The Clinical Emergency Data Registry: Structure, Use, and Limitations for Research.

The Clinical Emergency Data Registry (CEDR) is a qualified clinical data registry that collects data from participating emergency departments (EDs) in the United States for quality measurement, improvement, and reporting purposes. This article aims to provide an overview of the data collection and validation process, describe the existing data structure and elements, and explain the potential opportunities and limitations for ongoing and future research use. CEDR data are primarily collected for quality reporting purposes and are obtained from diverse sources, including electronic health records and billing data that are de-identified and stored in a secure, centralized database. The CEDR data structure is organized around clinical episodes, which contain multiple data elements that are standardized using common data elements and are mapped to established terminologies to enable interoperability and data sharing. The data elements include patient demographics, clinical characteristics, diagnostic and treatment procedures, and outcomes. Key limitations include the limited generalizability due to the selective nature of participating EDs and the limited validation and completeness of data elements not currently used for quality reporting purposes, including demographic data. Nonetheless, CEDR holds great potential for ongoing and future research in emergency medicine due to its large-volume, longitudinal, near real-time, clinical data. In 2021, the American College of Emergency Physicians authorized the transition from CEDR to the Emergency Medicine Data Institute, which will catalyze investments in improved data quality and completeness for research to advance emergency care.

Detection of COVID-19 using multimodal data from a wearable device: results from the first TemPredict Study.

Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

Use of the Sports Concussion Assessment Tool 3 in Emergency Department Patients With Psychiatric Disease.

OBJECTIVE: The Sports Concussion Assessment Tool 3 (SCAT3) Symptom Evaluation (SE) is used in the emergency department (ED). This study aimed to examine the effects of psychiatric history on the SCAT3 SE symptom severity score (SSS). SETTING: Three US EDs. PARTICIPANTS: A total of 272 ED patients with suspected concussion. DESIGN: Prospective, nonrandomized, nonblinded study. The SCAT3 SE SSS, demographic data, medical information, and self-reported psychiatric history were obtained from patients by clinical research staff when they presented to the ED seeking standard clinical care. Concussion diagnoses were determined following a comprehensive assessment by an ED physician trained in managing concussions and adjudicated by supervising physicians. MAIN MEASURES: The primary outcome measure was SSS. The association between SSS, self-reported psychiatric disease, and concussion diagnosis was analyzed using multivariable linear regression. RESULTS: 68.4% of subjects were diagnosed with a concussion. After controlling for age, sex, race, history of previous concussion, and interval from injury to ED presentation, self-reported psychiatric history (adjusted regression coefficient (ßa): 16.9; confidence interval [CI]: 10.1, 23.6), and concussion diagnosis (ßa: 21.7; CI: 14.2, 29.2) were both independently associated with a significant increase in SSS. Subjects with a history of concussion had a significantly higher SSS (ßa: 9.1; CI: 1.8, 16.5). Interval from injury to ED presentation was also associated with a significant increase in SSS (ßa: 1.6 per 6-hour increase; CI: 0.4, 2.8). CONCLUSION: Our findings demonstrate that a history of preexisting psychiatric disease, as self-reported by patients with a suspected concussion treated in the ED, is independently associated with significantly higher scores on the SCAT3 SE. This suggests that a history of psychiatric illness may need to be accounted for when the SCAT3 SE is used in the ED for the assessment of concussion.

Fair Play: Application of Normalized Scoring to Emergency Department Throughput Quality Measures in a National Registry.

STUDY OBJECTIVE: The measurement of emergency department (ED) throughput as a patient-centered quality measure is ubiquitous; however, marked heterogeneity exists between EDs, complicating comparisons for payment purposes. We evaluate 4 scoring methodologies for accommodating differences in ED visit volume and heterogeneity among ED groups that staff multiple EDs to improve the validity and "fairness" of ED throughput quality measurement in a national registry, with the goal of developing a volume-adjusted throughput measure that balances variation at the ED group level. METHODS: We conducted an ED group-level analysis using the 2017 American College of Emergency Physicians Clinical Emergency Data Registry data set, which included 548 ED groups inclusive of 889 unique EDs. We calculated ED throughput performance scores for each ED group by using 4 scoring approaches: plurality, simple average, weighted average, and a weighted standardized score. For comparison, ED groups (ie, taxpayer identification numbers) were grouped into 3 types: taxpayer identification numbers with only 1 ED; those with multiple EDs, but no ED with greater than 60,000 visits; and those with multiple EDs and at least 1 ED with greater than 60,000 visits. RESULTS: We found marked differences in the classification of ED throughput performance between scoring approaches. The weighted standardized score (z score) approach resulted in the least skewed and most uniform distribution across the majority of ED types, with a kurtosis of 12.91 for taxpayer identification numbers composed of 1 ED, 2.58 for those with multiple EDs without any supercenter, and 3.56 for those with multiple EDs with at least 1 supercenter, all lower than comparable scoring methods. The plurality and simple average scoring approaches appeared to disproportionally penalize ED groups that staff a single ED or multiple large-volume EDs. CONCLUSION: Application of a weighted standardized (z score) approach to ED throughput measurement resulted in a more balanced variation between different ED group types and reduced distortions in the length-of-stay measurement among ED groups staffing high-volume EDs. This approach may be a more accurate and acceptable method of profiling ED group throughput pay-for-performance programs.

Development of a qualified clinical data registry for emergency medicine.

The passage of the Medicare Access and CHIP Reauthorization Act (MACRA) in 2015 marked a fundamental transition in physician payment by the Centers for Medicare and Medicaid Services (CMS) from traditional fee-for service to value-based models. MACRA led to the creation of the CMS Quality Payment Program (QPP), which bases the value of physician care in large part on physician quality reporting. The QPP enabled a shift away from legacy CMS-stewarded quality measures that had limited applicability to individual specialties toward specialty-specific quality measures developed and stewarded by physician specialty societies using Qualified Clinical Data Registries (QCDRs). This article describes the development of the first nationally available emergency medicine QCDR as a means for emergency physicians to participate in the QPP, measure, and benchmark emergency physician quality.

Trends in Costs of Care for Medicare Beneficiaries Treated in the Emergency Department From 2011 to 2016.

Importance: There is little evidence regarding how total costs of care associated with an emergency department (ED) visit have changed, despite increasing policy focus on the value of acute care. Objective: To examine trends in total standardized 30-day costs of care associated with an ED visit. Design, Setting, and Participants: This cross-sectional study of 14 113 088 ED visits at 4730 EDs from 2011 to 2016 included a 20% national sample of traditional Medicare beneficiaries aged 65 years and older. Data analysis was conducted from August 2018 to April 2020. Exposures: Time (year) as a continuous variable. Main Outcomes and Measures: Trends in disposition from the ED and 30-day total standardized costs for all ED visits as well as the following spending components: index visit cost, physician costs, subsequent ED visit costs, subsequent inpatient costs, subsequent observation costs, non-ED outpatient care, postacute care, and aggregated total spending after the index ED visit. Results: The analytic sample consisted of 14 113 088 ED visits at 4730 EDs. The mean (SD) beneficiary age was 78.6 (8.6) years, 8 573 652 visits (60.7%) were among women, and 11 908 691 visits (84.7%) were among white patients. The proportion of patients discharged from the ED rose from 1 233 701 of 2 309 563 visits (53.4%) in 2011 to 1 279 701 of 2 268 363 visits (56.4%) in 2016. Total adjusted 30-day standardized costs of care declined from a mean (SE) of $8851 ($35.3) in 2011 to a mean (SE) of $8143 ($35.4) in 2016 (-$126/y; 95% CI, -$130 to -$121; P < .001) for all ED visits. This decrease was primarily associated with a decline in total spending on the index ED visit (-$48/y; 95% CI, -$50 to -$47; P < .001) as well as lower spending on postacute care (-$42/y; 95% CI, -$44 to -$41; P < .001) and subsequent inpatient care (-$34/y; 95% CI, -$36 to -$32; P < .001). There was an increase in spending after the index visit on downstream observation care ($3.6/y; 95% CI, $3.5 to $3.7; P < .001), outpatient ED care ($4.6/y; 95% CI, $4.4 to $4.8; P < .001), and other outpatient care ($15/y; 95% CI, $12 to $18; P < .001). Conclusions and Relevance: In this study, total 30-day standardized costs of ED care for Medicare beneficiaries decreased in recent years. It may be that more intensive ED spending up front is associated with reductions in total costs of an acute episode.

How normative multiculturalism relates to immigrant well-being.

OBJECTIVES: In this study we examine the relationship between contextual factors, that is, perceived multicultural norms, and immigrant well-being. Specifically, we test a model whereby each of the three dimensions of normative multiculturalism, perceived Multicultural Ideology, Multicultural Policies and Practices, and Multicultural Contact, positively predicts immigrant well-being both directly and indirectly via belongingness. METHOD: Korean immigrants in New Zealand (N = 306, 56% female) participated in the research. Their average age was 31.17 (SD = 10.46), and the average length of residence was 10.04 years (SD = 7.21). Participants completed a survey that included the Normative Multiculturalism Scale along with measures of belonging and well-being (flourishing, life satisfaction, and positive affect). RESULTS: Structural equation modeling showed that perceived normative Multicultural Policies and Practices exerted a direct positive effect on well-being and an indirect positive effect via belongingness; Multicultural Ideology exerted only an indirect effect; and Multicultural Contact did not significantly relate to belongingness or subjective well-being. IMPLICATIONS: The results are discussed in terms of everyday experiences of intercultural encounters, social norms and the contextual influences of diversity climates, as well as the importance of distinguishing the defining features of multiculturalism in diversity science research. We also propose that multicultural norm setting and norms marketing may lead to positive social and psychological outcomes for immigrants. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Trends in Mortality for Medicare Beneficiaries Treated in the Emergency Department From 2009 to 2016.

Importance: Emergency department (ED) visits are common and increasing. Whether outcomes associated with care in the ED are improving over time is largely unknown to date. Objective: To examine trends in 30-day mortality rates associated with ED care among Medicare beneficiaries aged 65 years or older. Design, Setting, and Participants: This cross-sectional study used a random 5% sample in 2009 and 2010 and a 20% sample from 2011 to 2016, for a total of 15 416 385 ED visits from 2009 to 2016 among Medicare beneficiaries aged 65 years or older. Exposures: Time (year) as a continuous variable. Main Outcomes and Measures: The primary outcome was 30-day mortality, overall and stratified by illness severity and hospital characteristics. Secondary outcomes included mortality rates on the day of the ED visit (day 0) as well as at 7 and 14 days. Changes in disposition from the ED (admission, observation, transfer, died in the ED, and discharged) over time were also examined. Results: The sample included 15 416 385 ED visits (60.8% women and 39.2% men; mean [SD] age, 78.6 [8.5] years) at 4828 acute care hospitals. The percentage of patients discharged from the ED increased from 53.6% in 2009 to 56.7% in 2016. Unadjusted 30-day mortality declined from 5.1% in 2009 to 4.6% in 2016 (-0.068% per year; 95% CI, -0.074% to -0.063% per year; P < .001). After adjusting for hospital random effects, patient demographics, and chronic conditions, the adjusted 30-day mortality trend was -0.198% per year (95% CI, -0.204% to -0.193% per year; P < .001). The magnitude of this trend was greatest for patients with a high severity of illness (-0.662%; 95% CI, -0.681% to -0.644%; P < .001), followed by those with a medium severity of illness (-0.103% per year; 95% CI, -0.108% to -0.097% per year; P < .001) and those with a low severity of illness (-0.009% per year; 95% CI, -0.006% to -0.011% per year; P < .001). Declines in mortality were seen in each category of ED disposition, including visits resulting in admission (-0.356% per year; 95% CI, -0.368% to -0.343% per year; P < .001) as well as those resulting in discharge (-0.059% per year; 95% CI, -0.064% to -0.055% per year; P < .001). The decline was greater for major teaching hospitals (compared with nonteaching hospitals), nonprofit hospitals (compared with for-profit hospitals), and urban hospitals (compared with rural hospitals). Conclusions and Relevance: Among Medicare beneficiaries receiving ED care in the United States, mortality within 30 days of an ED visit appears to have declined in recent years, particularly for patients with the highest severity of illness, even as fewer patients are being admitted from an ED visit. This study's findings suggest that further study is needed to understand the reasons for this decline and why certain types of hospitals are seeing greater improvements in outcomes.

Mechanisms underlying the J-curve for diastolic blood pressure: Subclinical myocardial injury and immune activation.

BACKGROUND: Low diastolic blood pressure (DBP) is associated with increased risk of cardiovascular events. In patients with coronary artery disease (CAD), limitations in coronary blood flow and immune activity are implicated mechanisms, but evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, inflammation, immune activation and incident events in patients with CAD. METHODS: We studied 2448 adults (mean age 65 ±â€¯12 years, 68% male, median follow-up 4.5 years) with CAD. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial injury (high sensitivity cardiac troponin-I [hs-cTnI]) and immune activity/inflammation (soluble urokinase plasminogen activator receptor [suPAR]) were dichotomized at their median values. DBP 70-79 mm Hg was used as the referent group, and individuals were followed prospectively for adverse outcomes. RESULTS: After adjusting for demographic and clinical covariates, individuals with DBP < 60 mm Hg had increased odds of elevated levels of hs-cTnI (OR = 1.68; 95% CI = 1.07, 2.65) and suPAR (OR = 1.71; 95% CI = 1.10, 2.65) compared to the referent group. Additionally, DBP < 60 mm Hg was associated with increased adjusted risk of cardiovascular death or MI (HR = 2.04; 95% CI = 1.32, 3.16) and all-cause mortality (HR = 2.41; 95% CI = 1.69, 3.45). CONCLUSION: In patients with CAD, DBP < 60 mm Hg is associated with subclinical myocardial injury, immune/inflammatory dysregulation and incident events. Aggressive BP control may be harmful in these patients, and further investigation is warranted to determine appropriate BP targets in patients with CAD.

Comparison of the Association Between High-Sensitivity Troponin I and Adverse Cardiovascular Outcomes in Patients With Versus Without Chronic Kidney Disease.

It is unknown whether the association of high-sensitivity troponin I (hs-TnI) with adverse cardiovascular outcomes varies by the presence of chronic kidney disease (CKD). We examined the association of hs-TnI with adverse cardiovascular outcomes in those with and without CKD in 4,107 (mean age, 64 years; 63% men; 20% black) patients from the Emory Cardiovascular Biobank who underwent coronary angiography. CKD (n = 1,073) was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 or urine albumin/creatinine ratio >30 mg/g at baseline. Cox regression was used to compute hazard ratios (HR) for the association between hs-TnI levels (per doubling of hs-TnI: log2[hs-TnI] + 1) and death, cardiovascular death, and major adverse cardiac events (MACE), separately. Hs-TnI was a stronger predictor of death (CKD: HR 1.23, 95% confidence interval [CI] 1.15 to 1.31; no CKD: HR 1.11, 95% CI 1.05 to 1.17, p-interaction = 0.023), cardiovascular death (CKD: HR 1.24, 95% CI 1.14 to 1.34; no CKD: HR 1.15, 95% CI 1.07 to 1.22, p-interaction = 0.12), and MACE (CKD: HR 1.18, 95% CI 1.11 to 1.25; no CKD: HR 1.11, 95% CI 1.06 to 1.16, p-interaction = 0.095) in CKD compared with non-CKD. The association between hs-TnI and death in patients with CKD was stronger for patients without obstructive coronary artery disease (no obstructive coronary artery disease: HR 1.60, 95% CI 1.27 to 2.01; obstructive coronary artery disease: HR 1.19, 95% CI 1.11 to 1.27, p-interaction = 0.041). In conclusion, hs-TnI is a stronger predictor of adverse cardiovascular events in patients who have CKD than those without, even in the absence of obstructive coronary artery disease. Hs-TnI may identify CKD patients who are high risk for adverse cardiovascular outcomes in whom aggressive risk factor modification strategies are warranted.

High-Sensitivity Troponin I Levels and Coronary Artery Disease Severity, Progression, and Long-Term Outcomes.

BACKGROUND: The associations between high-sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. METHODS AND RESULTS: In 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all-cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1-vessel CAD, 20% had 2-vessel CAD, and 26% had 3-vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18-0.44; P<0.001) and with CAD progression (log 2 ß=0.36; 95% confidence interval, 0.14-0.58; P=0.001). hsTnI level was also a significant predictor of incident death, cardiovascular death, myocardial infarction, revascularization, and cardiac hospitalizations, independent of the aforementioned covariates and CAD severity. CONCLUSIONS: Higher hsTnI levels are associated with the underlying burden of coronary atherosclerosis, more rapid progression of CAD, and higher risk of all-cause mortality and incident cardiovascular events. Whether more aggressive treatment aimed at reducing hsTnI levels can modulate disease progression requires further investigation.

Emergency Department Involvement in Accountable Care Organizations in Massachusetts: A Survey Study.

STUDY OBJECTIVE: We assess Massachusetts emergency department (ED) involvement and internal ED constructs within accountable care organization contracts. METHODS: An online survey was distributed to 70 Massachusetts ED directors. Questions attempted to assess involvement of EDs in accountable care organizations and the structures in place in EDs-from departmental resources to physician incentives-to help achieve accountable care organization goals of decreasing spending and improving quality. RESULTS: Of responding ED directors, 79% reported alignment between the ED and an accountable care organization. Almost all ED groups (88%) reported bearing no financial risk as a result of the accountable care organization contracts in which their organizations participated. Major obstacles to meeting accountable care organization objectives included care coordination challenges (62%) and lack of familiarity with accountable care organization goals (58%). The most common cost-reduction strategies included ED case management (85%) and information technology (61%). Limitations of this study include that information was self-reported by ED directors, a focus limited to Massachusetts, and a survey response rate of 47%. CONCLUSION: The ED directors perceived that the majority of physicians were not familiar with accountable care organization goals, many challenges remain in coordinating care for patients in the ED, and most EDs have no financial incentives tied to accountable care organizations. EDs in Massachusetts have begun to implement strategies aimed at reducing admissions, utilization, and overall cost, but these strategies are not widespread apart from case management, even in a state with heavy accountable care organization penetration. Our results suggest that Massachusetts EDs still lack clear directives and direct involvement in meeting accountable care organization goals.

An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes).

BACKGROUND: In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. METHODS AND RESULTS: Two thousand thirty-two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C-reactive protein >3 mg/L, heat shock protein-70 >0.313 ng/mL, and fibrin-degradation products >1 µg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of all-cause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; P<0.0001). All individual biomarkers decreased by 1 year, with ≈80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1-year BRS of 2 to 3 had a 4-year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P<0.0001). CONCLUSIONS: Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.

Mesenchymal Stem Cell Therapy for the Treatment of Heart Failure Caused by Ischemic or Non-ischemic Cardiomyopathy: Immunosuppression and Its Implications.

HF patients with signs and symptoms of worsening heart failure (HF), despite optimal medical therapy, have a poor prognosis. The pathways contributing to HF are multiple, probably accounting, in part, for current treatment approaches not being more effective. Stem cells, particularly mesenchymal stem cells (MSCs), have a broad range of activities, making them particularly interesting candidates for a new HF therapeutic. This review presents an overview of the studies examining the efficacy of stem cell studies administered to HF patients, focusing mainly on MSCs. It examines the issues surrounding autologous vs. allogenic stem cells, the results of different routes of administration, and implications deriving from the belief that for stem cells to be effective, they must engraft in the myocardium and exert local effects. Since intravenous administration of stem cells leads to sparse cardiac engraftment, stem cell delivery strategies have uniformly involved catheter-based delivery systems. This becomes problematic in a disease that will almost certainly require delivery of the therapeutic throughout the course of the disease. Importantly, it appears that a critical contributing cause of the progressive cardiac dysfunction experienced by HF patients is the existence of a persistent inflammatory response. Since MSCs exert potent anti-inflammatory effects through paracrine mechanisms, it is possible that intravenous delivery of MSCs may be therapeutically effective. If this concept is valid, it could lead to a transformational change in stem cell delivery strategies.

Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death.

BACKGROUND: Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification. METHODS AND RESULTS: C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden's index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43-2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points. CONCLUSIONS: SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.

Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy.

RATIONALE: Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. OBJECTIVE: To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. METHODS AND RESULTS: Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O2, were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×106) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×106 MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were randomized to tail-vein injection of 2×106 MSCs, with injection repeated at week 3 (n=16) versus PBS control (n=16). MSCs significantly increased LV ejection fraction and decreased LV end-systolic volume. CONCLUSIONS: Intravenously administered MSCs for acute myocardial infarction attenuate the progressive deterioration in LV function and adverse remodeling in mice with large infarcts, and in ischemic cardiomyopathy, they improve LV function, effects apparently modulated in part by systemic anti-inflammatory activities.