Christopher M. Bobba

Treatment of aortic arch pathology is rapidly evolving. Current techniques utilize a combination of open and endovascular approaches. Existing techniques s

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.

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.

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. Summary 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.

Myeloid derived suppressor cells (MDSCs) have gained significant attention for their immunosuppressive role in cancer and their ability to contribute to tumor progression and metastasis. Understanding the role of MDSCs in driving cancer cell migration, a process fundamental to metastasis, is essential to fully comprehend and target MDSC‐tumor cell interactions. This study employs microfabricated platforms, which simulate the structural cues present in the tumor microenvironment (TME) to elucidate the effects of MDSCs on the migratory phenotype of cancer cells at the single cell level. The results indicate that the presence of MDSCs enhances the motility of cancer‐epithelial cells when directional cues (either topographical or spatial) are present. This behavior appears to be independent of cell–cell contact and driven by soluble byproducts from heterotypic interactions between MDSCs and cancer cells. Moreover, MDSC cell‐motility is also impacted by the presence of cancer cells and the cancer cell secretome in the presence of directional cues. Epithelial dedifferentiation is the likely mechanism for changes in cancer cell motility in response to MDSCs. These results highlight the biochemical and biostructural conditions under which MDSCs can support cancer cell migration, and could therefore provide new avenues of research and therapy aimed at stemming cancer progression.

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.

Acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation maintains gas exchange in patients with ARDS, but exposes lung cells to physical forces that exacerbate lung injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during mechanical ventilation exacerbates lung injury. 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 exacerbates physiologic lung dysfunction during mechanical ventilation. Conversely, treatment with rapamycin at the time mechanical ventilation is initiated prevents physiologic lung injury (i.e. decreased compliance) without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during mechanical ventilation. Our data demonstrate that in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during mechanical ventilation exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator induced lung injury during ARDS.

During mechanical ventilation, injurious biophysical forces exacerbate lung injury. These forces disrupt alveolar capillary barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides such as 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 used humanized in-vitro systems, mouse models, and biospecimens from mechanically ventilated patients to elucidate the expression dynamics of miR-146a that might be required to decrease lung injury during mechanical ventilation. We found that the endogenous increase in miR-146a following injurious was relatively modest and not sufficient to prevent lung injury. However, when miR-146a was highly overexpressed using a nanoparticle-based delivery platform in vivo, it was sufficient to prevent lung injury. These data indicate that the endogenous increase in microRNA-146a during MV is a compensatory response that only partially limits VILI and that nanoparticle delivery approaches that significantly over-express microRNA-146a in AMs is an effective strategy for mitigating VILI.