhances cardiac contractility and lusitropy, increases adrenergic reserve, and improves energy utilization efficiency in a preclinical large animal model.
Management of intermediate degrees of mitral regurgitation (MR) during aortic valve replacement (AVR) for aortic stenosis remains controversial. We sought to evaluate the degree of reduction of MR in patients undergoing AVR, as well as the relationship between the pre-operative gradient across the aortic valve and the degree of reduction in MR.
We retrospectively analyzed demographic, intraoperative, and echocardiographic data on 802 patients that underwent AVR or aortic root replacement between January 2010 and March 2011. 578 patients underwent AVR or aortic root replacement without intervention on the mitral valve. We excluded 88 patients with severe aortic insufficiency, 3 patients that underwent ventricular assist device placement, 4 patients that underwent prior mitral valve replacement, and 21 patients with incomplete data yielding 462 patients for analysis. MR was graded for each patient and the degree of change in MR for each patient was determined by subtracting the grade of pre-operative MR from the degree of post-operative MR.
Of the 462 patients, 289 patients had at least mild MR. On average, MR was downgraded by 0.24 degrees per patient for this cohort of 289 patients. Of the 56 patients with at least moderate MR, MR was downgraded 0.54 degrees per patient. Of 62 patients that underwent AVR only, had at least mild MR, and no evidence of structural mitral valve disease, downgrading of MR was 0.24 degrees per patient. Linear regression analysis revealed no relationship between reduction in MR and pre-operative gradient across the aortic valve.
Reduction in MR after relief of aortic outflow tract obstruction is modest at best. Further, the magnitude of the pre-operative gradient across the aortic valve has little influence on the degree of reduction in MR. These observations argue in favor of performing a prospective evaluation of the clinical benefits of addressing moderate MR at the time of aortic valve intervention.
We hypothesized that most relapses in esophageal patients undergoing neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields.
Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who underwent esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years.
Of 267 patients, 82 (30.7%) were complete responders (CR) to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) being partial responders (PR) and non-responders (NR), respectively. Recurrence developed in 84 patients, (CR 18 /82 (21.4%), PR 39/108 (36.1%), NR 27/77 (35.1%) ,p=0.055, respectively.) Most patients recurred at distant sites (65/84;77.4) regardless of pathological response and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for partial and non-responding patients, but was longer for CR patients with distant recurrence whose median disease-free survival was 27.3 months (p=0.008).By multivariate analysis, no other factor except for pathological response to neoadjuvant therapy was associated with disease recurrence or death. PR and NR patients were 1.97 and 2.23 times more likely to recur than CR patients (p=0.024 and p=0.012, respectively).
Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathological response. Fewer patients achieving CR recur, and distant recurrences in these patients manifest later than in patients with PR and NR. Only pathological response is significantly associated with disease recurrence suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.
Esophageal Cancer; Recurrence; Outcomes
We used a whole blood assay to characterize the immune system’s response following cardiopulmonary bypass (CPB) in children to identify the risk for postoperative infections. We assessed the impact of CPB on histone methylation as a potential mechanism for altering gene expression necessary for the immune system’s capacity to defend against infections.
We prospectively enrolled patients <18 years old undergoing heart surgery requiring CPB at C.S. Mott Children’s Hospital. Blood was obtained from patients prior to CPB, on CPB and on postoperative days 1, 3 and 5. Ex vivo LPS-induced TNF-α production measured the capacity of the immune system. Serum cytokines were measured using a multiplex assay. Chromatin Immunoprecipitation (ChIP) to detect histone modifications at the interleukin (IL)-10 promoter was performed on circulating mononuclear cells from a subgroup of patients.
We enrolled 92 patients and postoperative day 1 samples identified a subpopulation of immunocompetent patients at low risk for infections with a specificity of 93% (C.I. 83–98%) and a negative predictive value of 88% (C.I. 77–95%; p=0.006). Patients classified as immunoparalyzed had serum IL-10 levels 2.4 fold higher than the immunocompetent group (mean 14.3 ± 18.3 pg/ml vs. 6.0 ± 5.0 pg/ml, p=0.01). In a subgroup of patients, we identified a greater percent of the “gene on” epigenetic signature, H3K4me3, associated with the IL-10 promoter following CPB.
Our data demonstrate that immunophenotyping patients after CPB can predict their risk of developing postoperative infections. Novel mechanistic data suggest that CPB impacts epigenetic alterations in IL-10 gene regulation.
Cardiopulmonary Bypass; Immunoparalysis; Post-translational histone modification; Interleukin-10; Epigenetics; Sepsis
Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations.
This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared.
Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7–5.1 days) versus 4.2 days (2.9–5.2days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents.
Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.
Our objective was to analyze 3-dimensional (3D) blood flow patterns within the total cavopulmonary connection (TCPC) using in vivo phase contrast magnetic resonance imaging (PC MRI).
Sixteen single-ventricle patients were prospectively recruited at 2 leading pediatric institutions for PC MRI evaluation of their Fontan pathway. Patients were divided into 2 groups. Group 1 comprised 8 patients with an extracardiac (EC) TCPC, and group 2 comprised 8 patients with a lateral tunnel (LT) TCPC. A coronal stack of 5 to 10 contiguous PC MRI slices with 3D velocity encoding (5–9 ms resolution) was acquired and a volumetric flow field was reconstructed.
Analysis revealed large vortices in LT TCPCs and helical flow structures in EC TCPCs. On average, there was no difference between LT and EC TCPCs in the proportion of inferior vena cava flow going to the left pulmonary artery (43% ± 7% vs 46% ± 5%; P = .34). However, for EC TCPCs, the presence of a caval offset was a primary determinant of inferior vena caval flow distribution to the pulmonary arteries with a significant bias to the offset side.
3D flow structures within LT and EC TCPCs were reconstructed and analyzed for the first time using PC MRI. TCPC flow patterns were shown to be different, not only on the basis of LT or EC considerations, but with significant influence from the superior vena cava connection as well. This work adds to the ongoing body of research demonstrating the impact of TCPC geometry on the overall hemodynamic profile.
The best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG–PET). Both FDG–PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non–small cell lung cancer (NSCLC). However, there are limited data correlating FDG–PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG–PET maximal standardized uptake values in NSCLC.
FDG–PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed.
FDG–PET correlated with T classification (P<.0001), N stage (P = .002), and greatest tumor dimension (P<.0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P<.0001) and p53 (P =.04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004).
FDG–PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG–PET with tumor biology will need to consider the effect of different tumor histologic types.