Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Unplanned postoperative catheterization during admission for coronary artery bypass grafting is neither cheap nor benign, but may rescue patients.

OBJECTIVE: Literature describing outcomes of myocardial ischemia after coronary artery bypass grafting is sparse. We hypothesized these patients had more complications and incurred higher costs of care. METHODS: Using adult cardiac surgery data and cardiac catheterization (CathPCI) data from the Virginia Cardiac Services Quality Initiative, we identified patients who underwent unplanned cardiac catheterization after coronary artery bypass grafting from 2018 to 2021. Adult cardiac surgery data were matched to CathPCI data examining earliest in-hospital catheterization. Patients not requiring catheterization served as the control group. RESULTS: We identified 10,597 patients who underwent isolated coronary artery bypass grafting, of whom 41 of 10,597 underwent unplanned cardiac catheterization. A total of 21 of 41 patients (51%) received percutaneous coronary intervention, most commonly for non-ST-elevation myocardial infarction (n = 7, 33%) and ST-elevation myocardial infarction (n = 6, 29%). Postoperative cardiac arrest occurred in 14 patients (40%). In patients who underwent percutaneous coronary intervention, 14 (67%) had a single lesion, 4 (19%) had 2 lesions, and 3 (14%) had 3 lesions. The left anterior descending artery (38%) was the most frequently intervened upon vessel. Patients who underwent catheterization were more likely to require balloon pump support (26% vs 11%), to have prolonged ventilation (57% vs 20%), to have renal failure (17% vs 7.1%), and to undergo reintubation (37% vs 3.8%, all P < .04). There was no statistical difference in operative mortality (4.9% vs 2.3%, P = .2) or failure to rescue (4.9% vs 1.6%, P = .14). Total costs were higher in patients who underwent unplanned catheterization ($81,293 vs $37,011, P < .001). CONCLUSIONS: Unplanned catheterization after coronary artery bypass grafting is infrequent but associated with more complications and a higher cost of care. Therefore, determination of an association with operative mortality in patients with suspected ischemia after coronary artery bypass grafting requires additional study.

Effect of Cardiopulmonary Bypass on SARS-CoV-2 Vaccination Antibody Levels.

Background Adults undergoing heart surgery are particularly vulnerable to respiratory complications, including COVID-19. Immunization can significantly reduce this risk; however, the effect of cardiopulmonary bypass (CPB) on immunization status is unknown. We sought to evaluate the effect of CPB on COVID-19 vaccination antibody concentration after cardiac surgery. Methods and Results This prospective observational clinical trial evaluated adult participants undergoing cardiac surgery requiring CPB at a single institution. All participants received a full primary COVID-19 vaccination series before CPB. SARS-CoV-2 spike protein-specific antibody concentrations were measured before CPB (pre-CPB measurement), 24 hours following CPB (postoperative day 1 measurement), and approximately 1 month following their procedure. Relationships between demographic or surgical variables and change in antibody concentration were assessed via linear regression. A total of 77 participants were enrolled in the study and underwent surgery. Among all participants, mean antibody concentration was significantly decreased on postoperative day 1, relative to pre-CPB levels (-2091 AU/mL, P<0.001). Antibody concentration increased between postoperative day 1and 1 month post CPB measurement (2465 AU/mL, P=0.015). Importantly, no significant difference was observed between pre-CPB and 1 month post CPB concentrations (P=0.983). Two participants (2.63%) developed symptomatic COVID-19 pneumonia postoperatively; 1 case of postoperative COVID-19 pneumonia resulted in mortality (1.3%). Conclusions COVID-19 vaccine antibody concentrations were significantly reduced in the short-term following CPB but returned to pre-CPB levels within 1 month. One case of postoperative COVID 19 pneumonia-specific mortality was observed. These findings suggest the need for heightened precautions in the perioperative period for cardiac surgery patients.

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.

Socioeconomic Distress Associated With Increased Use of Percutaneous Coronary Intervention Over Coronary Artery Bypass Grafting.

BACKGROUND: The influence of socioeconomic determinants of health on choice of percutaneous coronary intervention (PCI) vs coronary artery bypass grafting (CABG) for coronary artery disease is unknown. We hypothesized that higher Distressed Communities Index (DCI) scores, a comprehensive socioeconomic ranking by zip code, would be associated with more frequent PCI. METHODS: All patients undergoing isolated CABG or PCI in a regional American College of Cardiology CathPCI registry and The Society of Thoracic Surgeons database (2018-2021) were assigned DCI scores (0 = no distress, 100 = severe distress) based on education level, poverty, unemployment, housing vacancies, median income, and business growth. Patients who presented with ST-segment elevation myocardial infarction or emergent procedures were excluded. The most distressed quintile (DCI ≥80) was compared with all other patients. Multivariable logistic regression analyzed the association between DCI and procedure type. RESULTS: A total of 23 223 patients underwent either PCI (n = 16 079) or CABG (n = 7144) for coronary artery disease across 28 centers during the study period. Before adjustment, high socioeconomic distress occurred more frequently among CABG patients (DCI ≥80, 12.4% vs 8.42%; P < .001). After multivariable adjustment, high socioeconomic distress was associated with greater odds of receiving PCI, relative to CABG (odds ratio 1.26; 95% CI, 1.07-1.49; P = .007). High socioeconomic distress was significantly associated with postprocedural mortality (odds ratio 1.52; 95% CI, 1.02-2.26; P = .039). CONCLUSIONS: High socioeconomic distress is associated with greater risk-adjusted odds of receiving PCI, relative to CABG, as well as higher postprocedural mortality. Targeted resource allocation in high DCI areas may help eliminate barriers to CABG.

Steen solution protects pulmonary microvascular endothelial cells and preserves endothelial barrier after lipopolysaccharide-induced injury.

OBJECTIVES: Acute respiratory distress syndrome represents the devastating result of acute lung injury, with high mortality. Limited methods are available for rehabilitation of lungs affected by acute respiratory distress syndrome. Our laboratory has demonstrated rehabilitation of sepsis-injured lungs via normothermic ex vivo and in vivo perfusion with Steen solution (Steen). However, mechanisms responsible for the protective effects of Steen remain unclear. This study tests the hypothesis that Steen directly attenuates pulmonary endothelial barrier dysfunction and inflammation induced by lipopolysaccharide. METHODS: Primary pulmonary microvascular endothelial cells were exposed to lipopolysaccharide for 4 hours and then recovered for 8 hours in complete media (Media), Steen, or Steen followed by complete media (Steen/Media). Oxidative stress, chemokines, permeability, interendothelial junction proteins, and toll-like receptor 4-mediated pathways were assessed in pulmonary microvascular endothelial cells using standard methods. RESULTS: Lipopolysaccharide treatment of pulmonary microvascular endothelial cells and recovery in Media significantly induced reactive oxygen species, lipid peroxidation, expression of chemokines (eg, chemokine [C-X-C motif] ligand 1 and C-C motif chemokine ligand 2) and cell adhesion molecules (P-selectin, E-selectin, and vascular cell adhesion molecule 1), permeability, neutrophil transmigration, p38 mitogen-activated protein kinase and nuclear factor kappa B signaling, and decreased expression of tight and adherens junction proteins (zonula occludens-1, zonula occludens-2, and vascular endothelial-cadherin). All of these inflammatory pathways were significantly attenuated after recovery of pulmonary microvascular endothelial cells in Steen or Steen/Media. CONCLUSIONS: Steen solution preserves pulmonary endothelial barrier function after lipopolysaccharide exposure by promoting an anti-inflammatory environment via attenuation of oxidative stress, toll-like receptor 4-mediated signaling, and conservation of interendothelial junctions. These protective mechanisms offer insight into the advancement of methods for in vivo lung perfusion with Steen for the treatment of severe acute respiratory distress syndrome.

Barriers to atrial fibrillation ablation during mitral valve surgery.

BACKGROUND: Nearly 40% of patients with atrial fibrillation (AF) undergoing mitral valve surgery do not receive concomitant ablation despite societal guidelines. We assessed barriers to implementation of this evidence-based practice through a survey of cardiac surgeons in 2 statewide quality collaboratives. METHODS: Adult cardiac surgeons across 2 statewide collaboratives were surveyed on their knowledge and practice regarding AF ablation. Questions concerning experience, clinical practice, case scenarios, and barriers to implementation were included. RESULTS: Among 66 respondents (66 of 135; 48.9%), the majority reported "very comfortable/frequently use" cryoablation (53 of 66; 80.3%) and radiofrequency (55 of 66; 83.3%). Only 12.1% (8/66) were not aware of the recommendations. Approximately one-half of the respondents reported learning AF ablation in fellowship (50.0%; 33 of 66) or attending courses (47.0%; 31 of 66). Responses to clinical scenarios demonstrated wide variability in practice patterns. One-half of the respondents reported no barriers; others cited increased cross-clamp time, excessive patient risk, and arrhythmia incidence as obstacles. Desired interventions included cardiology/electrophysiology support, protocols, pacemaker rate information, and education in the form of site visits, videos and proctors. CONCLUSIONS: Knowledge of evidence-based recommendations and practice patterns vary widely. These data identify several barriers to implementation of concomitant AF ablation and suggest specific interventions (mentorship/support, protocols, research, and education) to overcome these barriers.

Hydroxychloroquine Attenuates Myocardial Ischemic and Post-Ischemic Reperfusion Injury by Inhibiting the Toll-Like Receptor 9 - Type I Interferon Pathway.

Background: We hypothesized that hydroxychloroquine (HCQ) attenuates myocardial ischemia/reperfusion injury (IRI) via TLR9 - type I interferon (IFN-I) pathway inhibition. Methods: The left coronary artery of wild-type (WT) C57BL/6 and congenic TLR9-/- mice was occluded for 40 minutes, with or without 60 minutes of reperfusion (40'/0' or 40'/60'). Either ODN-2088 or HCQ (TLR9 inhibitors), or ODN-1826 (TLR9 agonist) was administered to determine effect on infarct size (IS). After 40'/0', cardiac perfusate (CP) was collected from harvested hearts and administered to either intact WT mice after 20 minutes of ischemia or isolated splenocytes. Type-I interferon (IFNα and IFNß) levels were measured in plasma and splenocyte culture supernatant, and levels of damage associated molecular patterns HMGB1 and cell-free DNA (cfDNA) were measured in CP. Results: After 40'/60', WT mice treated with HCQ or ODN-2088 had significantly reduced IS. TLR9-/- mice and HCQ-treated WT mice undergoing 40'/0' and 40'/60' similarly attenuated IS, with significantly lower IFN-Is in CP after 40'/0' and in plasma after 40'/60'. IS was significantly increased in 40'/0' CP-treated and ODN-1826-treated 20'/60' WT mice. CP-treated WT splenocytes produced significantly higher IFN-I in culture supernatant, which was significantly reduced with HCQ. Conclusions: The TLR9-IFN-I-mediated inflammatory response contributes significantly to both ischemic and post-ischemic myocardial ischemia-reperfusion injury. HMGB1 and cfDNA released from ischemic myocardium activated the intra-myocardial TLR9 - IFN-I inflammatory pathway during ischemia and the extra-myocardial TLR9 - IFN-I inflammatory pathway during reperfusion. Hydroxychloroquine reduces production of IFN-I and attenuates myocardial IRI, likely by inhibiting the TLR9-IFN-I pathway.

Appropriateness of Surgical Aortic Valve Replacement for Severe Aortic Stenosis Is Increasing.

BACKGROUND: The adoption of transcatheter aortic valve replacement led to the development of appropriate use criteria (AUC) for transcatheter and surgical aortic valve replacement (SAVR) for aortic stenosis in 2017. This study hypothesized that appropriateness of SAVR improved after publication of AUC. METHODS: All patients undergoing isolated SAVR for severe aortic stenosis in a regional cardiac surgical quality collaborative were evaluated using data from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011-2021). After excluding endocarditis and emergency cases, appropriateness of SAVR (rarely appropriate, may be appropriate, or appropriate) was assigned to patients by using established criteria. The relationship of appropriateness with publication of AUC was assessed, as was variation in appropriateness over time and by center. RESULTS: Of 3035 patients across 17 centers, 106 (3.5%) underwent SAVR for an indication identified as rarely appropriate or may be appropriate. Patients who underwent SAVR for rarely or may be appropriate indications were significantly more likely to experience operative mortality (5.7% vs 1.6%, P = .001) as well as major morbidity (21.7% vs 10.5%, P < .001). Performance of rarely or may be appropriate SAVR significantly decreased over time (slope -0.51%/year, P trend < .001), and it was decreased after the release of the AUC (before release, 3.83% vs after release, 2.06%; P = .036). Substantial interhospital variation in appropriateness was observed (range of may be or rarely appropriate SAVR, 0%-10%). CONCLUSIONS: The majority of isolated SAVR for aortic stenosis was appropriate according to the 2017 AUC. Appropriateness improved after publication of AUC, and this improvement was associated with a significant reduction of major morbidity and mortality.

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: 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.

Topical Neck Cooling Without Systemic Hypothermia Attenuates Myocardial Ischemic Injury and Post-ischemic Reperfusion Injury.

Background: Following acute myocardial infarction (MI), irreversible damage to the myocardium can only be reduced by shortening the duration between symptom onset and revascularization. While systemic hypothermia has shown promising results in slowing pre-revascularization myocardial damage, it is resource intensive and not conducive to prehospital initiation. We hypothesized that topical neck cooling (NC), an easily implemented therapy for en route transfer to definitive therapy, could similarly attenuate myocardial ischemia-reperfusion injury (IRI). Methods: Using an in vivo mouse model of myocardial IRI, moderate systemic hypothermia or NC was applied following left coronary artery (LCA) occlusion and subsequent reperfusion, at early, late, and post-reperfusion intervals. Vagotomy was performed after late NC in an additional group. Hearts were harvested to measure infarct size. Results: Both hypothermia treatments equally attenuated myocardial infarct size by 60% compared to control. The infarct-sparing effect of NC was temperature-dependent and timing-dependent. Vagotomy at the gastroesophageal junction abolished the infarct-sparing effect of late NC. Cardiac perfusate isolated following ischemia had significantly reduced cardiac troponin T, HMGB1, cell-free DNA, and interferon α and ß levels after NC. Conclusions: Topical neck cooling attenuates myocardial IRI in a vagus nerve-dependent manner, with an effect comparable to that of systemic hypothermia. NC attenuated infarct size when applied during ischemia, with earlier initiation resulting in superior infarct sparing. This novel therapy exerts a cardioprotective effect without requiring significant change in core temperature and may be a promising practical strategy to attenuate myocardial damage while patients await definitive revascularization.

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.

Suppression of Neuroinflammation Attenuates Persistent Cognitive and Neurogenic Deficits in a Rat Model of Cardiopulmonary Bypass.

Post-operative cognitive dysfunction (POCD) can be a serious surgical complication, and patients undergoing cardiac procedures are at particular risk for POCD. This study examined the effect of blocking neuroinflammation on behavioral and neurogenic deficits produced in a rat model of cardiopulmonary bypass (CPB). Minocycline, a drug with established anti-inflammatory activity, or saline was administered daily for 30 days post-CPB. Treatment with minocycline reduced the number of activated microglia/macrophages observed in the dentate gyrus of the hippocampus at 6 months post-CPB, consistent with an anti-inflammatory action in this CPB model. Behavioral testing was conducted at 6 months post-CPB utilizing a win-shift task on an 8-arm radial maze. Minocycline-treated animals performed significantly better than saline-treated animals on this task after CPB. In addition, the CPB-induced reduction in adult neurogenesis was attenuated in the minocycline-treated animals. Together, these findings indicate that suppressing neuroinflammation during the early post-surgical phase can limit long-term deficits in both behavioral and neurogenic outcomes after CPB.