Targeted Antioxidant Therapy Reduces Hyperglycemic Exacerbation of Myocardial Ischemia-Reperfusion.

INTRODUCTION: Acute hyperglycemia (HG) enhances inflammatory and oxidative stress and exacerbates myocardial infarct size during ischemia-reperfusion injury by activating splenic leukocytes. Formyl peptide receptor 1 (FPR1) on leukocytes is activated by and mediates myocardial ischemia-reperfusion injury. We hypothesize that selective FPR1 antagonist cinnamoyl-F-(D)L-F-(D)L-F (CF) or potent reducing agent tris (2-carboxyethyl) phosphine hydrochloride (TCEP) could abrogate hyperglycemic infarct exacerbation, both alone and synergistically via a novel CF-TCEP compound that would target leukocytes for antioxidative effect. METHODS: Acute HG was induced in wild type mice with an intraperitoneal dextrose injection followed by left coronary artery occlusion (30 min) and reperfusion (60 min). In treatment groups, CF (0.1 mg/kg or 1 mg/kg), TCEP (1 mg/kg or 20 mg/kg), or the CF-TCEP conjugate (0.1 mg/kg) was administered intravenously before reperfusion. The hearts were harvested to measure infarct size (IF). RESULTS: HG resulted in >50% increase in IF compared to euglycemic mice (52.1 ± 3.0 versus 34.0 ± 3.2%, P < 0.05). Neither CF nor TCEP independently exerted an infarct-sparing effect at lower doses (46.2 ± 2.1% or 50.9 ± 4.1%, P > 0.05 versus HG control) but at high doses, significantly attenuated IF exacerbation (23.2 ± 5.2% or 33.9 ± 3.6%, P < 0.05 versus HG control). However, the low-dose CF-TCEP conjugate significantly reduced IF (39.1 ± 1.7%, P < 0.05 versus HG control). IF was decreased to near euglycemic control levels (P > 0.05). CONCLUSIONS: The CF-TECP conjugate synergistically attenuated HG infarct exacerbation at significantly lower respective doses of CF and TCEP. In addition to the intrinsic anti-inflammatory effect of blocking FPR1, CF is also a feasible tool for leukocyte-targeted therapy to treat IRI.

Adenosine 2A Receptor Agonism Improves Survival in Extracorporeal Cardiopulmonary Resuscitation.

INTRODUCTION: Despite resuscitation advances including extracorporeal cardiopulmonary resuscitation (ECPR), freedom from neurologic and myocardial insult after cardiac arrest remains unlikely. We hypothesized that adenosine 2A receptor (A2AR) agonism, which attenuates reperfusion injury, would improve outcomes in a porcine model of ECPR. METHODS: Adult swine underwent 20 min of circulatory arrest followed by defibrillation and 6 h of ECPR. Animals were randomized to receive saline vehicle or A2AR agonist (ATL1223 or Regadenoson) infusion during extracorporeal membrane oxygenation. Animals were weaned off extracorporeal membrane oxygenation and monitored for 24 h. Clinical and biochemical end points were compared. RESULTS: The administration of A2AR agonists increased survival (P = 0.01) after cardiac arrest compared to vehicle. Markers of neurologic damage including S100 calcium binding protein B and glial fibrillary acidic protein were significantly lower with A2AR agonist treatment. CONCLUSIONS: In a model of cardiac arrest treated with ECPR, A2AR agonism increased survival at 24 h and reduced neurologic damage suggesting A2AR activation may be a promising therapeutic target after cardiac arrest.

Postdoctoral National Institutes of Health F32 Grants: Broken Pipeline in the Development of Surgeon-Scientists.

OBJECTIVE: We examined trainees in surgery and internal medicine who received National Institutes of Health (NIH) F32 postdoctoral awards to determine their success rates in obtaining future NIH funding. BACKGROUND: Trainees participate in dedicated research years during residency (surgery) and fellowship (internal medicine). They can obtain an NIH F32 grant to fund their research time and have structured mentorship. METHODS: We collected NIH F32 grants (1992-2021) for Surgery Departments and Internal Medicine Departments from NIH RePORTER, an online database of NIH grants. Nonsurgeons and noninternal medicine physicians were excluded. We collected demographic information on each recipient, including gender, current specialty, leadership positions, graduate degrees, and any future NIH grants they received. A Mann-Whitney U test was used for continuous variables, and a χ 2 test was utilized to analyze categorical variables. An alpha value of 0.05 was used to determine significance. RESULTS: We identified 269 surgeons and 735 internal medicine trainees who received F32 grants. A total of 48 surgeons (17.8%) and 339 internal medicine trainees (50.2%) received future NIH funding ( P < 0.0001). Similarly, 24 surgeons (8.9%) and 145 internal medicine trainees (19.7%) received an R01 in the future ( P < 0.0001). Surgeons who received F32 grants were more likely to be department chair or division chiefs ( P =0.0055 and P < 0.0001). CONCLUSIONS: Surgery trainees who obtain NIH F32 grants during dedicated research years are less likely to receive any form of NIH funding in the future compared with their internal medicine colleagues who received F32 grants.

Gastric Aspiration and Ventilator-Induced Model of Acute Respiratory Distress Syndrome in Swine.

INTRODUCTION: Mainstays of current treatment for acute respiratory distress syndrome (ARDS) focus on supportive care and rely on intrinsic organ recovery. Animal models of ARDS are often limited by systemic injury. We hypothesize that superimposing gastric aspiration and ventilator-induced injury will induce a lung-specific injury model of severe ARDS. MATERIALS AND METHODS: Adult swine (n = 8) were subject to a 12 h injury development period followed by 24 h of post-injury monitoring. Lung injury was induced with gastric secretions (3 cc/kg body weight/lung, pH 1-2) instilled to bilateral mainstem bronchi under direct bronchoscopic vision. Ventilator settings within the injury period contradicted baseline settings using high tidal volumes and low positive end-expiratory pressure. Baseline settings were restored following the injury period. Arterial oxygenation and lung compliance were monitored. RESULTS: At 12 h, PaO2/FiO2 ratio and static and dynamic compliance were significantly reduced from baseline (P < 0.05). During the postinjury period, animals showed no signs of recovery in PaO2/FiO2 ratio and lung compliance. Lung edema (wet/dry weight ratio) of injured lungs was significantly elevated versus noninjured lungs (8.5 ± 1.7 versus 5.6 ± 0.3, P = 0.009). Expression of proinflammatory cytokines IL-6 and IL-8 were significantly elevated in injured lungs (P < 0.05). CONCLUSIONS: Twelve hours of high tidal volume and low positive end-expiratory pressure in conjunction with low-pH gastric content instillation produces significant acute lung injury in swine. This large animal model may be useful for testing severe ARDS treatment strategies.

Commentary: Should we "keep rollin'" for PA/VSD/MAPCA?

Pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (PA/VSD/MAPCA) represents an anatomically diverse and technically demanding spectrum of congenital disease. Here, we review a manuscript by Onalan et al. in the Journal of Cardiac Surgery detailing a retrospective, single-center cohort study of patients undergoing unifocalization for PA/VSD/MAPCA via either a pulmonary artery patch augmentation or pericardial roll technique. While they report statistically equivalent outcomes using both techniques, longer follow-up and increased sample size are necessary to determine efficacy and safety.

Commentary: Thinking inside and outside of the box with intraextracardiac Fontan.

What is the most optimal way to palliate univentricular physiology? We are reviewing a manuscript by Simsek and colleagues in the Journal of Cardiac Surgery-describing their experience with the intraextracardiac Fontan procedure (IECF). They report encouraging early results in 17 patients who underwent the procedure between 2014 and 2021 and clearly describe their operative technique and variant anatomy they encountered. There are now at least four generations of Fontan procedures, each attempting to palliate while maintaining appropriate hemodynamics as long as possible. IECF provides a good option for cavopulmonary bypass as it avoids pitfalls of prior generations. It may be even more favorable in situations with additional anatomic complexity. We look forward to seeing the long-term outcomes of the IECF.

Commentary: Extracardiac conduit-total cavopulmonary connection for heterotaxy-Is going the "extra" mile worth it.

Extracardiac conduit-total cavopulmonary connection (EC-TCPC) represents the latest evolution in Fontan palliation for single ventricle physiology. Here, we review a manuscript by Pan et al. in the Journal of Cardiac Surgery detailing a retrospective, single-center cohort study of patients with and without heterotaxy syndrome undergoing EC-TCPC. Although lacking a comparison to other techniques for single ventricle palliation, this approach appears to offer excellent outcomes for this complex patient cohort.

Commentary: Another layer to the "PPM conundrum".

How do manufacturer estimates of valve performance match up to reality and stress testing? We are reviewing a manuscript by Porterie et al. in the Journal of Cardiac Surgery detailing a single-center, assessment of Avalus™ bioprosthetic valve hemodynamics during stress echocardiography. At maximal stress, they found that indexed effective orifice area had better alignment with manufacturer estimates than measurements at rest. In addition, they found a significant difference between EOA and flow rates at rest versus maximal exertion and quantified it as the "opening reserve." Patients without patient prosthetic mismatch had much higher opening reserves. This interesting study helps us to understand how estimates align with reality and draws attention to the concept of the opening reserve. Could differences in opening flow impact the durability or longevity of prosthetics?

Commentary: The challenges of propensity score matching in cardiac surgery.

The advent of transcatheter valve technology for structural heart disease has led to heightened scrutiny of outcomes following surgical valve replacement. Here, we review a manuscript by Tsubota et al. in the Journal of Cardiac Surgery detailing a single-center, retrospective cohort study of patients undergoing mitral valve replacement from 2007 to 2018. While outcomes appear to be excellent, these results should be carefully interpreted in light of limited data regarding the propensity score match methodology utilized.

Commentary: Small patients with big wounds.

Some would argue that kids aren't just little adults, but what about their sternums? We are reviewing a manuscript by Horriat, McCandless, and colleagues in the Journal of Cardiac Surgery describing their experience with managing sternal wound infections (SWI) after congenital heart surgery. They report encouraging results in 14 patients who required plastic surgery consultation to manage their sternal wounds. The nature of congenital cardiac abnormalities and the necessary steps to repair them leads to physiologic derangements predisposing patients to SWI. Rates of SWI vary and have been reported at 1.53% in this population. There is little guidance on how the management of the congenital cardiac surgery patient should differ from the adult patient.

Meaningful Patient-centered Outcomes 1 Year Following Cardiac Surgery.

OBJECTIVE: To evaluate meaningful, patient-centered outcomes including alive-at-home status and patient-reported quality of life 1 year after cardiac surgery. BACKGROUND: Long-term patient-reported quality of life after cardiac surgery is not well understood. Current operative risk models and quality metrics focus on short-term outcomes. METHODS: In this combined retrospective/prospective study, cardiac surgery patients at an academic institution (2014-2015) were followed to obtain vital status, living location, and patient-reported outcomes (PROs) at 1 year using the NIH Patient-Reported Outcomes Measurement Information System (PROMIS). We assessed the impact of cardiac surgery, discharge location, and Society of Thoracic Surgeons perioperative predicted risk of morbidity or mortality on 1-year outcomes. RESULTS: A total of 782 patients were enrolled; 84.1% (658/782) were alive-at-home at 1 year. One-year PROMIS scores were global physical health (GPH) = 48.8 ±â€Š10.2, global mental health (GMH) = 51.2 ±â€Š9.6, and physical functioning (PF) = 45.5 ±â€Š10.2 (general population reference = 50 ±â€Š10). All 3 PROMIS domains at 1 year were significantly higher compared with preoperative scores (GPH: 41.7 ±â€Š8.5, GMH: 46.9 ±â€Š7.9, PF: 39.6 ±â€Š9.0; all P < 0.001). Eighty-two percent of patients discharged to a facility were alive-at-home at 1 year. These patients, however, had significantly lower 1-year scores (difference: GPH = -5.1, GMH = -5.1, PF = -7.9; all P < 0.001). Higher Society of Thoracic Surgeons perioperative predicted risk was associated with significantly lower PRO at 1 year (P < 0.001). CONCLUSIONS: Cardiac surgery results in improved PROMIS scores at 1 year, whereas discharge to a facility and increasing perioperative risk correlate with worse long-term PRO. One-year alive-at-home status and 1-year PRO are meaningful, patient-centered metrics that help define long-term quality and the benefit of cardiac surgery.

Commentary: Litigation risk in congenital cardiac surgery.

The risk of malpractice litigation is substantial for congenital cardiac surgeons. It is important for providers to be equipped with strategies to minimize this risk without compromising patient care. Below, we provide a commentary on a recent article from the Journal of Cardiac Surgery discussing litigation risk in this field. To minimize liability and provide optimal care, it is critical that congenital cardiac surgeons focus on both tangible objectives, such as decreasing procedural errors, and less tangible objectives, such as improving surgeon empathy and emotional intelligence.

Commentary: Malpractice in heart transplantation.

The field of heart transplantation is complex and carries substantial risk of medical malpractice. It is essential for heart transplant surgeons to understand litigation trends to minimize risk and continue to optimize patient care. Below we provide commentary on a recent article from the Journal of Cardiac Surgery discussing this topic. The risk of medical malpractice in heart transplantation may be decreased with seamless communication between provider teams, minimizing operative errors, thorough informed consent, and improved provider emotional intelligence.

Commentary: Predictors of postoperative adverse events after cone reconstruction for Ebstein's anomaly.

Prediction scores and metrics are being increasingly utilized throughout the fields of cardiothoracic and congenital cardiac surgery to identify areas for perioperative optimization or guide therapeutic intent. Here, we review a novel submission by Yang and colleagues to the Journal of Cardiac Surgery identifying preoperative factors that predict adverse postoperative outcomes from cone reconstruction for Ebstein's anomaly.

Commentary: When will the robots come marching in?

Minimally invasive techniques for coronary artery bypass grafting (CABG), specifically robotic-assisted CABG has increased in popularity despite conflicting evidence. Here, we review a report by Yokoyama and colleagues to the Journal of Cardiac Surgery investigating outcomes of robotic versus nonrobotic CABG utilizing the National Inpatient Sample (NIS).

Mixed type TAPVR-Measure twice, cut once.

Total anomalous pulmonary venous return (TAVR) can have varying drainage configurations. Here, we review a report by Nagulakonda et al. to the Journal of Cardiac Surgery detailing how additional computed tomography imaging revealed a mixed type presentation of TAPVR not identified on echocardiography.

Commentary: Cardiothoracic surgery training made SIMPL.

BACKGROUND: Effective cardiothoracic surgical training requires an emphasis on education through timely feedback and constructive criticism. AIMS: Review of the implementation of the System for Improving and Measuring Procedural Learning application within a cardiothoracic surgical training program. MATERIALS & METHODS: Here, we review a report by Bergquist et al. to the Journal of Cardiac Surgery detailing their implementation of the System for Improving and Measuring Procedural Learning application. CONCLUSION: It is feasible for the SIMPL application to be implemented with acceptable use in a cardiothoracic training program.

Topical Neck Cooling Prolongs Survival of Rats with Intra-Abdominal Feculent Sepsis by Activation of the Vagus Nerve.

Global hypothermia prolongs survival in rats with intraabdominal feculent sepsis by inhibiting inflammatory responses. We hypothesized that topical neck cooling (TNC) has similar benefits. Septic shock was induced by cecal ligation and incision (CLI) in Sprague Dawley rats. Rats were randomized to sham laparotomy, control with CLI, CLI with TNC, or vagotomy at the gastroesophageal junction before CLI and TNC. Two more groups underwent peritoneal washout with and without TNC two hours after CLI. TNC significantly lowered neck skin temperature (16.7 ± 1.4 vs. 30.5 ± 0.6 °C, p < 0.05) while maintaining core body normothermia. TNC rats recovered from anesthesia 70 min earlier than the control (p < 0.05). Three hours following CLI, the control and vagotomy with TNC groups had significantly more splenic contraction, fewer circulating leukocytes and higher plasma IL-1ß, IL-10 and TNF-α levels than TNC rats (p < 0.05). TNC prolonged survival duration after CLI by a median of four hours vs. control (p < 0.05), but no benefit was seen if vagotomy preceded TNC. Peritoneal washout alone increased survival by 3 h (9.2 (7.8-10.5) h). Survival duration increased dramatically with TNC preceding washout, to a 56% survival rate (>10 days). TNC significantly prolonged the survival of rats with severe intraabdominal sepsis by inhibiting systemic proinflammatory responses by activating vagal anti-inflammatory pathways.

One-Year Outcomes After MitraClip for Functional Mitral Regurgitation.

BACKGROUND: Secondary mitral regurgitation (SMR) occurs in the absence of organic mitral valve disease and may develop as the left ventricle dilates or remodels or as a result of leaflet tethering with impaired coaptation, most commonly from apical and lateral distraction of the subvalvular apparatus, with late annular dilatation. The optimal therapy for SMR is unclear. This study sought to evaluate the 1-year adjudicated outcomes of all patients with SMR undergoing the MitraClip procedure in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) Investigational Device Exemption program, which is comprised of the randomized clinical trial, the prospective High-Risk Registry, and the REALISM Continued Access Registry (Multicenter Study of the MitraClip System). METHODS: Patients with 3+/4+ SMR enrolled in EVEREST II were stratified by non-high surgical risk (non-HR) and high surgical risk (HR) status (defined as Society of Thoracic Surgeons risk of mortality ≥12% or predefined risk factors). Clinical, echocardiographic, and functional outcomes at 1 year were evaluated. RESULTS: A total of 616 patients (482 HR, 134 non-HR; mean age, 73.3±10.5 years; Society of Thoracic Surgeons risk, 10.2±6.9%) with SMR underwent the MitraClip procedure. At baseline, 80.5% of patients were in New York Heart Association class III/IV. Major adverse events at 30 days included death (3.6%), stroke (2.3%), and renal failure (1.5%). At discharge, 88.8% had MR ≤2+. At 1 year, there were 139 deaths, and the Kaplan-Meier estimate of freedom from mortality was 76.8%. The majority of surviving patients (84.7%) remained with MR ≤2+ and New York Heart Association class I/II (83.0%). Kaplan-Meier survival at 1 year was 74.1% in HR patients and 86.4% in non-HR patients ( P=0.0175). At 1 year, both groups achieved comparable MR reduction (MR ≤2+, 84.0% versus 87.0%) and improvement in left ventricular end-diastolic volume (-8.0 mL versus -12.7 mL), whereas New York Heart Association class I/II was found in 80.1% versus 91.8% ( P=0.008) of HR and non-HR patients, respectively. In HR patients, the annualized rate of heart failure hospitalizations decreased from 0.68 to 0.46 in the 12 months before to 12 months after the procedure ( P<0.0001). CONCLUSIONS: Transcatheter mitral valve repair with the MitraClip in patients with secondary MR is associated with acceptable safety, reduction of MR severity, symptom improvement, and positive ventricular remodeling. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov . Unique identifiers: NCT00209274, NCT01940120, and NCT01931956.

SPECT imaging of lung ischemia-reperfusion injury using [99mTc]cFLFLF for molecular targeting of formyl peptide receptor 1.

Primary graft dysfunction after lung transplantation, a consequence of ischemia-reperfusion injury (IRI), is a major cause of morbidity and mortality. IRI involves acute inflammation and innate immune cell activation, leading to rapid infiltration of neutrophils. Formyl peptide receptor 1 (FPR1) expressed by phagocytic leukocytes plays an important role in neutrophil function. The cell surface expression of FPR1 is rapidly and robustly upregulated on neutrophils in response to inflammatory stimuli. Thus, we hypothesized that use of [99mTc]cFLFLF, a selective FPR1 peptide ligand, would permit in vivo neutrophil labeling and noninvasive imaging of IRI using single-photon emission computed tomography (SPECT). A murine model of left lung IRI was utilized. Lung function, neutrophil infiltration, and SPECT imaging were assessed after 1 h of ischemia and 2, 12, or 24 h of reperfusion. [99mTc]cFLFLF was injected 2 h before SPECT. Signal intensity by SPECT and total probe uptake by gamma counts were 3.9- and 2.3-fold higher, respectively, in left lungs after ischemia and 2 h of reperfusion versus sham. These values significantly decreased with longer reperfusion times, correlating with resolution of IRI as shown by improved lung function and decreased neutrophil infiltration. SPECT results were confirmed using Cy7-cFLFLF-based fluorescence imaging of lungs. Immunofluorescence microscopy confirmed cFLFLF binding primarily to activated neutrophils. These results demonstrate that [99mTc]cFLFLF SPECT enables noninvasive detection of lung IRI and permits monitoring of resolution of injury over time. Clinical application of [99mTc]cFLFLF SPECT may permit diagnosis of lung IRI for timely intervention to improve outcomes after transplantation.