Research Spotlight

Posted October 15th 2019

Relationships between First Metatarsal and Sesamoid Positions and Other Clinically Relevant Parameters for Hallux Valgus Surgery.

Naohiro Shibuya D.P.M.

Naohiro Shibuya D.P.M.

Shibuya, N., J. Jasper, B. Peterson, J. Sessions and D. C. Jupiter (2019). “Relationships between First Metatarsal and Sesamoid Positions and Other Clinically Relevant Parameters for Hallux Valgus Surgery.” J Foot Ankle Surg Sep 25. [Epub ahead of print].

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Relationships between hallux valgus (HV) and other measurements within the first ray have been extensively studied. It is becoming more popular to correct HV deformity with tarsometatarsal joint arthrodesis while internally (varus) rotating the first metatarsal. This, in turn, reduces the sesamoid position when viewed in the dorsoplantar projection on radiographs. However, it has been shown that not all HV deformities have pathological external (valgus) rotation of the first metatarsal. In this study, we explored the relationships between frontal-plane rotations of the first metatarsal as well as the sesamoids, and other factors not limited to the first ray, to better understand the pathological process of HV deformity and to assist in surgical planning. We found that when adjusting for these covariates, the only factor associated with first metatarsal external rotation was having less metatarsus adductus. Sesamoid rotation, on the other hand, was independently associated with the HV angle, tibial sesamoid position, and medial column collapse. When surgically treating HV, correction of sesamoid rotation may need to be prioritized.


Posted October 15th 2019

Endovascular Repair of Ascending Aortic Disease in High-Risk Patients Yields Favorable Outcome (Commentary).

William Brinkman M.D.

William Brinkman M.D.

Schaffer, J. M. and W. T. Brinkman (2019). “Endovascular Repair of Ascending Aortic Disease in High-Risk Patients Yields Favorable Outcome (Commentary).” Ann Thorac Surg. Sep 28. [Epub ahead of print].

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In this issue of The Annals, the aortic team at the University of Maryland lead by Dr. Brad Taylor presents a series of patients treated endovascularly for ascending aortic pathology. All patients in their series were considered to have a prohibitive risk for open ascending aortic aneurysm repair, and thus would have been treated medically if not for the off-label use of endovascular technology they describe in this study. It is laudable that the “heart team concept” was used to both evaluate, risk stratify, and treat these patients. Cardiovascular surgeons, vascular surgeons, and interventional cardiologists were all important members of their aortic team. The study was limited by significant heterogeneity of underlying pathology as well as patient anatomy. Patient risk stratification was somewhat arbitrary and the follow up was short term (median 388 days only). In spite of these limitations, we believe that the results presented in this study are excellent, and that Ghoreishi and colleagues are appropriately finding solutions to address the unmet clinical need in patients with ascending aortic (zone 0) pathology at high risk or ineligible for traditional surgical treatment. At present, there only exists a smattering of institutional reports of endovascular repair of zone 0 aortic pathology in patients at very high risk or ineligible for traditional surgery. In aggregate, these reports involve a little over 100 patients, and outcomes are reviewed in an excellent review paper by Muetterties et al. Only 3 studies of in this review were series that involved 10 or more patients (Li, Tsilimparis, Roselli). Thus, the present case series of 13 patients represents a small but important incremental addition to the existing literature regarding this application of endovascular therapies to the treatment for zone 0 aortic pathology. The relative paucity of studies evaluating the utility of endovascular treatment of zone 0 aortic pathology is in contrast to the large unmet clinical need of such therapies for patients at high or extreme risk for traditional open repair. In the most recent era of the IRAD database, this cohort of “inoperable” patients with an acute type A aortic dissection is about 10%, and medical management of such patients continues to carry over a 50% mortality.6 Just as in 2004, with the naissance of transcatheter aortic valve replacement (TAVR) , the endovascular treatment of the ascending aorta will first be used for patients deemed at “high” or “extreme” risk for traditional open surgical techniques whose only available treatment is medical management. However, just as in the TAVR field, as endovascular therapies for the ascending aorta continue to mature, the in-hospital mortality (17-18%) and morbidity (10-13% risk of stroke) associated with traditional surgery for acute type A aortic dissections make endovascular treatment a low-hanging fruit to ultimately become the standard of care of treatment of this disease. To take this next step in changing the paradigm of treatment of ascending aortic pathology, we require devices specifically designed and intended for this indication. What is needed is an engineering collaboration and focus from industry and clinicians alike. (Excerpt from text of this article-in-press; not paginated.)


Posted October 15th 2019

Differential Expression and Release of Exosomal Mirnas by Human Islets under Inflammatory and Hypoxic Stress.

Bashoo Naziruddin Ph.D.

Bashoo Naziruddin Ph.D.

Saravanan, P. B., S. Vasu, G. Yoshimatsu, C. M. Darden, X. Wang, J. Gu, M. C. Lawrence and B. Naziruddin (2019). “Differential Expression and Release of Exosomal Mirnas by Human Islets under Inflammatory and Hypoxic Stress.” Diabetologia 62(10): 1901-1914.

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AIMS/HYPOTHESIS: Pancreatic islets produce non-coding microRNAs (miRNAs) that regulate islet cell function and survival. Our earlier investigations revealed that human islets undergo significant damage due to various types of stresses following transplantation and release miRNAs. Here, we sought to identify and validate exosomal miRNAs (exo-miRNAs) produced by human islets under conditions of cellular stress, preceding loss of cell function and death. We also aimed to identify islet stress signalling pathways targeted by exo-miRNAs to elucidate potential regulatory roles in islet cell stress. METHODS: Human islets were subjected to proinflammatory cytokine and hypoxic cell stress and miRNA from exosomes was isolated for RNA sequencing and analysis. Stress-induced exo-miRNAs were evaluated for kinetics of expression and release by intact islets for up to 48 h exposure to cytokines and hypoxia. A subset of stress-induced exo-miRNAs were assessed for recovery and detection as biomarkers of islet cell stress in a diabetic nude mouse xenotransplant model and in patients undergoing total pancreatectomy with islet auto-transplantation (TPIAT). Genes and signalling pathways targeted by stress-induced exo-miRNAs were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and direct interactions of miRNAs with downstream signalling targets were validated in human islet cells using the miRNA Tests for Read Analysis and Prediction (MirTrap) system. RESULTS: Global exo-miRNA sequencing revealed that 879 miRNA species were released from human islets and 190 islet exo-miRNAs were differentially expressed in response to proinflammatory cytokines, hypoxia or both. Release of exo-miRNAs hsa-miR-29b-3p and hsa-miR-216a-5p was detected within 6 h of exposure to cytokines and hypoxia. The remaining subset of stress-induced exo-miRNAs, including hsa-miR-148a-3p and islet cell damage marker hsa-miR-375, showed delayed release at 24-48 h, correlating with apoptosis and cell death. Stress and damage exo-miRNAs were significantly elevated in the circulation in human-to-mouse xenotransplant models and in human transplant recipients. Elevated blood exo-miRNAs negatively correlated with post-transplant islet function based on comparisons of stress and damage exo-miRNA indices with Secretory Unit of Islet Transplant Objects (SUITO) indices. KEGG analysis and further validation of exo-miRNA targets by MirTrap analysis revealed significant enrichment of islet mRNAs involved in phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase signalling pathways. CONCLUSIONS/INTERPRETATION: The study identifies exo-miRNAs differentially expressed and released by islets in response to damage and stress. These exo-miRNAs could serve as potential biomarkers for assessing islet damage and predicting outcomes in islet transplantation. Notably, exo-miRNAs 29b-3p and 216a-5p could be detected in islets prior to damage-released miRNAs and indicators of cellular apoptosis and death. Thus, these stress-induced exo-miRNAs may have potential diagnostic value for detecting early islet stress prior to progressive loss of islet cell mass and function. Further investigations are warranted to investigate the utility of these exo-miRNAs as early indicators of islet cell stress during prediabetic conditions.


Posted October 15th 2019

Effect of Bardoxolone Methyl on the Urine Albumin-to-Creatinine Ratio in Patients with Type 2 Diabetes and Stage 4 Chronic Kidney Disease.

Peter McCullough M.D.

Peter McCullough M.D.

Rossing, P., G. A. Block, M. P. Chin, A. Goldsberry, H. J. L. Heerspink, P. A. McCullough, C. J. Meyer, D. Packham, P. E. Pergola, B. Spinowitz, S. M. Sprague, D. G. Warnock and G. M. Chertow (2019). “Effect of Bardoxolone Methyl on the Urine Albumin-to-Creatinine Ratio in Patients with Type 2 Diabetes and Stage 4 Chronic Kidney Disease.” Kidney Int 96(4): 1030-1036.

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Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor kappaB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: -0.035 [95% confidence interval -0.031 to -0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.


Posted October 15th 2019

Lessons Learned from the Dapa-Hf Trial Concerning the Mechanisms of Benefit of Sglt2 Inhibitors on Heart Failure Events in the Context of Other Large-Scale Trials Nearing Completion.

Milton Packer M.D.

Milton Packer M.D.

Packer, M. (2019). “Lessons Learned from the Dapa-Hf Trial Concerning the Mechanisms of Benefit of Sglt2 Inhibitors on Heart Failure Events in the Context of Other Large-Scale Trials Nearing Completion.” Cardiovasc Diabetol 18(1): 129.

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Four large-scale trials in type 2 diabetes have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent the occurrence of serious heart failure events. Additionally, the DAPA-HF trial demonstrated a benefit of dapagliflozin to reduce major adverse outcomes in patients with established heart failure with a reduced ejection fraction. The trial sheds light on potential mechanisms. In DAPA-HF, the benefits of dapagliflozin on heart failure were seen to a similar extent in both patients with or without diabetes, thus undermining the hypothesis that these drugs mitigate glycemia-related cardiotoxicity. The action of SGLT2 inhibitors to promote ketogenesis is also primarily a feature of the action of these drugs in patients with diabetes, raising doubts that enhanced ketogenesis contributes to the benefit on heart failure. Also, dapagliflozin does not have a meaningful effect to decrease circulating natriuretic peptides, and it did not potentiate the actions of diuretics in DAPA-HF; moreover, intensification of diuretics therapy does not reduce cardiovascular death, questioning a benefit of SGLT2 inhibitors that is mediated by an action on renal sodium excretion. Finally, although hematocrit increases with SGLT2 inhibitors might favorably affect patients with coronary artery disease, in DAPA-HF, the benefit of dapagliflozin was similar in patients with or without an ischemic cardiomyopathy; furthermore, increases in hematocrit do not favorably affect the clinical course of patients with heart failure. Therefore, the results of DAPA-HF do not support many currently-held hypotheses about the mechanism of action of SGLT2 inhibitors in heart failure. Ongoing trials are likely to provide further insights.