Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction and Autoimmune markers (JAG-A): Clinical Associations and Response to Intravenous Immunoglobulin Therapy.

INTRODUCTION: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD). METHODS: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder (AIDX) with at least one positive seromarker of autoimmunity or at least two positive seromarkers by themselves. Three cohorts were studied: (a) Retrospective (n = 300); (b) Prospective validation cohort (n =133); and (c) Treatment cohort (n=40), administered open-label intravenous immunoglobulin (IVIG). RESULTS: AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had AIDX. Significantly more patients with AIM had elevations of C-reactive protein (31% versus 15%, p<0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% versus 29%; p<.001), small fiber neuropathy (20% versus 9%; p=.002).8) and HLADQ8 positivity (24% versus 13%, p=.01). JH/HSD patients were more likely to have AIM (43% versus 15%, p=.001) along with more severe autonomic and gastrointestinal symptom scores. IVIG treatment was associated with robust improvement in pain, gastrointestinal and autonomic symptoms but adverse events were experienced by 62% patients. CONCLUSIONS: Autoimmune markers and autonomic dysfunction are common in patients with unexplained gastrointestinal symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials.gov, NCT04859829.

Prognostic Value of Combined CT Angiography and Myocardial Perfusion Imaging versus Invasive Coronary Angiography and Nuclear Stress Perfusion Imaging in the Prediction of Major Adverse Cardiovascular Events: The CORE320 Multicenter Study.

Purpose To compare the prognostic importance (time to major adverse cardiovascular event [MACE]) of combined computed tomography (CT) angiography and CT myocardial stress perfusion imaging with that of combined invasive coronary angiography (ICA) and stress single photon emission CT myocardial perfusion imaging. Materials and Methods This study was approved by all institutional review boards, and written informed consent was obtained. Between November 2009 and July 2011, 381 participants clinically referred for ICA and aged 45-85 years were enrolled in the Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-Detector Row Computed Tomography (CORE320) prospective multicenter diagnostic study. All images were analyzed in blinded independent core laboratories, and a panel of physicians adjudicated all adverse events. MACE was defined as revascularization (>30 days after index ICA), myocardial infarction, or cardiac death; hospitalization for chest pain or congestive heart failure; or arrhythmia. Late MACE was defined similarly, except for patients who underwent revascularization within the first 182 days after ICA, who were excluded. Comparisons of 2-year survival (time to MACE) used standard Kaplan-Meier curves and restricted mean survival times bootstrapped with 2000 replicates. Results An MACE (49 revascularizations, five myocardial infarctions, one cardiac death, nine hospitalizations for chest pain or congestive heart failure, and one arrhythmia) occurred in 51 of 379 patients (13.5%). The 2-year MACE-free rates for combined CT angiography and CT perfusion findings were 94% negative for coronary artery disease (CAD) versus 82% positive for CAD and were similar to combined ICA and single photon emission CT findings (93% negative for CAD vs 77% positive for CAD, P < .001 for both). Event-free rates for CT angiography and CT perfusion versus ICA and single photon emission CT for either positive or negative results were not significantly different for MACE or late MACE (P > .05 for all). The area under the receiver operating characteristic curve (AUC) for combined CT angiography and CT perfusion (AUC = 68; 95% confidence interval [CI]: 62, 75) was similar (P = .36) to that for combined ICA and single photon emission CT (AUC = 71; 95% CI: 65, 79) in the identification of MACE at 2-year follow-up. Conclusion Combined CT angiography and CT perfusion enables similar prediction of 2-year MACE, late MACE, and event-free survival similar to that enabled by ICA and single photon emission CT. © RSNA, 2017 Online supplemental material is available for this article.

Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

RATIONALE: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. OBJECTIVE: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. METHODS AND RESULTS: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; P<0.01) and noninjected segments (-25.1 ± 7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9 ± 3.3-26.3 ± 3.5%; P=0.003) but not in noninjected scar segments (21.3 ± 2.6-23.5 ± 3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1 ± 1.2-19.9 ± 2.7%; n=18; P=0.003), versus <20% (31.7 ± 3.4-35.5 ± 3.3%; n=12; P=0.33, between-group comparison P<0.0001). CONCLUSIONS: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Comprehensive assessment of radiation dose estimates for the CORE320 study.

OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study ( ClinicalTrials.gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA-perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA-perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion.

Myeloid NCOA4 sequesters KEAP1 to reduce ferroptosis for protection against salmonellosis in mice.

Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.

Vitamin D deficiency is associated with silent coronary artery disease in cardiovascularly asymptomatic African Americans with HIV infection.

BACKGROUND: Growing evidence suggests that vitamin D deficiency Is associated with clinical coronary artery disease (CAD). The relationship between vitamin D deficiency and subclinical CAD in HIV-infected individuals is not well-characterized. METHODS: Computed tomographic (CT) coronary angiography was performed using contrast-enhanced 64-slice multidetector CT imaging, and vitamin D levels and the presence of traditional and novel risk factor for CAD were obtained in 674 HIV-infected African American (AA) participants aged 25-54 years in Baltimore, MD, without symptoms/clinical evidence of CAD. RESULTS: The prevalence of vitamin D deficiency (25-hydroxy vitamin D <10 ng/mL) was 20.0% (95% confidence interval [CI], 16.9-23.1). Significant (≥50%) coronary stenosis was present in 64 (9.5%) of 674 participants. Multiple logistic regression analysis revealed that male gender (adjusted odds ratio [OR], 2.19; 95% CI, 1.17-4.10), diastolic BP ≥85 mmHg (adjusted OR: 1.94, 95% CI: 1.02 -3.68), low-density lipoprotein cholesterol ≥100 mg/dL (adjusted OR, 1.95; 95% CI, 1.13-3.36), cocaine use for ≥15 years (adjusted OR, 1.77; 95% CI, 1.01-3.10), use of antiretroviral therapies for ≥6 months (adjusted OR, 2.26; 95% CI, 1.17-4.36), year of enrollment after 2005 (adjusted ORs for 2006-2007, 2008-2009, and 2010 were 0.32 [95% CI, 0.13-0.76], 0.26 [95% CI, 0.12-0.56], and 0.32 (95% CI, 0.15-0.65], respectively), and vitamin D deficiency (adjusted OR, 2.28; 95% CI, 1.23-4.21) were independently associated with significant coronary stenosis. CONCLUSIONS: Both vitamin D deficiency and silent CAD are prevalent in HIV-infected AAs. In addition to management of traditional CAD risk factors and substance abuse, vitamin D deficiency should be evaluated in HIV-infected AAs. These data support the conduct of a prospective trial of vitamin D in this high-risk patient population.

Comparison of allogeneic vs autologous bone marrow­derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

CONTEXT: Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. OBJECTIVE: To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN, SETTING, AND PATIENTS: A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION: Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES: Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. RESULTS: Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. CONCLUSIONS: In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01087996.

End-stage renal disease predicts complications in pacemaker and ICD implants.

INTRODUCTION: Patients with chronic kidney disease (CKD) have increased morbidity following invasive procedures. We hypothesized that patients with CKD have higher complication rates following device implantation than patients with normal renal function. METHODS: We reviewed the medical records of patients undergoing ICD or pacemaker implantation from August 2004 to August 2007. The estimated glomerular filtration rate (GFR) was calculated using the Cockroft-Gault equation. Those with GFR ≥ 90 cc/min served as controls. The remainder was grouped according to American Kidney Foundation stages of CKD. Bleeding complications were defined as need for pocket exploration or blood transfusion; cardiac tamponade; or hematoma requiring pressure dressing, change in medications or prolonged hospitalization. Infection was defined as infection of the pocket or lead system, or development of bacteremia/sepsis within 60 days. RESULTS: There were 82 bleeding complications (5.7%) and 7 infections (0.5%) temporally related to device implantation in 1,440 patients. End-stage renal disease (ESRD), defined as GFR < 15 mL/min or need for dialysis, was identified in 32 patients. Infection rates were significantly higher in patients with ESRD versus controls (12.5% vs 0.2%; P < 0.0001). A significant increase in bleeding complications was observed in ESRD versus controls (21.9% vs 3.2%, respectively; P<0.0001). Bleeding complications were considerably greater than controls in moderate (GFR 30-59 mL/min) and severe (GFR 15-29 mL/min) CKD (7.4% and 9.8% vs 3.2%, respectively; P < 0.005). CONCLUSION: ESRD markedly increases bleeding and device-related infections. The risk of both complications parallels the severity of CKD. Further research is needed to reduce adverse outcomes in this high-risk population.

High mid-term mortality following successful lead extraction for infection.

BACKGROUND: Transvenous lead extraction patients tend to have multiple medical problems complicated by prolonged infections that may result in high-mortality rates following a successful procedure. METHODS: All adult patients referred for lead extraction for infection over a 4-year period were included in this study. Mortality following the procedure was assessed using hospital records and the Social Security Death Index. RESULTS: Indications for extraction were systemic infection (n = 34) and isolated pocket infection (n = 33). Of the 67 patients, 47 (70%) were still alive at follow-up (6-55 months). No patient died during or within 24 hours of the procedure, and two were sent to emergent surgery and did well. However, five died during prolonged hospitalizations, and two were discharged to hospice care and died shortly thereafter. The remaining 13 deaths occurred after discharge from the hospital at a mean interval of 15 months (range, 24 days to 35 months) following the procedure. Notably, six of seven patients who died in the hospital, and nine of 13 who died after discharge, had bacteremia as their indication for extraction, for an overall mortality risk of 44% in patients with systemic infection. CONCLUSIONS: True risk assessment for lead extraction patients is underestimated and may be related to the focus on the procedural risks, while the underlying illness and physiologic state may account for the excess mortality following a successful extraction. In most cases, the infected hardware contributed to the length and severity of the illness, and thus earlier consideration for extraction may be warranted.

Acute Kidney Injury After Repeated Exposure to Contrast Material for Coronary Angiography.

OBJECTIVE: To assess the incidence of contrast-associated acute kidney injury (CAAKI) after repeated exposure to contrast material for computed tomography (CT) and conventional coronary angiography within short intervals. METHODS: We studied 651 patients enrolled in the CorE-64 (November 5, 2005-January 30, 2007) and CORE320 (October 21, 2009-August 17, 2011) multicenter studies. Participants with suspected obstructive coronary heart disease were referred for diagnostic cardiac catheterization and underwent coronary CT angiography for research before invasive angiography. Nonionic, low-osmolality iodinated contrast material was used for all imaging. RESULTS: The median age of the patients was 62 years, and 190 (29%) were women. Major risk factors for acute kidney injury were present in 277 of 651 (43%) patients. The median interval between CT imaging and invasive angiography was 3.1 days (interquartile range, 0.9-8.0 days). The median volume of contrast material was 100 mL for each test. In 16 (2.5%) of 651 patients, CAAKI developed. Of these cases, 1 occurred after the CT scan, whereas 6 were documented after invasive angiography (compared with post-CT creatinine concentration assessment). In 9 patients, CAAKI was found in comparing creatinine concentration after completion of both tests with baseline values (but not compared with post-CT imaging). CONCLUSION: Acute kidney injury after repeated exposure to iodinated contrast media within a few days is uncommon even in a population of patients with highly prevalent risk factors. Withholding of clinically indicated contrast-enhanced imaging may therefore not be justified in this setting.

Prognostic value of noninvasive combined anatomic/functional assessment by cardiac CT in patients with suspected coronary artery disease - Comparison with invasive coronary angiography and nuclear myocardial perfusion imaging for the five-year-follow up of the CORE320 multicenter study.

BACKGROUND: Few data exist on long-term outcome in patients undergoing combined coronary CT angiography (CTA) and myocardial CT perfusion imaging (CTP) as well as invasive coronary angiography (ICA) and single photon emission tomography (SPECT). METHODS: At 16 centers, 381 patients were followed for major adverse cardiac events (MACE) for the CORE320 study. All patients underwent coronary CTA, CTP, and SPECT before ICA within 60 days. Prognostic performance according binary results (normal/abnormal) was assessed by 5-year major cardiovascular events (MACE) free survival and area under the receiver-operating-characteristic curve (AUC). RESULTS: Follow up beyond 2-years was available in 323 patients. MACE-free survival rate was greater among patients with normal combined CTA-CTP findings compared to ICA-SPECT: 85 vs. 80% (95% confidence interval [CI] for difference 0.1, 11.3) though event-free survival time was similar (4.54 vs. 4.37 years, 95% CI for difference: -0.03, 0.36). Abnormal results by combined CTA-CTP was associated with 3.83 years event-free survival vs. 3.66 years after abnormal combined ICA-SPECT (95% CI for difference: -0.05, 0.39). Predicting MACE by AUC also was similar: 65 vs. 65 (difference 0.1; 95% CI -4.6, 4.9). When MACE was restricted to cardiovascular death, myocardial infarction, or stroke, AUC for CTA-CTP was 71 vs. 60 by ICA-SPECT (difference 11.2; 95% CI -1.0, 19.7). CONCLUSIONS: Combined CTA-CTP evaluation yields at least equal 5-year prognostic information as combined ICA-SPECT assessment in patients presenting with suspected coronary artery disease. Noninvasive cardiac CT assessment may eliminate the need for diagnostic cardiac catheterization in many patients. CLINICAL TRIAL REGISTRATION: NCT00934037.

Assessment of in-stent restenosis using 64-MDCT: analysis of the CORE-64 Multicenter International Trial.

OBJECTIVE: Evaluations of stents by MDCT from studies performed at single centers have yielded variable results with a high proportion of unassessable stents. The purpose of this study was to evaluate the accuracy of 64-MDCT angiography (MDCTA) in identifying in-stent restenosis in a multicenter trial. MATERIALS AND METHODS: The Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography Using 64 Detectors (CORE-64) Multicenter Trial and Registry evaluated the accuracy of 64-MDCTA in assessing 405 patients referred for coronary angiography. A total of 75 stents in 52 patients were assessed: 48 of 75 stents (64%) in 36 of 52 patients (69%) could be evaluated. The prevalence of in-stent restenosis by quantitative coronary angiography (QCA) in this subgroup was 23% (17/75). Eighty percent of the stents were or=50% stenosis by QCA was 0.25 (p=0.073). Quantitative assessment failed to improve the accuracy of MDCT over qualitative assessment. CONCLUSION: The results of our study showed that 64-MDCT has poor ability to detect in-stent restenosis in small-diameter stents. Evaluability and negative predictive value were better in large-diameter stents. Thus, 64-MDCT may be appropriate for stent assessment in only selected patients.

A survey of the practice of lead extraction in the United States.

BACKGROUND: Endovascular lead extraction is an important component of the management of patients with chronically implanted arrhythmia control devices. Although it is associated with the potential for significant morbidity and mortality, there is little information about its scope and practice. METHODS: We surveyed 1,000 physician members of the Heart Rhythm Society via e-mail solicitation. RESULTS: Of the 252 respondents (25%), 221 (88%) reported either performing extractions themselves (63%), or having privileges at a hospital where extractions are performed (25%). Electrophysiologists perform extractions at most sites (83%) but cardiac surgeons perform endovascular lead extraction at a significant minority of sites (20%). Most respondents report low annual volumes of extractions at their site: 15% reported <10 procedures/year, 42% 10-25 procedures/year, 23% 26-50 procedure/year, and only 19% reported >50 procedures/year. Thirty-six percent of respondents reported that extractions were done in the operating room (OR) with surgeon present or immediately available, 39% in the electrophysiology (EP) lab with surgeon and OR identified and available, and 25% in EP lab without a surgeon or OR identified. The overall risks of lead extraction were felt to be 1-5% of major complication and 0.5-1% of mortality, roughly in line with published data. CONCLUSIONS: While there is agreement as to the risk of major complication and death from lead extraction, the degree of surgical availability varies considerably. The new guidelines document recommends the ability to promptly initiate an emergent surgical procedure, and this should be an important goal for all extractionists.

Comparative effectiveness of coronary artery stenosis and atherosclerotic plaque burden assessment for predicting 30-day revascularization and 2-year major adverse cardiac events.

PURPOSE: To provide comparative prognostic information of coronary atherosclerotic plaque volume and stenosis assessment in patients with suspected coronary artery disease (CAD). METHODS: We followed 372 patients with suspected or known CAD enrolled in the CORE320 study for 2 years after baseline 320-detector row cardiac CT scanning and invasive quantitative coronary angiography (QCA). CT images were analyzed for coronary calcium scanning (CACS), semi-automatically derived total percent atheroma volume (PAV), segment stenosis score (SSS), in addition to traditional stenosis assessment (≥ 50%) by CT and QCA for (1) 30-day revascularization and (2) major adverse cardiac events (MACE). Area under the receiver operating characteristic curve (AUC) was used to compare accuracy of risk prediction. RESULTS: Sixty percent of patients had obstructive CAD by QCA with 23% undergoing 30-day revascularization and 9% experiencing MACE at 2 years. Most late events (20/32) were revascularization procedures. Prediction of 30-day revascularization was modest (AUC range 0.67-0.78) but improved after excluding patients with known CAD (AUC range 0.73-0.86, p < 0.05 for all). Similarly, prediction of MACE improved after excluding patients with known CAD (AUC range 0.58-0.73 vs. 0.63-0.77). CT metrics of atherosclerosis burden performed overall similarly but stenosis assessment was superior for predicting 30-day revascularization. CONCLUSIONS: Angiographic and coronary atherosclerotic plaque metrics perform only modestly well for predicting 30-day revascularization and 2-year MACE in high risk patients but improve after excluding patients with known CAD. Atherosclerotic plaque metrics did not yield incremental value over stenosis assessment for predicting events that predominantly consisted of revascularization procedures. CLINICAL TRIAL REGISTRATION: NCT00934037.

Contemporary Discrepancies of Stenosis Assessment by Computed Tomography and Invasive Coronary Angiography.

Background Ongoing advancements of coronary computed tomographic angiography (CTA) continue to challenge the role of invasive coronary angiography (ICA) as the gold standard for the evaluation of coronary artery disease (CAD). We sought to investigate the diagnostic accuracy of 320-slice CTA for detecting obstructive CAD in reference to ICA and nuclear myocardial perfusion imaging using single-photon emission computed tomography. Methods For the CORE320 study (Coronary Artery Evaluation Using 320-Row Multidetector Computed Tomography Angiography and Myocardial Perfusion), 381 patients at 16 centers underwent CTA, nuclear myocardial perfusion imaging by single-photon emission computed tomography, and ICA for the evaluation of CAD. Imaging studies were analyzed in blinded core laboratories, and a stenosis of ≥50% by quantitative coronary angiography was considered obstructive, whereas a stress difference score of ≥1 indicated inducible myocardial ischemia. The area under the receiver operating characteristic curve was used to evaluate diagnostic accuracy. Results Of 381 patients, 229 (60%) had obstructive CAD by quantitative coronary angiography. Diagnostic accuracy of CTA on a per-patient analysis revealed an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.87-0.93). Per-vessel and per-segment analysis revealed lower area under the receiver operating characteristic curve of 0.87 (0.84-0.90) and 0.81 (0.78-0.83), respectively. Median radiation dose was lower for CTA versus ICA: 3.16 (interquartile range, 2.82-3.59) versus 11.97 (interquartile range, 7.60-17.8) mSv ( P<0.001). Accuracy for identifying patients with inducible myocardial ischemia by SPECT-MPI was similar for CTA and ICA (area under the receiver operating characteristic curve, 0.68 versus 0.71 by quantitative coronary angiography and 0.68 by visual angiographic assessment; P>0.05). Furthermore, accuracy for identifying patients who subsequently underwent clinically driven coronary revascularization also was similar for CTA (0.76 [0.71-0.81]) and ICA (0.78 [0.74-0.83]; P=0.20). Conclusions Contemporary CTA accurately identifies patients with obstructive CAD by ICA at lower radiation exposure; however, agreement is lower in vessel- and segment-level analyses. Both CTA and ICA perform similarly for predicting clinically driven revascularization and for detecting myocardial ischemia by myocardial perfusion imaging using single-photon emission computed tomography, suggesting that limitations by both CTA and ICA contribute to variability of stenosis quantification. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00934037.

Intravascular Stem Cell Bioreactor for Prevention of Adverse Remodeling After Myocardial Infarction.

Background Prevention of adverse remodeling after myocardial infarction (MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor (IBR) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBRs were constructed using semipermeable membrane adhered to a clinical-grade catheter shaft. Mesenchymal stem cell (MSC) viability in and paracrine factor release from IBRs were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBRs containing 25 million allogeneic MSCs (IBR-MSCs) were compared with IBRs containing media alone (IBR-Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI, IBR-MSCs had no significant change in end-diastolic volume (+0.33±4.32 mL; P=0.89), end-systolic volume (+2.14±4.13 mL; P=0.21), and left ventricular ejection fraction (-2.27±2.94; P=0.33) while IBR-Placebo had significant increases in end-diastolic volume (+10.37±3.84 mL; P=0.01) and ESV (+11.35±2.88 mL; P=0.01), and a significant decrease in left ventricular ejection fraction (-5.78±1.70; P=0.025). Eight weeks after MI, adherent pericarditis was present in 0 of 8 IBR-MSCs versus 4 of 8 IBR-Placebo (P=0.02), suggesting an anti-inflammatory effect. In a separate study, 25 million allogeneic pig MSCs directly injected in the peri-infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR-MSCs. Conclusions MSCs deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI.