Activation of matrix metalloproteinases and the renin/angiotensin signaling pathways is under investigation with regard to their potential pathogenesis in dilatative pathology of the aorta. The purpose of this study was to explore matrix metalloproteinase-3 5A/6A and angiotensin-converting enzyme I/D polymorphisms as predisposing factors to dilatative pathology of the aorta.
We studied 107 patients who underwent aortic reconstruction surgery due to dilatative pathology of ascending thoracic aorta and a random sample of the population (n =773), all from Lithuania. The insertion/deletion (−1171 5A/6A) polymorphism in the promoter region of matrix metalloproteinase-3 studied by real-time polymerase-chain-reaction amplification and the D and I alleles were identified on the basis of standard polymerase-chain-reaction amplification of the respective fragments from intron 16 of the angiotensin-converting enzyme gene.
The frequency of the angiotensin-converting enzyme D allele was significantly higher in dilatative pathology of ascending thoracic aorta patients than in the reference group subjects (0.55 vs 0.48, respectively). The latter group had a significantly higher frequency of the angiotensin-converting enzyme I/I genotype than in dilatative pathology of ascending thoracic aorta patients (27.4% vs 16.5%, respectively). In the reference group, the frequency of combined angiotensin-converting enzyme I/I and matrix metalloproteinase-3 6A/6A genotypes was 7.5%, while in the dilatative pathology of ascending thoracic aorta patient group, there was no one carrying that combined genotype (p=0.001).
The present study showing a role of angiotensin-converting enzyme and matrix metalloproteinase-3 in the development of dilatative pathology of ascending thoracic aorta permits us to entertain a possible protective mechanism for the combined effects of the angiotensin-converting enzyme I/I and the matrix metalloproteinase-3 6A/6A genotypes.
Thoracic aorta; Aneurysm; Matrix metalloproteinase-3; Angiotensin-converting enzyme; Polymorphism
Mitochondrial ATP-sensitive potassium channels have been proposed to be myoprotective. The relevance and specificity of this mechanism in cardiac surgery was unknown. The purpose of this study was to examine the effects of the mitochondrial potassium ATP-sensitive channel opener diazoxide on regional and global myocardial protection using a model of acute myocardial infarction.
Pigs (n = 19) were placed on total cardiopulmonary bypass and then subjected to 30 min normothermic regional ischemia by snaring the left anterior descending coronary artery (LAD). The aorta was then crossclamped and cold blood Deaconess Surgical Associates cardioplegia (DSA; n = 6) or DSA containing 50 μM diazoxide (DZX; n = 6) was delivered via the aortic root and the hearts subjected to 30 min hypothermic global ischemia. The crossclamp and snare were removed and the hearts reperfused for 120 min.
No significant differences in preload recruitable stroke work relationship, Tau, proximal, distal or proximal/distal coronary flow, regional or global segmental shortening, systolic bulging or post-systolic shortening were observed within or between DSA and DZX hearts during reperfusion. Infarct was present only in the region of LAD occlusion in both DSA and DZX hearts. Infarct size (% of area at risk) was 33.6 ± 2.9% in DSA and was 16.8 ± 2.4% in DZX hearts (P < 0.01 versus DSA). Apoptosis as estimated by TUNEL positive nuclei was 120.3 ± 48.8 in DSA and was significantly decreased to 21.4 ± 5.3 in DZX hearts. Myocardial infarct was located centrally within the area at risk in both DSA and DZX hearts but was significantly increased at borderline zones within the area at risk in DSA hearts.
The addition of diazoxide to cardioplegia significantly decreases regional myocardial cell necrosis and apoptosis in a model of acute myocardial infarction and represents an additional modality for achieving myocardial protection.
Mitochondrial ATP-sensitive potassium (mitoKATP) channels; Myocardial cell necrosis; Apoptosis; Cardioplegia; Surgery
Despite rapid progress in surgical techniques, there is still a significant lack of surgery-supportive pharmacological treatments. The aim of this study was to test the hypothesis that ursolic acid (UA) may prevent intimal hyperplasia of venous bypass grafts.
The hypothesis was tested by means of primary cell isolation and culture followed by real-time polymerase chain reaction, western blotting, fluorescence microscopy and fluorescence-activated cell sorting analyses, as well as an in vivo rat model for intimal hyperplasia of venous bypass grafts and immunohistochemistry and histochemistry.
The local application of UA significantly inhibited intimal hyperplasia in vivo (intimal thickness control: 25 μm, UA group: 18 μM–8 weeks after surgery). The UA treatment of grafts significantly resulted in reduced endothelial vascular cell adhesion molecule-1 (VCAM-1) expression, reduced infiltration of the grafts vessel wall by CD45-positive cells and increased smooth muscle cell (SMC) death. In in vitro condition, it could be shown that UA inhibits VCAM-1 expression downstream of NFκB and is likely to interfere with VCAM-1 protein synthesis in endothelial cells. Quantification of cell death in vascular smooth muscle cells treated with UA indicated that UA is a potent inducer of SMC apoptosis.
Our results suggest that UA-mediated inhibition of endothelial VCAM-1 expression reduces the infiltration of venous bypass grafts by CD45-positive cells and inhibits intimal hyperplasia. Apoptosis induction in SMCs may be another method in which UA reduces intimal thickening. UA may constitute a surgery-supportive pharmacon that reduces intimal hyperplasia of vein grafts.
Ursolic acid; Sambucus ebulus; Adhesion molecule; Neointima hyperplasia; Coronary artery bypass surgery
The bidirectional Glenn procedure (BDG) is a routine intermediary step in single-ventricle palliation. In this study, we examined risk factors for death or transplant and failure to reach Fontan completion after BDG in patients, who had previously undergone stage one palliation (S1P).
All patients at our institution, who underwent BDG following S1P between 2002 and 2009 (n = 194), were included in the analysis.
Transplant-free survival through 18 months post BDG was 91%. Univariable competing risk analyses showed atrioventricular valve regurgitation (AVVR) >mild, age ≤3 months at BDG, ventricular dysfunction >mild, and prolonged hospital stay after S1P to be associated with increased risk of death or orthotopic heart transplant. Multivariable competing risk analysis through 5 years of follow-up showed >mild AVVR (hazard ratio (HR) 7.5, 95% confidence interval (CI) 3.0–18.8), prolonged hospitalization after S1P (HR 4.5, 95% CI 1.8–11.5), and age ≤3 months at BDG (HR 6.8, 95% CI 2.3–20.0) to be independent risk factors for death or transplant. Concomitantly, >mild AVVR and age ≤3 months were independently associated with an overall decreased rate of Fontan completion.
Pre-BDG AVVR, age ≤3 months at time of BDG, and prolonged hospitalization after S1P are independently associated with decreased successful progression of staged palliation in midterm follow-up after BDG.
Congenital heart disease; CHD; Hypoplastic left heart syndrome; Outcomes; Pediatric
Aortic valves have been implanted on self-expanding (SE) and balloon-expandable (BE) stents minimally invasively. We have demonstrated the advantages of transapical aortic valve implantation (tAVI) under real-time magnetic resonance imaging (rtMRI) guidance. Whether there are different advantages to SE or BE stents is unknown. We report rtMRI guided tAVI in a porcine model using both SE and BE stents, and compare the differences between the stents.
Twenty-two Yucatan pigs (45-57kgs.) underwent tAVI. Commercially available stentless bioprostheses (21-25mm) were mounted on either BE platinum-iridium stents or SE nitinol stents. rtMRI guidance was employed as the intraoperative imaging. Markers on both types of stents were used to enhance the visualization in rtMRI. Pigs were allowed to survive and had follow-up MRI scans and echocardiography at 1, 3 and 6 months postoperatively.
rtMRI provided excellent visualization of the aortic valve implantation mounted on both stent types. The implantation times were shorter with the SE stents (60±14 seconds) than BE (74±18s), (p=0.027). Total procedure time was 31 and 37 minutes respectively (p=0.12). It was considerably easier to manipulate the SE stent during deployment without hemodynamic compromise. This was not always the case with the BE stent and its placement occasionally resulted in coronary obstruction and death. Long-term results demonstrated stability of the implants with preservation of myocardial perfusion and function over time for both stents.
SE stents were easier to position and deploy thus leading to fewer complications during tAVI. Future optimization of SE stent design should improve clinical results.
transcatheter aortic valve implantation; rtMRI guidance; self-expanding stent; balloon-expandable stent
Age is an important risk factor for morbidity after lung resection. This study was performed to identify specific risk factors for complications after lung resection in octogenarians.
A prospective database containing patients aged 80 years or older who underwent lung resection at a single institution between January 2000 and June 2009 was reviewed. Preoperative, histopathologic, perioperative, and outcome variables were assessed. Morbidity was measured as a patient having any perioperative event as defined by the Society of Thoracic Surgeons General Thoracic Surgery Database. A multivariable risk model for morbidity was developed using a panel of established preoperative and operative variables. Survival was calculated using the Kaplan-Meier method.
During the study period, 193 patients aged 80 years or older (median age 82) underwent lung resection: wedge resection in 77, segmentectomy in 13, lobectomy in 96, bilobectomy in 4, and pneumonectomy in 3. Resection was accomplished via thoracoscopy in 149 patients (77%). Operative mortality was 3.6% (7 patients) and morbidity was 46% (89 patients). Patient discharge disposition was directly to home in 181 patients (94%). Postoperative events included atrial arrhythmia in 38 patients (20%), prolonged air leak in 24 patients (12%), postoperative transfusion in 22 patients (11%), delirium in 16 patients (8%), need for bronchoscopy in 14 patients (7%), and pneumonia in 10 patients (5%). Significant predictors of morbidity by multivariable analysis included resection greater than wedge (odds ratio 2.98, p=0.0064), thoracotomy as operative approach (odds ratio 2.64, p=0.034), and % predicted Forced Expiratory Volume in 1 second (odds ratio 1.28 for each 10% decrement, p=0.01).
Octogenarians can undergo lung resection with low mortality. Extent of resection, use of a thoracotomy, and impaired lung function increase the risk of complications. Careful evaluation is necessary to select the most appropriate approach in octogenarians being considered for lung resection.
Lung Surgery; Outcomes; Octogenarians
The adult response to myocardial infarction results in inflammation, scar formation, left ventricular dilatation, and loss of regional and global function. Regenerative scarless healing has been demonstrated in fetal dermis and tendon and is associated with diminished inflammation. We hypothesized that following fetal myocardial infarction there would be minimal inflammation, regenerative healing, and preservation of function.
Anteroapical myocardial infarction encompassing 20% of the left ventricle were created in adult or early gestation fetal sheep. Myocardial function was serially assessed using quantitative echocardiography. Infarct architecture was examined histologically for evidence of scar formation. Cellular inflammation, cellular proliferation, and apoptosis were assessed using immunohistochemistry.
In the adult sheep 4 weeks following myocardial infarction, there was a significant decline in ejection fraction (41±7.4% to 26±7.4%, p<0.05), and the akinetic myocardial segment increased in size (6.9±0.8 cm to 7.9±1.1 cm, p<0.05). In contrast, there was no decline in the fetal ejection fraction (53±8.1% to 55±8.8%) and no akinetic fetal myocardial segment 4 weeks post-infarction. The fetal infarcts lacked an inflammatory cell infiltrate and healed with minimal fibrosis, compared to the adults. Fetal infarcts also demonstrated BrdU+ proliferating cells, including cardiomyocytes, within the infarct.
These data demonstrate that the fetal response to myocardial infarction is dramatically different than the adult and is characterized by minimal inflammation, lack of fibrosis, myocardial proliferation, and restoration of cardiac function. Diminished inflammation is associated with fetal regenerative cardiac healing following injury. Understanding the mechanisms involved in fetal myocardial regeneration may lead to applications to alter the adult response following myocardial infarction.
myocardial infarction; heart failure; inflammation; apoptosis
To define the effects of annuloplasty rings (ARs) on the dynamic motion of anterior and posterior mitral leaflets (AML, PML).
Sheep had radiopaque markers inserted: 8 around the mitral annulus, four along the central meridian (from edge to annulus) of the AML (#A1–#A4) and one on the PML edge (#P1). True-sized Edwards Cosgrove (COS, n=12), St Jude RSAR (n=12), Carpentier-Edwards Physio (PHYSIO, n=12), Edwards IMR ETlogix (ETL, n=10) or Edwards GeoForm (GEO, n=12) ARs were implanted in a releasable fashion. Under acute open-chest conditions, 4-D marker coordinates were obtained using biplane videofluoroscopy with the ARs inserted (COS, RSAR, PHYSIO, ETL, GEO) and after release (COS-CONTROL, RSAR-CONTROL, PHYSIO-CONTROL, ETL-CONTROL, GEO-CONTROL). AML and PML excursions were calculated as the difference between minimum and maximum angles between the central mitral annular septal-lateral chord and the anterior mitral leaflet edge markers (α1exc – α4exc) and PML edge marker (β1exc) during the cardiac cycle.
Relative to CONTROL, 1.) RSAR, PHYSIO, ETL and GEO increased excursion of the AML annular (α4exc: 13±6° vs. 16±7°*, 16±7° vs. 23±10°*, 12±4° vs. 18±9°*, 15±1° vs. 20±9°*, respectively) and belly region (α2exc: 41±10° vs. 45±10°*, 42±8° vs. 45±6°, n.s., 33±13° vs. 42±14°*, 39±6° vs. 44±6°*, respectively, α3exc: 24±9° vs. 29±11°*, 28±10° vs. 33±10°*, 16±9° vs. 21±12°*, 25±7° vs. 29±9°*, respectively), but not of the AML edge (α1exc: 42±8° vs. 44±8°, 43±8° vs. 41±6°, 42±11 vs. 46±10°, 39±9° vs. 38±8°, respectively, all n.s.). COS did not affect AML excursion (α1exc: 40±8° vs. 37±8°, α2exc: 43±9° vs. 41±9°, α3exc: 27±11° vs. 27±10°, α4exc: 18±8° vs. 17±7°,, all n.s.). 2.) PML excursion (β1exc) was reduced with GEO (53±5° vs. 43±6°*), but unchanged with COS, RSAR, PHYSIO or ETL (53±13° vs. 52±15°, 50±13° vs. 49±10°, 55±5° vs. 55±7°, 52±8° vs. 58±6°, respectively, all n.s). *=p<0.05
RSAR, PHYSIO, ETL and GEO rings, but not COS, increase AML excursion of the AML annular and belly region suggesting higher anterior mitral leaflet bending stresses with rigid rings, which potentially could be deleterious with respect to repair durability. The decreased PML excursion observed with GEO could impair LV filling. Clinical studies are needed to validate these findings in patients.
Mitral valve; annuloplasty rings; leaflet dynamics
Objective: Magnesium (Mg2+) is cardioprotective and has been routinely used to supplement cardioplegic solutions during coronary artery bypass graft (CABG) surgery. However, there is no consensus about the Mg2+ concentration that should be used. The aim of this study was to compare the effects of intermittent antegrade warm-blood cardioplegia supplemented with either low- or high-concentration Mg2+. Methods: This study was a randomised controlled trial carried out in two cardiac surgery centres, Bristol, UK and Cuneo, Italy. Patients undergoing isolated CABG with cardiopulmonary bypass were eligible. Patients were randomised to receive warm-blood cardioplegia supplemented with 5 or 16 mmol l−1 Mg2+. The primary outcome was postoperative atrial fibrillation. Secondary outcomes were serum biochemical markers (troponin I, Mg2+, potassium, lactate and creatinine) and time-to-plegia arrest. Intra-operative and postoperative clinical outcomes were also recorded. Results: Data from two centres for 691 patients (342 low and 349 high Mg2+) were analysed. Baseline characteristics were similar for both groups. There was no significant difference in the frequency of postoperative atrial fibrillation in the high (32.8%) and low (32.0%) groups (risk ratio 1.03, 95% confidence interval, CI, 0.82–1.28). However, compared with the low group, troponin I release was 28% less (95% CI 55–94%, p = 0.02) in the high-Mg2+ group. The 30-day mortality was 0.72% (n = 5); all deaths occurred in the high-Mg2+ group but there was no significant difference between the groups (p = 0.06). Frequencies of other major complications were similar in the two groups. Conclusions: Warm-blood cardioplegia supplemented with 16 mmol l−1 Mg2+, compared with 5 mmol l−1 Mg2+, does not reduce the frequency of postoperative atrial fibrillation in patients undergoing CABG but may reduce cardiac injury. (This trial was registered as ISRCTN95530505.)
Myocardial protection; Cardioplegia; CABG; Surgery; Atrial fibrillation; Flutter
Currently, percutaneous aortic valve (PAV) replacement devices are being investigated to treat aortic stenosis in patients deemed to be of too high a risk for conventional open-chest surgery. Successful PAV deployment and function are heavily reliant on the tissue–stent interaction. Many PAV feasibility trials have been conducted with porcine models under the assumption that these tissues are similar to human; however, this assumption may not be valid. The goal of this study was to characterize and compare the biomechanical properties of aged human and porcine aortic tissues.
The biaxial mechanical properties of the left coronary sinus, right coronary sinus, non-coronary sinus, and ascending aorta of eight aged human (90.1 ± 6.8 years) and 10 porcine (6–9 months) hearts were quantified. Tissue structure was analyzed via histological techniques.
Aged human aortic tissues were significantly stiffer than the corresponding porcine tissues in both the circumferential and longitudinal directions (p < 0.001). In addition, the nearly linear stress–strain behavior of the porcine tissues, compared with the highly nonlinear response of the human tissues at a low strain range, suggested structural differences between the aortic tissues from these two species. Histological analysis revealed that porcine samples were composed of more elastin and less collagen fibers than the respective human samples.
Significant material and structural differences were observed between the human and porcine tissues, which raise questions on the validity of using porcine models to investigate the biomechanics involved in PAV intervention.
Percutaneous aortic valve; Aortic sinus; Ascending aorta; Mechanical properties; Animal trials
The effect of seasonal variation on postoperative outcomes following lung cancer resections is unknown. We hypothesized that postoperative outcomes following surgical resection for lung cancer within the United States would not be impacted by operative season.
From 2002 to 2007, 182 507 isolated lung cancer resections (lobectomy (n = 147 937), sublobar resection (n = 21 650), and pneumonectomy (n = 13 916)) were evaluated using the Nationwide Inpatient Sample (NIS) database. Patients were stratified according to operative season: spring (n = 47 382), summer (n = 46 131), fall (n = 45 370) and winter (n = 43 624). Multivariate regression models were applied to assess the effect of operative season on adjusted postoperative outcomes.
Patient co-morbidities and risk factors were similar despite the operative season. Lobectomy was the most common operation performed: spring (80.0%), summer (81.3%), fall (81.8%), and winter (81.1%). Lung cancer resections were more commonly performed at large, high-volume (>75th percentile operative volume) centers (P < 0.001). Unadjusted mortality was lowest during the spring (2.6%, P < 0.001) season compared with summer (3.1%), fall (3.0%) and winter (3.2%), while complications were most common in the fall (31.7%, P < 0.001). Hospital length of stay was longest for operations performed in the winter season (8.92 ± 0.11 days, P < 0.001). Importantly, multivariable logistic regression revealed that operative season was an independent predictor of in-hospital mortality (P < 0.001) and of postoperative complications (P < 0.001). Risk-adjusted odds of in-hospital mortality were increased for lung cancer resections occurring during all other seasons compared with those occurring in the spring.
Outcomes following surgical resection for lung cancer are independently influenced by time of year. Risk-adjusted in-hospital mortality and hospital length of stay were lowest during the spring season.
Season; Lung Cancer; Surgery; Outcomes
Incision into the ventricular septum in complex biventricular repair is controversial, and has been blamed for impairing left ventricular function. This retrospective study evaluates the risk of a ventricular septal incision in patients undergoing double outlet right ventricle (DORV) repair and Ross–Konno procedure.
From January 2003 to September 2007, 11 patients with DORV had a ventricular septum (VS) incision and 12 DORV patients did not. Sixteen patients had a Ross–Konno, and 16 had an isolated Ross procedure. The ventricular septal incision was made to match at least the diameter of a normal aortic annulus. In DORV, the VSD was enlarged superiorly and to the left. In the Ross–Konno, the aortic annulus was enlarged towards the septum posteriorly and to the left.
The median follow-up for the study is 19 months (1 month–4 years). For DORV, there were no significant differences in discharge mortality ( p = 0.22), late mortality ( p = 0.48), or late mortality plus heart transplant ( p = 0.093). Although patients with DORV and VSD enlargement have a more complex postoperative course, there were no differences in ECMO use ( p = 0.093), occurrence of permanent AV block ( p = 0.55), left ventricular ejection fraction (LVEF) ( p = 0.40), or shortening fraction (LVSF) ( p = 0.50). Similarly, for the Ross–Konno there were no significant differences in discharge mortality ( p = 0.30), late mortality ( p = NS), LVEF (p = 0.90) and LVSF ( p = 0.52) compared to the Ross, even though the Ross–Konno patients were significantly younger ( p < 0.0001).
Making a ventricular septal incision in DORV repair and in the Ross–Konno operation does not increase mortality and does not impair the LV function. The restriction of the VSD remains an important issue in the management of complex DORV. These encouraging results need to be confirmed by larger series.
Double outlet right ventricle; Ventricular septal defect; Ross–Konno
In expert hands, the intra-thoracic esophago-gastric anastamosis usually provides a low rate of strictures and leaks. However, anastomoses can be technically challenging and time consuming when minimally invasive techniques are used. We present our preliminary results of a standardized 25mm/4.8mm circular stapled anastomosis using a trans-orally placed anvil.
Materials and Methods
We evaluated a prospective cohort of 37 consecutive patients offered minimally invasive Ivor Lewis Esophagectomy at a tertiary referral center. The esophagogastric anastomosis was created using a 25mm anvil (Orvil, Autosuture, Norwalk, CT) passed trans-orally, in a tilted position, and connected to a 90cm long PVC delivery tube through an opening in the esophageal stump. The anastomosis was completed by joining the anvil to a circular stapler (EEA XL 25mm with 4.8mm Staples, Autosuture, Norwalk, CT) inserted into the gastric conduit. Primary outcomes were leak and stricture rates.
Thirty-seven patients (mean age 65 yrs) with distal esophageal adenocarcinoma (n=29), squamous cell cancer (n=5), or high-grade dysplasia in Barrett's Esophagus (n=3) underwent an Ivor Lewis Esophagectomy between October 2007 and August 2009. The abdominal portion of the operation was completed laparoscopically in 30 patients (81.1%). The thoracic portion was done using a muscle sparing mini-thoracotomy in 23 patients (62.2%) and thoracoscopic techniques in 14 patients (37.8%). There were no intra-operative technical failures of the anastomosis or deaths. Five patients had strictures (13.5%) and all were successfully treated with endoscopic dilations. One patient had an anastomotic leak (2.7%) that was successfully treated by re-operation and endoscopic stenting of the anastomosis.
The circular stapled anastomosis with the transoral anvil allows for an efficient, safe and reproducible anastomosis. This straightforward technique is particularly suited to the completely minimally invasive Ivor Lewis Esophagectomy.
Esophagectomy; Esophageal Cancer; Minimally Invasive; Anastomose; Stapler; Complications
Spinal cord blood flow (SCBF) after sacrifice of thoracoabdominal aortic segmental arteries (TAASA) during thoracoabdominal aortic aneurysm (TAAA) repair remains poorly understood. This study explored SCBF for 72h after sacrifice of all TAASA.
Fourteen juvenile Yorkshire pigs underwent complete serial TAASA sacrifice (T4-L5). Six control pigs underwent anesthesia and cooling to 32C with no TAASA sacrifice. In the experimental animals, spinal cord function was continuously monitored using motor evoked potentials (MEP) until 1 hour (h) after clamping the last TAASA. Fluorescent microspheres enabled segmental measurement of SCBF along the entire spinal cord before, and 5 min, 1h, 5h, 24h and 72h after complete TAASA sacrifice. A modified Tarlov score was obtained for 3 days after surgery.
All the pigs with complete TAASA sacrifice retained normal cord function (MEP) until 1h after TAASA ligation. 7 pigs (50%) with complete TAASA sacrifice recovered after 72h; 7 pigs suffered paraparesis or paraplegia. Intraoperatively— and until 1h postoperatively— SCBF was similar among the three groups along the entire cord. Postoperatively, SCBF did not decrease in any group, but significant hyperemia occurred at 5 hours in controls and recovery animals, but did not occur in pigs that developed paraparesis or paraplegia in the T8-L2 segments (p=.0002) and L3-S segments (p=.0007). At 24h, SCBF remained marginally lower from T8 caudally; at 72h, SCBF was similar among all groups along the entire cord. SCBF in the segments T8-L2 at 5h predicted functional recovery (p=.003).
This study suggests that critical spinal cord ischemia after complete TAASA sacrifice does not occur immediately (intraoperatively), but is delayed 1–5 hours or longer after clamping, and represents failure to mount a hyperemic response to rewarming and awakening. The short duration of low SCBF associated with spinal cord injury suggests that hemodynamic and metabolic manipulation lasting only 24–72 hours may allow routine preservation of normal cord function despite sacrifice of all TAASA secondary to surgical or endovascular repair of large TAAA.
Spinal Cord Perfusion / Protection; Paraparesis / Paraplegia; Segmental Artery Sacrifice; Thoracoabdominal Aortic Aneurysm Repair (TAA/A)
Intracorporeal suturing and knot tying can complicate, prolong or preclude minimally invasive surgical procedures, reducing their advantages over conventional approaches. An automated knot-tying device has been developed to speed suture fixation during minimally invasive cardiac surgery while retaining the desirable characteristics of conventional hand-tied surgeon's knots: holding strength and visual and haptic feedback. A rotating slotted disk (at the instrument's distal end) automates overhand throws, thereby eliminating the need to manually pass one suture end through a loop in the opposing end. Electronic actuation of this disk produces left or right overhand knots as desired by the operator.
To evaluate the effectiveness of this technology, 7 surgeons with varying laparoscopic experience tied knots within a simulated minimally invasive setting, using both the automated knot-tying tool and conventional laparoscopic tools. Suture types were 2-0 braided and 4-0 monofilament.
Mean knot-tying times were 246 ±116 seconds and 102 ±46 seconds for conventional and automated methods, respectively, showing an average 56% reduction in time per surgeon (p=0.003, paired t-test). The peak holding strength of each knot (the force required to break the suture or loosen the knot) was measured using tensile testing equipment. These peak holding strengths were normalized by the ultimate tensile strength of each suture type (57.5 N and 22.1 N for 2-0 braided and 4-0 monofilament, respectively). Mean normalized holding strengths for all knots were 68.2% and 71.8% of ultimate tensile strength for conventional and automated methods, respectively (p= 0.914, paired t-test).
Experimental data reveal that the automated suturing device has great potential for advancing minimally invasive surgery: it significantly reduced knot-tying times while providing equivalent or greater holding strength than conventionally tied knots.
automated suturing; knot-tying; fixation; minimally invasive surgery
Experimental testing of annuloplasty ring (AR) effects requires a control group if the AR is implanted conventionally. Our goal was to develop a reversible AR insertion method that allows for beating heart assessment with and without an AR, providing the ability to evaluate the effects of an AR in the same animal (internal control). We tested the feasibility of this technique in an in vivo ovine model using 4-D radiopaque marker tracking.
Before the operation, a rigid AR (Edwards Geoform®) was prepared by stitching the middle parts of eight double-armed sutures evenly spaced through the ring fabric using a Spring Eye needle. The resulting loops were “locked” with polypropylene sutures. In addition, two drawstring sutures were attached to the AR. Using cardiopulmonary bypass and cardioplegic arrest, twelve adult sheep had 16 radiopaque markers sewn to the mitral annulus. The AR was implanted by stitching the eight sutures equidistantly in a perpendicular direction through the mitral annulus. The sheep were transferred to the catheterization laboratory and 4-D marker coordinates were obtained using biplane videofluoroscopy (60Hz) with the AR inserted (Geo-AR). The locking sutures were then released, the AR was pulled up to the atrial roof using the drawstring sutures and another dataset was acquired (Control). Maximum and minimum mitral annular area (MAAmax, MAAmin) during the cardiac cycle were derived from implanted markers. Data is provided from one representative animal.
AR insertion and release was uneventful in all animals. Whereas the mitral annulus was dynamic in the Control state (MAAmax: 9.0cm2, MAAmin: 7.8cm2), mitral annular dynamics were abolished in the Geo-AR case (MAAmax: 6.2cm2, MAAmin: 6.0cm2).
This novel releasable AR implantation method is feasible and permits in vivo assessment of AR effects in the same heart. The new technique should facilitate experimental AR testing and promote the development of ARs based on physical criteria.
annuloplasty ring; reversible ring implantation; novel insertion method; ovine model
Hyperglycaemia has been associated with worse outcome following traumatic brain injury and cardiac surgery in adults. We have previously reported no relationship between early postoperative hyperglycaemia and worse neurodevelopmental outcome at 1 year following biventricular repair of congenital heart disease. It is not known if postoperative hyperglycaemia results in worse neurodevelopmental outcome after infant cardiac surgery for single-ventricle lesions.
Secondary analysis of postoperative glucose levels in infants <6 months of age undergoing Stage I palliation for various forms of single ventricle with arch obstruction. The patients were enrolled in a prospective study of genetic polymorphisms and neurodevelopmental outcomes assessed at 1 year of age with the Bayley Scales of Infant Development-II yielding two indices: mental developmental index (MDI) and psychomotor developmental index (PDI).
Stage I palliation was performed on 162 infants with 13 hospital and 15 late deaths (17.3% 1-year mortality). Neurodevelopmental evaluation was performed in 89 of 134 (66.4%) survivors. Glucose levels at admission to the cardiac intensive care unit and during the first 48 postoperative hours were available for 85 of 89 (96%) patients. Mean admission glucose value was 274 ± 91 mg dl−1; the maximum was 291 ± 90 mg dl−1, with 69 of 85 (81%) patients having at least one glucose value >200 mg dl−1. Only two patients had a value <50 mg dl−1. Mean MDI and PDI scores were 88 ± 16 and 71 ± 18, respectively. There were no statistically significant correlations between initial, mean, minimum or maximum glucose measurements and MDI or PDI scores. Only delayed sternal closure resulted in a statistically significant relationship between initial, minimum and maximum glucose values within the context of a multivariate analysis of variance model.
Hyperglycaemia following Stage I palliation in the neonatal period was not associated with lower MDI or PDI scores at 1 year of age.
Congenital heart disease; Hyperglycaemia; Patient outcomes; Postoperative care
As part of our ongoing quality improvement effort, we evaluated our conventional approach to post-oesophagectomy management by comparing it to an alternative postoperative management pathway.
Medical records from 386 consecutive patients undergoing oesophagectomy with gastric conduit for oesophageal cancer or Barrett’s oesophagus with high-grade dysplasia were analysed retrospectively (July 2004 to August 2008). The conventional pathway involved a routine radiographic contrast swallow study at 5—7 days after oesophagectomy with initiation of oral intake if no leak was detected. In the alternative pathway, a feeding jejunostomy was placed for enteral feeding and used exclusively until oral intake was gradually initiated at home at 4 weeks after oesophagectomy. No contrast swallow was obtained in the alternative pathway group unless indicated by clinical suspicion of an anastomotic leak. Each group was analysed on an intention-to-treat basis with respect to anastomotic leak rates, length of hospitalisation, re-admission and other complications.
A total of 276 (72%) patients underwent conventional postoperative management, 110 (28%) followed the alternative pathway. Patient characteristics were similar in both the groups. The anastomotic leak rate was lower in the alternative pathway with three clinically significant leaks (2.7%) versus 33 in the conventional pathway (12.0%; p = 0.01). Among patients undergoing a radiographic contrast swallow examination, a false-negative rate of 5.8% was observed. The swallow study of 14 patients (5.9%) was complicated by aspiration of oral contrast. Postoperatively, 7.3% of patients suffered from pneumonia. There were no significant differences overall in postoperative pulmonary or cardiac complications associated with either pathway. Median length of hospitalisation was 2 days shorter for the alternative pathway (7 days) than the conventional pathway (9 days; p < 0.001). There was no significant difference in unplanned re-admission rates.
An alternative postoperative pathway following oesophagectomy involving delayed oral intake and avoidance of a routine contrast swallow study is associated with a shortened length of hospitalisation without a higher risk of complication after hospital discharge.
Oesophageal cancer; Oesophageal surgery; Nutrition; Postoperative care; Outcomes
To better define early and long-term outcomes of patients undergoing thoracic metastasectomy for thyroid cancer.
We identified, reviewed, and analyzed the medical records of all patients who underwent thoracic metastasectomy for thyroid cancer in our institution from 1971 to 2006.
There were 48 patients (25 men, 23 women). A complete resection (R0) of all known disease was performed in 33 (69%) patients, while 15 (31%) underwent incomplete resection (R1 or R2). By histology, the majority were papillary 31 (65%), follicular 8 (17%), medullary 5 (10%), and Hürthle cell 4 (8%). Ninety percent were confined to a single side of the chest, with 10% presenting with bilateral metastases. Thoracotomy was performed in 28 (58%), sternotomy in 12 (25%), and thoracoscopy was used in 8 (17%). Operative mortality was zero and postoperative complications occurred in 8 patients (17%). There are currently 18 surviving patients from the cohort (37%) with a median follow-up of 10 years (range, 1 month to 17 years). The overall 5-year survival after thoracic metastasectomy was 60%. Based on histology, 5-year survival for papillary cancer was 64% compared to 37% for follicular and Hürthle cell neoplasms (p = 0.03). All five medullary thyroid cancer patients were alive at 5 years. Five-year survival was also improved for patients less than 45 years old at the time of diagnosis of their initial thyroid malignancy (94% vs 49%; p = 0.03). Disease-free interval of >3 years between initial thyroid malignancy diagnosis and thoracic metastasectomy demonstrated improved 5-year survival (67% vs 52%; p = 0.01).
Pulmonary resection for thyroid metastasis is safe with low morbidity and mortality. Retrospective analysis demonstrates improved long-term survival in patients with papillary histology, longer disease-free interval (>3 years) and younger age at diagnosis of initial thyroid malignancy. Excellent long-term survival was also achievable in selected patients with medullary thyroid metastasis.
Thoracic metastasectomy; Thyroid metastasis; Pulmonary metastasectomy; Thyroid cancer
Esophageal cancer tumor biology is best assessed clinically by FDG-PET. Both FDG-PET SUVmax and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumors markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer.
FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to (28/67) 42% of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known esophageal cancer tumor markers (GLUT1, p53, cyclin D1, EGFR, and VEGF). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p-value < 0.05 was considered significant.
There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (N=29, 43%), stage II (N=19, 28%), stage III disease (N=18, 27%), and stage IV disease (N=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor.
FDG-PET SUVmax correlates with an increased expression of GLUT1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.
esophageal cancer; tumor markers; FDG-PET
To determine the effect of recovery with mild hypothermia after cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on the activity of selected key proteins involved in initiation (Bax, Caspase-3) or inhibition of apoptotic injury (Bcl-2, increased ratio Bcl-2/Bax) in the brain of newborn piglets.
The piglets were placed on CPB, cooled with pH-stat management to 18 °C, subjected to 30 min of DHCA followed by 1 h of low flow at 20 ml/kg/min, rewarmed to 37 °C (normothermia) or to 33 °C (hypothermia), separated from CPB, and monitored for 6 h. Expression of above proteins was measured in striatum, hippocampus and frontal cortex by Western blots. The results are mean for six experiments ± SEM.
There were no significant differences in Bcl-2 level between normothermic and hypothermic groups. The Bax levels in normothermic group in cortex, hippocampus and striatum were 94 ± 9, 136 ± 22 and 125 ± 34 and decreased in the hypothermic group to 59 ± 17 ( p = 0.028), 70 ± 6 (p = 0.002) and 48 ± 8 (p = 0.01). In cortex, hippocampus and striatum Bcl-2/Bax ratio increased from 1.23, 0.79 and 0.88 in normothermia to 1.96, 1.28 and 2.92 in hypothermia. Expression of Caspase-3 was 245 ± 39, 202 ± 74 and 244 ± 31 in cortex, hippocampus and striatum in the normothermic group and this decreased to 146 ± 24 ( p = 0.018), 44 ± 16 ( p = 7 × 10−7) and 81 ± 16 ( p = 0.01) in the hypothermic group.
In neonatal piglet model of cardiopulmonary bypass with circulatory arrest, mild hypothermia during post bypass recovery provides significant protection from cellular apoptosis, as indicated by lower expression of Bax and Caspase-3 and an increased Bcl-2/Bax ratio. The biggest protection was observed in striatum probably by decreasing of neurotoxicity of striatal dopamine.
Newborn; Brain; Cardiopulmonary bypass; Circulatory arrest; Hypothermia; Apoptosis
To investigate the possible neuroprotective effects of selective cerebral perfusion (SCP) during deep hypothermic circulatory arrest on brain oxygenation and metabolism in newborn piglets.
Newborn piglets 2–4 days of age, anesthetized and mechanically ventilated, were used for the study. The animals were placed on cardiopulmonary bypass, cooled to 18 °C and put on SCP (20 ml/(kg min)) for 90 min. After rewarming, the animals were monitored through 2 h of recovery. Oxygen pressure in the microvasculature of the cortex was measured by oxygen-dependent quenching of phosphorescence. The extracellular level of dopamine in striatum was measured by microdialysis and hydroxyl radicals by ortho-tyrosine levels. Levels of phosphorylated cAMP response element binding protein (pCREB) in striatal tissue were measured by Western blots using antibodies specific for phosphorylated CREB. The results are presented as mean ± SD (p < 0.05 was significant).
Pre-bypass cortical oxygen pressure was 48.9 ± 11.3 mmHg and during the first 5 min of SCP, the peak of the histogram, corrected to 18 °C, decreased to 11.2 ± 3.8 mmHg (p < 0.001) and stayed near that value to the end of bypass. The mean value for the peak of the histograms measured at the end of SCP was 8 ± 3 mmHg (p < 0.001). SCP completely prevented the deep hypothermic circulatory arrest-dependent increase in extracellular dopamine and hydroxyl radicals. After SCP, there was a statistically significant increase in pCREB immunoreactivity (534 ± 60%) compared to the sham-operated group (100 ± 63%, p < 0.005). Measurements of total CREB showed that SCP did induce a statistically significant increase in CREB as compared to sham-operated animals (168 ± 31%, p < 0.05).
SCP, as compared to DHCA, improved cortical oxygenation and prevented increases in the extracellular dopamine and hydroxyl radicals. The increase in pCREB in the striatum following SCP may contribute to improved cellular recovery after this procedure.
Selective cerebral perfusion; Brain oxygenation; Dopamine; Hydroxyl radicals; cAMP response element binding protein
Objective: Coarctation of the aorta has often been described as a simple form of congenital heart disease. However, rates of re-coarctation reported in the literature vary from 7% to 60%. Re-coarctation of the aorta may lead to worsening systemic hypertension, coronary artery disease and/or congestive cardiac failure. We aimed to describe the rates of re-coarctation in subjects who had undergone early coarctation repair (<2 years of age) and referred for clinically indicated or routine magnetic resonance (MR) surveillance. Methods: We retrospectively identified 50 consecutive subjects (20.2 ± 6.9 years post-repair) imaged between 2004 and 2008. Patient characteristics, rates of re-coarctation and LV/aortic dimensions were examined. Results: Forty percent of subjects had bicuspid aortic valves (BAV). There were 40 cases of end-to-end repair and 10 cases of subclavian flap repair. Re-intervention with balloon angioplasty or repeat surgery had been performed in 32% of subjects. The MRI referrals were clinically indicated in 34% and routine in 66% of patients. Re-coarctation was considered moderate or severe in 34%, mild in 34% and no re-coarctation was identified in 32% of patients. There was no significant difference in the number of cases of re-coarctation identified in the clinically indicated versus routine referrals for MR imaging (p = 0.20). There were no cases of aortic dissection or aneurysm formation identified amongst the subjects. The mean indexed left ventricular mass and ejection fraction was 72 ± 16 g/m2 and 66 ± 6%, respectively. Amongst those subjects with BAV there were larger aortic sinus (30 ± 1 mm vs 27 ± 1 mm, p = 0.03) and ascending aortic (27 ± 1 mm vs 23 ± 1 mm, p = 0.01) dimensions when compared to subjects with morphologically tricuspid aortic valves. Conclusions: We demonstrate that many years after early repair of coarctation of the aorta, MR surveillance detects significant rates of re-coarctation. These findings were independent of whether or not there was a clinical indication for imaging. Those patients with BAV disease had larger ascending aortic dimensions and may require more frequent non-invasive surveillance.
Coarctation; Aorta; Surgery; Magnetic resonance imaging
Ischemia-reperfusion (I/R) injury, often encountered clinically, results in myocardial apoptosis and necrosis. Hydrogen sulfide (H2S) is produced endogenously in response to ischemia and thought to be cardioprotective, although its mechanism of action is not fully known. This study investigates cardioprotection provided by exogenous H2S, generated as sodium sulfide on apoptosis following myocardial I/R injury.
The mid-LAD coronary artery in Yorkshire swine (n=12) was occluded for 60 minutes, followed by reperfusion for 120 minutes. Controls (n=6) received placebo, and treatment animals (n=6) received sulfide 10 minutes prior to and throughout reperfusion. Hemodynamic, global, and regional functional measurements were obtained. Evans blue/TTC staining identified the area-at-risk (AAR) and infarction. Serum CK-MB, troponin I, and FABP were assayed. Tissue expression of bcl-2, bad, apoptosis-inducing-factor (AIF), total & cleaved caspase-3, and total & cleaved PARP were assessed. PAR and TUNEL staining were performed to assess apoptotic cell counts, and poly-ADP ribosylation, respectively.
Pre-I/R hemodynamics were similar between groups. Post-I/R, mean arterial pressure (mmHg) was reduced by 30.2±4.3 in controls vs. 8.2±6.9 in treatment animals (p=0.01). +LV dP/dt (mmHg/sec) was reduced by 1308±435 in controls vs. 403±283 in treatment animals (p=0.001). Infarct size (% of AAR) in controls was 47.4±6.2% vs. 20.1±3.3% in the treated group (p=0.003). In treated animals, CK-MB and FABP were lower by 47.0% (p=0.10) and 45.1% (p=0.01), respectively. AIF, caspase-3, and PARP expression was similar between groups, whereas cleaved caspase-3 and cleaved PARP was lower in treated animals (p=0.04). PAR staining was significantly reduced in sulfide treated groups (p=0.04). TUNEL staining demonstrated significantly fewer apoptotic cells in sulfide treated animals (p=0.02).
Sodium sulfide is efficacious in reducing apoptosis in response to I/R injury. Along with its known effects on reducing necrosis, sulfide’s effects on apoptosis may partially contribute to providing myocardial protection. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered.
Ischemia; Reperfusion; Apoptosis; Cardiac; Sulfide; Protection
Growth-factor based angiogenesis, with or without cell therapy, is a promising therapeutic modality for patients with coronary artery disease. We compared the relative efficacies of surgically delivered vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in a swine model of hypercholesterolemia-induced endothelial dysfunction which captures many of the pathophysiologic abnormalities of human coronary disease.
Yucatan mini-swine (20–30 kg), fed a high cholesterol diet (total 20 weeks), underwent circumflex ameroid placement to create chronic myocardial ischemia, followed three weeks later by perivascular administration of VEGF (2 μg; n=6), FGF-2 (100 μg; n=6), or placebo (n=7) in the ischemic territory. Normocholesterolemic animals (n=7) served as controls. Four weeks later, endothelial function, collateral-dependent perfusion, as well as myocardial protein and mRNA levels of angiogenic mediators were assessed.
Endothelial dysfunction was observed in all hypercholesterolemic animals as impaired microvessel relaxation in response to adenosine diphosphate and VEGF. VEGF administration improved baseline-adjusted collateral-dependent perfusion at rest(−0.03±0.05 vs. −0.12±0.04, VEGF vs. placebo, p=0.09), but FGF-2 delivery caused a significantly greater improvement in perfusion compared to either group (+0.15±0.03, p<0.05 vs. HC-placebo and HC-VEGF) at rest. Molecular analysis revealed increased eNOS expression (135% ± 8%, p=0.03 vs. placebo) in all growth factor treated animals and increased expression of FGF-2 receptor, FGFR1, (65 ± 26%, p = 0.04 vs. placebo) in FGF-2 treated animals. No significant changes were demonstrated in other angiogenic mediators including Akt, Syndecan-4.
In the setting of hypercholesterolemic endothelial dysfunction, FGF-2 is more effective than VEGF at enhancing collateral-dependent perfusion and thus, may be a better candidate than VEGF for angiogenic therapy in patients with end-stage CAD.
Endothelial Dysfunction; Vascular Endothelial Growth Factor; Fibroblast Growth Factor; Myocardial Ischemia; Angiogenesis; Molecular Biology