Background Aortic aneurysms and dissections are highly lethal diseases for which an effective treatment strategy is critically needed to prevent disease progression. The nucleotide‐binding oligomerization domain–like receptor pyrin domain containing 3 (NLRP3)–caspase‐1 inflammasome cascade was recently shown to play an important role in aortic destruction and disease development. In this study, we tested the effects of MCC950, a potent, selective NLRP3 inhibitor, on preventing aortic destruction and aortic aneurysm and dissection formation. Methods and Results In a model of sporadic aortic aneurysm and dissection induced by challenging wild‐type mice with a high‐fat, high‐cholesterol diet and angiotensin II infusion, MCC950 treatment significantly inhibited challenge‐induced aortic dilatation, dissection, and rupture in different thoracic and abdominal aortic segments in both male and female mice. Aortic disease reduction by MCC950 was associated with the prevention of NLRP3–caspase‐1 upregulation, smooth muscle cell contractile protein degradation, aortic cell death, and extracellular matrix destruction. Further investigation revealed that preventing matrix metallopeptidase 9 (MMP‐9) expression and activation in macrophages is an important mechanism underlying MCC950's protective effect. We found that caspase‐1 directly activated MMP‐9 by cleaving its N‐terminal inhibitory domain. Moreover, the genetic knockdown of Nlrp3 or Casp‐1 in mice or treatment of mice with MCC950 diminished the challenge‐induced N‐terminal cleavage of MMP‐9, MMP‐9 activation, and aortic destruction. Conclusions Our findings suggest that the NLRP3–caspase‐1 inflammasome directly activates MMP‐9. Targeting the inflammasome with MCC950 is a promising approach for preventing aortic destruction and aortic aneurysm and dissection development.

Central MessageMyocardial autophagy may be a mechanism of late failure after ventriculoplasty in a rat model of ischemic cardiomyopathy.See Article page e33. Myocardial autophagy may be a mechanism of late failure after ventriculoplasty in a rat model of ischemic cardiomyopathy. See Article page e33. The concept of autophagy as a vital metabolic process to recycle degradation products, maintain cellular function, and provide quality control is not new. Misfolded, senescent, or damaged proteins and organelles, via autophagosome formation, are catabolized by lysosomes into amino acids or fatty acids for further use.1Wu D. Zhang K. Hu P. The role of autophagy in acute myocardial infarction.Front Pharmacol. 2019; 10: 551Crossref PubMed Scopus (61) Google Scholar However, the role of autophagy in cardiovascular sciences remains in its infancy. Conflicting literature indicates that canonical activation can be protective, whereas noncanonical activation of autophagy can be maladaptive after myocardial infarction and affect myocardial remodeling.2Delbridge L.M.D. Mellor K.M. Taylor D.J. Gottlieb R.A. Myocardial stress and autophagy: mechanisms and interventional prospects.Nat Rev Cardiol. 2017; 14: 412-425Crossref PubMed Scopus (117) Google Scholar These differences can be explained by the wide biology of autophagy in mitochondrial dysfunction, apoptosis, inflammation, atherosclerosis, aneurysm formation, ischemia–reperfusion response, and myocardial development and remodeling.3Lavandero S. Chiong M. Rothermel B.A. Hill J.A. Autophagy in cardiovascular biology.J Clin Invest. 2015; 125: 55-64Crossref PubMed Scopus (244) Google Scholar In this issue of the Journal, Sugimoto and colleagues4Sugimoto S. Shingu Y. Doenst T. Yamakawa T. Asai H. Wakasa S. et al.Autophagy during left ventricular redilation after ventriculoplasty: insights from a rat model of ischemic cardiomyopathy.J Thorac Cardiovasc Surg. 2022; 163: e33-e40Abstract Full Text Full Text PDF Scopus (4) Google Scholar have attempted to examine how autophagy affects the myocardium after left ventriculoplasty in a rat model of ischemic cardiomyopathy. Sugimoto and colleagues4Sugimoto S. Shingu Y. Doenst T. Yamakawa T. Asai H. Wakasa S. et al.Autophagy during left ventricular redilation after ventriculoplasty: insights from a rat model of ischemic cardiomyopathy.J Thorac Cardiovasc Surg. 2022; 163: e33-e40Abstract Full Text Full Text PDF Scopus (4) Google Scholar used 10-week-old Sprague–Dawley rats that underwent left anterior descending artery (LAD) ligation with or without left ventriculoplasty (LVP) and followed the rats that underwent LVP for an additional 2 or 28 days. They found that in the group that underwent LAD ligation and LVP, the LC3-II expression, an autophagosome marker, was reduced in the early phase compared with control, increased late after LVP, and was further reduced through use of an autophagic inhibitor, 3-MA. Functionally, they found that the left ventricular end-diastolic diameter was smaller early after LVP but then increased late after LVP with use of 3-MA, exhibiting a left ventricular end-diastolic diameter the same as control. Although this study provides an indication of how autophagy may be related to left ventricular (LV) re-dilatation after LVP in a rat model, there are 3 main points that bear mentioning. First, it is difficult to extrapolate from a rat model to a human, given the altered cardiac vascular anatomy, timing, and surgical technique. More than one half of the rats that underwent LVP died, and almost one third of rats that underwent LAD ligation perished, suggesting that the current analysis is biased. Second, autophagy is a dynamic process (autophagic flux5Toit A.D. Hofmeyr J.H.S. Gniadek T.J. Loos B. Measuring autophagosome flux.Autophagy. 2018; 14: 1060-1071PubMed Google Scholar), with multiple steps involved that were not analyzed in this simplistic model. By analyzing only the levels of LCS-II, the authors provide only a static picture of a complex system. Third, the use of a nonselective phosphoinositide 3-kinase inhibitor has many more consequences than simply inhibiting autophagy. For instance, phosphoinositide 3-kinase is a main activator of Akt, which has multiple downstream effects, not to mention differential effects on Akt-1 and Akt-2 signaling, which can also lead to altered myocardial metabolism. Furthermore, their use of an inhibitor just 1 day after LVP is curious, given they wanted to examine the effects of LV re-dilatation after LVP. Perhaps this might explain why there wasn't much functional change. Nonetheless, despite these limitations, establishing the role of autophagy in LV re-dilatation after LVP is paramount in the effort to eventually develop pharmacologic interventions that can alter myocardial metabolism and remodeling in ischemic cardiomyopathy. Autophagy during left ventricular redilation after ventriculoplasty: Insights from a rat model of ischemic cardiomyopathyThe Journal of Thoracic and Cardiovascular SurgeryVol. 163Issue 1PreviewMyocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. Full-Text PDF

Central MessagePreclinical models of disease provide powerful tools to investigate pathology progression. Cardiothoracic surgeons are poised to contribute to understanding underlying mechanisms and affect treatment.See Article page 1719. Preclinical models of disease provide powerful tools to investigate pathology progression. Cardiothoracic surgeons are poised to contribute to understanding underlying mechanisms and affect treatment. See Article page 1719. In this month's issue of The Journal of Thoracic and Cardiovascular Surgery, Gensicke and colleagues1Gensicke N.M. Cavanaugh N.B. Andersen N.D. Huang T. Qian L. Dyle M.C. et al.Accelerated Marfan syndrome model recapitulates established signaling pathways.J Thorac Cardiovasc Surg. 2020; 159: 1719-1726Abstract Full Text Full Text PDF Scopus (5) Google Scholar present their data on their development of a preclinical murine model of Marfan syndrome with accelerated aortic aneurysm formation. The attempt to take complex clinical presentations and pathology and reduce them to a rather straightforward model that is reproducible, uses gene targeting, and recapitulates a meaningful clinical phenotype is daunting. Although from a broad application standpoint, developing a mouse that gets a marfanoid aneurysm is a far cry from the surgical treatment of aorta and aortic root aneurysms, the future effect on understanding the mechanisms of disease and developing novel targeted therapeutics is paramount to advancing multimodal interventions. Murine models of disease allow the development of knockout strains and numerous antibody-bases and analytic methods of analysis to be used. During the past 3 decades, we have come to understand the mutation of the fibrillin gene and its importance in the progression and presentation of Marfan syndrome.2Dietz H.C. Cutting G.R. Pyeritz R.E. Maslen C.L. Sakai L.Y. Corson G.M. et al.Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.Nature. 1991; 352: 337-339Crossref PubMed Scopus (1662) Google Scholar Gensicke and colleagues1Gensicke N.M. Cavanaugh N.B. Andersen N.D. Huang T. Qian L. Dyle M.C. et al.Accelerated Marfan syndrome model recapitulates established signaling pathways.J Thorac Cardiovasc Surg. 2020; 159: 1719-1726Abstract Full Text Full Text PDF Scopus (5) Google Scholar have used a murine model with a mutation in the fibrillin-1 gene and have supplemented it with angiotensin II. This combination of fibrillin mutation and angiotensin administered daily promote accelerated aneurysm formation. This approach builds on the interaction of transforming growth factor β (TGF-β) on aneurysm progression. The interaction of TGF-β and an angiotensin receptor blocker (eg, losartan) has been used in slowing disease progression clinically.3Matt P. Habashi J. Carrel T. Cameron D.E. Van Eyk J.E. Dietz H.C. Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan?.J Thorac Cardiovasc Surg. 2008; 135: 389-394Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Gensicke and colleagues1Gensicke N.M. Cavanaugh N.B. Andersen N.D. Huang T. Qian L. Dyle M.C. et al.Accelerated Marfan syndrome model recapitulates established signaling pathways.J Thorac Cardiovasc Surg. 2020; 159: 1719-1726Abstract Full Text Full Text PDF Scopus (5) Google Scholar are to be commended for pursuing basic and translational science research as busy academic surgeons and their effects continue to drive the field forward. The support of the senior author, Dr Turek, is a meaningful example of how societal support (American Association for Thoracic Surgery and The Marfan Foundation) and that of surgeon-scientists can advance scientific knowledge. Although the clinical effects are still in the early stages, the fundamental basis of this model and sharing it with the broader community are having an effect now.4Habashi J.P. Judge D.P. Holm T.M. Cohn R.D. Loeys B.L. Cooper T.K. et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1437) Google Scholar Accelerated Marfan syndrome model recapitulates established signaling pathwaysThe Journal of Thoracic and Cardiovascular SurgeryVol. 159Issue 5PreviewMarfan syndrome (MFS) represents a genetic disorder with a range of clinical features, including proximal aortic aneurysms. Extensive research has revealed an abundance of transforming growth factor beta from a mutation in fibrillin-1 to be the key biochemical mechanism of aneurysm formation. Many important signaling pathways downstream of transforming growth factor beta have been further characterized. Our laboratory has previously demonstrated a unique murine model of MFS resulting in the accelerated formation of ascending aortic aneurysms and dilated cardiomyopathies. Full-Text PDF Open Archive

Central MessageNucloephosmin promotes vascular inflammation and endothelial dysfunction in an NF-kB dependent pathway.See Article page e377. Nucloephosmin promotes vascular inflammation and endothelial dysfunction in an NF-kB dependent pathway. See Article page e377. Endothelial activation, which involves alterations in chemokine receptor activity, endothelial permeability, and paracrine factor secretion, is a central hallmark of vascular inflammation,1Galkina E. Ley K. Vascular adhesions molecules in atherosclerosis.Arterioscler Thromb Vasc Biol. 2007; 27: 2292-2301Crossref PubMed Scopus (551) Google Scholar which in turn is a critical step in the pathogenesis of atherogenesis. Increasing evidence shows that endothelial activation is nuclear factor κ light chain enhancer of activated B cells (NF-kB)-dependent. NF-kB activation can lead to an inflammatory phenotypic change through transcription of genes associated with chemokines, adhesion molecules, and cytokines.2Tak P.P. Firestein G.S. NF-kappaB: a key role in inflammatory disease.J Clin Invest. 2001; : 107-111PubMed Google Scholar Nucleophosmin (NPM) is a multifunctional nuclear phosphoprotein that has been implicated in multiple pathways, such as transcriptional gene regulation, ribosome biogenesis, DNA repair processes, apoptosis, and cell differentiation.2Tak P.P. Firestein G.S. NF-kappaB: a key role in inflammatory disease.J Clin Invest. 2001; : 107-111PubMed Google Scholar Although the function of NPM in the oxidative stress response is known, the function of NPM in arterial vascular pathogenesis is not as well characterized.3Csiszar A. Wang M. Lakatta E. Ungvari Z. Inflammation and endothelial dysfunction during aging: role of NK-kB.J Appl Physiol. 2008; 105: 1333-1341Crossref PubMed Scopus (341) Google Scholar In this issue of the Journal, Rao and colleagues4Rao C. Liu B. Huang D. Chen R. Huang K. Li F. et al.Nucleophosmin contributes to vascular inflammation and endothelial dysfunction in atherosclerosis progression.J Thorac Cardiovasc Surg. 2021; 161: e377-e393Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar have attempted to elucidate the role of NPM in vascular inflammation and the progression of atherogenesis. The authors first used human atherosclerotic plaques to demonstrate that, compared with aortic tissue from patients needing aortic valve replacement, NPM levels were increased and colocalized to endothelial cells. Second, they found that injection of adenovirus containing NPM shRNA into ApoE-/- mice fed a high-fat diet and knockdown of NPM attenuated atherosclerotic lesion formation, reduced vascular inflammation, and decreased NK-kB p65 phosphorylation. Third, using an in vitro model consisting of human umbilical vein endothelial cells, they found that stimulation with palmitic acid increased NPM levels and induced the expression of inflammatory cytokines, whereas NPM knockdown with siRNA attenuated this effect. Furthermore, they found that NPM physically interacted with the NF-kB p65 subunit, promoted its nuclear transposition, and increased the transcriptional activity of NF-kB promoter and enhanced binding to proinflammatory target genes, such as ICAM-1, E-selectin, IL-1b, and IL-6. Although this study provides evidence of the role of NPM in vascular inflammation and atherosclerosis, there are a number of important points that bear mentioning when considering this study. First, the use of aorta as a control of carotid plaques is not necessarily the ideal comparison, as the pathogenesis of central vascular disease differs from that of peripheral vascular disease. Second, in using the ApoE-/-, model the authors did not investigate the role of NPM in dyslipidemia. Use of NPM-/- mice or double deletion might have revealed whether NPM was involved in vascular inflammation through pathways affecting dyslipidemia. Third, using CD68 as a single identifier of macrophages ignores the multiple roles of macrophages (polarization) and monocytes during inflammation. Fourth, although undoubtedly there is evidence of the involvement of NPM in vascular inflammation, the authors provide no evidence of the role of NPM in plaque stability, which is critical in cardiovascular events. Finally, whether NPM can regulate the other key regulator of vascular inflammation, namely vascular smooth muscle cells, was not investigated. Nonetheless, the authors should be commended on their investigation into the role of NPM in vascular inflammation and atherosclerosis, which has the potential to lead to the development of a new therapeutic target in the battle against cardiovascular disease. Nucleophosmin contributes to vascular inflammation and endothelial dysfunction in atherosclerosis progressionThe Journal of Thoracic and Cardiovascular SurgeryVol. 161Issue 5PreviewIt is unclear whether nucleophosmin (NPM) participates in cardiovascular disease. The present study aimed to investigate the role and underlying mechanisms of NPM in atherosclerosis. Full-Text PDF

Central MessageNitric oxide plays a critical role in myocardial ischemia-reperfusion injury and may further augment myocardial protection strategies related to cardiopulmonary bypass.See Article page 2328. Nitric oxide plays a critical role in myocardial ischemia-reperfusion injury and may further augment myocardial protection strategies related to cardiopulmonary bypass. See Article page 2328. Ischemia-reperfusion injury during cardiopulmonary bypass (CPB) is inevitable, and the quest to ameliorate this injury has been pursued for decades. In their study in this issue of the Journal, Kamenshcikov and colleagues1Kamenshchikov N.O. Mandel I.A. Podoksenov Y.K. Svirko Y.S. Lomivorotov V.V. Mikheev S.L. et al.Nitric oxide provides myocardial protection when added to the cardiopulmonary bypass circuit during cardiac surgery: randomized trial.J Thorac Cardiovasc Surg. 2019; 157: 2328-2336Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar have taken on this challenge, hypothesizing that nitric oxide (NO) in the cardiopulmonary bypass circuit will reduce myocardial injury during coronary artery bypass grafting (CABG) surgery. The salutary effects of NO have been the subject of intense investigation, which indeed culminated with the Nobel Prize in Medicine in 1998.2Mitka M. 1998 NObel Prize winners are announced: three discoverers of nitric oxide activity.JAMA. 1998; 280: 1648Crossref PubMed Scopus (15) Google Scholar For adult cardiac surgery, the use of NO and phosphodiesterase inhibitors has primarily affected the management of pulmonary hypertension. NO, however, has multiple potential effects on cardiac myocytes, including enhancement of myocyte relaxation and inhibition of myocardial oxygen consumption.3Heusch G. Post H. Michel M.C. Kelm M. Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia.Circ Res. 2000; 87: 146-152Crossref PubMed Scopus (128) Google Scholar This is also precisely the goal of myocardial protection and cardioplegia during cardiac surgery. The use of NO during CPB has previously been evaluated in in congenital heart surgery has been shown to reduce myocardial injury and improve outcomes.4Checchia P.A. Bronicki R.A. Muenzer J.T. Dixon D. Raithel S. Gandhi S.K. et al.Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children—a randomized trial.J Thorac Cardiovasc Surg. 2013; 146: 530-536Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 5James C. Millar J. Horton S. Brizard C. Molesworth C. Butt W. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial.Intensive Care Med. 2016; 42: 1744-1752Crossref PubMed Scopus (55) Google Scholar Kamenshchikov and colleagues1Kamenshchikov N.O. Mandel I.A. Podoksenov Y.K. Svirko Y.S. Lomivorotov V.V. Mikheev S.L. et al.Nitric oxide provides myocardial protection when added to the cardiopulmonary bypass circuit during cardiac surgery: randomized trial.J Thorac Cardiovasc Surg. 2019; 157: 2328-2336Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar present a single-institution prospective study of 60 CABG patients randomly allocated to receive 40 ppm of NO versus control. Myocardial injury was assessed with biomarkers (cardiac troponin I, creatine kinase isoenzyme MB) at 6 and 24 hours postoperatively. They found that both cardiac troponin I and creatine kinase isoenzyme MB were lower in the NO-treated group. In addition, vasoactive inotropic support scores were calculated within the first 48 hours of surgery. They found that NO-treated patients had decreased vasoactive inotrope requirements relative to controls. There are 3 main points that bear mentioning when considering this study. First, this study is limited by a small cohort of low-risk patients undergoing CABG, making it difficult to draw any strong conclusions. It is unclear whether CABG represents the best patient cohort to evaluate the potential benefit of NO. Overall, CABG has become a low-risk cardiac surgery operation, especially for patients with normal ventricular function undergoing an elective operation. A more salient clinical benefit might be detected in patients with ventricular dysfunction, recent myocardial infarction, incomplete revascularization, or more complex operations. Second, it is unclear whether cardiac injury biomarkers are independently prognostic of clinical outcomes. Beller and colleagues6Beller J.P. Hawkins R.B. Mehaffey J.H. LaPar D.J. Kron I.L. Yarboro L.T. et al.Does preoperative troponin level impact outcomes after coronary artery bypass grafting?.Ann Thorac Surg. 2018; 106: 46-51Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar found that peak troponin does not influence CABG outcomes after myocardial infarction. Furthermore, there are many randomized control trials demonstrating decreased biomarkers of injury in off-pump CABG, but little change in outcome. Third, the systemic effects of NO should be considered. These systemic effects may prove to have a benefit independent of myocardial injury. In a study by Cecchia and colleagues4Checchia P.A. Bronicki R.A. Muenzer J.T. Dixon D. Raithel S. Gandhi S.K. et al.Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children—a randomized trial.J Thorac Cardiovasc Surg. 2013; 146: 530-536Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar in pediatric patients undergoing tetralogy of Fallot repair, the addition of NO to the CPB circuit led to improved fluid balance.4Checchia P.A. Bronicki R.A. Muenzer J.T. Dixon D. Raithel S. Gandhi S.K. et al.Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children—a randomized trial.J Thorac Cardiovasc Surg. 2013; 146: 530-536Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Furthermore, in a study by Lei and colleagues,7Lei C. Berra L. Rezoagli E. Yu B. Dong H. Yu S. et al.Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery.Am J Respir Crit Care Med. June 22, 2018; ([Epub ahead of print])Google Scholar the addition of NO to the CPB circuit in patients undergoing mitral valve replacement led to less acute kidney injury.7Lei C. Berra L. Rezoagli E. Yu B. Dong H. Yu S. et al.Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery.Am J Respir Crit Care Med. June 22, 2018; ([Epub ahead of print])Google Scholar These findings suggest that systemic effects of NO may be beneficial. This pilot study shows that administration of NO during CPB is safe, feasible, and economical. Further randomized trials and larger investigational studies are needed. Future studies should be performed in a cohort of higher risk patients, with outcomes that assess myocardial protection and systemic benefits. Nitric oxide provides myocardial protection when added to the cardiopulmonary bypass circuit during cardiac surgery: Randomized trialThe Journal of Thoracic and Cardiovascular SurgeryVol. 157Issue 6PreviewThe aim of this pilot study was to elucidate the effects of exogenous nitric oxide (NO) supply to the extracorporeal circulation circuit for cardioprotection against ischemia–reperfusion injury during coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Full-Text PDF Open Archive

Between 2000 and 2008, the mitral valve (MV) repair rate in patients with severe mitral regurgitation at our low-volume Veterans Affairs hospital was 21%. After instituting a multidisciplinary valve team in 2009, we determined whether this rate increased and characterized the outcomes of patients with degenerative disease. We retrospectively reviewed data from 103 MV operations performed at our hospital between 1/2009 and 8/2016. MV pathology was categorized as degenerative, rheumatic, endocarditis, ischemic, hypertrophic cardiomyopathy, or failed prior MV repair. The surgical techniques used for MV repair were reviewed. For the patients with degenerative disease who underwent MV repair, we assessed leaflet involvement and postoperative valve function. For the full cohort, the MV repair rate was 67% and the 30-day mortality rate was 0.97%. Of the 74 patients with degenerative disease, 64 (86.5%) underwent MV repair (none required reoperation). For these patients, the MV repair rate was significantly higher when the surgical approach was sternotomy rather than minimally invasive right minithoracotomy (92.5% vs 71.4%, P = 0.03). After MV repair, 95.3% of the degenerative disease patients had mild or less mitral regurgitation; median echocardiography follow-up time was 555days. Anatomic features associated with a reduced MV repair rate in patients with degenerative disease were dystrophic leaflet calcification and severe mitral annular calcification. In an institution with a low volume of MV operations, preoperative surgical planning with a multidisciplinary valve team was associated with improved MV repair rates and excellent repair quality in patients with degenerative valve disease.

Background. Although reducing the incidence of unplanned readmission after thoracoabdominal aortic aneurysm (TAAA) repair represents an important opportunity to improve outcomes, predictors of read-missions are not known. We sought to characterize and identify factors associated with unplanned readmission after discharge in survivors of open TAAA repair. Methods. Through prospective phone contact and retrospective record review, we determined the frequency and characteristics of unplanned readmissions within 30 days of discharge in 363 patients who were discharged after open TAAA repair. We used univariate and multi variable analyses to identify factors associated with readmission. Results. There were 44 unplanned readmissions in 40 patients (11%). After readmission, 11 patients underwent operations, and 17 underwent nonsurgical procedures, the most common of which was thoracentesis (n = 9). Readmitted patients tended to have lower preoperative estimated glomerular filtration rates (p = 0.045), higher frequencies of preoperative sleep apnea (p = 0.009) and postoperative pulmonary (p = 0.04) and infection (p = 0.02) complications, and longer hospital stays (p = 0.01) than patients without readmissions. Patient age, urgency of operation, and extent of TAAA repair were similar in patients with and without readmissions. Multivariable analysis identified sleep apnea (relative risk ratio [RRR] 3.21, 95% confidence interval [CI]: 1.51 to 6.82, p = 0.002), postoperative infection (RRR 4.34, 95% CI: 1.32 to 14.25, p = 0.02), renal failure necessitating dialysis (RRR 3.14, 95% CI: 1.04 to 9.46, p = 0.04), and visceral artery stenting (RRR 2.43, 95% CI: 1.09 to 5.44, p = 0.03) as significant predictors of readmission. Conclusions. Patients with renal dysfunction, sleep apnea, or postoperative infection were particularly likely to be readmitted; optimizing the management of these factors may reduce early readmission after TAAA repair. (C) 2018 by The Society of Thoracic Surgeons

Chylothorax is a potentially deadly complication that can occur after thoracoabdominal aortic aneurysm (TAAA) repair. We describe our contemporary experience (2005-2014) with this complication, our efforts to identify perioperative variables associated with it, and our attempts to assess treatment outcomes. We reviewed the records of 1092 consecutive patients who underwent TAAA repair between 2005 and 2014. Standard bivariate analysis was used to test for between-group differences. Eleven patients (0.9%) developed postoperative chylothorax. Nonoperative management was used in 8 of these patients (73%); 1 patient died after a lengthy hospital stay (297 days). The other 3 patients required thoracotomy with direct ligation; 1 of these patients required a second operation. Patients who developed chylothorax appeared to be similar to other patients in age, sex, extent of aneurysm, and metabolic or cardiovascular comorbidities. Patients who developed postoperative chylothorax were more likely to require drainage of a pleural effusion (P = 0.005), tracheostomy (P = 0.02), and longer stays in the intensive care unit (median, 6 [2-24] days, P < 0.001) and the hospital (median, 35 [24-88] days, P = 0.001), and these patients were more likely to develop a graft infection (n = 2, P < 0.001). The extent of TAAA repair (Crawford I-IV), reoperation, and clamping proximal to the left subclavian artery were not significantly associated with postoperative chylothorax. Chylothorax after TAAA repair can often be managed nonoperatively. Development of postoperative chylothorax may lead to significant morbidity, longer hospitalization, and increased likelihood of graft infection.

Objective— Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain–like receptor family, pyrin domain containing 3)–caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. Approach and Results— We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3–caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II–induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II–induced AAD formation. Conclusions— Inflammasome-caspase-1–mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.

Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency ( Adamts-4−/− ) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4−/− mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

It is well known that dysregulation of transforming growth factor-beta (TGFβ) activation plays a critical role in aortic damage, fibrosis, and subsequent dysfunction during the development of thoracic aortic aneurysms and dissections (TAAD), particularly those involving the ascending aorta. However, the mechanisms leading to TGFb's activation in TAAD remain to be identified. Having recently found that activation of the NLRP3 inflammasome cascade promotes TAAD, we hypothesized that this cascade amplifies TGFβ signaling and causes aortic degeneration in the ascending aortic wall in response to acute stress.

BACKGROUND:D-dimer levels are elevated in patients with acute aortic dissection (AAD). Although D-dimer levels have been used to rule out AAD within 24 h of symptom onset, it is unknown whether they may be used reliably after 24 h but within the acute period. Here, we tested the hypothesis that D-dimer levels remain elevated in AAD patients for at least 10 d after dissection onset. MATERIALS AND METHODS:D-dimer levels were measured in preoperative heparinized plasma samples from 100 patients with confirmed AAD for up to 10 d after onset of dissection. When possible, serial samples were obtained for ≥2 d. D-dimer levels were measured in fibrinogen equivalent units using a BCS XP automated coagulation analyzer, which is approved for citrated samples. Therefore, we first validated our samples by comparing D-dimer levels in heparinized and citrated plasma samples from 29 individuals, including patients with and without aortic disease and healthy donors. RESULTS:The correlation between heparinized and citrated plasma samples was 0.991 (P ≤ 0.001). At a threshold of 1.6 μg/mL, the overall sensitivity of the D-dimer assay in AAD patients up to 10 d after onset of dissection was 95.3%. CONCLUSIONS:D-dimer levels remained elevated in AAD patients over a 10-d period after dissection onset and may be helpful in ruling out AAD in patients who seek treatment after the first 24 h but within the acute period. Heparinized plasma samples may be substituted for citrated samples when evaluating D-dimer levels using the BCS XP coagulation analyzer.

Background Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) can lead to aortic wall failure. We hypothesized that patients with aneurysms resulting from chronic descending thoracic aortic dissection have elevated tissue and plasma levels of specific MMPs and decreased tissue levels of TIMPs. Materials and methods Aortic tissue was obtained from 25 patients who required surgical repair of descending thoracic aortic aneurysm due to chronic aortic dissection and from 17 organ-donor controls without aortic disease. Tissue levels of MMP-1, -2, -3, -9, -12, and -13 and TIMP-1 and -2 were measured by colorimetric activity assay or enzyme-linked immunosorbent assay and confirmed by Western blot and immunohistochemistry. Blood obtained from the 25 patients and 15 controls without aortic diseases was used to compare plasma levels of MMP-3, -9, and -12. Results Total MMP-1, total MMP-9, and active MMP-9 levels were higher and total MMP-2 levels were lower in dissection tissue than in control tissue. Additionally, the MMP-9 to TIMP-1 and active to total MMP-2 ratios were higher and the MMP-2 to TIMP-2 ratio was lower in dissection tissue. Furthermore, patients had higher plasma active to total MMP-9 ratios than the controls. Age and hypertension were associated with increased MMP levels. Conclusions Increased levels of several MMPs and increased MMP to TIMP ratios in aortic tissue from patients suggest an environment that favors proteolysis, which may promote progressive extracellular matrix destruction and medial degeneration after aortic dissection. An elevated active to total MMP-9 ratio in plasma may be a biomarker for end-stage aneurysm development in patients with chronic thoracic aortic disease.

We previously showed that the NLRP3 inflammasome (NLRP3-ASC-Caspase-1) can activate matrix metalloproteinase-9 (MMP-9), a protease that degrades the extracellular matrix (ECM). We hypothesized that genetic deletion of NLRP3 and pharmacologic inhibition of the NLRP3 inflammasome with glyburide would prevent tissue destruction and thoracic aortic aneurysm and dissection (AAD) development.

BACKGROUND:After thoracoabdominal aortic aneurysm (TAAA) repair, blood tests assessing hepatopancreaticobiliary (HPB) organs commonly have abnormal results. The clinical significance of such abnormalities is difficult to determine because the expected postoperative levels have not been characterized. Therefore, we sought to establish expected trends in HPB laboratory values after TAAA repair. METHODS:This 5-year study comprised 155 patients undergoing elective Crawford extent II TAAA repair. In accordance with a prospective study protocol, all repairs involved left-sided heart bypass, selective visceral perfusion, and cold renal perfusion. Blood levels of aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin, amylase, and lipase were measured before TAAA repair and for 7 days afterward. Ratios between postoperative and baseline levels were compared for each time point with 95% confidence intervals. RESULTS:Temporal patterns for the laboratory values varied greatly. Amylase, lipase, and AST underwent significant early increases before decreasing to preoperative levels. LDH increased immediately and remained significantly elevated, whereas ALT increased more gradually. GGT remained near baseline through postoperative day 4, and then increased to more than twice baseline. Total bilirubin never differed significantly from baseline. After adjusted analysis, the ischemic time predicted the maximum AST, lipase, GGT, and LDH values. CONCLUSIONS:Although most HPB laboratory values increase significantly after elective TAAA repair, the temporal trends for different values vary substantially. The ischemic time predicts the maximum AST, lipase, GGT, and LDH levels. These trends should be considered when laboratory values are assessed after TAAA repair.

Excessive matrix metalloproteinase (MMP) activity during inflammation disrupts aortic wall homeostasis, causing progression of thoracic aortic aneurysms and dissections (TAAD). The NLRP3-ASC-caspase-1 inflammasome complex is critically involved in the activation and secretion of inflammatory factors. However, the role of this complex in regulating MMP activity remains unknown. We hypothesize that the NLRP3 inflammasome complex activates MMP-9, leading to cleavage of contractile proteins, resulting in thoracic aortic smooth muscle cell (SMC) dysfunction.

Rationale: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. Objective: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. Methods and Results: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2- deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2 -deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II–infused Akt2- deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters. Conclusions: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.

Abstract Background: Thoracic aortic dissection (TAD) is a highly lethal cardiovascular disease. Injury to the intima and media allows pulsatile blood to enter the media, leading to dissection formation. Inflammatory cells then infiltrate the site of aortic injury to clear dead cells and damaged tissue. This excessive inflammation may play a role in aneurysm formation after dissection. Methods: Using immunohistochemistry, we compared aortic tissues from patients with acute TAD (n = 11), patients with chronic TAD (n = 35), and donor controls (n = 20) for the presence of CD68+ macrophages, neutrophils, mast cells, and CD3+ T lymphocytes. Results: Tissue samples from patients with acute or chronic TAD generally had significantly more inflammatory cells in both the medial and adventitial layers than did the control samples. In tissues from patients with acute TAD, the adventitia had more of the inflammatory cells studied than did the media. The pattern of increase in inflammatory cells was similar in chronic and acute TAD tissues, except for macrophages, which were seen more frequently in the adventitial layer of acute TAD tissue than in the adventitia of chronic TAD tissue. Conclusions: The inflammatory cell content of both acute and chronic TAD tissue was significantly different from that of control tissue. However, the inflammatory cell profile of aneurysmal chronic TAD was similar to that of acute TAD. This may reflect a sustained injury response that contributes to medial degeneration and aneurysm formation.