Less invasive replacement of aortic root, ascending aorta and hemiarch via partial upper sternotomy: a propensity-score matched comparison with full sternotomy.

OBJECTIVES: Less invasive surgery has emerged as an option for aortic pathologies. The current study compared our experience on early postoperative results of patients with aortic surgery between partial upper sternotomy (PUS) and full sternotomy (FS). METHODS: We performed a retrospective analysis of the data of patients undergoing aortic root surgery with concomitant ascending aorta and hemiarch replacement. Exclusion criteria were type A aortic dissection and other concomitant major cardiac surgery. After propensity-score matching, we compared the perioperative outcomes of patients undergoing surgery with PUS vs FS. RESULTS: 161 patients operated on between January 2013 and September 2022 met the inclusion criteria (PUS: n = 22, FS: n = 139). Propensity score matching yielded 22 pairs with a balanced distribution of propensity scores and covariates between the compared groups. There was no evidence that PUS affects cardiopulmonary bypass [108(67-119) vs 113(87-148) min, p = 0.154; PUS vs FS] and circulatory arrest duration [9(7-10) vs 9(8-13) min, p = 0.264; PUS vs FS]. There was a reduced cross-clamp duration in the PUS group [88(58-96) vs 92(71-122) min, p = 0.032]. Cumulative sum charts (CUSUM) have shown consistently low cross-clamp and circulatory arrest duration for two experienced surgeons who performed 20 of the procedures in the PUS group (10 each). Perioperative mortality and morbidity were low, with no in-hospital mortality in the PUS group [0 vs 1(4.5%), p > 0.999] and absence of strokes in both groups. CONCLUSIONS: In summary, our initial experience suggests that less invasive aortic root, ascending aorta, and hemiarch replacement via partial upper sternotomy could be performed in our patient cohort as safely as via full sternotomy. Advantages for the patient are reduced surgical trauma, improved cosmetic results, and-presumably-less pain.

NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1ß and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-ß/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

Restored TDCA and valine levels imitate the effects of bariatric surgery.

Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Results: Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. Funding: This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).

CD11c+ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A.

BACKGROUND: Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. METHODS AND RESULTS: Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells augmenting CD4+ and CD8+ T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c+ dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A(-/-) mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. CONCLUSIONS: These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.

Total arterial off-pump surgery provides excellent outcomes and does not compromise complete revascularization.

OBJECTIVES: The combination of aortic 'no-touch' off-pump surgery (OPCAB) and total arterial revascularization (TAR) can reduce peri-procedural morbidity and yields excellent long-term outcomes albeit at a reported risk of incomplete revascularization. The feasibility of OPCAB-TAR with specific regards to the complete revascularization (CR) in patients with multi-vessel disease was evaluated. METHODS: From 2003 to 2010, 712 patients underwent TAR including 526 patients who had OPCAB-TAR and 186 patients who received on-pump TAR [(ONCAB grafting (ONCABG)-TAR)]. Of these, 52% (n = 272; OPCAB) vs. 83% (n = 155; ONCABG) had triple-vessel disease (TVD). To balance patient characteristics, a non-parsimonious, propensity score (PS) model was applied. Endpoints evaluated were mortality, stroke, major adverse cardiac and cerebrovascular events (MACCE). To evaluate CR, an 'Index of CR' (ICOR) was calculated, defined as the number of distal anastomoses divided by the number of the diseased coronary vessels. CR was assumed when the following requirements were fulfilled: the number of distal anastomoses was equal to or higher than that of diseased vessels (ICOR ≥ 1), and all affected coronary territories (left anterior descending, circumflex artery and/or right coronary artery) were grafted. RESULTS: Mortality was comparable between groups, whereas OPCAB patients suffered from significantly decreased rates of MACCE [3.0 vs. 7.0%; propensity-adjusted odd ratio (PAOR) = 0.24; confidence interval (CI) 95% 0.08-0.66; P = 0.006] including a clear trend towards reduced stroke and myocardial infarction. In the subgroup with TVD, OPCAB patients presented with significantly reduced rates for MACCE (1.8 vs. 5.8%; PAOR = 0.07; CI 95% 0.01-0.65; P = 0.02), including a significantly lower rate for stroke. For all-comers, the number of diseased vessels was lower after OPCAB (2.36 ± 0.73 vs. 2.87 ± 0.39; P < 0.001) and consequently, these patients received an overall lower number of distal anastomoses (2.42 ± 1.15 vs. 3.06 ± 0.98; P < 0.001). Although the ICOR was slightly lower (1.04 ± 0.37 vs. 1.07 ± 0.37; P = 0.02), CR was achieved more frequently in OPCAB patients (82.1 vs. 73.1%; P = 0.01). In the subgroup with TVD, the number of distal anastomoses (2.99 ± 1.14 vs. 3.10 ± 0.98; P = 0.19) and the ICOR (1.00 ± 0.38 vs. 1.03 ± 0.33; P = 0.19) was comparable between groups. The frequency of CR was slightly higher (75 vs. 67.7%; P = 0.11), and the proportion of complete in situ grafting was significantly higher after OPCAB (37.1 vs. 23.9%; P = 0.005). CONCLUSIONS: Aortic 'no-touch' OPCAB-TAR leads to a significant reduction of MACCE. It does not compromise CR in patients with TVD and thus can be safely applied to these patients.