SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis.

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

Safety of Contemporary Heart Failure Therapy in Patients with Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: Limited data are available concerning the safety, optimal administration and benefits of contemporary heart failure therapy in patients after left ventricular assist device (LVAD) implantation. METHODS: Between 2015 and 2019, 257 patients underwent LVAD implantation and were included in this observational study. Oral heart failure therapy was initiated and uptitrated during the further course. After propensity matching and excluding patients with immediate postoperative treatment in an affiliated center with different medical standards, hospitalization rates and mortality within 12 months after LVAD implantation were compared between 83 patients who received medical therapy including an angiotensin receptor neprilysin inhibitor (ARNI) and 83 patients who did not receive an ARNI. RESULTS: The overall use of heart-failure medications after 12 months was high: prescriptions: beta-blockers, 85%; angiotensin inhibiting drugs, 90% (angiotensin-converting-enzyme inhibitors 30%, angiotensin receptor blockers 23%, ARNI 37%); mineralocorticoid receptor antagonists, 80%. No serious drug-related adverse events occurred. The conditional 1-year survival in the group with ARNIs was 97% (95% CI: 94%-100%) compared to 88% in the group without an ARNI (95% CI: 80%-96%); P = 0.06. CONCLUSIONS: Contemporary heart failure therapy is safe in patients with LVADs. No increase in serious adverse events was seen in patients receiving ARNIs. No significant difference in the conditional 1-year survival was seen between the ARNI group and the nonARNI group.

Evaluation of PEEP and prone positioning in early COVID-19 ARDS.

BACKGROUND: In face of the Coronavirus Disease (COVID)-19 pandemic, best practice for mechanical ventilation in COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) is intensely debated. Specifically, the rationale for high positive end-expiratory pressure (PEEP) and prone positioning in early COVID-19 ARDS has been questioned. METHODS: The first 23 consecutive patients with COVID-19 associated respiratory failure transferred to a single ICU were assessed. Eight were excluded: five were not invasively ventilated and three received veno-venous ECMO support. The remaining 15 were assessed over the first 15 days of mechanical ventilation. Best PEEP was defined by maximal oxygenation and was determined by structured decremental PEEP trials comprising the monitoring of oxygenation, airway pressures and trans-pulmonary pressures. In nine patients the impact of prone positioning on oxygenation was investigated. Additionally, the effects of high PEEP and prone positioning on pulmonary opacities in serial chest x-rays were determined by applying a semiquantitative scoring-system. This investigation is part of the prospective observational PA-COVID-19 study. FINDINGS: Patients responded to initiation of invasive high PEEP ventilation with markedly improved oxygenation, which was accompanied by reduced pulmonary opacities within 6 h of mechanical ventilation. Decremental PEEP trials confirmed the need for high PEEP (17.9 (SD ± 3.9) mbar) for optimal oxygenation, while driving pressures remained low. Prone positioning substantially increased oxygenation (p<0.01). INTERPRETATION: In early COVID-19 ARDS, substantial PEEP values were required for optimizing oxygenation. Pulmonary opacities resolved during mechanical ventilation with high PEEP suggesting recruitment of lung volume. FUNDING: German Research Foundation, German Federal Ministry of Education and Research.

Viscosity Prediction in a Physiologically Controlled Ventricular Assist Device.

OBJECTIVE: We present a novel machine learning model to accurately predict the blood-analog viscosity during support of a pathological circulation with a rotary ventricular assist device (VAD). The aim is the continuous monitoring of the hematocrit (HCT) of VAD patients with the benefit of a more reliable pump flow estimation and a possible early detection of adverse events, such as bleeding or pump thrombosis. METHODS: A large dataset was generated with a blood pump connected to a hybrid mock circulation by varying the pump speed, the physiological requirements of the modeled circulation, and the viscosity of the blood-analog. The inlet pressure and the intrinsic signals of the pump were considered as inputs for the model. Gaussian process yielded models with the best performance, which were then combined using a variant of stacked generalization to derive the final model. The final model was evaluated with unseen testing data from the dataset created. RESULTS: For these data, the model yielded a mean absolute deviation of 1.81% from the true HCT, while it proved to correctly predict the direction of the HCT change. It showed to be independent of the set speed and of the condition of the simulated cardiovascular circulation. CONCLUSION: The accuracy of the prediction model allows an improvement of the quality of flow estimators and the detection of adverse events at an early stage. The evaluation of this approach with blood is suggested for further validation. SIGNIFICANCE: Its clinical application could provide the clinicians with reliable and important hemodynamic information of the patient and, thus, enhance patient monitoring and supervision.

Adjusting preoperative risk models of post heart transplant survival to a European cohort in the age of a new cardiac allocation score in Europe.

Background Several risk models target the issue of posttransplant survival, but none of them have been validated in a large European cohort. This aspect is important, in a time of the planned change of the Eurotransplant allocation system to a scoring system. Material and Methods Data of 761 heart transplant recipients from the Eurotransplant region with a total follow up of 5027 patient-years were analyzed. We assessed 30-day to 10-year freedom from graft failure. Existing post-transplant mortality risk models, IMPACT, Meld-XI and Columbia Risk Stratification Score were (RSS) were evaluated. A new risk model was created and the predictive accuracy was compared with the existing risk scores, with a focus on LVAD patients. Results Thirty-day, 1-year, 5-year and 10-year rates of freedom from graft failure were 78.3±1.5%, 68.8±1.71%, 59.1±1.8% and 44.1±1.9. The 1-year incidence of graft failure varied from 14.1% to 50% (RSS), from 22.9% to 57.1 (IMPACT) and from 24.9% to 42.6% using MELD-XI. Our newly adjusted risk score showed an improved area under the curve (AUC) of 0.69 (95% CI 0.64-0.72) with better discrimination in the intermediate to moderate risk cohort (CABDES Score). Conclusion IMPACT, Meld-XI and RSS were suitable to predict posttransplant graft failure only in a high and low risk cohort. CABDES Score, might be an alternative scoring system, with donor age and eGFR beeing the strongest predictors. Implementation of the IMPACT score within the new Eurotransplant Cardiac Allocation Score for patient prioritization for heart transplantation, should be reevaluated.

Response of a physiological controller for ventricular assist devices during acute patho-physiological events: an in vitro study.

The current paper analyzes the performance of a physiological controller for turbodynamic ventricular assist devices (tVADs) during acute patho-physiological events. The numerical model of the human blood circulation implemented on our hybrid mock circulation was extended in order to simulate the Valsalva maneuver (VM) and premature ventricular contractions (PVCs). The performance of an end-diastolic volume (EDV)-based physiological controller for VADs, named preload responsive speed (PRS) controller was evaluated under VM and PVCs. A slow and a fast response of the PRS controller were implemented by using a 3 s moving window, and a beat-to-beat method, respectively, to extract the EDV index. The hemodynamics of a pathological circulation, assisted by a tVAD controlled by the PRS controller were analyzed and compared with a constant speed support case. The results show that the PRS controller prevented suction during the VM with both methods, while with constant speed, this was not the case. On the other hand, the pump flow reduction with the PRS controller led to low aortic pressure, while it remained physiological with the constant speed control. Pump backflow was increased when the moving window was used but it avoided sudden undesirable speed changes, which occurred during PVCs with the beat-to-beat method. In a possible clinical implementation of any physiological controller, the desired performance during frequent clinical acute scenarios should be considered.

Surgical management of driveline infections in patients with left ventricular assist devices.

BACKGROUND AND AIM OF THE STUDY: Driveline infections in patients with implantable left ventricular assist devices (VAD) carry increasing risk for pump infection, thromboembolic events, decreased quality of life, and increased hospitalization. We report our experience with a surgical technique for refractory driveline infections without mediastinitis consisting of translocation and wrapping of the driveline with greater omentum tissue. METHODS: We retrospectively reviewed data of VAD patients who underwent surgical treatment by translocation and wrapping with omentum for severe chronic driveline infection. RESULTS: Thirteen patients were treated between January 2010 and October 2015; 12 (92%) were male, and the mean age was 56 ± 14 years. Ten patients (77%) were managed with driveline sheathing with omentum and repositioning with a new exit site, and three (23%), suffering from driveline fistula, with driveline covering with omentum maintaining the previous exit site. Three episodes of postoperative bleeding (23%) required surgical revision. Twelve patients (92%) were discharged from the hospital and one (8%) died. Nine patients (69%) were free from infection at the time of discharge, and three (23%) had recurrence of infection within the first postoperative year. Only four patients (31%) required admission to the intensive care unit; overall median hospital stay was 23 days (range 7-205 days). CONCLUSIONS: Driveline relocation with use of omentum is a feasible and effective procedure in selected cases of chronic severe driveline infection. The risk for perioperative bleeding should be taken into consideration and carefully monitored.

A Physiological Controller for Turbodynamic Ventricular Assist Devices Based on Left Ventricular Systolic Pressure.

The current article presents a novel physiological feedback controller for turbodynamic ventricular assist devices (tVADs). This controller is based on the recording of the left ventricular (LV) pressure measured at the inlet cannula of a tVAD thus requiring only one pressure sensor. The LV systolic pressure (SP) is proposed as an indicator to determine the varying perfusion requirements. The algorithm to extract the SP from the pump inlet pressure signal used for the controller to adjust the speed of the tVAD shows robust behavior. Its performance was evaluated on a hybrid mock circulation. The experiments with changing perfusion requirements were compared with a physiological circulation and a pathological one assisted with a tVAD operated at constant speed. A sensitivity analysis of the controller parameters was conducted to identify their limits and their influence on a circulation. The performance of the proposed SP controller was evaluated for various values of LV contractility, as well as for a simulated pressure sensor drift. The response of a pathological circulation assisted by a tVAD controlled by the introduced SP controller matched the physiological circulation well, while over- and underpumping events were eliminated. The controller presented a robust performance during experiments with simulated pressure sensor drift.

Surgical Treatment of Mediastinitis with Omentoplasty in Ventricular Assist Device Patients: Report of Referral Center Experience.

Mediastinitis is more frequent in patients with implantable ventricular assist devices (VADs) than in other cardiac surgery patients and carries significant mortality. We report our experience with a stepwise approach including aggressive debridement, jet lavage, vacuum assisted closure dressing, and finally coverage with well-vascularized and immune-active omental flaps in VAD patients with infective mediastinitis. We retrospectively collected and analyzed data of patients with continuous flow VAD who underwent plasty with the omental flap because of mediastinitis at Deutsches Herzzentrum Berlin between January 1, 2008 and October 30, 2015. Eight hundred forty-five patients underwent VAD implantation during the study period. Omentoplasty due to infective mediastinitis was performed in 17 cases. Nine had a HeartWare HVAD as left ventricular assist device (LVAD), three patients had two Heart-Ware HVAD as biventricular assist device (BIVAD), four had a HeartMate II LVAD device, and one patient had a Berlin Heart Incor LVAD. The microorganisms most frequently isolated from the sternal wound were Gram-positive Staphylococcus spp. Four cases of bleeding requiring surgical revision were recorded: three of intraabdominal and one of wound bleeding. Eight patients (47%) survived, whereas the other nine patients (53%) died. Sixteen (94%) required intensive care unit admission, and median hospital stay was 21 (1-182) days. Postoperative renal failure requiring dialysis and septic shock requiring vasopressors were associated with hospital mortality (p = 0.009 and p = 0.05, respectively). Early surgical treatment of mediastinitis after VAD implantation with omentoplasty is a valuable strategy in an otherwise dead-end situation. Bleeding should be meticulously controlled in these anticoagulated and fragile patients.

Diagnosis and Treatment Algorithm for Blood Flow Obstructions in Patients With Left Ventricular Assist Device.

BACKGROUND: Thrombosis is an uncommon, but severe complication of left ventricular assist devices (LVADs). OBJECTIVES: This study analyzed experience with obstruction of blood flow through the LVAD with the purpose of developing optimal diagnosis and treatment of LVAD-related thrombosis. METHODS: Between October 2009 and July 2015, a total of 652 LVAD were implanted in 557 patients. Blood flow abnormalities in patients with LVAD (n = 524) were identified and classified as "high-power" and "low-flow" events. RESULTS: Three types of late blood flow obstructions were identified: 1) pre-pump via thrombus obstructing the inflow cannula (26 events; 0.037 events per patient-year); 2) intra-pump (70 events; 0.1 events per patient-year); and 3) post-pump via thrombosis of the outflow graft or stenosis of the anastomosis to the aorta (4 events; 0.006 events per patient-year). Pre-pump obstruction was treated by washout maneuver in 9 cases (success rate, 100%), thrombolysis in 9 patients (success rate, 56%), and pump exchange in 9 cases (success rate, 100%); 1 patient died without treatment and 2 were weaned from LVAD. Intra-pump obstruction was treated by thrombolysis (n = 9; success rate, 33%), pump exchange (n = 53; success rate, 94%), and removal due to myocardial recovery (n = 3; success rate, 100%); 7 patients died without treatment and parameters spontaneously normalized in 2 cases. Post-pump obstruction was treated in 2 patients by stenting (success rate, 100%), and was left untreated in 2 cases. CONCLUSIONS: We identified 3 types of LVAD-related blood flow obstruction, and developed an algorithm for optimal diagnosis and treatment.