Michael Samuel Hughes

All Publications

• Efficacy and Safety of a Tubeless AID System Compared With Pump Therapy With CGM in the Treatment of Type 1 Diabetes in Adults With Suboptimal Glycemia: A Randomized, Parallel-Group Clinical Trial. Diabetes care Renard, E., Weinstock, R. S., Aleppo, G., Bode, B. W., Brown, S. A., Castorino, K., Hirsch, I. B., Kipnes, M. S., Laffel, L. M., Lal, R. A., Penfornis, A., Riveline, J., Shah, V. N., Thivolet, C., Ly, T. T., OP5-003 Research Group, Renard, E., Farret, A., Villard, O., Masri, M. A., Weinstock, R. S., Stone, S. L., Bzdick, S., Aleppo, G., Kravarusic, J., Guevara, E., Herrmann, S., Penn, S., Bode, B. W., Ownby, J., Johnson, J., Tabb, C., Maxson, A., Dunn, E., Lewis, M., Reed, D., Wilby, C., Brown, S. A., Stumpf, M., Fuller, M., Alix, C., Castorino, K., Church, M. M., Thorsell, A., Shelton, N., Blanscet, H., Hirsch, I. B., Malik, F., Averkiou, X., Dong, X., Mandava, P., Kipnes, M. S., Salhin, A., Christie, K., Beltran, S., Ramon, V., Oliver, D., Rosas, K., Mulvey, S., Ryan, T., Hernandez, J., Pour, F. M., Hirchak, C., Laffel, L. M., Isganaitis, E., Ambler-Osborn, L., Goroza, E., Doolan, J., Turcotte, C., Herndon, C., Volkening, L., Oliveri, M., Kollar, L., Lal, R. A., Buckingham, B. A., Hughes, M., Norlander, L., Kingman, R., Suh, B., Hsu, L., Penfornis, A., Petit, C., Siadoua, M., Riveline, J., Gautier, J., Vidal-Trecan, T., Julia, J. B., Potier, C., Bellili, D., Shah, V. N., Akturk, H. K., Joseph, H., Moore, A., Downs, A., Beatson, C., Walker, S., Bloks, T., Qamar, L., Wodetzki, D., Shoemaker, R., Thivolet, C., Fimbel, S. V., Hami, R., Kivilaid, K., Ly, T. T., Dumais, B., Vienneau, T., Huyett, L. M., Conroy, L. R. 2024

  Abstract

  OBJECTIVE: To examine the efficacy and safety of the tubeless Omnipod 5 Automated Insulin Delivery (AID) System compared with pump therapy with a continuous glucose monitor (CGM) in adults with type 1 diabetes with suboptimal glycemic outcomes.RESEARCH DESIGN AND METHODS: In this 13-week multicenter, parallel-group, randomized controlled trial performed in the U.S. and France, adults aged 18-70 years with type 1 diabetes and HbA1c 7-11% (53-97 mmol/mol) were randomly assigned (2:1) to intervention (tubeless AID) or control (pump therapy with CGM) following a 2-week standard therapy period. The primary outcome was a treatment group comparison of time in range (TIR) (70-180 mg/dL) during the trial period.RESULTS: A total of 194 participants were randomized, with 132 assigned to the intervention and 62 to the control. TIR during the trial was 4.2h/day higher in the intervention compared with the control group (mean difference 17.5% [95% CI 14.0%, 21.1%]; P < 0.0001). The intervention group had a greater reduction in HbA1c from baseline compared with the control group (mean ± SD -1.24 ± 0.75% [-13.6 ± 8.2 mmol/mol] vs. -0.68 ± 0.93% [-7.4 ± 10.2 mmol/mol], respectively; P < 0.0001), accompanied by a significantly lower time <70 mg/dL (1.18 ± 0.86% vs. 1.75 ± 1.68%; P = 0.005) and >180 mg/dL (37.6 ± 11.4% vs. 54.5 ± 15.4%; P < 0.0001). All primary and secondary outcomes were met. No instances of diabetes-related ketoacidosis or severe hypoglycemia occurred in the intervention group.CONCLUSIONS: Use of the tubeless AID system led to improved glycemic outcomes compared with pump therapy with CGM among adults with type 1 diabetes, underscoring the clinical benefit of AID and bolstering recommendations to establish AID systems as preferred therapy for this population.

  View details for DOI 10.2337/dc24-1550

  View details for PubMedID 39423118

• Regional citrate anticoagulation with continuous renal replacement therapy as a cause of hypercalcemia. Archives of osteoporosis Needleman, L., Hughes, M. S., Fatehi, P., Sellmeyer, D. E. 2024; 19 (1): 78

  Abstract

  Awareness of the causes of hypercalcemia is essential for timely diagnosis of calcium disorders and optimal treatment. Citrate is commonly used as an anticoagulant during continuous renal replacement therapy (CRRT). Accumulation of citrate in the systemic circulation during CRRT may induce several metabolic disturbances, including total hypercalcemia and ionized hypocalcemia. The aim of the present study is to increase awareness of citrate accumulation and toxicity as a cause of hypercalcemia by relating three cases and reviewing the pathophysiology and clinical implications.We utilized electronic health records to examine the clinical cases and outlined key studies to review the consequences of citrate toxicity and general approaches to management.Citrate toxicity is associated with high mortality. A safe threshold for tolerating hypercalcemia during citrate anticoagulation is not clearly defined, and whether citrate toxicity independently increases mortality has not been resolved. Greater attention to citrate toxicity as a cause of hypercalcemia may lead to earlier detection, help to optimize the management of systemic calcium levels, and foster interest in future clinical studies.

  View details for DOI 10.1007/s11657-024-01434-y

  View details for PubMedID 39180669

  View details for PubMedCentralID 1265599

• Empowering Hospitalized Patients With Diabetes: Implementation of a Hospital-wide CGM Policy With EHR-Integrated Validation for Dosing Insulin. Diabetes care Lee, M. Y., Seav, S. M., Ongwela, L., Lee, J. J., Aubyrn, R., Cao, F. Y., Kalinsky, A., Aparicio Ramos, O., Gu, Y., Kingston, K., Ivanovic, M., Buckingham, B. A., Desai, D., Lal, R. A., Tan, M., Basina, M., Hughes, M. S. 2024

  Abstract

  We aimed to assess the feasibility, clinical accuracy, and acceptance of a hospital-wide continuous glucose monitoring (CGM) policy with electronic health record (EHR)-integrated validation for insulin dosing.A hospital policy was developed and implemented at Stanford Health Care for using personal CGMs in lieu of fingerstick blood glucose (FSBG) monitoring. It included requirements specific to each CGM, accuracy monitoring protocols, and EHR integration. User experience surveys were conducted among a subset of patients and nurses.From November 2022 to August 2023, 135 patients used the CGM protocol in 185 inpatient encounters. This included 27% with type 1 diabetes and 24% with automated insulin delivery systems. The most-used CGMs were Dexcom G6 (44%) and FreeStyle Libre 2 (43%). Of 1,506 CGM validation attempts, 87.8% met the %20/20 criterion for CGM-based insulin dosing and 99.3% fell within Clarke zones A or B. User experience surveys were completed by 27 nurses and 46 patients. Most nurses found glucose management under the protocol effective (74%), easy to use (67%), and efficient (63%); 80% of nurses preferred inpatient CGM to FSBG. Most patients liked the CGM protocol (63%), reported positive CGM interactions with nursing staff (63%), and felt no significant interruptions to their diabetes management (63%).Implementation of a hospital-wide inpatient CGM policy supporting multiple CGM types with real-time accuracy monitoring and integration into the EHR is feasible. Initial feedback from nurses and patients was favorable, and further investigation toward broader use and sustainability is needed.

  View details for DOI 10.2337/dc24-0626

  View details for PubMedID 39140891

• Multicenter Evaluation of Ultra-Rapid Lispro (URLi) Insulin with Control-IQ Technology in Adults, Adolescents and Children with Type 1 Diabetes. Diabetes technology & therapeutics Levy, C., Bailey, R., Laffel, L. M., Forlenza, G. P., DiMeglio, L. A., Hughes, M. S., Brown, S., Aleppo, G., Bhargava, A., Shah, V., Clements, M. A., Kipnes, M. S., Bruggeman, B., Daniels, M., Rodriguez, H., Calhoun, P., Lum, J., Sasson-Katchalski, R., Pinsker, J. E., Pollom, R., Beck, R. W. 2024

  Abstract

  To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teens and adults living with type 1 diabetes (T1D).At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology followed by a 13-week period in which URLi insulin was used in the pump.The trial included 179 individuals with type 1 diabetes (T1D) age 6 to 75 years. With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No DKA events occurred. Two participants stopped URLi use due to infusion site discomfort and one stopped after developing a rash. Mean time 70-180 mg/dL (TIR) increased from 65%±15% with lispro to 67%±13% with URLi (P=0.004). Mean insulin treatment satisfaction questionnaire (ITSQ) score improved from 75±13 at screening to 80±11 after 13 weeks of URLi use (mean difference = 6; 95% CI 4 to 8; P<0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment related impact measure-diabetes (TRIM-D) score improved from 74±12 to 80±12 (P<0.001), and mean TRIM-Diabetes Device (TRIM-DD) score improved from 82±11 to 86±12 (P<0.001).URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with type 1 diabetes, with quality of life benefits of URLi use perceived by the study participants.

  View details for DOI 10.1089/dia.2024.0048

  View details for PubMedID 38696672

• Development of a Real-time Force-based Algorithm for Infusion Failure Detection. Journal of diabetes science and technology Blanco, L. E., Wilcox, J. H., Hughes, M. S., Lal, R. A. 2024: 19322968241247530

  Abstract

  Continuous subcutaneous insulin infusion (CSII) is a common treatment option for people with diabetes (PWD), but insulin infusion failures pose a significant challenge, leading to hyperglycemia, diabetes burnout, and increased hospitalizations. Current CSII pumps' occlusion alarm systems are limited in detecting infusion failures; therefore, a more effective detection method is needed.We conducted five preclinical animal studies to collect data on infusion failures, utilizing both insulin and non-insulin boluses. Data were captured using in-line pressure and flow rate sensors, with additional force data from CSII pumps' onboard sensors in one study. A novel classifier model was developed using this dataset, aimed at detecting different types of infusion failures through direct utilization of force sensor data. Performance was compared against various occlusion alarm thresholds from commercially available CSII pumps.The testing dataset included 251 boluses. The Bagging classifier model showed the highest performance metrics among the models tested, exhibiting high accuracy (96%), sensitivity (94%), and specificity (98%), with lower false-positive and false-negative rate compared with traditional occlusion alarm pressure thresholds.Our study developed a novel non-threshold classifier that outperforms current occlusion alarm systems in CSII pumps in detecting infusion failures. This advancement has the potential to reduce the risk of hyperglycemia and hospitalizations due to undetected infusion failures, offering a more reliable and effective CSII therapy for PWD. Further studies involving human participants are recommended to validate these findings and assess the classifier's performance in a real-world setting.

  View details for DOI 10.1177/19322968241247530

  View details for PubMedID 38654491

• Digital Technology for Diabetes. Reply. The New England journal of medicine Hughes, M. S., Addala, A., Buckingham, B. 2024; 390 (10): 963-964

  View details for DOI 10.1056/NEJMc2315000

  View details for PubMedID 38446694

• Digital Technology for Diabetes. The New England journal of medicine Hughes, M. S., Addala, A., Buckingham, B. 2023; 389 (22): 2076-2086

  View details for DOI 10.1056/NEJMra2215899

  View details for PubMedID 38048189

• Regional citrate anticoagulation with continuous renal replacement therapy: a rare cause of hypercalcemia Needleman, L., Hughes, M. S., Mohty, R., Fatehi, P., Sellmeyer, D. OXFORD UNIV PRESS. 2023: 120

  View details for Web of Science ID 001266167000353

• Automated Insulin Delivery with Remote Real-Time Continuous Glucose Monitoring for Hospitalized Patients with Diabetes: A Multi-Center, Single-arm, Feasibility Trial. Diabetes technology & therapeutics Davis, G. M., Hughes, M. S., Brown, S., Sibayan, J., Perez-Guzman, M. C., Stumpf, M., Thompson, Z., Basina, M., Patel, R., Hester, J., Abraham, A., Ly, T. T., Chaney, C., Tan, M., Hsu, L. J., Kollman, C., Beck, R. W., Lal, R. A., Buckingham, B. A., Pasquel, F. 2023

  Abstract

  Introduction Multiple daily injection (MDI) insulin therapy frequently fails to meet hospital glycemic goals and is prone to hypoglycemia. Automated insulin delivery (AID) with remote glucose monitoring offers a solution to these shortcomings. Research Design and Methods In a single-arm multicenter pilot trial, we tested the feasibility, safety, and effectiveness of the Omnipod 5 AID System with real-time continuous glucose monitoring (CGM) for up to 10 days in hospitalized patients with insulin-requiring requiring diabetes on non-ICU medical-surgical units. Primary endpoints included the proportion of time in automated mode and percent time in range (TIR, 70-180 mg/dl) among participants with >48 hours of CGM data. Safety endpoints included incidence of severe hypoglycemia and diabetes-related ketoacidosis (DKA). Additional glycemic endpoints, CGM accuracy, and patient satisfaction were also explored. Results Twenty-two participants were enrolled; eighteen used the system for a total of 96 days (mean 5.3±3.1 days per patient), and sixteen had sufficient CGM data required for analysis. Median percent time in automated mode was 95% (IQR 92-98%) for the 18 system users, and the 16 participants with >48 hours of CGM data achieved an overall TIR of 68±16%, with 0.17±0.3% time <70 mg/dl and 0.06±0.2% time <54 mg/dl. Sensor mean glucose was 167±21 mg/dl. There were no DKA or severe hypoglycemic events. All participants reported satisfaction with the system at study end. Conclusions The use of AID with a disposable tubeless patch-pump along with remote real-time CGM is feasible in the hospital setting.

  View details for DOI 10.1089/dia.2023.0304

  View details for PubMedID 37578778

• Swimming With the Omnipod 5 Automated Insulin Delivery System: Connectivity in the Water. Diabetes care Hughes, M. S., Kingman, R. S., Hsu, L., Lal, R. A., Buckingham, B. A., Zaharieva, D. P. 2023

  View details for DOI 10.2337/dc23-0470

  View details for PubMedID 37311429

• Frequency and detection of insulin infusion site failure in the Type 1 Diabetes Exchange Online Community. Diabetes technology & therapeutics Hughes, M. S., Douvas, J. L., Layfield-Bryan, M., Blanco, L. E., Gray, J. C., Zapotoczny, G., Espinoza, J., Wilcox, J. H., Lal, R. A. 2023

  Abstract

  Insulin infusion site (IIS) failures are a weakness in insulin pump therapy. We examined experience with IIS failures among US individuals with diabetes on insulin pump via survey distributed to the T1D Exchange Online Community. Demographic factors, IIS characteristics, and diabetes-related perceptions were assessed by logistic regression to determine odds of higher (≥1 per month) or lower (<1 per month) reported IIS failure frequency. IIS failures were common; 41.4% reported ≥1 per month. IIS failure is usually detected through development of hyperglycemia rather than pump alarm. No assessed demographic factor or IIS characteristic was predictive; however, higher odds of ≥1 failure per month was associated with feelings of burnout (OR 1.489 [1.024, 2.165]) and considering pump discontinuation (OR 2.233 [1.455, 3.427]). IIS failures are frequent and unpredictable, typically require hyperglycemia for detection, and are associated with negative perceptions. More should be done toward preventing IIS failures and/or detecting them sooner.

  View details for DOI 10.1089/dia.2023.0005

  View details for PubMedID 36856574

• Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes. The New England journal of medicine Russell, S. J., Beck, R. W., Damiano, E. R., El-Khatib, F. H., Ruedy, K. J., Balliro, C. A., Li, Z., Calhoun, P., Wadwa, R. P., Buckingham, B., Zhou, K., Daniels, M., Raskin, P., White, P. C., Lynch, J., Pettus, J., Hirsch, I. B., Goland, R., Buse, J. B., Kruger, D., Mauras, N., Muir, A., McGill, J. B., Cogen, F., Weissberg-Benchell, J., Sherwood, J. S., Castellanos, L. E., Hillard, M. A., Tuffaha, M., Putman, M. S., Sands, M. Y., Forlenza, G., Slover, R., Messer, L. H., Cobry, E., Shah, V. N., Polsky, S., Lal, R., Ekhlaspour, L., Hughes, M. S., Basina, M., Hatipoglu, B., Olansky, L., Bhangoo, A., Forghani, N., Kashmiri, H., Sutton, F., Choudhary, A., Penn, J., Jafri, R., Rayas, M., Escaname, E., Kerr, C., Favela-Prezas, R., Boeder, S., Trikudanathan, S., Williams, K. M., Leibel, N., Kirkman, M. S., Bergamo, K., Klein, K. R., Dostou, J. M., Machineni, S., Young, L. A., Diner, J. C., Bhan, A., Jones, J. K., Benson, M., Bird, K., Englert, K., Permuy, J., Cossen, K., Felner, E., Salam, M., Silverstein, J. M., Adamson, S., Cedeno, A., Meighan, S., Dauber, A. 2022; 387 (13): 1161-1172

  Abstract

  Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting.In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed.A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group.In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

  View details for DOI 10.1056/NEJMoa2205225

  View details for PubMedID 36170500

• Swimming with Hybrid Closed-Loop: Connectivity Data from Seven Swimmers in the Omnipod 5 Trial Hughes, M. S., Kingman, R. S., Hsu, L., Lal, R., Buckingham, B. A., Zaharieva, D. P. AMER DIABETES ASSOC. 2022

  View details for DOI 10.2337/db22-782-P

  View details for Web of Science ID 000854899301283

• Swimming with Hybrid Closed Loop: Encouraging Data from Three Swimmers in the Omnipod 5 Trial Hughes, M. S., Kingman, R. S., Lal, R., Buckingham, B. A., Zaharieva, D. P. AMER DIABETES ASSOC. 2021

  View details for DOI 10.2337/db21-694-P

  View details for Web of Science ID 000728369702281

• Off-label use of SGLT inhibitors among adults in T1D Exchange Registry. Diabetes, obesity & metabolism Hughes, M. S., Bailey, R., Calhoun, P., Shah, V. N., Lyons, S. K., DeSalvo, D. J. 2021

  View details for DOI 10.1111/dom.14556

  View details for PubMedID 34545988

• Real-World Evidence of SGLT2 Inhibitor (SGLT2i) Use among Adults in the T1D Exchange Registry (T1DX) Hughes, M. S., Bailey, R., Calhoun, P., Lyons, S., Desalvo, D., Shah, V. N. AMER DIABETES ASSOC. 2020

  View details for DOI 10.2337/db20-1111-P

  View details for Web of Science ID 000554509802355

• Checking the Checkpoint Inhibitors: A Case of Autoimmune Diabetes After PD-1 Inhibition in a Patient with HIV. Journal of the Endocrine Society Hughes, M. S., Pietropaolo, M. n., Vasudevan, M. M., Marcelli, M. n., Nguyen, H. n. 2020; 4 (12): bvaa150

  Abstract

  Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a known immune-related adverse event (irAE) following treatment with programmed cell death protein 1 (PD-1), with a reported 0.9% incidence. We hereby present the first case, to our knowledge, of ICI-DM following ICI use in a human immunodeficiency virus (HIV) patient. In this case, a 48-year-old man with HIV stable on highly active antiretroviral therapy (HAART) was diagnosed with Hodgkin lymphoma and initiated treatment with the PD-1 inhibitor nivolumab. His lymphoma achieved complete response after 5 months. However, at month 8, he reported sudden polydipsia and polyuria. Labs revealed a glucose level of 764 mg/dL and glycated hemoglobin A1c (HbA1c) of 7.1%. Low C-peptide and elevated glutamic acid decarboxylase 65 (GAD65) antibody levels confirmed autoimmune DM, and he was started on insulin. Major histocompatibility complex class II genetic analysis revealed homozygous HLA DRB1*03-DQA1*0501-DQB1*02 (DR3-DQ2), which is a known primary driver of genetic susceptibility to type 1 DM. Autoimmune DM has been reported as an ICI-associated irAE. However, patients with immunocompromising conditions such as HIV are usually excluded from ICI trials. Therefore, little is known about such irAEs in this population. In this case, risk of ICI-DM as an irAE was likely increased by several factors including family history, a high-risk genetic profile, islet-related immunologic abnormalities, active lymphoma, and HIV infection with a possible immune reconstitution event. Clinicians should maintain a high index of suspicion for development of irAEs associated with ICI, particularly as use of these therapies broadens. Thorough investigation for presence of higher-risk features should be conducted and may warrant inclusion of pre-therapy genetic and/or autoantibody screening.

  View details for DOI 10.1210/jendso/bvaa150

  View details for PubMedID 33225197

  View details for PubMedCentralID PMC7660136

• Checking the Checkpoints: A Case of Type 1 Diabetes following PD-1 Inhibition in a Patient with HIV Hughes, M. S., Bedrose, S., Vasudevan, M., Marcelli, M. AMER DIABETES ASSOC. 2019

  View details for DOI 10.2337/db19-1739-P

  View details for Web of Science ID 000501366904140

• Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice. Scientific reports Ren, P. n., Hughes, M. n., Krishnamoorthy, S. n., Zou, S. n., Zhang, L. n., Wu, D. n., Zhang, C. n., Curci, J. A., Coselli, J. S., Milewicz, D. M., LeMaire, S. A., Shen, Y. H. 2017; 7 (1): 12351

  Abstract

  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.

  View details for DOI 10.1038/s41598-017-12248-z

  View details for PubMedID 28955046

  View details for PubMedCentralID PMC5617887

• Valve-sparing aortic root replacement: early and midterm outcomes in 83 patients. The Annals of thoracic surgery Coselli, J. S., Hughes, M. S., Green, S. Y., Price, M. D., Zarda, S. n., de la Cruz, K. I., Preventza, O. n., LeMaire, S. A. 2014; 97 (4): 1267–73; discussion 1273–74

  Abstract

  Valve-sparing aortic root replacement (VSARR) is an alternative to traditional composite valve graft (CVG) root replacement. We examined early and midterm outcomes after VSARR.A combined retrospective/prospective study was performed in 83 patients who underwent VSARR (16%) among 515 patients who underwent aortic root replacement during a nearly 12-year period. Thirty-six patients (43%) had a connective tissue disorder, 3 patients (4%) had acute aortic dissection, and 40 (48%) patients had at least moderate aortic regurgitation (AR). Twenty-eight patients (34%) had left ventricular hypertrophy or dilatation. The reimplantation VSARR technique was used in 82 patients (99%), and the Florida sleeve technique was used in 1 patient. Thirty-two patients (39%) underwent concomitant aortic arch replacement. For early survivors, the median duration of follow-up was 3.5 years (range, 5 days-12.2 years).One patient had severe AR after VSARR that necessitated intraoperative conversion to a mechanical CVG. The 1 operative death and 1 stroke occurred in a patient with acute dissection. Actuarial survival was 96.4%±2.0% at 2 years and 86.9%±5.6% at 8 years. Six patients (7%) had late valve-related complications: 1 died of endocarditis, 4 underwent reoperation for severe AR and received replacement valves, and 1 had severe AR and is being monitored. Freedom from repair failure (reoperation, endocarditis, or severe AR) was 94.8%±2.6% at 2 years and 87.3%±5.7% at 8 years.Valve-sparing aortic root replacement can have excellent early and respectable midterm outcomes, even when combined with arch repair. Further follow-up remains necessary to evaluate the long-term durability of VSARR.

  View details for DOI 10.1016/j.athoracsur.2013.10.076

  View details for PubMedID 24424011

• Outcomes of open distal aortic aneurysm repair in patients with chronic DeBakey type I dissection. The Journal of thoracic and cardiovascular surgery Coselli, J. S., Green, S. Y., Zarda, S. n., Nalty, C. C., Price, M. D., Hughes, M. S., Preventza, O. n., de la Cruz, K. I., LeMaire, S. A. 2014; 148 (6): 2986–93.e1–2

  Abstract

  In patients with acute DeBakey type I dissection, endovascular repair of the descending thoracic aorta during proximal aortic repair is an increasingly popular approach to preventing distal aortic sequelae and subsequent repair. To better define the risks and outcomes associated with these secondary operations, we examined our contemporary experience with open distal aortic repair in patients with chronic type I aortic dissection.Data were collected between January 2005 and June 2013 regarding 198 consecutive open descending thoracic (n = 27) or thoracoabdominal (n = 171) aortic repairs performed in patients with chronic type I dissection. The median interval between the dissection onset and the subsequent distal operation was 5.0 years (interquartile range, 2.4-10.5 years). A total of 110 repairs (56%) were performed in patients with genetic disorders.There were 14 early deaths (7%). Permanent paraplegia developed in 2 patients (1%), 5 patients (3%) had permanent stroke, and 9 patients (5%) had permanent renal failure. Factors associated with early death included greater age (P = .01), chronic obstructive pulmonary disease (P = .01), clamping proximal to the left subclavian artery (P = .004), and use of hypothermic circulatory arrest (P = .002). The use of cold renal perfusion (P < .001) was associated with early survival. Early death was not associated with genetic disorders, emergency surgery, or extent of aortic repair. There were 36 late deaths, yielding an actuarial 8-year survival of 65.6% ± 5.9%. At 7 years, freedom from repair failure was 95.7% ± 1.7%, and freedom from subsequent repair for disease progression was 84.8% ± 4.6%.In survivors of DeBakey type I aortic dissection with distal aneurysm, open repair of the descending thoracic or thoracoabdominal aorta can be performed with excellent early survival, acceptable morbidity, and relatively few late aortic events.

  View details for DOI 10.1016/j.jtcvs.2014.07.048

  View details for PubMedID 25212053