A highly penetrant ACTA2 mutation of thoracic aortic disease.

BACKGROUND: The role of ACTA2 mutations in Familial Aortic Disease has been increasingly recognized. We describe a highly penetrant variant (R118Q) in a family with aortic disease. CASE REPORT: A patient presented to us for elective repair of an ascending aortic aneurysm with a family history of his mother expiring after aortic dissection. Genetic testing revealed he was a heterozygous carrier of the ACTA2 missense mutation R118Q. Subsequently, all living family members were tested for this variant and a full medical history was obtained to compile a family tree for the variant and penetrance of an aortic event (defined as lifetime occurrence of aortic surgery / dissection). In total 9 family members were identified and underwent genetic testing with 7/9 showing presence of the ACTA2 R118Q mutation or an aortic event. All patients over the age of 50 (n = 4) had an aortic event. Those events occurred at ages 54, 55, 60, and 62 (mean event at 57.8 ± 3.9 years). Three family members with the variant under the age of 40 have not had an aortic event and most are undergoing regular aortic surveillance via CT scan. CONCLUSIONS: Existing studies of known ACTA2 mutations describe a 76% aortic event rate by 85 years old. The R118Q missense mutation is a less common ACTA2 variant, estimated to be found in about 5% of patients with known mutations. Prior studies have predicted the R118Q mutation to have a slightly decreased risk of aortic events compared to other ACTA2 mutations. In this family, however, we demonstrate 100% penetrance of aortic disease above age 50. In today's era of excellent outcomes in elective aortic surgery, our team aggressively offers elective repair. We advocate for strict aortic surveillance for patients with this variant and would consider elective aortic replacement at 4.5 cm, or at an even smaller diameter in patients with a strong family history of dissection who are identified with this mutation.

Biologic Augmentation during Meniscal Repair.

We reviewed the literature regarding utility of biologic augmentation in meniscal repair. We hypothesized that the addition of biologic augmentation during meniscal repair improves postoperative knee function and reduces risk of repair failure. PubMed and Embase databases were systematically searched. Included studies were clinical studies in humans, published in English, and reported use of biologic augmentation techniques in addition to meniscal repair (including platelet-rich plasma [PRP], fibrin clot, bone marrow stimulation, meniscal wrapping, and bioscaffolds) for treatment of knee meniscal tears. Outcome measures included repair failure, repeat knee arthroscopic surgery, and magnetic resonance imaging), visual analog scale for pain, the International Knee Documentation Committee questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index Lysholm's Knee Scoring Scale, and the Knee Injury and Osteoarthritis Outcome Score. Study quality was assessed using the modified Coleman methodology score. Nineteen studies reported repair of 1,092 menisci including six studies that investigated fibrin clot augmentation, five studies that investigated PRP augmentation, three studies that investigated bone marrow stimulation augmentation, two studies that used meniscal wrapping augmentation, and three studies that used other techniques. The level of evidence ranged from I to IV and mean modified Coleman methodology score was 43 (range: 17-69), with higher scores noted in studies completed in recent years. PRP and bone marrow stimulation augmentation appear to decrease risk of failure in patients undergoing isolated meniscal repair but do not improve knee symptom scores. Fibrin clot and trephination augmentation techniques do not have sufficient evidence to support decreased failure risk at this time. Meniscal wrapping augmentation and scaffold implantation augmentation appear to be an attractive option to meniscectomy in complicated tears that are not candidates for repair alone, but further confirmatory studies are needed to support initial data. Evidence supporting augmentation of meniscal repair is limited at this time but suggests that the highest likelihood for effectiveness of augmentation is in the settings of isolated meniscal repair or meniscal repairs that would normally not be amenable to repair.

Continuous renal replacement therapy and extracorporeal membrane oxygenation: implications in the COVID-19 era.

The novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (coronavirus Disease 19 (COVID-19)) was identified as the causative agent of viral pneumonias in Wuhan, China in December 2019, and has emerged as a pandemic causing acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. Interim guidance by the World Health Organization states that extracorporeal membrane oxygenation (ECMO) should be considered as a rescue therapy in COVID-19-related ARDS. International registries tracking ECMO in COVID-19 patients reveal a 21%-70% incidence of acute renal injury requiring renal replacement therapy (RRT) during ECMO support. The indications for initiating RRT in patients on ECMO are similar to those for patients not requiring ECMO. RRT can be administered during ECMO via a temporary dialysis catheter, placement of a circuit in-line hemofilter, or direct connection of continuous RRT in-line with the ECMO circuit. Here we review methods for RRT during ECMO, RRT initiation and timing during ECMO, anticoagulation strategies, and novel cytokine filtration approaches to minimize COVID-19's pathophysiological impact.

Cerebral protection using deep hypothermic circulatory arrest versus retrograde cerebral perfusion for aortic hemiarch reconstruction.

BACKGROUND: With evolutions in technique, recent data encourage the use of cerebral perfusion during aortic arch repair. However, a randomized data have demonstrated higher rates of neurologic injury according to MRI lesions using antegrade cerebral perfusion during hemiarch reconstruction. METHODS: This was a retrospective review of two institutional aortic center databases to identify adult patients who underwent aortic hemiarch reconstruction for elective aortic aneurysm or acute type A aortic dissection. Patients were stratified according to cerebral protection method: (1) deep hypothermic circulatory arrest (DHCA) group versus (2) DHCA/retrograde cerebral perfusion (RCP) group. RESULTS: A total of 320 patients and 245 patients underwent hemiarch reconstruction for aortic aneurysm electively and aortic dissection, respectively. In aneurysmal pathology, the DHCA group included 133 patients and the DHCA/RCP group included 187 patients. Operative mortality was 0.8% in the DHCA group and 2.7% in the DHCA/RCP group (p = 0.41). Kaplan-Meier survival estimates revealed comparable 2-year survival (p = 0.14). In dissection, 43 patients and 202 patients were included in the DHCA group and the DHCA/RCP group, respectively. Operative mortality was equivalent between the two groups (11.6% in the DHCA group and 9.4% in the DHCA/RCP group, p = 0.58). Long-term survival was similar at 2 years between the groups (p = 0.06). Multivariable analysis showed cerebral perfusion strategy was not associated with the composite outcome of operative mortality and stroke. CONCLUSIONS: In treating both elective and acute ascending aortic pathologies with hemiarch reconstruction, both DHCA alone or in combination with RCP yield comparable results.

Trends in Donation After Circulatory Death in Lung Transplantation in the United States: Impact Of Era.

Background: Use of lungs donated after circulatory death (DCD) has expanded, but changes in donor/recipient characteristics and comparison to brain dead donors (DBD) has not been studied. We examined the evolution of the use of DCD lungs for transplantation and compare outcomes to DBD lungs. Methods: The SRTR database was used to construct three 5-year intervals. Perioperative variables and survival were compared by era and for DCD vs. DBD. Geographic variation was estimated using recipient permanent address. Results: 728 DCD and 27,205 DBD lung transplants were identified. DCD volume increased from Era 1 (n = 73) to Era 3 (n = 528), representing 1.1% and 4.2% of lung transplants. Proportionally more DCD recipients were in ICU or on ECMO pre-transplant, and had shorter waitlist times. DCD donors were older, had lower PaO2/FiO2 ratios compared to DBD, more likely to be bilateral, had longer ischemic time, length of stay, post-op dialysis, and increased use of lung perfusion. There was no difference in overall survival. Geographically, use was heterogeneous. Conclusion: DCD utilization is low but increasing. Despite increasing ischemic time and transplantation into sicker patients, survival is similar, which supports further DCD use in lung transplantation. DCD lung transplantation presents an opportunity to continue to expand the donor pool.

mTORC1 is a mechanosensor that regulates surfactant function and lung compliance during ventilator-induced lung injury.

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.

Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation.

Mechanical ventilation generates injurious forces that exacerbate lung injury. These forces disrupt lung barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides including microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We use humanized in-vitro systems, mouse models, and biospecimens from patients to elucidate the expression dynamics of miR-146a needed to decrease lung injury during mechanical ventilation. We find that the endogenous increase in miR-146a following injurious ventilation is not sufficient to prevent lung injury. However, when miR-146a is highly overexpressed using a nanoparticle delivery platform it is sufficient to prevent injury. These data indicate that the endogenous increase in microRNA-146a during mechanical ventilation is a compensatory response that partially limits injury and that nanoparticle delivery of miR-146a is an effective strategy for mitigating lung injury during mechanical ventilation.

A Novel Negative Pressure-Flow Waveform to Ventilate Lungs for Normothermic Ex Vivo Lung Perfusion.

Ex vivo lung perfusion (EVLP) is increasingly used to treat and assess lungs before transplant. Minimizing ventilator induced lung injury (VILI) during EVLP is an important clinical need, and negative pressure ventilation (NPV) may reduce VILI compared with conventional positive pressure ventilation (PPV). However, it is not clear if NPV is intrinsically lung protective or if differences in respiratory pressure-flow waveforms are responsible for reduced VILI during NPV. In this study, we quantified lung injury using novel pressure-flow waveforms during normothermic EVLP. Rat lungs were ventilated-perfused ex vivo for 2 hours using tidal volume, positive end-expiratory pressure (PEEP), and respiratory rate matched PPV or NPV protocols. Airway pressures and flow rates were measured in real time and lungs were assessed for changes in compliance, pulmonary vascular resistance, oxygenation, edema, and cytokine secretion. Negative pressure ventilation lungs demonstrated reduced proinflammatory cytokine secretion, reduced weight gain, and reduced pulmonary vascular resistance (p < 0.05). Compliance was higher in NPV lungs (p < 0.05), and there was no difference in oxygenation between the two groups. Respiratory pressure-flow waveforms during NPV and PPV were significantly different (p < 0.05), especially during the inspiratory phase, where the NPV group exhibited rapid time-dependent changes in pressure and airflow whereas the PPV group exhibited slower changes in airflow/pressures. Lungs ventilated with PPV also had a greater transpulmonary pressure (p < 0.05). Greater improvement in lung function during NPV EVLP may be caused by favorable airflow patterns and/or pressure dynamics, which may better mimic human respiratory patterns.

Continuous-Flow Left Ventricular Assist Devices and the Aortic Valve: Interactions, Issues, and Surgical Therapy.

PURPOSE OF REVIEW: Concomitant valve disease is common in patients undergoing continuous-flow left ventricular assist device (CF-LVAD) implantation. In this review, we characterize the epidemiology and management of aortic valve disease following CF-LVAD. RECENT FINDINGS: Studies suggest that 20-40% of patients have mild or greater aortic insufficiency (AI) at baseline and that AI progresses following CF-LVAD implantation. AI, either pre-existing or de novo, can have deleterious effects on LVAD efficacy and clinical outcomes. Surgical methods to correct AI in patients supported with CF-LVAD include central oversewing of the aortic valve, complete closure of the aortic valve, patch closure of the ventriculo-aortic junction, or aortic valve replacement with a bioprosthesis. Transcatheter options have recently emerged as feasible modalities to address AI. CF-LVADs contribute to the progression of aortic insufficiency (AI) and its development de novo. Prompt recognition, assessment, and treatment are important. Aortic valve repairs and replacements, now including TAVR, are the primary surgical methods to correct AI.