Acute type A aortic syndromes: outcomes are independent of aortic root/valve management.

Purpose: Clinical outcomes following various surgical intervention strategies for aortic root and valve pathology during repair of acute type A aortic syndromes were studied and compared. Methods: From 2004 to 2019, 634 patients underwent acute type A aortic repair. Patients were divided into 4 groups: Valve Resuspension (n = 456), Isolated Valve Replacement (AVR) (n = 24), Valve and Root Replacement (ROOT) (n = 97), and Valve Sparing Root Replacement (VSRR) (n = 57). The primary endpoint was midterm survival and multivariable risk factor analysis was performed. Results: The mean age was 55.4 ± 13 years, 424 (67%) were male, and overall early mortality was 12%. Early mortality was 13%, 8%, 11%, and 7% for the Valve Resuspension, AVR, ROOT, and VSRR groups respectively, p = 0.43. Five-year survival was 74%, 86%, 73%, and 84% for the Valve Resuspension, AVR, ROOT, and VSRR groups respectively, p = 0.46. There was no difference in late stroke, renal failure, heart block, and late bleeding (p > 0.05 for all). At late follow-up, AVR and ROOT patients had a higher mean gradient versus Valve Resuspension and VSRR patients, p < 0.0001. For the total cohort, risk factors for late mortality included preoperative peripheral vascular disease (hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2-4.4, p = 0.009) and preoperative dialysis (HR 2.8, 95% CI 1.3-6.1, p = 0.01). Conclusion: Mid-term survival following repair of acute type A aortic dissection is not independently associated with a specific type of aortic valve intervention. Native valve preservation leads to acceptable mid-term valve hemodynamics and should be the preferred therapy in this emergent clinical setting. Supplementary Information: The online version contains supplementary material available at 10.1007/s12055-023-01602-8.

Aortic Arch Management During Acute and Subacute Type A Aortic Syndromes.

BACKGROUND: The purpose of this study was to compare the outcomes of no arch intervention, hemiarch replacement, and total arch replacement during type A aortic syndromes in a contemporary series. METHODS: From 2004 to 2019, 634 patients have required acute type A dissection repair; these patients were divided into three groups based on type of arch intervention performed: no arch (n = 130), hemiarch (n = 397), and total arch (n = 107). The primary endpoint was mortality; a multivariable risk factor analysis was performed. Secondary endpoints were reoperation and early and late complications. RESULTS: Operative age was 55 ± 14 years for the cohort and was similar between groups (P = .34). The incidence of peripheral artery disease, heart failure, and prior coronary artery bypass graft surgery differed between the groups (P < .05). Median cardiopulmonary bypass time, aortic cross-clamp time, and length of stay were longest for the total arch group (P < .0001). Early mortality was 20%, 10%, and 10% for the no-arch, hemiarch, and total arch groups, respectively (P = .01). Ten-year survival was 54%, 66%, and 65% for the no-arch, hemiarch, and total arch groups, respectively (P = .01). There was no difference in incidence or timing of redo aortic interventions (P > .05). For the entire cohort, risk factors for late mortality included preoperative peripheral artery disease (hazard ratio 2.3; 95% confidence interval, 1.2 to 4.4; P = .009) and preoperative dialysis (hazard ratio 2.8; 95% confidence interval, 1.3 to 6.1; P = .01). CONCLUSIONS: Despite longer cardiopulmonary bypass and aortic cross-clamp times, arch intervention was not associated with worse operative or long-term outcome in this series. Patients with peripheral vascular disease and preoperative renal failure remain at highest risk for mortality after type A aortic dissection repair.

Isolated Redo Aortic Valve Replacement Versus Valve-in-Valve Transcatheter Valve Replacement.

BACKGROUND: Clinical outcomes of redo surgical aortic valve replacement (redo-SAVR) compared with valve-in-valve transcatheter aortic valve replacement (VIV-TAVR) are poorly understood. This study compared short- and midterm outcomes of patients undergoing isolated redo-SAVR vs VIV-TAVR after previous SAVR. METHODS: A single-institutional review of the initial use of VIV-TAVR from 2012 to 2019 identified 273 patients undergoing VIV-TAVR (n = 187) or redo-SAVR (n = 86) after prior SAVR. Outcomes analysis included a univariate analysis and Kaplan-Meier survival analysis. RESULTS: The Society of Thoracic Surgeons predicted risk of mortality was higher for VIV-TAVR (6.3%; interquartile range [IQR], 3.6%-10.5%) vs redo-SAVR (4.2%; IQR, 2.4%-6.9%; P < .01). VIV-TAVR patients (76 years; IQR, 67.5-82.5 years) were older than redo-SAVR patients (64 years; IQR, 54-72; P < .01). Redo-SAVR and VIV-TAVR had similar early mortality (1.2% vs 1.6%, P = .92). Two redo-SAVR (2.3%) and 3 VIV-TAVR patients (1.6%) died 4.8 ± 0.5 years and 4.8 ± 1.5 months after discharge, respectively. Redo-SAVR had an increased stroke rate (7.0% vs 1.1%, P = .02). Postoperative mean valve gradients were similar between VIV-TAVR (14 mm Hg; IQR, 9-21 mm Hg) and redo-SAVR patients (12 mm Hg; IQR, 8-20 mm Hg; P = .08). Postprocedure transesophageal echocardiography showed at least mild aortic insufficiency for 24 VIV-TAVR patients (16%) and 2 redo-SAVR patients (2.9%) (P = .01). The cumulative incidence of aortic valve reintervention was 5.2% for the redo-SAVR patients and 28.5% for the VIV-TAVR patients (P = .07). CONCLUSIONS: After previous SAVR, redo-SAVR and VIV-TAVR can both be performed with acceptable operative results. Despite treating a high-risk patient population, we found redo-SAVR and VIV-TAVR both carry similar operative outcomes. Improved valve hemodynamics were observed in redo-SAVR patients compared with VIV-TAVR patients.

Gαs proteins activate p72(Syk) and p60-c-Src tyrosine kinases to mediate sickle red blood cell adhesion to endothelium via LW-αvß3 and CD44-CD44 interactions.

G protein-coupled receptors (GPCRs) have been suggested as new drug targets to treat a variety of diseases. In sickle cell disease (SCD), the LW erythrocyte adhesion receptor can be activated by stimulation of ß2 adrenergic receptors (ß2ARs), to mediate sickle erythrocyte (SSRBC) adhesion to endothelium. However, the involvement of tyrosine protein kinases in ß2AR signaling to activate SSRBC adhesion to endothelium has not been thoroughly elucidated. Either direct activation with Cholera toxin of Gαs protein, which acts downstream of ß2ARs, or inhibition with Pertussis toxin of Gαi, mediating suppression of adenylyl cyclase, increased SSRBC adhesion to endothelium over baseline adhesion. This effect involved the non-receptor tyrosine kinases, p72(Syk) and p60-c-Src, which were more abundant in SSRBCs than in normal erythrocytes. In contrast, Pertussis toxin and Cholera toxin failed to increase adhesion of normal erythrocytes. SSRBC Gαi inhibition also increased phosphorylation of p72(Syk) and p60-c-Src. Further, we investigated the relevance of activation of p72(Syk) and p60-c-Src, and identified LW (ICAM-4, CD242) and CD44 as the erythroid adhesion molecules both physically interacting with activated p60-c-Src. As a result, SSRBC LW underwent increased tyrosine phosphorylation, leading to SSRBC LW and CD44 binding to endothelial αvß3 integrin and CD44, respectively. These data provide in vitro mechanistic evidence that p60-c-Src, which could act downstream of Gαs/p72(Syk), associates with LW and CD44 on SSRBCs leading to their interactions with endothelial αvß3 and CD44, respectively. Thus, increased activation of these signaling mechanisms in SSRBCs could initiate or exacerbate vascular occlusion, the hallmark of SCD.

Proteomic analysis of ERK1/2-mediated human sickle red blood cell membrane protein phosphorylation.

BACKGROUND: In sickle cell disease (SCD), the mitogen-activated protein kinase (MAPK) ERK1/2 is constitutively active and can be inducible by agonist-stimulation only in sickle but not in normal human red blood cells (RBCs). ERK1/2 is involved in activation of ICAM-4-mediated sickle RBC adhesion to the endothelium. However, other effects of the ERK1/2 activation in sickle RBCs leading to the complex SCD pathophysiology, such as alteration of RBC hemorheology are unknown. RESULTS: To further characterize global ERK1/2-induced changes in membrane protein phosphorylation within human RBCs, a label-free quantitative phosphoproteomic analysis was applied to sickle and normal RBC membrane ghosts pre-treated with U0126, a specific inhibitor of MEK1/2, the upstream kinase of ERK1/2, in the presence or absence of recombinant active ERK2. Across eight unique treatment groups, 375 phosphopeptides from 155 phosphoproteins were quantified with an average technical coefficient of variation in peak intensity of 19.8%. Sickle RBC treatment with U0126 decreased thirty-six phosphopeptides from twenty-one phosphoproteins involved in regulation of not only RBC shape, flexibility, cell morphology maintenance and adhesion, but also glucose and glutamate transport, cAMP production, degradation of misfolded proteins and receptor ubiquitination. Glycophorin A was the most affected protein in sickle RBCs by this ERK1/2 pathway, which contained 12 unique phosphorylated peptides, suggesting that in addition to its effect on sickle RBC adhesion, increased glycophorin A phosphorylation via the ERK1/2 pathway may also affect glycophorin A interactions with band 3, which could result in decreases in both anion transport by band 3 and band 3 trafficking. The abundance of twelve of the thirty-six phosphopeptides were subsequently increased in normal RBCs co-incubated with recombinant ERK2 and therefore represent specific MEK1/2 phospho-inhibitory targets mediated via ERK2. CONCLUSIONS: These findings expand upon the current model for the involvement of ERK1/2 signaling in RBCs. These findings also identify additional protein targets of this pathway other than the RBC adhesion molecule ICAM-4 and enhance the understanding of the mechanism of small molecule inhibitors of MEK/1/2/ERK1/2, which could be effective in ameliorating RBC hemorheology and adhesion, the hallmarks of SCD.