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Objective: To evaluate whether a machine-learning algorithm (ie, the "NightSignal" algorithm) can be used for the detection of postoperative complications before symptom onset after cardiothoracic surgery., Background: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed., Methods: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90 days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection., Results: A total of 56 patients undergoing cardiothoracic surgery met the inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (Interquartile range: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events at a median of 2 (Interquartile range: 1-3) days before symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively., Conclusions: Machine-learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-before symptom onset-after cardiothoracic surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Disclosures The author has no conflicts of interest to disclose.

A 63-year-old woman with history of mediastinal radiation was admitted for decompensated heart failure due to severe post-radiation aortic and mitral valve disease. To reduce cardiopulmonary bypass time and postoperative pulmonary complications, she underwent a hybrid approach with robotic mitral valve replacement and transcatheter aortic valve replacement., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Donation after circulatory death (DCD) and ex-vivo lung perfusion (EVLP) have been adopted to expand the donor pool in lung transplantation, but outcomes data have been conflicting. This study explores outcomes of DCD and EVLP lung transplantation in the modern era., Methods: The United Network for Organ Sharing database was queried for adult lung transplants from January 1, 2015 to March 1, 2023. Loss to follow-up, multiorgan, and prior lung transplants were excluded. DCD versus donation after brain death (DBD) lung transplants were compared with subgroup analysis +/- EVLP. Outcomes were survival and postoperative complications., Results: The study included 1,103 DCD (221 with EVLP and 882 without) and 17,973 DBD lung transplants (524 with EVLP and 17,449 without). Median follow-up was 3 years. DCD donors were less likely to be CDC high risk (19.3% vs 24.1%, p < 0.001), have purulence on bronchoscopy (13.3% vs 18.3%, p < 0.001), or infiltrates on chest X-ray (66.7% vs 67.8%, p = 0.013). EVLP was more likely to be used for DCD transplants (20.0% vs 2.9%, p < 0.001). After transplant, DCD recipients were more likely to be reintubated (24.3% vs 18.5%, p < 0.001) and require ECMO within 72 hours (14.9% vs 7.8%, p < 0.001), and DCD donation was an independent risk factor for these complications on multivariable logistic regression. Overall survival did not differ significantly between DCD and DBD transplants on adjusted survival analysis in the early or modern era (p = 0.774 and p = 0.468, respectively). On subgroup analysis, the DCD+EVLP cohort had significantly worse survival in the modern era, which remained significant after adjusting for donor and recipient factors (p = 0.005). EVLP was an independent risk factor for graft failure in the DCD cohort (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.00-1.77, p = 0.047) but did not significantly affect DBD graft survival (p = 0.870). Risk factors for graft failure and mortality in the DCD+EVLP cohort included pulmonary hypertension (HR 77.5, 95% CI 6.15-979, p < 0.001), transfusion before transplant (HR 2.60, 95% CI 1.07-6.31, p = 0.035), elevated creatinine (HR 2.82, 95% CI 1.34-5.90, p = 0.006), and higher allocation score (HR 1.02, 95% CI 1.00-1.04, p = 0.017) CONCLUSIONS: Study findings suggest increased risks of mortality and perioperative complications following transplantation with DCD lungs that have undergone EVLP. DCD lung transplantation without EVLP confers equivalent survival but with some increase in perioperative complications. Further investigation and careful recipient selection are warranted to optimize the use of these extended criteria donors in the modern era., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Degenerative mitral regurgitation is associated with heart failure, arrhythmia and mortality. The impact of sex on timing of surgical referral and outcomes has not been reported comprehensively. We examined preoperative status and surgical outcomes of male versus female degenerative mitral valve regurgitation patients undergoing surgery., Methods: We reviewed our institutional database for all patients undergoing surgery for degenerative mitral regurgitation between 2013 and 2021. Preoperative clinical and echocardiographic variables, surgical characteristics and outcomes were compared, and left atrial strain in available images., Results: Of 963 patients, 314 (32.6%) were female. Women were older (67 vs 64 years, P = 0.031) and more often had bileaflet prolapse (19.4% vs 13.8%, P = 0.028), mitral annular calcification (12.1% vs 5.4%, P < 0.001) and tricuspid regurgitation (TR; 31.8% vs 22.5%, P = 0.001). Indexed left ventricular end-diastolic and end-systolic diameters were higher in women, with 29.4 vs 26.7 mm/m2 (P < 0.001) and 18.2 vs 17 mm/m2 (P < 0.001), respectively, and left atrial conduit strain lower (17.6% vs, 21.2%, P = 0.001). Predicted risk of mortality was 0.73% vs 0.54% in men (P = 0.023). Women required mechanical circulatory support more frequently (1.3% vs 0%, P = 0.011), had longer intensive care unit stay (29 vs 26 h, P < 0.001), mechanical ventilation (5.4 vs 5 h, P = 0.036), and overall hospitalization (7 vs 6 days, P < 0.001). There was no difference in long-term reoperation-free survival (P = 0.35)., Conclusions: Women undergoing mitral valve repair are older and show indicators of more advanced disease with long-standing left ventricular impairment. Guidelines may need to be adjusted and address this disparity, to improve postoperative recovery times and outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Static ice storage has long been the standard-of-care for lung preservation, although freezing injury limits ischemic time (IT). Controlled hypothermic storage (CHS) at elevated temperature could safely extend IT. This retrospective analysis assesses feasibility and safety of CHS with IT > 15 hours. Three lung transplant (LuTx) centers (April-October 2023) included demographics, storage details, IT, and short-term outcome from 13 LuTx recipients (8 male, 59 years old). Donor lungs were preserved in a portable CHS device at 7 (5-9.3)°C. Indication was overnight bridging and/or long-distance transport. IT of second-implanted lung was 17.3 (15.1-22) hours. LuTx were successful, 4/13 exhibited primary graft dysfunction grade 3 within 72 hours and 0/13 at 72 hours. Post-LuTx mechanical ventilation was 29 (7-442) hours. Intensive care unit stay was 9 (5-28) and hospital stay 30 (16-90) days. Four patients needed postoperative extracorporeal membrane oxygenation (ECMO). One patient died (day 7) following malpositioning of an ECMO cannula. This multicenter experience demonstrates the possibility of safely extending IT > 15 hours by CHS., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Since the beginning of the pandemic, coronavirus disease 2019 (COVID-19) has caused debilitating lung failure in many patients. Practitioners have understandably been hesitant to use lungs from donors with COVID-19 for transplantation. This study aimed to analyze the characteristics and short-term outcomes of lung transplantation from donors with recent positive COVID-19 testing results., Methods: Lung transplantations performed between January 2020 and June 2022 were queried from the United Network for Organ Sharing database. Pediatric, multiorgan, and repeat lung transplantations were excluded. Propensity scoring matched recipients of lungs from donors with recent positive COVID-19 testing results to recipients of lungs from donors with negative COVID-19 testing results, and comparisons of 30-day mortality, 3-month mortality, and perioperative outcomes were performed., Results: A total of 5270 patients underwent lung transplantation during the study dates, including 51 patients who received lungs from donors with recent positive COVID-19 testing results. Forty-five recipients of lungs from donors with recent positive COVID-19 testing results were matched with 135 recipients of lungs from donors with negative COVID-19 testing results. After matching, there was no difference in 30-day (log-rank P = .42) and 3-month (log-rank P = .42) mortality. The incidence of other perioperative complications was similar between the groups., Conclusions: The 30-day and 3-month survival outcomes were similar between recipients of lungs from donors with recent positive COVID-19 testing results and recipients of lungs from donors with negative COVID-19 testing results. This finding suggests that highly selected COVID-19-positive donors without evidence of active infection may be safely considered for lung transplantation. Further studies should explore long-term outcomes to provide reassurance about the safety of this practice., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Afterload from moderate aortic stenosis (AS) may contribute to adverse outcomes in patients with heart failure with reduced ejection fraction (HFrEF)., Objectives: The authors evaluated clinical outcomes in patients with HFrEF and moderate AS relative to those without AS and with severe AS., Methods: Patients with HFrEF, defined by left ventricular ejection fraction (LVEF) <50% and no, moderate, or severe AS were retrospectively identified. The primary endpoint, defined as a composite of all-cause mortality and heart failure (HF) hospitalization, was compared across groups and within a propensity score-matched cohort., Results: We included 9,133 patients with HFrEF, of whom 374 and 362 had moderate and severe AS, respectively. Over a median follow-up time of 3.1 years, the primary outcome occurred in 62.7% of patients with moderate AS vs 45.9% with no AS (P < 0.0001); rates were similar with severe and moderate AS (62.0% vs 62.7%; P = 0.68). Patients with severe AS had a lower incidence of HF hospitalization (36.2% vs 43.6%; P < 0.05) and were more likely to undergo AVR within the follow-up period. Within a propensity score-matched cohort, moderate AS was associated with an increased risk of HF hospitalization and mortality (HR: 1.24; 95% CI: 1.04-1.49; P = 0.01) and fewer days alive outside of the hospital (P < 0.0001). Aortic valve replacement (AVR) was associated with improved survival (HR: 0.60; CI: 0.36-0.99; P < 0.05)., Conclusions: In patients with HFrEF, moderate AS is associated with increased rates of HF hospitalization and mortality. Further investigation is warranted to determine whether AVR in this population improves clinical outcomes., Competing Interests: Funding Support and Author Disclosures Dr Tanguturi has received a research grant from Edwards Lifesciences. Dr Elmariah has received research grants from the American Heart Association (19TPA34910170), National Institutes of Health (R01 HL151838), Edwards Lifesciences, Svelte Medical, Abbott Vascular, and Medtronic; and has received consulting fees from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with mitral valve prolapse (MVP) requiring surgical repair (MVr) are increasingly operated using minimally invasive strategies. Skill acquisition may be facilitated by a dedicated MVr program. We present here our institutional experience in establishing minimally invasive MVr (starting in 2014), laying the foundation to introduce robotic MVr., Methods: We reviewed all patients that had undergone MVr for MVP via sternotomy or mini-thoracotomy between January 2013 and December 2020 at our institution. In addition, all cases of robotic MVr between January 2021 and August 2022 were analyzed. Case complexity, repair techniques, and outcomes are presented for the conventional sternotomy, right mini-thoracotomy and robotic approaches. A subgroup analysis comparing only isolated MVr cases via sternotomy vs. right mini-thoracotomy was conducted using propensity score matching., Results: Between 2013 and 2020, 799 patients were operated for native MVP at our institution, of which 761 (95.2%) received planned MVr (263 [34.6%] via mini-thoracotomy) and 38 (4.8%) received planned MV replacement. With increasing proportions of minimally invasive procedures (2014: 14.8%, 2020: 46.5%), we observed a continuous growth in overall institutional volume of MVP ( n  = 69 in 2013; n  = 127 in 2020) and markedly improved institutional rates of successful MVr, with 95.4% in 2013 vs. 99.2% in 2020. Over this period, a higher complexity of cases were treated minimally-invasively and increased use of neochord implantation ± limited leaflet resection was observed. Patients operated minimally invasively had longer aortic cross-clamp times (94 vs. 88 min, p  = 0.001) but shorter ventilation times (4.4 vs. 4.8 h, p  = 0.002) and hospital stays (5 vs. 6 days, p  < 0.001) than those operated via sternotomy, with no significant differences in other outcome variables. A total of 16 patients underwent robotically assisted MVr with successful repair in all cases., Conclusion: A focused approach towards minimally invasive MVr has transformed the overall MVr strategy (incision; repair techniques) at our institution, leading to a growth in MVr volume and improved repair rates without significant complications. On this foundation, robotic MVr was first introduced at our institution in 2021 with excellent outcomes. This emphasizes the importance of building a competent team to perform these challenging operations, especially during the initial learning curve., Competing Interests: MB's hospital receives speaker's honoraria and/or consulting fees on his behalf from Edwards Lifesciences, Medtronic, Abbott and Artivion. SM receives speaker's honoraria from Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 van Kampen, Goudot, Butte, Paneitz, Borger, Badhwar, Sundt, Langer and Melnitchouk.)

Objective: The study objective was to assess the safety and efficacy of a preemptive direct-acting antiviral therapy in lung transplants from hepatitis C virus donors to uninfected recipients., Methods: This study is a prospective, open-label, nonrandomized, pilot trial. Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Recipients of nucleic acid test positive lungs were compared with recipients of lungs from nucleic acid test negative donors. Primary end points were Kaplan-Meier survival and sustained virologic response. Secondary outcomes included primary graft dysfunction, rejection, and infection., Results: Fifty-nine lung transplantations were included: 16 nucleic acid test positive and 43 nucleic acid test negative. Twelve nucleic acid test positive recipients (75%) developed hepatitis C virus viremia. Median time to clearance was 7 days. All nucleic acid test positive patients had undetectable hepatitis C virus RNA by week 3, and all alive patients (n = 15) remained negative during follow-up with 100% sustained virologic response at 12 months. One nucleic acid test positive patient died of primary graft dysfunction and multiorgan failure. Three of 43 nucleic acid test negative patients (7%) had hepatitis C virus antibody positive donors. None of them developed hepatitis C virus viremia. One-year survival was 94% for nucleic acid test positive recipients and 91% for nucleic acid test negative recipients. There was no difference in primary graft dysfunction, rejection, or infection. One-year survival for nucleic acid test positive recipients was similar to a historical cohort of the Scientific Registry of Transplant Recipients (89%)., Conclusions: Recipients of hepatitis C virus nucleic acid test positive lungs have similar survival as recipients of nucleic acid test negative lungs. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission., (© 2023 The Authors.)

Objectives: We provide a contemporary consideration of long-term outcomes and trends of induction therapy use following lung transplantation in the United States., Methods: We reviewed the United Network for Organ Sharing registry from 2006 to 2018 for first-time, adult, lung-only transplant recipients. Long-term survival was compared between induction classes (Interleukin-2 inhibitors, monoclonal or polyclonal cell-depleting agents, and no induction therapy). A 1:1 propensity score match was performed, pairing patients who received basiliximab with similar risk recipients who did not receive induction therapy. Outcomes in matched populations were compared using Cox, Kaplan-Meier and Logistic regression modeling., Measurements and Main Results: 22 025 recipients were identified; 8003 (36.34%) were treated with no induction therapy, 11 045 (50.15%) with basiliximab, 1556 (7.06%) with alemtuzumab and 1421 (6.45%) with anti-thymocyte globulin. Compared with those who received no induction, patients receiving basiliximab, alemtuzumab or anti-thymocyte globulin were found on multivariable Cox-regression analyses to have lower long-term mortality (all p < .05). Following propensity score matching of basiliximab and no induction populations, analyses demonstrated a statistically significant association between basiliximab use and long- term survival (p < .001). Basiliximab was also associated with a lower risk of acute rejection (p < .001) and renal failure (p = .002)., Conclusion: Induction therapy for lung transplant recipients-specifically basiliximab-is associated with improved long-term survival and a lower risk of renal failure or acute rejection., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mitral annular calcification (MAC) in mitral valve surgery constitutes a major challenge. Debridement with patch reconstruction of the mitral annulus facilitates valve repair or replacement, however, there is a perception that this procedure may elevate operative risk. This study sought to review a single-center experience with mitral annular debridement and patch reconstruction in patients with MAC., Methods: Data were collected on patients operated on from January 2017 to December 2020 in the setting of significant MAC. Patients underwent a systematic approach to MAC excision, involving complete removal of the entire calcium bar. This was followed by patch reconstruction of the debridement area before either valve repair or replacement., Results: The investigators identified 38 patients (24 female, 12 male) whose median age was 72 years (interquartile range, 62-80 years). There were 14 mitral valve repairs and 24 replacements. Twenty-five patients underwent a concomitant cardiac procedure. Seven cases were redo sternotomies. There were 2 (5%) 30-day mortalities. Median length of intensive care unit stay was 2.4 days, and median hospital stay was 8.5 days. One patient required postoperative extracorporeal support. There were 4 late deaths. Actuarial survival at 1 and 2 years was 89% and 82%, respectively. No patient has required reoperation for valvular dysfunction., Conclusions: A systematic approach to MAC debridement, involving excision of the entire calcium bar and annular reconstruction, can be used in patients undergoing either isolated or combined complex mitral valve surgery. This strategy can be performed with a low risk of perioperative mortality despite relatively longer operative times., (© 2022 The Authors.)

Objective: This manuscript describes the rationale and design of a randomized, controlled trial comparing outcomes with Warfarin vs Novel Oral Anticoagulant (NOAC) therapy in patients with new onset atrial fibrillation after cardiac surgery., Background: New onset atrial fibrillation commonly occurs after cardiac surgery and is associated with increased rates of stroke and mortality. in nonsurgical patients with atrial fibrillation, NOACs have been shown to confer equivalent benefits for stroke prevention with less bleeding risk and less tedious monitoring requirements compared with Warfarin. However, NOAC use has yet to be adopted widely in cardiac surgery patients., Methods: The NEW-AF study has been designed as a pragmatic, prospective, randomized controlled trial that will compare financial, convenience and safety outcomes for patients with new onset atrial fibrillation after cardiac surgery that are treated with NOACs versus Warfarin., Results: Study results may contribute to optimizing the options for stroke prophylaxis in cardiac surgery patients and catalyze more widespread application of NOAC therapy in this patient population., Conclusions: The study is ongoing and actively enrolling at the time of the publication. The trial is registered with clinicaltrials.gov under registration number NCT03702582., Competing Interests: The authors declare no conflict of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background Many patients with severe aortic stenosis (AS) and an indication for aortic valve replacement (AVR) do not undergo treatment. The reasons for this have not been well studied in the transcatheter AVR era. We sought to determine how patient- and process-specific factors affected AVR use in patients with severe AS. Methods and Results We identified ambulatory patients from 2016 to 2018 demonstrating severe AS, defined by aortic valve area [Formula: see text]1.0 cm 2 . Propensity scoring analysis with inverse probability of treatment weighting was used to evaluate associations between predictors and the odds of undergoing AVR at 365 days and subsequent mortality at 730 days. Of 324 patients with an indication for AVR (79.3±9.7 years, 57.4% men), 140 patients (43.2%) did not undergo AVR. The odds of AVR were reduced in patients aged >90 years (odds ratio [OR], 0.24 [95% CI, 0.08-0.69]; P =0.01), greater comorbid conditions (OR, 0.88 per 1-point increase in Combined Comorbidity Index [95% CI, 0.79-0.97]; P =0.01), low-flow, low-gradient AS with preserved left ventricular ejection fraction (OR, 0.11 [95% CI, 0.06-0.21]), and low-gradient AS with reduced left ventricular ejection fraction (OR, 0.18 [95% CI, 0.08-0.40]) and were increased if the transthoracic echocardiogram ordering provider was a cardiologist (OR, 2.46 [95% CI, 1.38-4.38]). Patients who underwent AVR gained an average of 85.8 days of life (95% CI, 40.9-130.6) at 730 days. Conclusions The proportion of ambulatory patients with severe AS and an indication for AVR who do not receive AVR remains significant. Efforts are needed to maximize the recognition of severe AS, especially low-gradient subtypes, and to encourage patient referral to multidisciplinary heart valve teams.

Background: Despite the rapid growth of aortic valve replacement (AVR) for aortic stenosis (AS), limited data suggest symptomatic severe AS remains undertreated., Objectives: This study sought to investigate temporal trends in AVR utilization among patients with a clinical indication for AVR., Methods: Patients with severe AS (aortic valve area <1 cm 2 ) on transthoracic echocardiograms from 2000 to 2017 at 2 large academic medical centers were classified based on clinical guideline indications for AVR and divided into 4 AS subgroups: high gradient with normal left ventricular ejection fraction (LVEF) (HG-NEF), high gradient with low LVEF (HG-LEF), low gradient with normal LVEF (LG-NEF), and low gradient with low LVEF (LG-LEF). Utilization of AVR was examined and predictors identified., Results: Of 10,795 patients, 6,150 (57%) had an indication or potential indication for AVR, of whom 2,977 (48%) received AVR. The frequency of AVR varied by AS subtype with LG groups less likely to receive an AVR (HG-NEF: 70%, HG-LEF: 53%, LG-NEF: 32%, LG-LEF: 38%, P < 0.001). AVR volumes grew over the 18-year study period but were paralleled by comparable growth in the number of patients with an indication for AVR. In patients with a Class I indication, younger age, coronary artery disease, smoking history, higher hematocrit, outpatient index transthoracic echocardiogram, and LVEF ≥0.5 were independently associated with an increased likelihood of receiving an AVR. AVR was associated with improved survival in each AS-subgroup., Conclusions: Over an 18-year period, the proportion of patients with an indication for AVR who did not receive AVR has remained substantial despite the rapid growth of AVR volumes., Competing Interests: Funding Support and Author Disclosures This study was funded by Edwards Lifesciences. Dr Inglessishas has received institutional research support from Medtronic, St. Jude Medical, and W.L. Gore and Associates; and is a proctor for Medtronic and Edwards Lifesciences. Dr Shah has received educational grants from Edwards Lifesciences, Medtronic, and Abbott Vascular; has received consulting fees from Edwards Lifesciences; has been a proctor for Edwards Lifesciences; and has been an advisory board member for Xenter. Dr Passeri has received institutional research support from Edwards Lifesciences; has been a speaker at an educational symposium sponsored by Medtronic; and has received consulting fees from Medtronic. Dr Kaneko has received consulting fees from Edwards Lifesciences, Medtronic, 4C Medical, CardioMech, Cook Medical; and has been a speaker for Abbott and Baylis. Dr Elmariah has received research grants from American Heart Association (19TPA34910170), National Institutes of Health (R01 HL151838), Edwards Lifesciences, Svelte Medical, Abbott Vascular, and Medtronic; and has received consulting fees from Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The novel coronavirus disease-2019 (COVID-19) pandemic has created uncertainty in the management of patients with severe aortic stenosis. This population experiences high mortality from delays in treatment of valve disease but is largely overlapping with the population of highest mortality from COVID-19. The authors present strategies for managing patients with severe aortic stenosis in the COVID-19 era. The authors suggest transitions to virtual assessments and consultation, careful pruning and planning of necessary testing, and fewer and shorter hospital admissions. These strategies center on minimizing patient exposure to COVID-19 and expenditure of human and health care resources without significant sacrifice to patient outcomes during this public health emergency. Areas of innovation to improve care during this time include increased use of wearable and remote devices to assess patient performance and vital signs, devices for facile cardiac assessment, and widespread use of clinical protocols for expedient discharge with virtual physical therapy and cardiac rehabilitation options., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To better understand morbidity and mortality in patients with a low left ventricular ejection fraction (LVEF) undergoing aortic root replacement., Methods: All patients who underwent aortic root replacement at our institution between 2005 and 2013 (n = 595) were retrospectively reviewed and included in the study. The primary outcome was mortality. Secondary outcomes were in-hospital mortality and perioperative morbidity. Restricted cubic spline analysis showed a relatively linear inverse relationship between LVEF and the hazard ratio for mortality in patients with an LVEF <50% with no unique cutoff. Therefore, LVEF was treated as a continuous variable. Patients were divided into 3 groups (LVEF <40%, LVEF 40%-49%, and LVEF ≥50%) in order to illustrate the impact of LVEF on mortality., Results: LVEF <40% patients had greater in-hospital mortality (14.0% vs 5.0% vs 1.0%, P < .001) and longer median hospital and intensive care unit stays (10.5 vs 8 vs 6 days, P < .001 and 4 vs 2 vs 2 days, P < .001) than patients with LVEF 40% to 49% or greater than 50%, respectively. Patients with LVEF <40% had more reoperations for bleeding (18% vs 5.0% vs 5.8%, P = .004), postoperative respiratory failure (16% vs 6.7% vs 4.9%, P = .008), and need for mechanical circulatory support (8.0% vs 5.0% vs 1.4%, P = .005). Using multivariable Cox proportional hazards analysis, we found that reduced LVEF, age, previous, cardiac surgery, and type A dissection were independent predictors of mortality., Conclusions: Reduced LVEF negatively impacts mortality as well as in-hospital death and perioperative morbidity after aortic root replacement. Careful patient selection and risk discussion are vital in this high-risk population., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Surgical strategy and long-term outcomes of patients with rupture of the ascending aorta, aortic arch and supra-aortic vessels following blunt thoracic trauma have been rarely reported. We reviewed our institutional experience between 1995 and 2016. We identified 2 patients with an innominate artery ruptures, 2 with an aortic arch ruptures and 1 with an ascending aorta rupture; all were induced by the posterior displacement of the anterior chest wall. All patients underwent open surgical repair. Cardiopulmonary bypass with antegrade cerebral perfusion was required in 2 cases. All patients were alive at the end of the follow-up (median 18 months; from 3 to 180 months) including 1 patient with cortical blindness.

Background: Chronic thromboembolic pulmonary hypertension results from chronic mechanical obstruction of the pulmonary arteries after acute venous thromboembolism. However, the mechanisms that result in the progression from unresolved thrombus to fibrotic vascular remodeling are unknown. We hypothesized that pulmonary artery endothelial cells contribute to this phenomenon via paracrine growth factor and cytokine signaling., Methods: Using enzyme-linked immunosorbent assay and cell migration assays, we investigated the circulating growth factors and cytokines of chronic thromboembolic pulmonary hypertension patients as well as the cross talk between pulmonary endothelial cells and pulmonary artery smooth muscle cells and monocytes from patients with chronic thromboembolic pulmonary hypertension in vitro., Results: Culture medium from the pulmonary endothelial cells of chronic thromboembolic pulmonary hypertension patients contained higher levels of growth factors (fibroblast growth factor 2), inflammatory cytokines (interleukin 1β, interleukin 6, monocyte chemoattractant protein 1), and cell adhesion molecules (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1). Furthermore, exposure to the culture medium of pulmonary endothelial cells from patients with chronic thromboembolic pulmonary hypertension elicited marked pulmonary artery smooth muscle cell growth and monocyte migration., Conclusions: These findings implicate pulmonary endothelial cells as key regulators of pulmonary artery smooth muscle cell and monocyte behavior in chronic thromboembolic pulmonary hypertension and suggest a potential mechanism for the progression from unresolved thrombus to fibrotic vascular remodeling., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The experience with transcatheter aortic valve replacement is increasing worldwide; however, the incidence of potentially catastrophic cardiac or aortic complications has not decreased. In most cases, significant injuries to the aorta, aortic valve annulus, and left ventricle require open surgical repair. However, the transcatheter aortic valve replacement patient presents a unique challenge as many patients are at high or prohibitive surgical risk and, therefore, an open surgical procedure may not be feasible or appropriate. Consequently, prevention of these potentially catastrophic injuries is vital, and practitioners need to understand when open surgical repair is required and when alternative management strategies can be used. The goal of this article is to provide an overview of current management and prevention strategies for major complications involving the aorta, aortic valve annulus, and left ventricle., (© 2016 American Heart Association, Inc.)

Background: Complete, en bloc resection offers the greatest chance of long-term survival in T4 non-small cell lung cancer (NSCLC). The use of cardiopulmonary bypass (CPB) to achieve an en bloc resection is controversial because of potentially increased bleeding, lung dysfunction, and tumor dissemination. We reviewed our institutional experience to assess CPB's effect on survival., Methods: All patients who underwent resection for T4 NSCLC at our institution between 1980 and 2013 were retrospectively reviewed and stratified according to whether they did (CPB group, n = 20) or did not (No CPB group, n = 355) undergo CPB. Primary outcomes of interest were overall and disease-free survival and perioperative complications., Results: Baseline characteristics and medical therapy were similar between the groups. Median overall survival for all patients was 31 months, with 1-, 3-, 5-, and 10-year survival of 73%, 47%, 40%, and 26%, respectively. Median disease-free survival for all patients was 19 months, with 1-, 3-, 5-, and 10-year disease-free survival of 61%, 40%, 33%, and 21%, respectively. No difference was found in overall or disease-free survival at 1, 3, 5, and 10 years between the No CPB and CPB groups (p = 0.89 and p = 0.88). In addition, no differences were found in the rates of major perioperative complications., Conclusions: The use of CPB allows for complete, en bloc resection in otherwise inoperable patients with T4 NSCLC and offers similar overall and disease-free survival to patients resected without CPB. All thoracic surgeons who manage T4 NSCLC should consider the use of CPB if it is necessary to achieve a complete, en bloc resection., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Two patients experienced compression of a coronary artery bypass graft or native coronary artery by mediastinal drains placed after cardiac surgery. Both events were identified in the catheterization laboratory and resolved after removal of the drains. One patient required concomitant percutaneous thrombectomy of the bypass graft. Although both patients' cardiac function was initially severely impaired, neither patient had permanent cardiac damage and both were successfully discharged home., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Throughout the modern era of cardiac surgery, most operations have been performed via median sternotomy with cardiopulmonary bypass. This paradigm is changing, however, as cardiovascular surgery is increasingly adopting minimally invasive techniques. Advances in patient evaluation, instrumentation, and operative technique have allowed surgeons to perform a wide variety of complex operations through smaller incisions and, in some cases, without cardiopulmonary bypass. With patients desiring less invasive operations and the literature supporting decreased blood loss, shorter hospital length of stay, improved postoperative pain, and better cosmesis, minimally invasive cardiac surgery should be widely practiced. Here, we review the incisions and approaches currently used in minimally invasive cardiovascular surgery.

Mitochondrial iron is essential for the biosynthesis of heme and iron-sulfur ([Fe-S]) clusters in mammalian cells. In developing erythrocytes, iron is imported into the mitochondria by MFRN1 (mitoferrin-1, SLC25A37). Although loss of MFRN1 in zebrafish and mice leads to profound anemia, mutant animals showed no overt signs of porphyria, suggesting that mitochondrial iron deficiency does not result in an accumulation of protoporphyrins. Here, we developed a gene trap model to provide in vitro and in vivo evidence that iron regulatory protein-1 (IRP1) inhibits protoporphyrin accumulation. Mfrn1(+/gt);Irp1(-/-) erythroid cells exhibit a significant increase in protoporphyrin levels. IRP1 attenuates protoporphyrin biosynthesis by binding to the 5'-iron response element (IRE) of alas2 mRNA, inhibiting its translation. Ectopic expression of alas2 harboring a mutant IRE, preventing IRP1 binding, in Mfrn1(gt/gt) cells mimics Irp1 deficiency. Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation.

Rationale: Heme plays a critical role in gas exchange, mitochondrial energy production, and antioxidant defense in cardiovascular system. The mitochondrial transporter ATP-binding cassette (ABC) B10 has been suggested to export heme out of the mitochondria and is required for normal hemoglobinization of erythropoietic cells and protection against ischemia-reperfusion injury in the heart; however, its primary function has not been established., Objective: The aim of this study was to identify the function of ABCB10 in heme synthesis in cardiac cells., Methods and Results: Knockdown of ABCB10 in cardiac myoblasts significantly reduced heme levels and the activities of heme-containing proteins, whereas supplementation with δ-aminolevulinic acid reversed these defects. Overexpression of mitochondrial δ-aminolevulinic acid synthase 2, the rate-limiting enzyme upstream of δ-aminolevulinic acid export, failed to restore heme levels in cells with ABCB10 downregulation. ABCB10 and heme levels were increased by hypoxia, and reversal of ABCB10 upregulation caused oxidative stress and cell death. Furthermore, ABCB10 knockdown in neonatal rat cardiomyocytes resulted in a significant delay of calcium removal from the cytoplasm, suggesting a relaxation defect. Finally, ABCB10 expression and heme levels were altered in failing human hearts and mice with ischemic cardiomyopathy., Conclusions: ABCB10 plays a critical role in heme synthesis pathway by facilitating δ-aminolevulinic acid production or export from the mitochondria. In contrast to previous reports, we show that ABCB10 is not a heme exporter and instead is required for the early mitochondrial steps of heme biosynthesis.

Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.

Objective: Most patients with erythropoietic protoporphyria have deficient ferrochelatase (FECH) activity due to changes in FECH DNA. We evaluated seven patients with erythropoietic protoporphyria phenotype in whom abnormalities of FECH DNA were not found by conventional analysis. The major focus was mitoferrin-1 (MFRN1), the mitochondrial transporter of Fe used for heme formation by FECH and for 2Fe2S cluster synthesis, which is critical to FECH activity/stability., Materials and Methods: Four patients had a deletion in ALAS2 that causes enzyme gain-of-function, resulting in increased formation of protoporphyrin; one had a heterozygous major deletion in FECH DNA. All had an abnormal transcript of MFRN1 in messenger RNA extracted from blood leukocytes and/or liver tissue. The abnormal transcript contained an insert of intron 2 that had a stop codon. The consequences of abnormal MFRN1 expression were examined using zebrafish and yeast MFRN-deficient strains and cultured lymphoblasts from the patients., Results: Abnormal human MFRN1 complementary DNA showed loss-of-function in zebrafish and yeast mutants, whereas normal human MFRN1 complementary DNA rescued both. Using cultured lymphoblasts, quantitative reverse transcription polymerase chain reaction showed increased formation of abnormal transcript that was accompanied by decreased formation of normal transcript and reduced FECH activity in patients compared to normal lines. A positive correlation coefficient (0.75) was found between FECH activity and normal MFRN1 messenger RNA in lymphoblasts. However, no obvious cause for increased formation of abnormal transcript was identified in MFRN1 exons and splice junctions., Conclusions: Abnormal MFRN1 expression can contribute to erythropoietic protoporphyria phenotype in some patients, probably by causing a reduction in FECH activity., (Copyright © 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Drug-induced immune hemolytic anemia is a rare but underdiagnosed and potentially fatal condition. We report a case of severe hemolytic anemia induced by cefoxitin in a 45-year-old woman admitted with menometrorrhagia. Hemoglobin levels reached a nadir of 4.7 g/dl approximately 72 h after cefoxitin initiation, and hemolysis resolved when cefoxitin was discontinued and prednisone 1 mg/kg was initiated. A transfusion reaction workup revealed no abnormalities. Direct antiglobulin testing was weakly positive with anti-C3. The patient's plasma and RBC eluate reacted with cefoxitin-treated RBCs but not with untreated RBCs in the presence or absence of cefoxitin., (Copyright © 2010 S. Karger AG, Basel.)

The nuclear protein FOG-1 binds transcription factor GATA-1 to facilitate erythroid and megakaryocytic maturation. However, little is known about the function of FOG-1 during myeloid and lymphoid development or how FOG-1 expression is regulated in any tissue. We used in situ hybridization, gain- and loss-of-function studies in zebrafish to address these problems. Zebrafish FOG-1 is expressed in early hematopoietic cells, as well as heart, viscera, and paraspinal neurons, suggesting that it has multifaceted functions in organogenesis. We found that FOG-1 is dispensable for endoderm specification but is required for endoderm patterning affecting the expression of late-stage T-cell markers, independent of GATA-1. The suppression of FOG-1, in the presence of normal GATA-1 levels, induces severe anemia and thrombocytopenia and expands myeloid-progenitor cells, indicating that FOG-1 is required during erythroid/myeloid commitment. To functionally interrogate whether GATA-1 regulates FOG-1 in vivo, we used bioinformatics combined with transgenic assays. Thus, we identified 2 cis-regulatory elements that control the tissue-specific gene expression of FOG-1. One of these enhancers contains functional GATA-binding sites, indicating the potential for a regulatory loop in which GATA factors control the expression of their partner protein FOG-1.

Mitoferrin-1 (Mfrn1; Slc25a37), a member of the solute carrier family localized in the mitochondrial inner membrane, functions as an essential iron importer for the synthesis of mitochondrial heme and iron-sulfur clusters in erythroblasts. The biochemistry of Mfrn1-mediated iron transport into the mitochondria, however, is poorly understood. Here, we used the strategy of in vivo epitope-tagging affinity purification and mass spectrometry to investigate Mfrn1-mediated mitochondrial iron homeostasis. Abcb10, a mitochondrial inner membrane ATP-binding cassette transporter highly induced during erythroid maturation in hematopoietic tissues, was found as one key protein that physically interacts with Mfrn1 during mouse erythroleukemia (MEL) cell differentiation. Mfrn1 was shown previously to have a longer protein half-life in differentiated MEL cells compared with undifferentiated cells. In this study, Abcb10 was found to enhance the stabilization of Mfrn1 protein in MEL cells and transfected heterologous COS7 cells. In undifferentiated MEL cells, cotransfected Abcb10 specifically interacts with Mfrn1 to enhance its protein stability and promote Mfrn1-dependent mitochondrial iron importation. The structural stabilization of the Mfrn1-Abcb10 complex demonstrates a previously uncharacterized function for Abcb10 in mitochondria. Furthermore, the binding domain of Mfrn1-Abcb10 interaction maps to the N terminus of Mfrn1. These results suggest the tight regulation of mitochondrial iron acquisition and heme synthesis in erythroblasts is mediated by both transcriptional and posttranslational mechanisms, whereby the high level of Mfrn1 is stabilized by oligomeric protein complexes.

Objective: A missense mutation in the microtubule-associated serine/threonine-like kinase gene (MASTL, FLJ14813) on human chromosome 10 was previously linked to a novel form of autosomal dominant inherited thrombocytopenia in a single pedigree. The mutation results in an amino acid change from glutamic acid at position 167 to aspartic acid and segregates perfectly with thrombocytopenic individuals within this extended family. The phenotype is characterized by mild thrombocytopenia with an average platelet count of 60,000 platelets per microliter of blood. We wanted to determine the expression and localization of MASTL, as well as its role in developing thrombocytes using an in vivo model system., Materials and Methods: Northern blot analysis allowed us to examine expression patterns. Morpholino knockdown assays in zebrafish (Danio rerio) were employed to determine in vivo contribution to thrombocyte development. Transient expression in baby hamster kidney cells resulted in localization of both the wild-type and E167D mutant forms of MASTL kinase to the nucleus., Results: Northern blot analysis indicates that MASTL messenger RNA is restricted in its expression to hematopoietic and cancer cell lines. A transient knockdown of MASTL in zebrafish results in deficiency of circulating thrombocytes. Transient expression of recombinant MASTL kinase in vitro demonstrates localization to the nucleus., Conclusions: Functional studies presented here demonstrate a direct relationship between transient knockdown of MASTL kinase gene expression and reduction of circulating thrombocytes in zebrafish. This transient knockdown of MASTL in zebrafish correlates with a decrease in the expression of the thrombopoietin receptor, c-mpl, and the CD41 platelet adhesion protein, GpIIb, but has no effect on essential housekeeping zebrafish gene, EF1alpha.

Objective: Inherited or acquired mutations in the heme biosynthetic pathway leads to a debilitating class of diseases collectively known as porphyrias, with symptoms that can include anemia, cutaneous photosensitivity, and neurovisceral dysfunction. In a genetic screen for hematopoietic mutants, we isolated a zebrafish mutant, montalcino (mno), which displays hypochromic anemia and porphyria. The objective of this study was to identify the defective gene and characterize the phenotype of the zebrafish mutant., Materials and Methods: Genetic linkage analysis was utilized to identify the region harboring the mno mutation. Candidate gene analysis together with reverse transcriptase polymerase chain reaction was utilized to identify the genetic mutation, which was confirmed via allele-specific oligo hybridizations. Whole mount in situ hybridizations and o-dianisidine staining were used to characterize the phenotype of the mno mutant. mRNA and morpholino microinjections were performed to phenocopy and/or rescue the mutant phenotype., Results: Homozygous mno mutant embryos have a defect in the protoporphyrinogen oxidase (ppox) gene, which encodes the enzyme that catalyzes the oxidation of protoporphyrinogen. Homozygous mutant embryos are deficient in hemoglobin, and by 36 hours post-fertilization are visibly anemic and porphyric. The hypochromic anemia of mno embryos was partially rescued by human ppox, providing evidence for the conservation of function between human and zebrafish ppox., Conclusion: In humans, mutations in ppox result in variegate porphyria. At present, effective treatment for acute attacks requires the administration intravenous hemin and/or glucose. Thus, mno represents a powerful model for investigation, and a tool for future screens aimed at identifying chemical modifiers of variegate porphyria.

A complete understanding of the transcriptional regulation of developmental lineages requires that all relevant factors be identified. Here, we have taken a proteomic approach to identify novel proteins associated with GATA-1, a lineage-restricted zinc finger transcription factor required for terminal erythroid and megakaryocytic maturation. We identify the Krüppel-type zinc finger transcription factor ZBP-89 as being a component of multiprotein complexes involving GATA-1 and its essential cofactor Friend of GATA-1 (FOG-1). Using chromatin immunoprecipitation assays, we show that GATA-1 and ZBP-89 cooccupy cis-regulatory elements of certain erythroid and megakaryocyte-specific genes, including an enhancer of the GATA-1 gene itself. Loss-of-function studies in zebrafish and mice demonstrate an in vivo requirement for ZBP-89 in megakaryopoiesis and definitive erythropoiesis but not primitive erythropoiesis, phenocopying aspects of FOG-1- and GATA-1-deficient animals. These findings identify ZBP-89 as being a novel transcription factor involved in erythroid and megakaryocytic development and suggest that it serves a cooperative function with GATA-1 and/or FOG-1 in a developmental stage-specific manner.