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A significant percentage of patients have coronary artery disease that is too advanced or diffuse for percutaneous or surgical intervention. Therapeutic angiogenesis is a treatment modality to induce vessel formation that is being developed for patients with advanced coronary disease not amenable to currently available interventions. A number of approaches to induce coronary collateralization are being developed. These include gene, protein, cellular and miRNA modalities, each of which have advantages and disadvantages. At this time, no modality has emerged as the single clear choice, and combination therapies may provide synergistic benefits. However, there have been a number of recent studies advancing our knowledge as to how we can refine procollateralizing treatments. In this article, we will examine some recent successes and future obstacles in the effort to bring therapeutic angiogenesis to patients. [ABSTRACT FROM AUTHOR]

Background: Emerging data suggest women have worse outcomes than men following cardioplegia and cardiopulmonary bypass (CP/CPB). Altered coronary microvascular function affecting myocardial perfusion may contribute, but human translational studies are lacking., Methods: Viable coronary microvessels (<200 μ m) were dissected from human atrial samples collected before and after CP/CPB from a subset of 108 patients enrolled. Ex vivo contractile responses to vasopressin were assessed using video microscopy. RNA deep-sequencing and immunoblotting were used to quantify gene and protein expression, respectively., Results: Coronary microvessels exhibited increased vasopressin-induced contractile responses post-CP/CPB in males and females (p ​< ​0.0001). Females exhibited a decrease in microvascular contractile response versus males pre- (p ​= ​0.1) and post-CP/CPB (p ​= ​0.09) which approached significance. Myocardial vasopressin 1a receptor levels were increased in females versus males (p ​= ​0.001). Vasopressin-induced vasoconstriction predicted postoperative cardiac index., Conclusions: Impaired coronary microvascular contractile responses in females jeopardizing myocardial perfusion may underlie worse outcomes following cardiac surgery., Competing Interests: Declaration of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

As cardiovascular care continues to advance and with an aging population with higher comorbidities, the epidemiology of the cardiac intensive care unit has undergone a paradigm shift. There has been increasing emphasis on the development of multidisciplinary teams (MDTs) for providing holistic care to complex critically ill patients, analogous to heart teams for chronic cardiovascular care. Outside of cardiovascular medicine, MDTs in critical care medicine focus on implementation of guideline-directed care, prevention of iatrogenic harm, communication with patients and families, point-of-care decision-making, and the development of care plans. MDTs in acute cardiovascular care include physicians from cardiovascular medicine, critical care medicine, interventional cardiology, cardiac surgery, and advanced heart failure, in addition to nonphysician team members. In this document, we seek to describe the changes in patients in the cardiac intensive care unit, health care delivery, composition, logistics, outcomes, training, and future directions for MDTs involved in acute cardiovascular care. As a part of the comprehensive review, we performed a scoping of concepts of MDTs, acute hospital care, and cardiovascular conditions and procedures., Competing Interests: Declaration of competing interest JDA reports research funding from Boston Scientific, Shockwave, Med Alliance, and Microport, and consults for Medtronic, Abbott, Penumbra, and Recor. All other authors have no relevant financial or intellectual conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cardiogenic shock (CS) is a syndrome of low cardiac output resulting in critical end-organ hypoperfusion and hypoxia. The mainstay of management involves optimizing preload, afterload and contractility. In medically refractory cases, temporary percutaneous mechanical support (MCS) is used as a bridge to recovery, surgical ventricular assist device, or transplant. Anticoagulation is recommended to prevent device-related thromboembolism. However, MCS can be fraught with hemorrhagic complications, compounded by incident multisystem organ failure often complicating CS. Currently, there are limited data on optimal anticoagulation strategies that balance the risk of bleeding and thrombosis, with most centers adopting local antithrombotic stewardship practices. In this review, we detail anticoagulation protocols, including anticoagulation agents, therapeutic monitoring, and complication mitigation in CS requiring MCS. This review is intended to provide an evidence-based framework in this population at high risk for in-hospital bleeding and mortality., Competing Interests: Disclosures JDA receives research funding from Boston Scientific, Shockwave and Med Alliance and serves as a consultant for Abbott, Medtronic, Penumbra, and Recor. All other authors report no relevant conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There has been an evolution in the disease severity and complexity of patients presenting to the cardiac intensive care unit (CICU). There are limited data evaluating the role of palliative care in contemporary CICU practice., Methods: PubMed Central, CINAHL, EMBASE, Medline, Cochrane Library, Scopus, and Web of Science databases were evaluated for studies on palliative care in adults (≥18 years) admitted with acute cardiovascular conditions - acute myocardial infarction, cardiogenic shock, cardiac arrest, advanced heart failure, post-cardiac surgery, spontaneous coronary artery dissection, Takotsubo cardiomyopathy, and pulmonary embolism - admitted to the CICU, coronary care unit or cardiovascular intensive care unit from 1/1/2000 to 8/8/2022. The primary outcome of interest was the utilization of palliative care services. Secondary outcomes of included studies were also addressed. Meta-analysis was not performed due to heterogeneity., Results: Of 5711 citations, 30 studies were included. All studies were published in the last seven years and 90 % originated in the United States. Twenty-seven studies (90 %) were retrospective analyses, with a majority from the National Inpatient Sample database. Heart failure was the most frequent diagnosis (47 %), and in-hospital mortality was reported in 67 % of studies. There was heterogeneity in the timing, frequency, and background of the care team that determined palliative care consultation. In two randomized trials, there appeared to be improvement in quality of life without an impact on mortality., Conclusions: Despite the growing recognition of the role of palliative care, there are limited data on palliative care consultation in the CICU., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite the importance of informed consent in healthcare, the readability and specificity of consent forms often impede patients' comprehension. This study investigates the use of GPT-4 to simplify surgical consent forms and introduces an AI-human expert collaborative approach to validate content appropriateness. Consent forms from multiple institutions were assessed for readability and simplified using GPT-4, with pre- and post-simplification readability metrics compared using nonparametric tests. Independent reviews by medical authors and a malpractice defense attorney were conducted. Finally, GPT-4's potential for generating de novo procedure-specific consent forms was assessed, with forms evaluated using a validated 8-item rubric and expert subspecialty surgeon review. Analysis of 15 academic medical centers' consent forms revealed significant reductions in average reading time, word rarity, and passive sentence frequency (all P < 0.05) following GPT-4-faciliated simplification. Readability improved from an average college freshman to an 8th-grade level (P = 0.004), matching the average American's reading level. Medical and legal sufficiency consistency was confirmed. GPT-4 generated procedure-specific consent forms for five varied surgical procedures at an average 6th-grade reading level. These forms received perfect scores on a standardized consent form rubric and withstood scrutiny upon expert subspeciality surgeon review. This study demonstrates the first AI-human expert collaboration to enhance surgical consent forms, significantly improving readability without sacrificing clinical detail. Our framework could be extended to other patient communication materials, emphasizing clear communication and mitigating disparities related to health literacy barriers., (© 2024. The Author(s).)

Introduction: Neurocognitive decline (NCD) is a common complication after cardiac surgery with implications for outcomes and quality of life. Identifying risk factors can help surgeons implement preventative measures, optimize modifiable risk factors, and counsel patients about risk and prognosis., Methods: Prospective cohort study at a single academic center. 104 patients planned to undergo cardiac surgery were enrolled. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to measure neurocognitive function preoperatively, on postoperative day four, and postoperative day 30. NCD is defined as a change in RBANS scaled score of < -8 from baseline to postoperative day 4. Patient charts were reviewed for medication history: beta-blockers, angiotensin-converting enzyme and angiotensin receptor blockers, calcium channel blockers, statins, oral hypoglycemic agents, and psychoactive medications. Charts were also reviewed to calculate postoperative opioid usage., Results: NCD was detected in 42.9% of patients. Incidence of NCD was significantly higher in patients taking a psychoactive medication (56.8%) than patients not (31.9%), P < 0.03. There was no relationship between historical use of beta-blocker, calcium-channel blocker, statin, or oral hypoglycemic medications and incidence of NCD. Simple linear regression showed no relationship between change in RBANS total scaled score and opioid usage. There was no difference in incidence of NCD at 1 mo., Conclusions: Patients with a history of taking psychoactive medications prior to cardiac surgery have an increased risk of acute postoperative NCD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies., Methods: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%., Discussion: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs., (© 2023. The Author(s).)

Background: The clinical applicability of machine learning predictions of patient outcomes following cardiac surgery remains unclear. We applied machine learning to predict patient outcomes associated with high morbidity and mortality after cardiac surgery and identified the importance of variables to the derived model's performance., Methods: We applied machine learning to the Society of Thoracic Surgeons Adult Cardiac Surgery Database to predict postoperative hemorrhage requiring reoperation, venous thromboembolism (VTE), and stroke. We used permutation feature importance to identify variables important to model performance and a misclassification analysis to study the limitations of the model., Results: The study dataset included 662,772 subjects who underwent cardiac surgery between 2015 and 2017 and 240 variables. Hemorrhage requiring reoperation, VTE, and stroke occurred in 2.9%, 1.2%, and 2.0% of subjects, respectively. The model performed remarkably well at predicting all 3 complications (area under the receiver operating characteristic curve, 0.92-0.97). Preoperative and intraoperative variables were not important to model performance; instead, performance for the prediction of all 3 outcomes was driven primarily by several postoperative variables, including known risk factors for the complications, such as mechanical ventilation and new onset of postoperative arrhythmias. Many of the postoperative variables important to model performance also increased the risk of subject misclassification, indicating internal validity., Conclusions: A machine learning model accurately and reliably predicts patient outcomes following cardiac surgery. Postoperative, as opposed to preoperative or intraoperative variables, are important to model performance. Interventions targeting this period, including minimizing the duration of mechanical ventilation and early treatment of new-onset postoperative arrhythmias, may help lower the risk of these complications., Competing Interests: Conflict of Interest Statement D.B. receives research support from and consults for LivaNova; has served medical advisory boards for Abiomed, Xenios, Medtronic, Inspira and Cellenkos; is the President-elect of the Extracorporeal Life Support Organization (ELSO) and the Chair of the Executive Committee of the International ECMO Network (ECMONet). C.E.V. has served as a consultant for Regeneron, Merck, and Janssen, outside of the submitted work. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Neurocognitive decline (NCD) is a common complication of cardiac surgery. Understanding risk factors helps surgeons counsel patients pre- and perioperatively about risk, prevention, and treatment., Study Design: Patients undergoing cardiac surgery using cardiopulmonary bypass underwent pre- and postoperative neurocognitive testing. Neurocognitive data are presented as a change from baseline to either postoperative day 4 or to 1 month. The score is standardized with respect to age., Results: Eighty-four patients underwent surgery and completed postoperative neurocognitive testing. There was no significant difference in baseline neurocognitive function. NCD was more common in female patients (71%) than male patients (26.4%) on postoperative day 4. By 1 month, the incidence of NCD is similar between female (15.0%) and male patients (14.3%). Of note, female patients differed from male patients in preoperative hematocrit, preoperative creatinine, and type of surgery., Conclusions: In the acute postoperative period, female patients are both more likely to experience NCD and experience a more severe change from baseline cognitive function. This difference between male and female patients resolves by the 1 month follow-up point. Female patients had a lower preoperative hematocrit and were more likely to receive intraoperative and perioperative blood transfusion. Lower preoperative hematocrit appears to mediate the difference in NCD between male and female patients., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Whether perioperative glycemic control is associated with neurocognitive decline (NCD) after cardiac surgery was examined., Methods: Thirty patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) were screened for NCD preoperatively and on postoperative day 4 (POD4). Indices of glucose control were examined. Serum cytokine levels were measured and human transcriptome analysis was performed on blood samples. Neurocognitive data are presented as a change from baseline to POD4 in a score standardized with respect to age and gender., Results: A decline in neurocognitive function was identified in 73% (22/30) of patients on POD4. There was no difference in neurocognitive function between patients with elevated HbA1c levels preoperatively (p = .973) or elevated fasting blood glucose levels the morning of surgery (>126 mg/dl, p = .910), or a higher maximum blood glucose levels during CPB (>180 mg/dl, p = .252), or higher average glucose levels during CPB (>160 mg/dl, p = .639). Patients with postoperative leukocytosis (WBC ≥ 10.5) had more NCD when compared to their baseline function (p = .03). Patients with elevated IL-8 levels at 6 h postoperatively had a significant decline in NCD at POD4 (p = .04). Human transcriptome analysis demonstrated unique and differential patterns of gene expression in patients depending on the presence of DM and NCD., Conclusions: Perioperative glycemic control does not have an effect on NCD soon after cardiac surgery. The profile of gene expression was altered in patients with NCD with or without diabetes., (© 2021 Wiley Periodicals LLC.)

Competing Interests: Disclosure: C.E.V. served as a past consultant for Maquet Cardiovascular. The other authors have no conflicts of interest to report.

Pneumonia causes short- and long-term cognitive dysfunction in a high proportion of patients, although the mechanism(s) responsible for this effect are unknown. Here, we tested the hypothesis that pneumonia-elicited cytotoxic amyloid and tau variants: (1) are present in the circulation during infection; (2) lead to impairment of long-term potentiation; and, (3) inhibit long-term potentiation dependent upon tau. Cytotoxic amyloid and tau species were recovered from the blood and the hippocampus following pneumonia, and they were present in the extracorporeal membrane oxygenation oxygenators of patients with pneumonia, especially in those who died. Introduction of immunopurified blood-borne amyloid and tau into either the airways or the blood of uninfected animals acutely and chronically impaired hippocampal information processing. In contrast, the infection did not impair long-term potentiation in tau knockout mice and the amyloid- and tau-dependent disruption in hippocampal signaling was less severe in tau knockout mice. Moreover, the infection did not elicit cytotoxic amyloid and tau variants in tau knockout mice. Therefore, pneumonia initiates a tauopathy that contributes to cognitive dysfunction., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background Mesenchymal stem cell-derived extracellular vesicles (EVs) promote angiogenesis in the ischemic myocardium. This study examines the difference in vascular density, myocardial perfusion, molecular signaling, and gene expression between normal diet (ND) and high fat diet (HFD) groups at baseline and following intramyocardial injection of EVs. Methods and Results Intact male Yorkshire swine fed either an ND (n=17) or HFD (n=14) underwent placement of an ameroid constrictor on the left circumflex coronary artery. Subsequently, animals received either intramyocardial injection of vehicle-saline as controls; (ND-controls n=7, HFD-controls, n=6) or EVs; (ND-EVs n=10, HFD-EVs n=8) into the ischemic territory. Five weeks later, myocardial function, perfusion, vascular density, cell signaling, and gene expression were examined. EVs improved indices of myocardial contractile function, myocardial perfusion, and arteriogenesis in both dietary cohorts. Interestingly, quantification of alpha smooth muscle actin demonstrated higher basal arteriolar density in HFD swine compared with their ND counterparts; whereas EVs were associated with increased CD31-labeled endothelial cell density only in the ND tissue, which approached significance. Levels of total endothelial nitric oxide synthase, FOXO1 (forkhead box protein O1) , transforming growth factor-β, phosphorylated VEGFR2 (vascular endothelial growth factor receptor 2), and phosphorylated MAPK ERK1/ERK2 (mitogen-activated protein kinase) were higher in ischemic myocardial lysates from ND-controls compared with HFD-controls. Conversely, HFD-control tissue showed increased expression of phosphorylated endothelial nitric oxide synthase, phosphorylated FOXO1, VEGFR2, and MAPK ERK1/ERK2 with respect to ND-controls. Preliminary gene expression studies indicate differential modulation of transcriptional activity by EVs between the 2 dietary cohorts. Conclusions HFD produces a profound metabolic disorder that dysregulates the molecular mechanisms of collateral vessel formation in the ischemic myocardium, which may hinder the therapeutic angiogenic effects of EVs.

Background: Mesenchymal stem cell-derived extracellular vesicles (EVs) appear to be a very exciting treatment option for heart disease. Here, we used a swine model of chronic myocardial ischemia to evaluate the efficacy of a less-invasive method of injection of EVs via a peripheral intravenous route., Methods: Sixteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex (LCx) artery at age 11 weeks to induce chronic myocardial ischemia. Two weeks later, they were divided into two groups: control (CON; n = 8), and intravenous injection of EVs (EVIV; n = 8). At 18 weeks of age, animals underwent final analysis and euthanasia. The chronically ischemic myocardium (LCx territory) was harvested for analysis., Results: Intravenous injection (IV) of EVs induced several pro-angiogenic markers such as MAPK, JNK but not Akt. Whereas IV injections of EVs decreased VEGFR2 expression and inhibited apoptotic signaling (caspase 3), they increased expression of VEGFR1 that is believed to be anti-angiogenic. Injection of EVs did not result in an increase in vessel density and blood flow when compared to the control group., Conclusions: Although IV injection of EVs upregulated several pro-angiogenic signaling pathways, it failed to induce changes in vascular density in the chronically ischemic myocardium. Thus, a lack of increase in vascular density at the doses tested failed to elicit a functional response in ischemic myocardium., Competing Interests: The authors have declared that no competing interests exist.

Background: Diabetic (DM) inactivation of small conductance calcium-activated potassium (SK) channels contributes to coronary endothelial dysfunction. However, the mechanisms responsible for this down-regulation of endothelial SK channels are poorly understood. Thus, we hypothesized that the altered metabolic signaling in diabetes regulates endothelial SK channels and human coronary microvascular function., Methods: Human atrial tissue, coronary arterioles and coronary artery endothelial cells (HCAECs) obtained from DM and non-diabetic (ND) patients (n = 12/group) undergoing cardiac surgery were used to analyze metabolic alterations, endothelial SK channel function, coronary microvascular reactivity and SK gene/protein expression/localization., Results: The relaxation response of DM coronary arterioles to the selective SK channel activator SKA-31 and calcium ionophore A23187 was significantly decreased compared to that of ND arterioles (p < 0.05). Diabetes increases the level of NADH and the NADH/NAD + ratio in human myocardium and HCAECs (p < 0.05). Increase in intracellular NADH (100 μM) in the HCAECs caused a significant decrease in endothelial SK channel currents (p < 0.05), whereas, intracellular application of NAD + (500 μM) increased the endothelial SK channel currents (p < 0.05). Mitochondrial reactive oxygen species (mROS) of HCAECs and NADPH oxidase (NOX) and PKC protein expression in the human myocardium and coronary microvasculature were increased respectively (p < 0.05)., Conclusions: Diabetes is associated with metabolic changes in the human myocardium, coronary microvasculature and HCAECs. Endothelial SK channel function is regulated by the metabolite pyridine nucleotides, NADH and NAD + , suggesting that metabolic regulation of endothelial SK channels may contribute to coronary endothelial dysfunction in the DM patients with diabetes., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cardiopulmonary bypass may be associated with postoperative neurocognitive dysfunction; however, risk factors have not been clearly identified. We hypothesize that lower hematocrit levels are correlated with postoperative neurocognitive dysfunction., Methods: A total of 30 patients underwent cardiac operations utilizing cardiopulmonary bypass and screening for neurocognitive dysfunction preoperatively and on postoperative day 4. Patients were analyzed according to hematocrit preoperatively, 6 hours postoperatively, and on postoperative day 4, and whether they received intra or postoperative transfusions of packed red blood cells. Neurocognitive data is presented as a difference in Repeatable Battery for the Assessment of Neuropsychological Status standardized score from baseline to postoperative day 4 and analyzed by unpaired two-tailed Spearman test and unpaired Mann-Whitney U test., Results: There was a significant correlation between patients with lower hematocrit before surgery and a decline in neurocognitive function at postoperative day 4 (P < .05). All patients experienced a decrease in hematocrit during their hospital stay, but the hematocrit 6 hours postoperatively and postoperative day 4 did not impact cognition. Receiving a transfusion was also not associated with neurocognitive dysfunction. Patients with low hematocrit preoperatively had a consistently lower hematocrit throughout their stay. Prolonged total length of stay was also significantly associated with neurocognitive decline., Conclusion: A lower preoperative hematocrit and prolonged length of hospital stay are correlated with neurocognitive decline after cardiac surgery utilizing cardiopulmonary bypass., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite advances in left ventricular assist device (LVAD) technology, right ventricular failure (RVF) continues to be a complication after implantation. Most patients undergoing LVAD implantation have underlying right ventricular (RV) dysfunction (either as a result of prolonged LV failure or systemic disorders) that becomes decompensated post-implantation. Additional insults include intra-operative factors or a sudden increase in preload in the setting of increased cardiac output. The current literature estimates post-LVAD RVF from 3.9% to 53% using a diverse set of definitions. A few of the risk factors that have been identified include markers of cardiogenic shock (e.g., dependence on inotropes and Interagency Registry for Mechanically Assisted Circulatory Support profiles) as well as evidence of cardiorenal or cardiohepatic syndromes. Several studies have devised multivariable risk scores; however, their performance has been limited. A new functional assessment of RVF and a novel hepatic marker that describe cholestatic properties of congestive hepatopathy may provide additional predictive value. Furthermore, future studies can help better understand the relationship between pulmonary hypertension and post-LVAD RVF. To achieve our ultimate goal-to prevent and effectively manage RVF post-LVAD-we must start with a better understanding of the risk factors and pathophysiology. Future research on the different etiologies of RVF-ranging from acute post-surgical complication to late-onset RV cardiomyopathy-will help standardize definitions and tailor therapies appropriately.

There has been rapid adoption of extracorporeal life support (ECLS) in adult patients with severe acute respiratory failure. Extracorporeal membrane oxygenation (ECMO) is used to rescue patients with severe hypoxemic and hypercapnic respiratory failure refractory to optimal therapy and extracorporeal carbon dioxide removal (ECCO2R) supports hypercapnic respiratory failure and allows very low tidal volume ventilation to minimize the risk of ventilator-induced lung injury. Currently over 3,000 cases of ECLS (ECMO and ECCO2R) in adults with respiratory failure are reported annually to the Extracorporeal Life Support Organization registry. Advances in the care of patients with acute respiratory distress syndrome, technological innovations in extracorporeal circuitry, and insights from modern clinical trials of ECLS have led to favorable outcomes and a renewed interest in the use of this technology. Significant gaps in knowledge about best practices remain, however. This review will summarize indications for respiratory support in adults, current evidence available from clinical trials and our institution's experience with adult respiratory ECLS.

Background Ischemic heart disease continues to be a leading cause of mortality in patients. Extracellular vesicles (EVs) provide a potential for treatment that may induce collateral vessel growth to increase myocardial perfusion. Methods and Results Nineteen male Yorkshire pigs were given a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs received either intramyocardial vehicle (n=6), EVs (high-fat diet with myocardial EV injection [HVM]; n=8), or HVM and calpain inhibition (n=5). Five weeks later, myocardial function, perfusion, coronary vascular density, and cell signaling were examined. Perfusion in the collateral-dependent myocardium was increased during rapid ventricular pacing in the HVM group in both nonischemic (P=0.04) and ischemic areas of the ventricle (P=0.05). Cardiac output and stroke volume were significantly improved in the HVM group compared with the control group during ventricular pacing (P=0.006). Increased arteriolar density was seen in the HVM group in both nonischemic and ischemic myocardium (P=0.003 for both). However, no significant changes in the capillary density were observed between the control, HVM, and HVM and calpain inhibition groups (P=0.07). The group that received EVs with oral calpain inhibition had neither increased vessel density (P>0.99) nor improvement in blood flow or cardiac function (P=0.48) when compared with the control group. Conclusions These findings suggest that EVs promote angiogenesis in areas of chronic myocardial ischemia and improve cardiac function under conditions of diet-induced metabolic syndrome.

Background: Transfusion of blood products commonly occur in patients undergoing repair of acute type A aortic dissection (AADA)., Materials and Methods: The medical records of 102 AADA patients were retrospectively reviewed and stratified into cohorts by packed red blood cell (PRBC) and platelet units received: PRBC ≤2 units (n = 68) versus PRBC >2 units (n = 34); platelets ≤1 unit (n = 74) versus platelets >1 unit (n = 28). Continuous and categorical variables were assessed by analysis of variance testing and chi-square or Fisher's testing as appropriate. Multivariate logistic regression was applied to derive P values for post-transfusion complications. Kaplan-Meier survival analyses were used to compare the hospital length of stay (LOS) and survival rate at 1 mo and 1 y., Results: Patients receiving >2 units of PRBC had a median LOS of 14 d versus 9 d for those receiving ≤2 units (P < 0.002). Transfusion of >2 units of PRBC was a risk factor for postoperative infection (odds ratio [OR] = 5.4, 95% confidence interval [CI]: 1.5-19.0, P = 0.009). Survival at 1 mo was 91% versus 94% (P = 0.783) and 1 y survival was 82% versus 93% (P = 0.269) between the two groups. Patients receiving >1 unit of platelets had a median LOS of 15 d versus 10 d for those receiving ≤1 unit (P = 0.005). Transfusion of >1 unit of platelets was a risk factor for postoperative atrial fibrillation and acute kidney injury (OR = 2.9, 95% CI: 1.1-7.6, P = 0.031; OR = 3.3, 95% CI: 1.2-9.4, P = 0.025, respectively). Survival at 1 mo was 93% versus 93% (P = 0.872) and 1 y survival was 81% versus 92% (P = 0.582) between the two groups., Conclusions: Transfusion of PRBC and platelets above a threshold increases the incidence of postoperative complications and hospital LOS among patients undergoing repair of AADA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Transcatheter aortic valve replacement (TAVR) exposes patients to radiation., Objectives: We sought to identify factors associated with higher radiation exposure and to quantify their relative influence, which may inform reduction of this hazard., Methods: All TAVR procedures at Rhode Island Hospital between March 20, 2012 and February 12, 2017 were included. Procedures were performed by two co-primary operators using a Siemens Artis Zeego system. Radiation metrics were generated by the imaging system. The primary metric was dose-area product (DAP, Gy*cm 2 ), and secondary metrics were reference point air kerma (mGy) and fluoroscopy time (minutes). Data collected for the STS/ACC TVT Registry were utilized to develop a multivariable linear regression model predicting DAP., Results: In 294 TAVRs, median DAP was 169 Gy*cm 2 [interquartile range (IQR) 106-238]. The r 2 values for the full 27-variable DAP model and reduced eight-variable model were 0.457 and 0.420, respectively. Valve area, aortic insufficiency, and procedure year (suggesting absence of a learning curve) were non-significant predictors in the full model, while increasing weight, cutdown transfemoral access, higher pre-procedure creatinine and hemoglobin, and vascular complications predicted higher DAP in both models. Results were unchanged when DAP was log-transformed. Secondary models for air kerma and fluoroscopy time revealed similar predictors., Conclusion: Factors associated with increased procedural complexity and duration as well as radiation attenuation and scatter predict increased patient radiation exposure during TAVR. Modification of procedural technique, especially using percutaneous femoral vascular access, may facilitate reduction in exposure., (© 2017 Wiley Periodicals, Inc.)

Background: Mesenchymal stem cell-derived extracellular vesicles (EVs) are believed to be cardioprotective in myocardial infarct. The objective of this study was to examine the effects of human mesenchymal cell-derived EV injection on cardiac function, myocardial blood flow, and vessel density in the setting of chronic myocardial ischemia., Methods and Results: Twenty-three Yorkshire swine underwent placement of an ameroid constrictor on their left circumflex artery. Two weeks later, the animals were split into 2 groups: the control group (CON; n=7) and the EV myocardial injection group (MVM; n=10). The MVM group underwent myocardial injection of 50 μg of EVs in 2 mL 0.9% saline into the ischemic myocardium. Five weeks later, the pigs underwent a harvest procedure, and the left ventricular myocardium was analyzed. Absolute blood flow and the ischemic/nonischemic myocardial perfusion ratio were increased in the ischemic myocardium in the MVM group compared with the CON group. Pigs in the MVM group had increased capillary and arteriolar density in the ischemic myocardial tissue compared with CON pigs. There was an increase in expression of the phospho-mitogen-activated protein kinase/mitogen-activated protein kinase ratio, the phospho-endothelial nitric oxide synthase/endothelial nitric oxide synthase ratio, and total protein kinase B in the MVM group compared with CON. There was an increase in cardiac output and stroke volume in the MVM group compared with CON., Conclusions: In the setting of chronic myocardial ischemia, myocardial injection of human mesenchymal cell-derived EVs increases blood flow to ischemic myocardial tissue by induction of capillary and arteriolar growth via activation of the protein kinase B/endothelial nitric oxide synthase and mitogen-activated protein kinase signaling pathways resulting in increased cardiac output and stroke volume., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: Glycogen synthase kinase 3β (GSK-3β) inhibition has been reported to increase microvascular density and improve myocardial blood flow in a porcine model of chronic myocardial ischemia and metabolic syndrome. Inhibition of GSK-3β can also be cardioprotective by modulating fibrosis signaling and mitochondrial-induced apoptosis. We hypothesized GSK-3β inhibition would have a beneficial effect on myocardial fibrosis and oxidative stress in a porcine model of chronic myocardial ischemia and metabolic syndrome., Methods: Pigs were fed a high fat diet for 4 weeks followed by placement of an ameroid constrictor to the left circumflex coronary artery. Three weeks later animals received either no drug or a GSK-3β inhibitor. The diets and placebo/GSK-3β inhibition were continued for an additional 5 weeks, the pigs were then euthanized, and the myocardial tissue was harvested. Collagen expression was analyzed via Picrosirius staining. Oxidative stress was analyzed via Oxyblot analysis. Protein expression was analyzed via Western blot., Results: GSK-3β inhibition was associated with decreased collagen expression and oxidative stress in the ischemic and nonischemic myocardial tissue compared with control. There was a decrease in profibrotic proteins transforming growth factor-β, p-SMAD2/3, and matrix metalloproteinase-9, and in proapoptotic and oxidative stress proteins, apoptosis inducing factor, the cleaved caspase 3/caspase 3 protein ratio and phosphorylated myeloid cell leukemia sequence-1 in the GSK-3β inhibited group compared with the control., Conclusions: In the setting of metabolic syndrome and chronic myocardial ischemia, inhibition of GSK-3β decreases collagen formation and oxidative stress in myocardial tissue. GSK-3β inhibition might be having this beneficial effect by downregulating transforming growth factor-β/SMAD2/3 signaling and decreasing mitochondrial induced cellular stress., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Coronary artery disease (CAD) is the number one cause of death among men and women in the USA. Genetic predisposition and environmental factors lead to the development of atherosclerotic plaques in the vessel walls of the coronary arteries, resulting in decreased myocardial perfusion. Treatment includes a combination of revascularization procedures and medical therapy. Because of the high surgical risk of many of the patients undergoing revascularization procedures, medical therapies to reduce ischemic disease are an area of active research. Small molecule, cytokine, endothelial progenitor cell, stem cell, gene, and mechanical therapies show promise in increasing the collateral growth of blood vessels, thereby reducing myocardial ischemia.

Development of membranous ventricular septal defects (VSD) is a rare complication of transcatheter aortic valve replacements (TAVR), and is recognized using intraoperative and postoperative imaging. We present two cases of this rare but serious complication; one was successfully managed conservatively and the other with valve-in-valve therapy. Management strategies for post-TAVR VSDs varies, but should be individualized to the clinical scenario. We performed a literature search and sought to identify various risk factors which may predispose patients to the development of VSD after TAVR., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3β (GSK-3β) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome., Methods: Pigs were fed a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor to the left circumflex artery. Three weeks later, the animals received no drug (high-cholesterol controls [HCC]), a high-dose calpain inhibitor (HCI), a low-dose calpain inhibitor (LCI), or a GSK-3β inhibitor (GSK-3βI). The diets and drug regimens were continued for 5 weeks and the myocardial tissue was harvested., Results: Calpain and GSK-3β inhibition caused an increase in myocardial perfusion ratios at rest and during pacing compared with controls. Pigs in the LCI and HCI groups had increased vessel density in the ischemic myocardium, and pigs in the GSK-3βI group had increased vessel density in the ischemic and nonischemic myocardium compared with the HCC group. Calpain inhibition modulates proteins involved in the insulin/PI3K and WNT/β-catenin pathways. Quantitative proteomics revealed that calpain and GSK-3β inhibition significantly modulated the expression of proteins enriched in cytoskeletal regulation, metabolism, respiration, and calcium-binding pathways., Conclusions: In the setting of metabolic syndrome, calpain or GSK-3β inhibition increases vessel density in both ischemic and nonischemic myocardial tissue. Calpain inhibition may exert these effects through the inhibition of GSK-3β and up-regulation of downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: The use of novel oral anticoagulants such as dabigatran has been increasing over the last five years. Indicated for use in the prevention of thromboembolic complications from non-valvular atrial fibrillation and for the treatment and prevention of venous thromboembolic disease, dabigatran is increasingly encountered clinically. Lack of an efficacious reversal agent has been a challenge for increased clinical 10 adoption, and for management of patients with bleeding complications while taking dabigatran, or those requiring urgent procedures while taking dabigatran. Idarucizumab, a monoclonal antibody fragment, has recently been approved for use to reverse anticoagulation with dabigatran in patients with serious bleeding., Areas Covered: Herein we discuss the development and early clinical data evaluating the use of idarucizumab for dabigatran reversal. Expert commentary: Idarucizumab has been shown to be an efficacious reversal agent for patients receiving dabigatran. The drug provides a novel and clinically useful agent for patients with significant bleeding while receiving dabigatran, or those needing urgent invasive procedures.

Background: Inhibition of glycogen synthase kinase 3β (GSK-3β) has been reported to be cardioprotective during stressful conditions., Methods and Results: Pigs were fed a high-fat diet for 4 weeks to develop metabolic syndrome, then underwent placement of an ameroid constrictor to their left circumflex artery to induce chronic myocardial ischemia. Two weeks later, animals received either: no drug (high cholesterol control group [HCC]) or a GSK-3β inhibitor (GSK-3β inhibited group [GSK-3βI]), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK-3βI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK-3βI group compared to the HCC group: vascular endothelial growth factor receptor 1 , vascular endothelial cadherin, γ-catenin, β-catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2., Conclusions: In the setting of metabolic syndrome, inhibition of GSK-3β increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include β-catenin signaling and AKT/FOXO1, through which GSK-3β appears to improve vessel density and blood flow. These results may provide a potential mechanism for medical therapy of patients suffering from coronary artery disease and metabolic syndrome., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objectives: Previous animal studies have demonstrated that endothelial adherens-junction molecules are significantly altered in animal myocardium and microvasculature after cardioplegia and cardiopulmonary bypass (CP/CPB). We investigated the effects of diabetes on expression/phosphorylation/localization of vascular endothelial (VE)-cadherin, β- and γ-catenin in human atrial myocardium and coronary vasculature in the setting of CP/CPB., Methods: Right atrial tissue was harvested pre- and post-CP/CPB from non-diabetic (ND) [haemoglobin A1c (HbA1c): 5.4 ± 0.15], controlled (CDM) (HbA1c: 6.3 ± 0.14) and uncontrolled diabetic (UDM) (HbA1c: 9.9 ± 0.72) patients (n = 10/group). Expression/phosphorylation/localization of VE-cadherin, β- and γ-catenin were assessed by immunoblotting, immunoprecipitation and immunohistochemistry. In vitro atrial microvascular reactivity was assessed by videomicroscopy in response to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP)., Results: There were no significant differences in VE-cadherin protein expression between pre- and post-CP/CPB among groups. There were significant decreases in VE-cadherin densities in vessels of the UDM group versus the ND group at baseline or post-CP/CPB, respectively (P < 0.05). The level of basal phosphorylated VE-cadherin tends to be higher in the UDM compared with the ND group (P < 0.05). CP/CPB induced more phosphorylation of VE-cadherin in all groups (versus pre-CP/CPB; P < 0.05, respectively) and this effect was more pronounced in the UDM group (P < 0.05 versus ND or CDM). The protein levels of both catenins (β and γ) were lower in post-CP/CPB in UDM than ND patients (P < 0.05). There were significant decreases in vasodilatory response to endothelial-dependent vasodilator ADP after CP/CPB (P < 0.05). This alteration was more pronounced in UDM patients (P < 0.05)., Conclusions: These data suggest that poorly controlled diabetes down-regulates endothelial adherens-junction protein activation/expression/localization in the setting of CP/CPB. The increased tyrosine phosphorylation and deterioration of VE-cadherin indicate the damage of the cell-cell endothelial junctions in the diabetic vessels undergoing CP/CPB and cardiac surgery. These alterations may lead to increase in vascular permeability and endothelial dysfunction and affect outcomes in diabetic patients after cardiac surgery., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)