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There are currently no clinically utilized pharmacological agents for the induction of metabolic tolerance to spinal cord ischemia-reperfusion injury in the setting of complex aortic intervention. Nicorandil, a nitric oxide donor and ATP-sensitive potassium (KATP) channel opener, has shown promise in neuroprotection. However, the optimized clinical application of the drug and its mechanism of neuroprotection remains unclear. We hypothesized that 3-days pretreatment would confer the most effective neuroprotection, mediated by mitochondrial KATP channel activation. Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Time course: mice received 0.1 mg/kg nicorandil for 10 min, 4 hours, and 3 consecutive days prior to ischemia compared with control. Dose challenge: mice received 3-days nicorandil pretreatment comparing 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, and saline administration. Mitochondrial KATP channel blocker 5-hydroxy-decanoate (5HD) was co-administered to elucidate mechanism. Limb motor function was evaluated, and viable anterior horn neurons quantified. Nicorandil pretreatment at 4 hours and 3 days before ischemia demonstrated significant motor function preservation; administration 10 minutes before ischemia showed no neuroprotection. All nicorandil doses showed significant motor function preservation. Three days administration of Nicorandil 1.0 mg/kg was most potent. Neuroprotection was completely abolished by 5HD co-administration. Histological analysis showed significant neuron preservation with nicorandil pretreatment, which was attenuated by 5HD co-administration. Three days administration of Nicorandil 1.0 mg/kg showed near-total motor function preservation in a murine spinal cord ischemia-reperfusion model, mediated by the mitochondrial KATP channel.

INTRODUCTION Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is utilized as a life-saving procedure and bridge to myocardial recovery for patients in refractory cardiogenic shock. Despite technical advancements, VA-ECMO retains high mortality. This study aims to identify the clinical predictors of in-hospital mortality after VA-ECMO to improve risk stratification for this tenuous patient population. METHODS The REgistry for Cardiogenic Shock: Utility and Efficacy of Device Therapy database is a multicenter, observational registry of ECMO patients. From 2013 to 2018, 789 patients underwent VA-ECMO. Bivariate analysis was performed on more than 300 variables regarding their association with in-hospital mortality. Logistic regression analyses were performed with variables chosen based upon clinical and statistical significance in the bivariate analysis. Tests were considered significant at a two-sided P

Background Paraplegia remains a significant complication of thoracoabdominal aortic intervention. We previously reported that diazoxide (DZ), enhances the neuroprotective efficacy of erythropoietin (EPO). We hypothesized that DZ and EPO combined treatment attenuates spinal cord ischemic injury through upregulation of nerve growth factor (NGF). Methods DZ (pretreatment) was given to adult male C57/BL6 mice by oral gavage and EPO (before surgery) was intraperitoneally injected 32 h after administration of DZ. Spinal cords were harvested 0, 2, 4, and 6 h after injection of EPO. NGF expression was analyzed by western blot. After determining the optimal time, NGF expression was compared between DZ (pretreatment) + EPO (before surgery), DZ + PBS, PBS + EPO, and PBS + PBS (ischemic control). Four groups were studied to compare the motor function after ischemia: DZ + EPO (n = 11), ischemic control (n = 9), DZ + EPO + tropomyosin receptor kinase A receptor inhibitor (n = 9), and sham (without cross-clamp, n = 4). Spinal cord ischemia was induced by a 4-min thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-h intervals until 48 h, and spinal cords were harvested for evaluation of NGF expression and histological changes. Results NGF expression was significantly upregulated 4 h after administration of EPO. At 4 h after injection of EPO, NGF expression in the DZ + EPO group was significantly higher than that in the other groups. DZ + EPO significantly preserved motor function compared with all other groups. At 48 h after reperfusion, the level of NGF expression in the DZ + EPO group, was significantly higher than in all other groups. Conclusions DZ + EPO attenuates spinal cord ischemic injury through upregulation of NGF. Better understanding of this mechanism may serve to further prevent ischemic complications for aortic intervention.

Introduction: Pharmacologic induction of metabolic tolerance to spinal cord ischemia-reperfusion injury (SCI) after thoracoabdominal aortic intervention is not well established. We previously demonstrated that nicorandil pretreatment preserved motor function in a murine SCI model via direct mitochondrial ATP-sensitive potassium (KATP) channel activation and nitric oxide (NO) donation. However, the independent role of NO-mediated neuroprotection has not been elucidated. Hypothesis: Nitroglycerin pretreatment will induce neuroprotection through NO-mediated KATP channel activation. Methods: SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Pretreatment constituted intraperitoneal injection 3 consecutive days before injury. Experimental groups: sham (no pretreatment or ischemia, n=10), SCI control (normal saline, n=20), nitroglycerin 1 mg/kg (n=18), nitroglycerin 1 mg/kg + 5-hydroxydecanonate 5 mg/kg (5HD, mitochondrial KATP channel blocker, n=13), 5HD 5 mg/kg (n=10), nitroglycerin 1 mg/kg + carboxy-PTIO (cPTIO) 1 mg/kg (NO scavenger, n=16), and cPTIO 1 mg/kg (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results: Compared to SCI control, motor function was significantly preserved in the nitroglycerin pretreatment group at every time point after ischemia. In the nitroglycerin+5HD and nitroglycerin+cPTIO groups, motor preservation was significantly attenuated compared to nitroglycerin pretreatment (p Conclusions: Nitroglycerin pretreatment significantly preserved motor function in a murine SCI model through NO-mediated KATP channel activation.

Neurologic injury is a potentially devastating complication of aortic surgery. The methods used in aortic surgery, including systemic cooling, initiation of circulatory arrest, and rewarming during the replacement of the aortic arch, are the most complex circulatory management and surgical procedures performed in modern-day surgery. Despite the plethora of published literature, neuroprotection in aortic surgery is largely based on observational studies and institutional-based practices. This article summarizes the current evidence and emerging strategies for neuroprotection in aortic arch operations.

Aortic arch surgery remains one of the most technically challenging procedures in cardiac surgery. It demands consideration of myocardial, brain, spinal cord, and lower body protection and rigorous surgical technique. Novel surgical approaches and refinements in brain and end organ protection strategies, liberal use of antegrade cerebral perfusion and moderate hypothermia have made arch repair safer. As endovascular technology and open surgical techniques evolve, aortic surgeons will need to continue to learn and incorporate these methods into practice in order to improve outcomes.

Background The aortic valve interstitial cell (AVIC) has been implicated in the pathogenesis of aortic stenosis. In response to proinflammatory stimulation, the AVIC undergoes a phenotypic change from that of a myofibroblast phenotype to that of osteoblast-like cell. Matrix Gla-protein (MGP) has been identified as an important inhibitor of vascular calcification. We therefore hypothesized that MGP expression is reduced in diseased AVICs, and loss of this protective protein contributes to calcification of the aortic valve. Our purpose was to compare MGP expression in normal versus diseased AVICs. Materials and methods Human AVICs were isolated from normal aortic valves from explanted hearts ( n = 6) at the time of heart transplantation. AVICs were also isolated from calcified, diseased valves of patients ( n = 6) undergoing aortic valve replacement. AVICs were grown in culture until they reached passages 2–6 before experimentation. Immunofluorescent staining, reverse transcriptase-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay were used to compare levels of MGP in normal and diseased AVICs. Statistics were performed using the Mann–Whitney U test ( P Results MGP expression was significantly decreased in diseased AVICs relative to normal AVICs by immunofluorescent staining, reverse transcriptase-polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay. Conclusions An important anti–calcification defense mechanism is deficient in calcified aortic valves. MGP expression is significantly lower in diseased relative to normal AVICs. Lack of this important “anti-calcification” protein may contribute to calcification of the aortic valve.

Purpose Left ventricular assist devices (LVAD) are utilized in patients diagnosed with advanced heart failure. Right ventricular (RV) failure can affect up to 20% of patients undergoing LVAD implantation. In this case study, we evaluated perioperative RV performance with simultaneous use of Swan-Ganz catheterization and high-fidelity conductance catheters to generate real time RV pressure- volume (PV) loops. Methods A 75- year old male patient undergoing LVAD implantation was chosen for evaluation. A high-fidelity conductance catheter was advanced into the RV. The catheter was removed on postoperative day one. Data obtained from the catheter were used to evaluate RV work, contractility, diastolic function, and compliance. These results were compared to standard measurements of the patient's clinical status and biventricular performance. Consent and IRB approval was obtained as part of an ongoing study. Results The patient developed RV dysfunction in the immediate perioperative period, as demonstrated by increasing central venous pressure to pulmonary artery pressure ratio, decreased cardiac index, and evidence of elevated filling pressures by echocardiogram. Using a high-fidelity catheter, we demonstrated a uniform reduction in preload recruitable stroke work and Starling contractile index on postoperative day one. Pressure-volume loops initially demonstrated appropriate ventricular unloading, however RV dysfunction was exposed with changes in loading conditions over time (figure 1). Conclusion Pressure-volume loop analysis represents a novel method for evaluation of RV performance during LVAD implantation. Compared to standard monitoring, PV loops provide increased granularity in understanding RV function.

Background: Coronary artery fluid dynamics may be altered because of the nonphysiological flow seen in continuous-flow left ventricular assist devices (CF-LVADs). Our aim was to study the structure and composition of coronary vessels after CF-LVAD. Methods and Results: Coronary arteries were collected from patients with heart failure (HF) at the time of transplantation, of whom 15 were supported with a CF-LVAD before transplant (HF+LVAD group) and 9 were not (HF non-LVAD group). In addition, coronary samples were obtained from 5 nonfailing age-matched donors (nonfailing group). Histological analysis was performed to quantify coronary morphology, composition, vascular fibrosis, and vasa vasorum density. The age and sex mix of the 3 groups were similar, and the mean duration of LVAD support was 213 days. Compared with patients with HF and nonfailing donors, the arteries from patients with HF+LVAD had expansion of the adventitia, breakdown of the internal elastic lamina, and increased adventitial collagen deposition and density of vasa vasorum. Conclusions: Among patients supported with CF-LVADs, the coronary arteries develop marked remodeling with increased adventitial fibrosis. The physiological consequences of these structural changes are unknown, but it is possible that arterial contractility may be impaired, thus limiting coronary flow reserve and promoting myocardial ischemia. This may contribute to CF-LVAD complications, such as ventricular arrhythmias and right ventricular failure. As more patients receive CF-LVADs and new pump technology attempts to modulate flow profiles and pulsatility, further research is needed to understand the mechanisms and long-term sequela of these changes in coronary arteries and other vascular beds.

Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury.Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting.By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P.01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours.Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention.

Item does not contain fulltext Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-kappaB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.

Anomalous origin of the coronary arteries may limit the applicability of aortic valve sparing techniques during root replacement. We report a case of a right coronary artery that originated from the left sinus and coursed intramurally in a patient with an aortic root aneurysm. Attention to the anatomic relation between the anomalous coronary and aortic root structures and right coronary safety button reconstruction allowed safe aortic root replacement while preserving the native aortic valve.

Objectives: Venoarterial (VA) ECMO has emerged as a successful modality for bridging patients with critical cardiogenic shock to durable support. However, LV distention on ECMO impairs RV and lung recovery and can result in the need for a temporary RVAD. Additionally, patients on VA ECMO with organ dysfunction may require ongoing LV assistance for recovery prior to durable LVAD conversion. Placement of a large apical LV vent allows bedside conversion to LVAD and provides time for organ recovery prior to elective durable device implantation. Hypothesis: We hypothesized that LV venting on ECMO accelerates RV recovery, hastening conversion to LVAD. Methods: ECMO cases from January 2012 to April 2014 were reviewed following IRB approval. Sixteen patients met INTERMACS Category 1 criteria who were placed on VA ECMO for cardiogenic or post-cardiotomy shock. Eight patients had LV venting and eight had standard peripheral cannulation. Refractory pulmonary edema, CPR during cannulation, and severe LV distention were indications for LV venting. A 32 French malleable cannula was placed by limited anterolateral thoracotomy into the LV apex. Bedside LVAD conversion was performed by percutaneous decannulation of the venous line and removal of oxygenator from circuit. Results: Conversion to temporary LVAD was successful in all LV vent cases at a mean timepoint of 5.9 (±1.3) days after LV venting compared with 13.5 (±4.9) days in non-vented patients (p = 0.07). RVAD requirement was 25% in non-vented patients and 0% in vented patients. 30-day mortality was 25% for both groups. Conclusions: LV venting as an adjunct to VA ECMO facilitates RV recovery to enable early LVAD conversion at the bedside. It also provides organ recovery time and obviates the need for a temporary RVAD at the time of durable LVAD implantation. In conclusion, the LV apical venting technique allows staged recovery of critically ill patients in biventricular and multiple organ failure with a high survival rate.

Objectives C-terminal tensin-like (Cten) protein, a component of focal adhesions, contributes to cell motility and invasion in multiple human cancers. Epidermal growth factor can activate signal transducer and activator of transcription 3, and both contribute to invasion through focal adhesion interactions. We hypothesize that Cten may mediate invasion of lung cancer cells provided by epidermal growth factor via signal transducer and activator of transcription 3. Methods Four human non–small cell lung cancer cell lines were treated with epidermal growth factor to evaluate activation of the signal transducer and activator of transcription 3 pathway and induction of Cten expression. Chemical inhibition of signal transducer and activator of transcription 3 was used to evaluate the effect on epidermal growth factor–induced Cten expression. Protein expression was quantified by Western blot. H125 and A549 cells were transduced with short-hairpin RNA via lentiviral vector to knockdown expression of Cten. An in vitro transwell invasion assay was used to assess the effects of Cten knockdown on cell invasion (n = 3 for all experiments). Results Stimulation of lung cancer cells with epidermal growth factor activated the signal transducer and activator of transcription 3 pathway and induced expression of Cten in all cell lines. Signal transducer and activator of transcription 3 inhibition significantly reduced epidermal growth factor–induced expression of Cten in H125 ( P P = .006), and H441 ( P = .014) cells in a dose-dependent manner. Knockdown of Cten expression resulted in significant decreases in cellular invasion in both H125 ( P = .0036) and A549 ( P = .0006) cells. Conclusions These are the first findings in lung cancer to demonstrate that Cten expression mediates invasion of human lung cancer cells and is upregulated by epidermal growth factor via signal transducer and activator of transcription 3 pathway. Cten should be considered a potential therapeutic target for lung cancer.

Although calcific aortic stenosis is common, calcification of the other three heart valves is not. The aortic valve interstitial cell (VIC) has been implicated in the pathogenesis of aortic stenosis. Proinflammatory stimulation of aortic VICs induces an osteogenic and inflammatory phenotypic change. We hypothesized that the VICs of the other heart valves do not undergo these changes. Using isolated human VICs from normal aortic, mitral, pulmonary, and tricuspid valves, our purpose was to compare the osteogenic response to proinflammatory stimulation via toll-like receptor 4 (TLR-4).Aortic, pulmonic, mitral, and tricuspid (n=4 for each valve type) VICs were isolated from hearts valves explanted from patients undergoing cardiac transplantation. Cells were cultured and grown to confluence in passage 2-6 before treatment with Lipopolysaccharide (LPS) (100-200 ng/mL) for 24 or 48 h. Cells were characterized by immunofluorescent staining. TLR-4 expression was analyzed (immunoblotting, flow cytometry). Bone morphogenetic protein 2 and intercellular adhesion molecule 1 production were determined (immunoblotting). Monocyte chemoattractant protein 1 levels were determined by enzyme-linked immunosorbent assay. Statistics were by Mann-Whitney U test.TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P0.05). Intra-cellular adhesion molecule 1 production and monocyte chemoattractant protein 1 secretion increased in a similar fashion among TLR-4-stimulated VICs from all four valves.Proinflammatory stimulation induces an osteogenic phenotype in aortic VICs but not mitral, pulmonic, or tricuspid VICs. We conclude that this differential osteogenic response of aortic VICs contributes to the pathogenesis of calcific aortic stenosis.

Background Endoluminal revascularization has supplanted open techniques for most aortoiliac occlusive disease with open surgery reserved for endovascular failure or long-segment aortoiliac occlusions. A number of clinical and anatomic issues can preclude the use of the infrarenal aorta for inflow. Our approach in these select patients is minimal thoracotomy thoracic bifemoral (mini-TBF) bypass. Methods Mini-TBF bypass used a 2-team approach. The cardiac surgery team focused on arterial inflow from the distal descending aorta via a ≤8-cm thoracotomy at ninth interspace. The vascular surgery team focused on groin reconstruction and graft tunneling. The body of the graft was tunneled through the posterior left hemidiaphragm. The left limb was tunneled retroperitoneal over the psoas and the right limb anterior to the abdominal fascia below the umbilicus to the groin. Results Thirteen patients (mean age, 64; 82% male) underwent mini-TBF bypass between 2009 and 2012 for claudication in 9 (69%) and critical limb ischemia in 4 (31%). Five patients had prior failed iliac endovascular revascularizations and 2 patients had failed prior infrarenal aortobifemoral bypass. The indication for use of thoracic aortic inflow was prior abdominal operations in 4 (31%), pelvic anatomy with a critical inferior mesenteric artery (IMA) in 5 (38%), and the condition of the infrarenal/juxtarenal aorta in 4 (31%). Median operative time was 240 min (range 181–513 min). Median length of stay was 8 days. There was no perioperative mortality. Postoperative complications occurred in 5 patients, stroke 1, pulmonary 2 (both contralateral lung issues), and 2 limb occlusion secondary to outflow disease. At median follow-up of 18 months, 2 patients required amputations, both from preexisting tissue loss despite secondary patent grafts. Conclusions Mini-TBF bypass provides another alternative to successfully revascularize Trans-Atlantic Inter-Society Consensus II type D lesions in patients with prior abdominal revascularization, pelvic anatomy with a critical IMA, or calcification/thrombus of the infrarenal/juxtarenal aorta precludes control.