Research Spotlight

Posted February 15th 2020

Over-Testing for Suspected Pulmonary Embolism in American Emergency Departments: The Continuing Epidemic.

John S. Garrett M.D.
John S. Garrett M.D.

Kline, J. A., J. S. Garrett, E. J. Sarmiento, C. C. Strachan and D. M. Courtney (2020). “Over-Testing for Suspected Pulmonary Embolism in American Emergency Departments: The Continuing Epidemic.” Circ Cardiovasc Qual Outcomes Jan 20. [Epub ahead of print]

Full text of this article.

BACKGROUND: No recent data have investigated rates of diagnostic testing for pulmonary embolism (PE) in US emergency departments (EDs), and no data have examined computed tomographic pulmonary angiography (CTPA) rates in subgroups at high risk for adverse imaging outcomes, including young women and children. We hypothesized that over-testing for PE remains a problem. METHODS AND RESULTS: We used electronic health record and billing data for 16 EDs in Indiana and 11 hospitals in the Dallas-Fort Worth area from 2016 to 2019 to locate ED patients who had any of the following: D-dimer, CTPA, scintillation ventilation perfusion lung scanning or formal pulmonary angiography. The primary outcomes were ED encounter volume-adjusted CTPA rate, PE yield rate with subgroup reporting for children (<18 years) and women under 45 years. We also examined the most frequent diagnoses. From a total visit volume of 1 828 010 patient encounters, 97 125 (5.3% of the total volume) had a diagnostic test for PE, including 25 870 patients who had CTPA order without D-dimer (59% of all tests for PE). The yield rate for PE from CTPA scans was 1.3% (1.1%-1.5%) in Indiana and 4.8% (4.2%-5.1%) in Dallas-Fort Worth (pooled rate 3.1%). Linear regression showed that increased D-dimer ordering correlated with increased PE yield rate (Pearson's R(2)=0.43; P<0.001). From the pooled sample, 59% of CTPAs done were in women, with 21% of all CTPAs performed on women under 45 years of age, and 1.4% (1.3%-1.5%) on children. The most frequent diagnoses were symptom-based descriptions of chest pain (34%) and shortness of breath (6.5%) and the condition-based diagnosis of pneumonia (4.1%). CONCLUSIONS: Over-testing for PE in American EDs remains a major public health problem. Centers with higher D-dimer ordering had higher yield of PE on CTPA. These data suggest the potential for implementation of D-dimer based protocols to reduce low-yield CTPA ordering.


Posted February 15th 2020

The Effect and Relationship of Frailty Indices on Survival After Transcatheter Aortic Valve Replacement.

Michael J. Mack M.D.
Michael J. Mack M.D.

Kiani, S., A. Stebbins, V. H. Thourani, J. Forcillo, S. Vemulapalli, A. S. Kosinski, V. Babaliaros, D. Cohen, S. K. Kodali, A. J. Kirtane, J. B. Hermiller, Jr., J. Stewart, A. Lowenstern, M. J. Mack, R. A. Guyton and C. Devireddy (2020). “The Effect and Relationship of Frailty Indices on Survival After Transcatheter Aortic Valve Replacement.” JACC Cardiovasc Interv 13(2): 219-231.

Full text of this article.

OBJECTIVES: This study sought to evaluate the ability of individual markers of frailty to predict outcomes after transcatheter aortic valve replacement (TAVR) and of their discriminatory value in different age groups. BACKGROUND: Appropriate patient selection for TAVR remains a dilemma, especially among the most elderly and potentially frail. METHODS: The study evaluated patients >/=65 years of age in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry, linked to Centers for Medicare and Medicaid administrative claims data, receiving elective TAVR from November 2011 to June 2016 (n = 36,242). Indices of frailty included anemia, albumin level, and 5-m walk speed. We performed Cox proportional hazards regression for 30-day and 1-year mortality, adjusting for risk factors known to be predictive of 30-day mortality in the Transcatheter Valve Therapy registry, as well as survival analysis. RESULTS: These indices are independently associated with mortality at 30 days and 1 year and provide incremental value in risk stratification for mortality, with low albumin providing the largest value (hazard ratio: 1.52). Those with low albumin and slower walking speed had longer lengths of stay and higher rates of bleeding and readmission (p < 0.001). Those with anemia also had higher rates of bleeding, readmission, and subsequent myocardial infarction (p < 0.001). CONCLUSIONS: This represents the largest study to date of the role of frailty indices after TAVR, further facilitating robust modeling and adjusting for a large number of confounders. These simple indices are easily attainable, and clinically relevant markers of frailty that may meaningfully stratify patients at risk for mortality after TAVR.


Posted February 15th 2020

Evaluation of Serotonin Release Assay and Enzyme-Linked Immunosorbent Assay Optical Density Thresholds for Heparin-Induced Thrombocytopenia in Patients on Extracorporeal Membrane Oxygenation.

Vivek Kataria, Pharm.D.
Vivek Kataria, Pharm.D.

Kataria, V., L. Moore, S. Harrison, O. Hernandez, N. Vaughan and G. Schwartz (2020). “Evaluation of Serotonin Release Assay and Enzyme-Linked Immunosorbent Assay Optical Density Thresholds for Heparin-Induced Thrombocytopenia in Patients on Extracorporeal Membrane Oxygenation.” Crit Care Med 48(2): e82-e86.

Full text of this article.

OBJECTIVES: Heparin-induced thrombocytopenia is a recognized concern in patients on extracorporeal life support. The purpose of this study was to evaluate the applicability of an enzyme-linked immunosorbent assay optical density threshold less than 1 to rule out heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation. DESIGN: Retrospective, single-center study. SETTING: Patients were recruited from a prospectively maintained database of all patients on extracorporeal membrane oxygenation from 2012 to 2018 at a tertiary referral center. PATIENTS: Forty-seven patients on extracorporeal membrane oxygenation support. INTERVENTIONS: The primary objective was to evaluate the application of enzyme-linked immunosorbent assay optical density thresholds and the serotonin release assay in patients on extracorporeal membrane oxygenation. Patients were divided into two cohorts, serotonin release assay negative and serotonin release assay positive. In order to perform a sensitivity and specificity analysis of enzyme-linked immunosorbent assay optical density thresholds, heparin-induced thrombocytopenia negative was defined as an optical density less than 1.0 and heparin-induced thrombocytopenia positive as an optical density greater than or equal to 1.0. MEASUREMENTS AND MAIN RESULTS: Utilizing the prespecified optical density thresholds, a specificity and negative predictive value of 89% and 95% were achieved, respectively. CONCLUSIONS: This assessment has helped to identify optical density thresholds for patients undergoing extracorporeal membrane oxygenation. Our data suggest that an optical density threshold of 1.0 may aid clinicians in objectively ruling out heparin-induced thrombocytopenia without sending a confirmatory serotonin release assay. Increasing the optical density threshold to 1.0 resulted in a high specificity and negative predictive value.


Posted February 15th 2020

Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.

J. Michael DiMaio, M.D.
J. Michael DiMaio, M.D.

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 (2020). “Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.” Ann Thorac Surg 109(2): 465-471.

Full text of this article.

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 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or 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, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.


Posted February 15th 2020

In Barrett’s Epithelial Cells, Weakly Acidic Bile Salt Solutions Cause Oxidative DNA Damage with Response and Repair Mediated by p38.

Rhonda Souza M.D.
Rhonda Souza M.D.

Huo, X., K. B. Dunbar, X. Zhang, Q. Zhang, S. J. Spechler and R. F. Souza (2020). “In Barrett’s Epithelial Cells, Weakly Acidic Bile Salt Solutions Cause Oxidative DNA Damage with Response and Repair Mediated by p38.” Am J Physiol Gastrointest Liver Physiol Jan 27. [Epub ahead of print].

Full text of this article.

The frequency of esophageal adenocarcinoma is rising despite widespread use of PPIs, which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Since p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38-dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced BrdU incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with Ref-1/APE1. Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus.