Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Circulation research [journal]
- Release Kinetics of Inflammatory Biomarkers in a Clinical Model of Acute Myocardial Infarction. [JOURNAL ARTICLE]
- Circ Res 2014 Dec 16.
Rationale: Inflammation in the setting of acute myocardial infarction (AMI) has been linked to risk stratification; however, the release kinetics of inflammatory biomarkers in patients with AMI has been difficult to establish. Objective: The aim of this study was to determine the kinetics of changes in the levels of a number of biomarkers specifically linked to inflammation following transcoronary ablation of septal hypertrophy (TASH), a procedure that mimics AMI. Methods and Results: We analyzed release kinetics of C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), interleukin 6 (IL-6), soluble CD40 ligand (sCD40L) and peripheral blood leukocyte subsets in patients (n=21) undergoing TASH. Blood samples were collected prior to TASH and at various times after TASH. Serum levels of CRP were increased at 24 h (1.0 mg/dL [IQR 0.7-1.75] vs. 0.2 mg/dL [IQR 0.1-1.05] at BL; p<0.001), whereas hs-CRP increased as early as 8 h (2.68 mg/L [IQR 1.23-11.80] vs. 2.17 mg/L [IQR 1.15-5.06] at BL; p=0.002). IL-6 was significantly increased at 45 min (2.59 pg/mL [IQR 1.69-5.0] vs. 1.5 pg/mL [IQR 1.5-2.21] at BL; p=0.002), and sCD40L was significantly decreased at 60 min (801.6 pg/mL [IQR 675.0-1653.5] vs. 1750.0 pg/mL [IQR 1151.0-2783.0] at BL; p=0.016). Elevated counts of polymorphonuclear neutrophils were detectable at 15 min, with a significant increase at 2 h (6415 cells/µL [IQR 5288-7827] vs. 4697 cells/µL [IQR 2892-5620] at BL; p=0.004). Significant monocytosis was observed at 24 h (729 cells/µL [IQR 584-1344] vs. 523 cells/µL [IQR 369-701] at BL; p=0.015). Conclusions: IL-6 and neutrophil granulocytes showed a continuous rise at all pre-specified time points after induction of myocardial infarction. Our results provide valuable additional evidence of the diagnostic value of inflammatory biomarkers in the setting of early AMI.
- Randomized Phase 2 Trial of Intra-Coronary Nitrite During Acute Myocardial Infarction. [JOURNAL ARTICLE]
- Circ Res 2014 Dec 15.
Rationale: Pre-clinical evidence demonstrates that inorganic nitrite, following its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. Objective: We investigated whether intra-coronary injection of nitrite during primary percutaneous coronary intervention (PCI) might improve infarct size in ST-elevated myocardial infarction (STEMI). Methods and Results: Patients undergoing primary PCI (n=80) were randomised to receive intracoronary (10mL) sodium nitrite (1.8μmol) or NaCl (placebo) before balloon inflation. The primary endpoint was infarct size assessed by measuring creatine kinase (CK) release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac magnetic resonance imaging (CMR) on day 2. Baseline characteristics were similar between the groups. No evidence of differences in CK release (p=0.92), troponin T (p=0.85) or CMR-assessed infarct size (p=0.254) were evident. In contrast there was a reduction in myocardial salvage index (p=0.05) and MACE at 1 year (2.6% vs 15.8%, p=0.04) in the nitrite group. In a 66-patient sub-group with TIMI≤1 flow there was reduced serum CK (p=0.030) and a 19% reduction in CMR-determined infarct size (p=0.034) with nitrite. No adverse effects of nitrite were detected. Conclusions: In this phase II study intra-coronary nitrite infusion did not alter infarct size although a trend to improved myocardial salvage index and a significant reduction in MACE was evident. In a sub-group of patients with TIMI flow≤1 nitrite reduced infarct size and MACE and improved myocardial salvage index indicating that a phase III clinical trial assessing intra-coronary nitrite administration as an adjunct to PCI in STEMI patients is warranted. Clinical Trial Registration: http://clinicaltrials.gov - NCT01584453.
- The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR): A New Paradigm for Rigorous, Accurate, and Reproducible Evaluation of Putative Infarct-Sparing Interventions in Mice, Rabbits, and Pigs. [JOURNAL ARTICLE]
- Circ Res 2014 Dec 11.
Rationale: Despite four decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. Objective: To develop a multicenter randomized controlled trial (RCT)-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies. Methods and Results: With NHLBI support, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning (IPC) to reduce infarct size in three species (at two sites/species): mice (n=22-25/group), rabbits (n=11-12/group), and pigs (n=13/group). During this validation phase, i) we established protocols that gave similar results between Centers and confirmed that IPC significantly reduced infarct size in all species, and ii) we successfully established a multi-center structure to support CAESAR's operations, including two surgical Centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center - all with the oversight of an external Protocol Review and Monitoring Committee. Conclusions: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter RCTs. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of-the-art, detailed protocols ("CAESAR protocols") for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible.
- Transcriptional Reversion of Cardiac Myocyte Fate During Mammalian Cardiac Regeneration. [JOURNAL ARTICLE]
- Circ Res 2014 Dec 4.
Rationale:Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level.
Objective:The objectives of our study were to determine if myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process.
Methods and Results:We derived a core transcriptional signature of injury-induced cardiac myocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiac myocyte differentiation, in vitro cardiac myocyte explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of cardiac myocyte differentiation processes including reactivation of latent developmental programs similar to those observed during de-stabilization of a mature cardiac myocyte phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13 (IL13), which induced cardiac myocyte cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of IL13 signaling in cardiac myocytes. These downstream signaling molecules are also modulated in the regenerating mouse heart.
Conclusions:Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration.
- Correction. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e95.
- Correction. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e94.
- Macrophage functions in atherosclerosis. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e83-5.
- Recent developments in vascular biology. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e79-82.
- Recent developments in cardiovascular stem cells. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e71-8.
- Circulation research "in this issue" anthology. [Journal Article]
- Circ Res 2014 Dec 5; 115(12):e40-70.