Research Spotlight

Iribarne, A., S. Pan, J. N. McCullough, J. P. Mathew, J. Hung, X. Zeng, P. Voisine, P. T. O’Gara, N. M. Sledz, A. C. Gelijns, W. C. Taddei-Peters, S. R. Messe, A. J. Moskowitz, V. H. Thourani, M. Argenziano, M. A. Groh, G. Giustino, J. R. Overbey, J. M. DiMaio and P. K. Smith (2019). “Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.” Ann Thorac Surg Aug 7. [Epub ahead of print].

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BACKGROUND: Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS: SAVR patients in a randomized trial of two embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core-laboratory. Aortic atherosclerosis was quantified with Katz atheroma grade and patients were categorized into mild (grade I-II) versus moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging (DW-MRI), delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Of the 383 randomized patients, 326 (85.1%) had pre-cannulation epiaortic ultrasound data available. Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. While there were no significant differences in the composite of death, stroke or cerebral infarction on DW-MRI by 7 days, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio [OR]: 2.63; 95% confidence interval [CI]: 1.24-5.58; p=0.01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke or AKI (adjusted OR: 1.97; 95%CI: 1.04-3.71; p=0.04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events following SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.

Hollander, P. A., J. Kiljanski, E. Spaepen and C. J. Harris (2019). “Risk of clinically relevant hypoglycaemia in patients with type 2 diabetes self-titrating insulin glargine U-100.” Diabetes Obes Metab Sep 4. [Epub ahead of print].

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AIMS: We evaluated risk factors for clinically relevant hypoglycaemia (blood glucose <3 mmol/L) in patients with type 2 diabetes during insulin glargine self-titration. Data were from two clinical trials in which patients were able to improve glycaemic control by self-titration of insulin glargine using a simple algorithm. MATERIALS AND METHODS: We performed post hoc analyses of pooled treatment groups from each of two Phase 3 studies comparing LY2963016 with LANTUS: ELEMENT-2 (double-blind) and ELEMENT-5 (open label). Clinically relevant hypoglycaemia was analysed by category of HbA1c (<7%, 7%-8.5%, >8.5%) at Week 12 (titration period) and at Week 24 (overall study), and by subgroups of age (<65, >/=65 years) and previous insulin use (naive or not). RESULTS: In the ELEMENT-2 study (N = 756), there were no overall differences in rate or incidence of hypoglycaemia among HbA1c categories. In the ELEMENT-5 study (N = 493), patients with HbA1c greater than 8.5% had a lower rate and incidence of hypoglycaemia throughout the study compared to those in the lower HbA1c categories. In both studies, patients 65 years of age or older, compared to those less than 65 years, had a higher rate and incidence of hypoglycaemia during the titration phase, had lower baseline HbA1c, and experienced smaller increases in dose, with no differences in HbA1c post baseline. The rate and incidence of hypoglycaemia was similar between naive patients and patients previously using basal insulin, across all levels of glycaemic control. With the exception of the older subgroup, hypoglycaemia rates were similar during titration and maintenance periods. CONCLUSION: Our results support broader use of self-titration algorithms for patients with type 2 diabetes.

Gupta, A. and S. K. Asrani (2019). “Role of Living Donor Liver Transplantation in Acute Liver Failure.” Liver Transpl 25(9): 1308-1309.

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The etiology of acute liver failure (ALF) varies widely, with drug toxicity being the leading cause in Western countries, whereas viral hepatitis predominates in Asia.1, 2 The varying etiologies may lead to a different phenotype and clinical course of ALF by location. Without liver transplantation (LT), ALF is frequently fatal due to cerebral edema and multisystem organ failure. In the West, where LT with deceased donors is well established, most eligible ALF patients receive whole liver allografts, often with the highest priority on the waiting list. As a result, living donor liver transplantation (LDLT) is rarely undertaken for ALF patients. In contrast, many countries around the world do not have access to adequate deceased donors and, thus, rely on LDLT for almost all patients, including those with ALF. Pamecha et al. describe a large center in India evaluating outcomes of patients (adult and pediatric) that underwent LDLT for ALF as compared with others that underwent elective LDLT.3 Approximately 15% of their LDLT recipients between 2011 and 2018 underwent transplantation for ALF. All patients transplanted for ALF met King’s College criteria. At the time of transplant, median Model for End‐Stage Liver Disease score was 37; 66% of patients had grade 3 or 4 encephalopathy; and a majority of them were intubated. A total of 51% met the systemic inflammatory response syndrome (SIRS) criteria. A positive culture was detected in almost half of the patients. Though computed tomography scans were not uniformly done during the initial years, among those with imaging, 51% had moderate or severe cerebral edema. Continuous renal replacement therapy was used in a minority of patients (1.6%). The 5‐year actuarial survival was 65.6%, which is lower than the 80% survival seen with elective LDLT but substantially higher than the 22% survival of patients meeting King’s College criteria who did not undergo transplantation. Most of the deaths (76%) were within the first 30 days. Sepsis and cerebral edema were the most common causes of early mortality. On adjusted analysis, cerebral edema, SIRS, and sepsis were drivers of mortality. Median time to donor evaluation was 18 hours. The donor operation was safe, and donor morbidity was 13%. No donor mortality was reported. Overall, the authors demonstrate that LDLT is feasible and safe for ALF in a highly selected group of patients with an experienced team. (Excerpt from text of authors’ commentary on the article, Pamecha V, Vagadiya A, Sinha PK, Sandhyav R, Parthasarathy K, Sasturkar S, et al. Living donor liver transplantation for acute liver failure: donor safety and recipient outcome. Liver Transpl 2019; 25: 1408– 1421.)

Goldsweig, A. M., H. J. Tak, L. W. Chen, H. D. Aronow, B. Shah, D. S. Kolte, P. Velagapudi, N. Desai, M. Szerlip and J. D. Abbott (2019). “The Evolving Management of Aortic Valve Disease: 5-Year Trends in SAVR, TAVR, and Medical Therapy.” Am J Cardiol 124(5): 763-771

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Aortic stenosis (AS) and regurgitation (AR) may be treated with surgical aortic valve replacement (SAVR), transcatheter AVR (TAVR), or medical therapy (MT). Data are lacking regarding the usage of SAVR, TAVR, and MT for patients hospitalized with aortic valve disease and the characteristics of the patients and hospitals associated with each therapy. From the Nationwide Readmissions Database, we determined utilization trends for SAVR, TAVR, and MT in patients with aortic valve disease admitted from 2012 to 2016 for valve replacement, heart failure, unstable angina, non-ST-elevation myocardial infarction, or syncope. We also performed multinomial logistic regressions to investigate associations between patient and hospital characteristics and treatment. Among 366,909 patients hospitalized for aortic valve disease, there was a 48.1% annual increase from 2012 through 2016. Overall, 19.9%, 6.7%, and 73.4% of patients received SAVR, TAVR, and MT, respectively. SAVR decreased from 21.9% in 2012 to 18.5% in 2016, whereas TAVR increased from 2.6% to 12.5%, and MT decreased from 75.5% to 69.0%. Older age, female sex, greater severity of illness, more admission diagnoses, not-for-profit hospitals, large hospitals, and urban teaching hospitals were associated with greater use of TAVR. In multivariable analysis, likelihood of TAVR relative to SAVR increased 4.57-fold (95% confidence interval 4.21 to 4.97). TAVR has increased at the expense of both SAVR and MT, a novel finding. However, this increase in TAVR was distributed inequitably, with certain patients more likely to receive TAVR certain hospitals more likely to provide TAVR. With the expected expansion of indications, inequitable access to TAVR must be addressed.

Fovet, C. M., L. Stimmer, V. Contreras, P. Horellou, A. Hubert, N. Seddiki, C. Chapon, S. Tricot, C. Leroy, J. Flament, J. Massonneau, N. Tchitchek, B. A. t Hart, S. Zurawski, P. Klucar, P. Hantraye, K. Deiva, G. Zurawski, S. Oh, R. Le Grand and C. Serguera (2019). “Intradermal vaccination prevents anti-MOG autoimmune encephalomyelitis in macaques.” EBioMedicine Sep 3. [Epub ahead of print].

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BACKGROUND: Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation. METHODS: We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4(+) lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen). FINDINGS: rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a(+) DCs or CD163(+) cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4(+) T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4(+)CD25(+)FOXP3(+)CD39(+) regulatory lymphocytes and favoured an upsurge in systemic TGFbeta and IL-8 upon rhMOG re-administration in vivo. INTERPRETATION: We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.