CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Transcatheter edge-to-edge repair of the tricuspid valve: The US experience.

OBJECTIVES: To examine the trends in utilization and outcomes of tricuspid valve (TV) transcatheter edge-to-edge repair (TEER). BACKGROUND: Surgery for isolated tricuspid regurgitation is associated with high morbidity and mortality and is rarely performed. TV TEER is an attractive alternative. METHODS: The Nationwide Readmissions Database was queried using the International Classification of Diseases, 10th Revision, procedure code for TV TEER for years 2016-2019. The main outcomes were trends in utilization and in-hospital all-cause mortality. RESULTS: We identified 918 hospitalizations for TV TEER. There was an uptrend in its utilization from 13 cases in the first quarter of 2016 to 122 cases in the last quarter of 2019 (p trend \u3c 0.001). Concomitant mitral valve (MV) TEER was performed in 42.1% of admissions. The overall in-hospital mortality was 2.1%. Surgical TV replacement was needed in 1.1% of admissions; none of them died during the index hospitalization. Unplanned rehospitalizations were common at 30 days (15.7%); 38.2% of those were due to heart failure. There was no difference in in-hospital mortality between isolated TV TEER and combined MV and TV TEER (1.7% vs. 2.6%, p = 0.359). However, admissions receiving combined procedure had lower length of stay and urgent readmission rate. CONCLUSION: The current study showed that there was an increase in the utilization of TV TEER over 2016-2019 in the United States. TV TEER was associated with low rates of in-hospital mortality; however, the rate of urgent readmission remains high, mainly due to heart failure

Prevalence and clinical correlates of extended mechanical support in patients undergoing high-risk percutaneous coronary intervention in current clinical practice: Insights from the cVAD registry

BACKGROUND: High-risk percutaneous coronary interventions (HR-PCI) are prone to hemodynamic instability, resulting in poor outcomes. Acute mechanical circulatory support (AMCS) devices are used during HR-PCI to improve outcomes. However, the clinical criteria for extended AMCS have not been well characterized. The aim of this study was to describe the prevalence and clinical correlates of extended AMCS in patients undergoing elective or urgent HR-PCI. METHODS: We retrospectively analyzed 507 patients enrolled in the catheter-based ventricular assist device (cVAD) registry who underwent elective or urgent HR-PCI with prophylactic use of Impella. The study population was divided into two groups: Impella support removed immediately after PCI (Group A, n = 464) and extended support after PCI (Group B, n = 43). Multivariable regression analysis was used to identify independent predictors of extended AMCS. RESULTS: Baseline characteristics were similar between the groups. Non-ST-elevation myocardial infarction in 26.3% in Group A vs 41.8% in Group B (p = 0.03). PCI of left main was common in Group A (p = 0.02), whereas the right coronary artery was common in Group B (p \u3c 0.001). The mean duration of Impella support 1.1 ± 0.6 h in Group A vs 11.4 ± 16.8 h in Group B (p \u3c 0.001). Death and vascular complications were higher with extended Impella support. Revascularization of chronic total occlusion (CTO) was an independent predictor of extended Impella support (OR 3.2, 95% CI 1.20-8.53). CONCLUSIONS: About 9% of patients enrolled in the cVAD registry undergoing elective or urgent HR-PCI received extended Impella support. In-hospital mortality was about 12% in patients requiring extended Impella support. CTO was associated with a higher likelihood of extended AMCS. The hemodynamic benefits of extended AMCS support must be weighed in terms of risk of complications

Coarctation of the Aorta: Management, Indications for Intervention, and Advances in Care

Opinion statement Coarctation of the aorta (CoAo) accounts for 9 % of congenital heart defects. Balloon angioplasty has been the conventional endovascular treatment of choice for both native and recurrent coarctation in adults. Recent advancement in stent technology with the development of the covered stents has enhanced the scope for percutaneous management of both native CoAo and post-surgical CoAo. Stent implantation provides better hemodynamic results with larger acute diameter gain and better long-term hemodynamic benefit. Stenting also decreases the incidence of aneurysm formation. The development of biodegradable stents may revolutionize the percutaneous management of coarctation, as the degradation of the stent scaffold within 6 months of implantation will further decrease the incidence of restenosis. In the future stenting may suffice and obviate the need for open repair. Until then, surgical repair of CoAo is the preferred method in both infants and complicated lesions, leaving stenting to adults with focal and uncomplicated disease

Contemporary National Trends and Outcomes of Pulmonary Embolism in the United States

Contemporary data on the national trends in pulmonary embolism (PE) admissions and outcomes are scarce. We aimed to analyze trends in mortality and different treatment methods in acute PE. We queried the Nationwide Readmissions Database (2016 to 2019) to identify hospitalizations with acute PE using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. We described the national trends in admissions, in-hospital mortality, readmissions, and different treatment methods in acute PE. We identified 1,427,491 hospitalizations with acute PE, 2.4% of them (n = 34,446) were admissions with high-risk PE. The rate of in-hospital mortality in all PE hospitalizations was 6.5%, and it remained unchanged throughout the study period. However, the rate of in-hospital mortality in high-risk PE decreased from 48.1% in the first quarter of 2016 to 38.9% in the last quarter of 2019 (p-trend \u3c0.001). The rate of urgent 30-day readmission was 15.2% in all PE admissions and 19.1% in high-risk PE admissions. In all PE admissions, catheter-directed interventions (CDI) were used more often (2.5%) than systemic thrombolysis (ST) (2.1%). However, in admissions with high-risk PE, ST remained the most frequently used method (ST vs CDI: 11.3% vs 6.6%). In conclusion, this study showed that the rate of in-hospital mortality in high-risk PE decreased from 2016 to 2019. ST was the most frequently used method for achieving pulmonary reperfusion in high-risk PE, whereas CDI was the most frequently used method in the entire PE cohort. In-hospital death and urgent readmissions rates remain significantly high in patients with high-risk PE

Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270

1-year outcomes of transcatheter mitral valve replacement in patients with severe mitral annular calcification

BACKGROUND: The risk of surgical mitral valve replacement in patients with severe mitral annular calcification (MAC) is high. Several patients worldwide with severe MAC have been treated successfully with transcatheter mitral valve replacement (TMVR) using balloon-expandable aortic transcatheter valves. The TMVR in MAC Global Registry is a multicenter registry that collects data on outcomes of these procedures. OBJECTIVES: The goal of this study was to evaluate 1-year outcomes in this registry. METHODS: This study was a multicenter retrospective review of clinical outcomes. RESULTS: A total of 116 extreme surgical risk patients with severe MAC underwent TMVR; 106 had a procedure date \u3e1 year before data-lock and were included in the analysis. Their mean age was 73 ± 12 years, and 68% were female. The mean Society of Thoracic Surgeons score was 15.3 ± 11.6%, and 90% were in New York Heart Association functional class III or IV. Thirty-day and 1-year all-cause mortality was 25% and 53.7%, respectively. Most patients who survived 30 days were alive at 1 year (49 of 77 [63.6%]), and the majority (71.8%) were in New York Heart Association functional class I or II. Echocardiography data at 1 year were available in 34 patients. Mean left ventricular ejection fraction was 58.6 ± 11.2%, mean mitral valve area was 1.9 ± 0.5 cm CONCLUSIONS: TMVR with balloon-expandable aortic valves in extreme surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. Most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms and transcatheter valve performance. The role of TMVR in patients with MAC requires further evaluation in clinical trials