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Background: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.Methods: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.Results: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Background: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. Methods: We queried Veterans Affairs' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. Results: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P <0.001)> P <0.001).> Conclusions: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population. * In a large sample of US veterans, the ratio of saturation-to-wedge (RSW) can be calculated easily from parameters obtained from most right heart catheterizations by dividing the percentage of mixed venous oxygen saturation by the pulmonary capillary wedge pressure. * Larger values of RSW were associated with significantly lower risks of all-cause mortality and hospitalization/emergency department presentation, with and without adjustment for clinical characteristics. * In comparison to other hemodynamic measurements, including cardiac index measured by Fick and thermodilution methods, and pulmonary capillary wedge pressure alone, RSW had the strongest association with clinical outcomes. * The principle of RSW relates mixed venous oxygen saturation and pulmonary capillary wedge pressure, lower values indicating a hemodynamic profile of cold and wet and poor outcomes. * The RSW is a superior and easy to calculate index that offers prognostic value over conventional hemodynamic measurements for risk stratification of patients undergoing right heart catheterization. [ABSTRACT FROM AUTHOR]

In the article, the author discusses the prevention of platelet thrombosis with protease-activated receptor (PAR) 1 Pepducin. Platelet arterial thrombosis occurs after atherosclerotic plaque rupture, erosion and percutaneous coronary interventions (PCI) is the cause of myocardial infarctions and many ischemic strokes. protease-activated receptor (PAR) 1 when cleaved by thrombin triggers intracellular signaling events resulting in secretion of granule contents including ADP.

Rationale: Despite direct immediate intervention and therapy, ST-segment-elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death., Objective: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI., Methods and Results: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months (P<0.001). In secondary analyses, when adjusted for time of ischemia, a consistently favorable cell dose-dependent effect was observed in the change in left ventricular ejection fraction and infarct size, and the duration of time subjects was alive and out of hospital (P=0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively., Conclusions: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01495364., (© 2016 American Heart Association, Inc.)