Importance of social vulnerability on long-term outcomes after heart transplantation.

The relationship between social determinants of health and outcomes after heart transplantation has not been examined. The social vulnerability index (SVI) uses United States census data to determine the social vulnerability of every census tract based on 15 factors. This retrospective study seeks to examine the impact of SVI on outcomes after heart transplantation. Adult heart recipients who received a graft between 2012 and 2021 were stratified into SVI percentiles of <75% and SVI of ≥75%. The primary endpoint was survival. The median SVI was 48% (interquartile range: 30%-67%) among 23 700 recipients. One-year survival was similar between groups (91.4 vs 90.7%, log-rank P = .169); however, 5-year survival was lower among individuals living in vulnerable communities (74.8% vs 80.0%, P < .001). This finding persisted despite risk adjustment for other factors associated with mortality (survival time ratio 0.819, 95% confidence interval: 0.755-0.890, P < .001). The incidences of 5-year hospital readmission (81.4% vs 75.4%, P < .001) and graft rejection (40.3% vs 35.7%, P = .004) were higher among individuals living in vulnerable communities. Individuals living in vulnerable communities may be at increased risk of mortality after heart transplantation. These findings suggest there is an opportunity to focus on these recipients undergoing heart transplantation to improve survival.

Optimizing Nicorandil for Spinal Cord Protection in a Murine Model of Complex Aortic Intervention.

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.

Synergetic Induction of NGF With Diazoxide and Erythropoietin Attenuates Spinal Cord Ischemic Injury.

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.

Innominate Versus Axillary Artery Cannulation for the Hemiarch Repair.

BACKGROUND: Innominate artery cannulation has gained some popularity over the last decade as an alternative to axillary artery cannulation for providing selective antegrade cerebral perfusion during repair of the ascending aorta and arch. Innominate artery cannulation provides several advantages including avoidance of an additional incision and use of a larger caliber artery to provide less resistance to high flow during bypass and selective antegrade cerebral perfusion. We hypothesize that these advantages make innominate artery cannulation superior to axillary artery cannulation as it can decrease operative times and potentially decrease blood loss. METHODS: This was a single-center retrospective analysis of 206 patients who underwent hemiarch replacement between 2009 and 2017. All patients qualified including emergent cases. Groups were separated by mode of cannulation: axillary and innominate. Outcomes evaluated included cardiopulmonary bypass (CPB) time, cross-clamp time, circulatory arrest (CA) time, postoperative transfusions, intensive care unit length of stay, development of any neurological complications, end-organ failure, and mortality. Subgroup analysis was performed for elective and emergent cases. RESULTS: Axillary and innominate artery cannulation accounted for 37% (n = 77) and 67% (n = 129) of cases, respectively. There was no difference in patient characteristics except for a higher incidence of renal disease in the axillary group (16% versus 6%, P = 0.05). More emergent cases were performed in the axillary group (61% versus 17%, P < 0.001). Innominate cases had shorter CPB times (189 versus 150 min, P < 0.001) and CA (22.5 versus 11 min, P < 0.001) times overall. In the elective subgroup, CA times were shorter for the innominate cases. However, the emergent subgroup displayed no difference in operative times. Less transfusions were given in the innominate group including units of red blood cells (2 [0-6] versus 0 [0-2], P < 0.001), units of platelets (2 [1-3] versus 1 [0-2], P = 0.001), and units of plasma (6 [2-9] versus 2 [0-4], P < 0.001). A similar trend was observed in the elective subgroup. No difference in transfusions was observed in the emergent subgroup. There was no statistical difference in remaining outcomes between cases of axillary and innominate cannulation in the combined, elective, and emergent groups. CONCLUSIONS: Alternate cannulation strategies for open arch anastomoses are evolving with a trend toward using the innominate artery. These data suggest that innominate cannulation is at least equivalent to, and may be superior to, axillary cannulation. The innominate artery provides a larger conduit vessel for perfusion and this decrease in resistance to flow, allowing for faster cooling and rewarming, maybe why CPB times were lower in this group. Innominate cannulation is a safe and potentially advantageous technique for hemiarch repair.

Aortic Arch Pathology: Surgical Options for the Aortic Arch Replacement.

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.

Neuroprotection Strategies in Aortic Surgery.

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.

Matrix Gla protein regulates calcification of the aortic valve.

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 < 0.05). 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.

C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3.

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 < .0001), H358 (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.

Erythropoietin activates the phosporylated cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aortic valve calcification is mediated by a differential response of aortic valve interstitial cells to inflammation.

BACKGROUND: 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). MATERIALS AND METHODS: 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. RESULTS: TLR-4 stimulation induced bone morphogenetic protein 2 production only in aortic VICs (P<0.05). 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. CONCLUSIONS: 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.