Afterload-induced Decreases in Fatty Acid Oxidation Develop Independently of Increased Glucose Utilization.

Background: Metabolic substrate utilization in HFpEF (heart failure with preserved ejection fraction), the leading cause of heart failure worldwide, is pivotal to syndrome pathogenesis and yet remains ill defined. Under resting conditions, oxidation of free fatty acids (FFA) is the predominant energy source of the heart, supporting its unremitting contractile activity. In the context of disease-related stress, however, a shift toward greater reliance on glucose occurs. In the setting of obesity or diabetes, major contributors to HFpEF pathophysiology, the shift in metabolic substrate use toward glucose is impaired, sometimes attributed to the lower oxygen requirement of glucose oxidation versus fat metabolism. This notion, however, has never been tested conclusively. Furthermore, whereas oxygen demand increases in the setting of increased afterload, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a "preference" for glucose has been proposed. Methods and Results: Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. As PDK4 (PDC kinase 4) is up-regulated in HFpEF, we over-expressed PDK4 in cardiomyocytes, ensuring that PDC is phosphorylated and thereby inhibited. This leads to diminished use of pyruvate as energy substrate, mimicking the decline in glucose oxidation in HFpEF. Importantly, distinct from HFpEF-associated obesity, this model positioned us to abrogate the load-induced shift to glucose utilization in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac performance at baseline. However, they manifested a rapid and severe decline in contractile performance when challenged with modest increases in afterload triggered either by L-NAME or surgical transverse aortic constriction (TAC). This decline in function was not accompanied by an exacerbation of the myocardial hypertrophic growth response. Surprisingly, metabolic flux analysis revealed that, after TAC, fractional FAO decreased, even when glucose/pyruvate utilization was clamped at very low levels. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically downregulated after TAC regardless of genotype. Conclusions: These data demonstrate that cardiomyocytes in a setting in which glucose utilization is robustly diminished and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use.

Treating Atrial Fibrillation is No Maze: A Reminder to Heart Teams for Concomitant Surgical Ablation for Atrial Fibrillation With Cardiac Surgery.

Atrial fibrillation (AF) is the most prevalent arrhythmia and is often found during times of other cardiac pathologies that require surgical management including coronary revascularization and valve surgery. Surgical ablation of AF, most frequently performed through the Cox-Maze IV procedure, is highly effective in restoring sinus rhythm. Despite robust society guideline recommendations for concomitant surgical ablation (CSA) for AF, the practice has yet to be widely adopted. In this review, we discuss the current indications for CSA, its efficacy in maintaining freedom from atrial tachyarrhythmias, stroke, and adverse long-term outcomes, the safety profile of SA when performed alongside cardiac surgical cases, and challenges with its implementation across the most common concomitant cardiac operations. In conclusion, we present a reminder to multidisciplinary heart teams to consider CSA when indicated for their patients.

Effects of RBT-1 on preconditioning response biomarkers in patients undergoing coronary artery bypass graft or heart valve surgery: a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: RBT-1 is a combination drug of stannic protoporfin (SnPP) and iron sucrose (FeS) that elicits a preconditioning response through activation of antioxidant, anti-inflammatory, and iron-scavenging pathways, as measured by heme oxygenase-1 (HO-1), interleukin-10 (IL-10), and ferritin, respectively. Our primary aim was to determine whether RBT-1 administered before surgery would safely and effectively elicit a preconditioning response in patients undergoing cardiac surgery. Methods: This phase 2, double-blind, randomised, placebo-controlled, parallel-group, adaptive trial, conducted in 19 centres across the USA, Canada, and Australia, enrolled patients scheduled to undergo non-emergent coronary artery bypass graft (CABG) and/or heart valve surgery with cardiopulmonary bypass. Patients were randomised (1:1:1) to receive either a single intravenous infusion of high-dose RBT-1 (90 mg SnPP/240 mg FeS), low-dose RBT-1 (45 mg SnPP/240 mg FeS), or placebo within 24-48 h before surgery. The primary outcome was a preoperative preconditioning response, measured by a composite of plasma HO-1, IL-10, and ferritin. Safety was assessed by adverse events and laboratory parameters. Prespecified adaptive criteria permitted early stopping and enrichment. This trial is registered with ClinicalTrials.gov, NCT04564833. Findings: Between Aug 4, 2021, and Nov 9, 2022, of 135 patients who were enrolled and randomly allocated to a study group (46 high-dose, 45 low-dose, 44 placebo), 132 (98%) were included in the primary analysis (46 high-dose, 42 low-dose, 44 placebo). At interim, the trial proceeded to full enrollment without enrichment. RBT-1 led to a greater preconditioning response than did placebo at high-dose (geometric least squares mean [GLSM] ratio, 3.58; 95% CI, 2.91-4.41; p < 0.0001) and low-dose (GLSM ratio, 2.62; 95% CI, 2.11-3.24; p < 0.0001). RBT-1 was generally well tolerated by patients. The primary drug-related adverse event was dose-dependent photosensitivity, observed in 12 (26%) of 46 patients treated with high-dose RBT-1 and in six (13%) of 45 patients treated with low-dose RBT-1 (safety population). Interpretation: RBT-1 demonstrated a statistically significant cytoprotective preconditioning response and a manageable safety profile. Further research is needed. A phase 3 trial is planned. Funding: Renibus Therapeutics, Inc.

Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Clinical and radiological septic joint analysis of spontaneous sternoclavicular joint infections: achieving the best outcomes-a systems engineering approach.

OBJECTIVES: Spontaneous sternoclavicular joint infection (SSCJI) is a rare and poorly understood disease process. This study aims to identify factors guiding effective management strategies for SSCJI by using data mining. METHODS: An Institutional Review Board-approved retrospective review of patients from 2 large hospitals (2010-2022) was conducted. SSCJI is defined as a joint infection without direct trauma or radiation, direct instrumentation or contiguous spread. An interdisciplinary team consisting of thoracic surgeons, radiologists, infectious disease specialists, orthopaedic surgeons, hospital information experts and systems engineers selected relevant variables. Small set data mining algorithms, utilizing systems engineering, were employed to assess the impact of variables on patient outcomes. RESULTS: A total of 73 variables were chosen and 54 analysed against 11 different outcomes. Forty-seven patients [mean age 51 (22-82); 77% male] met criteria. Among them, 34 underwent early joint surgical resection (<14 days), 5 patients received delayed surgical intervention (>14 days) and 8 had antibiotic-only management. The antibiotic-only group had comparable outcomes. Indicators of poor outcomes were soft tissue fluid >4.5 cm, previous SSCJI, moderate/significant bony fragments, HgbA1c >13.9% and moderate/significant bony sclerosis. CONCLUSIONS: This study suggests that targeted antibiotic-only therapy should be considered initially for SSCJI cases while concurrently managing comorbidities. Patients displaying indicators of poor outcomes or no symptomatic improvement after antibiotic-only therapy should be considered for surgical joint resection.

Safety-Net Hospital Status Is Associated With Coronary Artery Bypass Grafting Outcomes at an Urban Academic Medical Center.

INTRODUCTION: Socioeconomic disparities impact outcomes after cardiac surgery. At our institution, cardiac surgery cases from the safety-net, county funded hospital (CH), which primarily provides care for underserved patients, are performed at the affiliated university hospital. We aimed to investigate the association of socioeconomic factors and CH referral status with outcomes after coronary artery bypass grafting (CABG). METHODS: The institutional Adult Cardiac Surgery database was queried for perioperative and demographic data from patients who underwent isolated CABG between January 2014 and June 2020. The primary outcome was major adverse cardiovascular event (MACE), a composite of postoperative myocardial infarction, stroke, or death. Secondary outcomes included individual complications. Chi-square, Wilcoxon rank-sum, and logistic regression analyses were used to compare differences between CH and non-CH cohorts. RESULTS: We included 836 patients with 472 (56.5%) from CH. Compared to the non-CH cohort, CH patients were younger, more likely to be Hispanic, non-English speaking, and be completely uninsured or require state-specific financial assistance. CH patients were more likely to have a history of tobacco and drug use, liver disease, diabetes, prior myocardial infarction, and greater degrees of left main coronary and left anterior descending artery stenosis. CH cases were less likely to be elective. The incidence of MACE was significantly higher in the CH cohort (16.3% versus 8.2%, P = 0.001). There were no significant differences in 30-d mortality, home discharge, prolonged mechanical ventilation, bleeding, sepsis, pneumonia, new dialysis requirement, cardiac arrest, or multiorgan system failure between cohorts. CH patients were more likely to develop renal failure and less likely to develop atrial fibrillation. On multivariable analysis, CH status (odds ratio 2.39, 95% confidence interval 1.25-4.55, P = 0.008) was independently associated with MACE. CONCLUSIONS: CH patients undergoing CABG presented with greater comorbidity burden, more frequently required nonelective surgery, and are at significantly higher risk of postoperative MACE.

Maintenance of pig brain function under extracorporeal pulsatile circulatory control (EPCC).

Selective vascular access to the brain is desirable in metabolic tracer, pharmacological and other studies aimed to characterize neural properties in isolation from somatic influences from chest, abdomen or limbs. However, current methods for artificial control of cerebral circulation can abolish pulsatility-dependent vascular signaling or neural network phenomena such as the electrocorticogram even while preserving individual neuronal activity. Thus, we set out to mechanically render cerebral hemodynamics fully regulable to replicate or modify native pig brain perfusion. To this end, blood flow to the head was surgically separated from the systemic circulation and full extracorporeal pulsatile circulatory control (EPCC) was delivered via a modified aorta or brachiocephalic artery. This control relied on a computerized algorithm that maintained, for several hours, blood pressure, flow and pulsatility at near-native values individually measured before EPCC. Continuous electrocorticography and brain depth electrode recordings were used to evaluate brain activity relative to the standard offered by awake human electrocorticography. Under EPCC, this activity remained unaltered or minimally perturbed compared to the native circulation state, as did cerebral oxygenation, pressure, temperature and microscopic structure. Thus, our approach enables the study of neural activity and its circulatory manipulation in independence of most of the rest of the organism.

Homelessness and Race are Mortality Predictors in US Veterans Undergoing CABG.

Coronary artery disease requiring surgical revascularization is prevalent in United States Veterans. We aimed to investigate preoperative predictors of 30-day mortality following coronary artery bypass grafting (CABG) in the Veteran population. The Veterans Affairs Surgical Quality Improvement (VASQIP) national database was queried for isolated CABG cases between 2008 and 2018. The primary outcome was 30-day mortality. A multivariable logistic regression was performed to assess for independent predictors of the primary outcome. A P-value of <0.05 was considered statistically significant. A total of 32,711 patients were included. The 30-day mortality rate was 1.37%. Multivariable analysis identified the following predictors of 30-day mortality: African-American race (OR 1.46, 95% CI 1.09-1.96); homelessness (OR 6.49, 95% CI 3.39-12.45); female sex (OR 2.15, 95% CI 1.08-4.30); preoperative myocardial infarction within 7 days (OR 1.49, 95% CI 1.06-2.10) or more than 7 days before CABG (OR 1.34, 95% CI 1.04-1.72); partially/fully dependent functional status (OR 1.44, 95% CI 1.07-1.93); chronic obstructive pulmonary disease (OR 1.54, 95% CI 1.24-1.92); mild (OR 1.48, 95% CI 1.04-2.11) and severe aortic stenosis (OR 2.06, 95% CI 1.37-3.09); moderate (OR 1.88, 95% CI 1.31-2.72), or severe (OR 2.99, 95% CI 1.71-5.22) mitral regurgitation; cardiomegaly (OR 1.73, 95% CI 1.35-2.22); NYHA Class III/IV heart failure (OR 2.05, 95% CI 1.10-3.83); and urgent/emergent operation (OR 1.42, 95% CI 1.08-1.87). The 30-day mortality rate in US Veterans undergoing isolated CABG between 2008 and 2018 was 1.37%. In addition to established clinical factors, African-American race and homelessness were independent demographic predictors of 30-day mortality.

Training Cardiothoracic Residents in Robotic Lobectomy Is Cost-Effective With No Change in Clinical Outcomes.

Objective: Our objective was to evaluate for any changes in quality or cost when robotic lung resection is used with significant trainee participation. Methods: All anatomic lung resections between January 2006 and June 2016 were identified from a prospectively maintained database. Clinical data were recorded by double entry. Cost and cancer-related data were gathered from the business analytics department and tumor registry. Robotic outcomes were compared to an ongoing thoracotomy and video-assisted thoracic surgery (VATS) experience. Propensity scores using age, sex, and comorbidities were assigned for statistical analysis. Survival was evaluated using the Kaplan-Meier method. Results: Of 523 consecutive cases, 483 were included (211 robotic, 210 thoracotomy, 62 VATS). There were 74 robotic cases (35%) performed by trainees as the console surgeon. Length of stay was shortest for robotics (3 days) compared to thoracotomy (7 days, P < 0.001) and VATS (5 days, P = 0.010). Complications occurred in 33% of robotic cases, 42% of VATS cases (P = 0.854), and 52% of thoracotomy cases (P < 0.001). Stage I non-small cell lung cancer 3-year overall survival for robotics, thoracotomy, and VATS was 79.5%, 74.3%, and 74.0%, respectively (P > 0.25). There was no significant difference in negative margin rates. Total cost related to the hospitalization for surgery was $5,721 less for robotics compared to thoracotomy (P = 0.003) but comparable to VATS. Trainees served as console surgeon in 0% of cases in the first 2 years of robotics but increased to 79% in the last year of the study. Conclusions: Robotic lung resection can be safely performed and taught in an academic medical center without sacrificing quality or cost.

Minimally Invasive Mitral Valve Surgery After Transcatheter Edge-to-Edge Repair.

OBJECTIVE: Up to 28% of patients may need mitral valve (MV) surgery after transcatheter edge-to-edge repair (TEER). This study evaluates the outcomes of minimally invasive MV surgery after TEER. Methods: International multicenter registry of minimally invasive MV surgery after TEER between 2013 and 2020. Subgroups were stratified by the number of devices implanted (≤1 vs >1), as well as time interval from TEER to surgery (≤1 year vs >1 year). Results: A total of 56 patients across 13 centers were included with a mean age of 73 ± 11 years, and 50% were female. The median Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) score for MV replacement was 8% (Q1-Q3 = 5% to 11%) and the ratio of observed to expected mortality was 0.9. The etiology of mitral regurgitation (MR) prior to TEER was primary MR in 75% of patients and secondary MR in 25%. There were 30 patients (54%) who had >1 device implanted. The median time between TEER and surgery was 252 days (33 to 636 days). Hemodynamics, including MR severity, MV area, and mean gradient, significantly improved after minimally invasive surgery and sustained to 1-year follow-up. In-hospital and 30-day mortality was 7.1%, and 1-year actuarial survival was 85.6% ± 6%. Conclusions: Minimally invasive MV surgery after TEER may be achieved as predicted by the STS PROM. Most patients underwent MV replacement instead of repair. As TEER is applied more widely, patients should be informed about the potential need for surgical intervention over time after TEER. These discussions will allow better informed consent and post-procedure planning.

Lung transplantation: how we do it.

Lung transplantation is considered the gold standard for patients with chronic end-stage pulmonary disease. However, due to the complexity of management and relatively lower median survival as compared to other solid organs, many programs across the world have been slow to adopt the same. In our institution, we started lung transplantation in September 1990. And since then, we performed close to 900 lung transplantations. Here, we describe in detail the operative steps adopted in our institution for a successful lung transplantation. There have been very few variations over the years. We believe that having a standardized technique is one of the important features for success of a lung transplant program.

Ex vivo lung perfusion: how we do it.

Lung transplantation is an established treatment for patients with end-stage lung disease. However, a shortage of donors, low lung utilization among potential donors, and waitlist mortality continue to be challenges. In the last decade, ex vivo lung perfusion (EVLP) has expanded the donor pool by allowing prolonged evaluation of marginal donor lungs and allowing reparative therapies for lungs, which are otherwise considered not transplantable. In this review, we describe in detail our experience with EVLP including our workflow, setup, operative technique, and protocols. Our multidisciplinary EVLP program functions with the collaboration of surgeons, pulmonologists, and EVLP nurses who run the pump. EVLP program has been a valuable addition to our program. Since Food and Drug Administration (FDA) approval in 2019, we experienced incremental increased lung transplant volume of 12% annually.

Preemptive Alcohol Septal Ablation Prior to Valve-in-Valve Transcatheter Mitral Valve Replacement With Bioprosthetic Balloon Fracture.

A 78-year-old woman with bioprosthetic mitral valve degeneration at high risk for reoperation was referred for transcatheter mitral valve replacement. We describe the use of a preemptive alcohol septal ablation pre-procedurally to minimize the risk of acute left ventricular outflow tract obstruction given the anticipated need for a bioprosthetic valve fracture. (Level of Difficulty: Advanced.).

Consensus on validation of forensic voice comparison.

Since the 1960s, there have been calls for forensic voice comparison to be empirically validated under casework conditions. Since around 2000, there have been an increasing number of researchers and practitioners who conduct forensic-voice-comparison research and casework within the likelihood-ratio framework. In recent years, this community of researchers and practitioners has made substantial progress toward validation under casework conditions becoming a standard part of practice: Procedures for conducting validation have been developed, along with graphics and metrics for representing the results, and an increasing number of papers are being published that include empirical validation of forensic-voice-comparison systems under conditions reflecting casework conditions. An outstanding question, however, is: In the context of a case, given the results of an empirical validation of a forensic-voice-comparison system, how can one decide whether the system is good enough for its output to be used in court? This paper provides a statement of consensus developed in response to this question. Contributors included individuals who had knowledge and experience of validating forensic-voice-comparison systems in research and/or casework contexts, and individuals who had actually presented validation results to courts. They also included individuals who could bring a legal perspective on these matters, and individuals with knowledge and experience of validation in forensic science more broadly. We provide recommendations on what practitioners should do when conducting evaluations and validations, and what they should present to the court. Although our focus is explicitly on forensic voice comparison, we hope that this contribution will be of interest to an audience concerned with validation in forensic science more broadly. Although not written specifically for a legal audience, we hope that this contribution will still be of interest to lawyers.