Susan S. Smyth

Platelets as immune mediators: their role in host defense responses and sepsis.

Platelets occupy a central role at the interface between thrombosis and inflammation. At sites of vascular damage, adherent platelets physically and functionally interact with circulating leukocytes. Activated platelets release soluble factors into circulation that may have local and systemic effects on blood and vascular cells. Platelets can also interact with a wide variety of microbial pathogens. Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes involving tissue injury, immune responses and repair that underlie diverse diseases such as atherosclerosis, autoimmune disorders, inflammatory lung and bowel disorders, host-defense responses and sepsis. In this review, we summarize the general mechanisms by which platelets may contribute to immune function, and then discuss evidence for their role in host defense responses and sepsis from preclinical and clinical studies.

Evidence of Mobilization of Pluripotent Stem Cells into Peripheral Blood of Patients with Myocardial Ischemia

OBJECTIVEnThe ischemic myocardium releases multiple chemotactic factors responsible for the mobilization and recruitment of bone marrow-derived cells to injured myocardium. However, the mobilization of primitive pluripotent stem cells (PSCs) enriched in very small embryonic-like stem cells (VSELs) in various cardiac ischemic scenarios is not well understood.nnnMATERIALS AND METHODSnFifty-four ischemic heart disease patients, including subjects with stable angina, non-ST elevation myocardial infarction, and ST elevation myocardial infarction (STEMI) and 12 matched controls were enrolled. The absolute numbers of circulating stem/primitive cells in samples of peripheral blood (PB) were quantitated by ImageStream analysis and conventional flow cytometry. Gene expression of PSC (Oct-4 and Nanog), early cardiomyocyte (Nkx-2.5 and GATA-4), and endothelial (von Willebrand factor) markers was analyzed by real-time polymerase chain reaction.nnnRESULTSnThe absolute numbers of PSCs, stem cell populations enriched in VSELs, and hematopoietic stem cells present in PB were significantly higher in STEMI patients at presentation and declined over time. There was a corresponding increase in pluripotent, cardiac, and endothelial gene expression in unfractionated PB cells and sorted PB-derived primitive CD34(+) cells. The absolute numbers of circulating VSELs and hematopoietic stem cells in STEMI correlated negatively with patient age.nnnCONCLUSIONSnMyocardial ischemia mobilizes primitive PSCs including pluripotent VSELs into the circulation. The peak of mobilization occurs within 12 hours in patients presenting with STEMI, which may represent a therapeutic window for future clinical applications. Reduced stem cell mobilization with advancing age could explain, in part, the observation that age is associated with poor prognosis in patients with myocardial infarction.

Plasma levels of sphingosine 1-phosphate are strongly correlated with haematocrit, but variably restored by red blood cell transfusions

Anaemia and RBC (red blood cell) transfusion may be associated with worse clinical outcomes, especially with longer blood storage duration prior to transfusion. The mechanisms underlying these harmful effects are unknown. RBCs have been proposed to buffer plasma S1P (sphingosine 1-phosphate), a lysophospholipid essential for the maintenance of endothelial integrity and important in the regulation of haematopoietic cell trafficking. The present study examined the effect of anaemia, RBC transfusion and RBC storage duration on plasma S1P levels. Plasma S1P from 30 individuals demonstrated a linear correlation with Hct (haematocrit; R2=0.51, P<0.001) with no evidence for a plateau at Hct values as low as 19%. RBC transfusion in 23 anaemic patients with baseline mean Hct of 22.2±0.34% (value is the mean±S.D.) increased Hct to 28.3±0.6% at 72 h. Despite an Hct increase, RBC transfusion failed to elevate plasma S1P consistently. A trend towards an inverse correlation was observed between RBC storage duration and the post-transfusion increase in plasma S1P. After 30 days of storage, RBC S1P decreased to 19% of that observed in fresh (3–7-day-old) RBC segments. RBC membranes contain low levels of both S1P phosphatase and S1P lyase activities that may account for the decline in S1P levels with storage. Our results support a role for RBCs in buffering plasma S1P and identify a disturbance in the capacity after transfusion. Changes in S1P content may contribute to an RBC storage lesion. Further studies should investigate the clinical significance of alterations in circulating S1P levels and the potential value of enriching stored RBCs with S1P.

Incidence, predictors, and outcomes associated with pneumothorax during cardiac electronic device implantation: A 16-year review in over 3.7 million patients

BACKGROUNDnPneumothorax (PTX) is a potential complication of vascular access during cardiac implantable electronic device (CIED) procedures and is being scrutinized as a health care-acquired condition.nnnOBJECTIVEnThe purpose of this study was to determine the trends in PTX incidence in the United Stated over a 16-year period and to determine whether PTX is associated with increased mortality after adjustment for other factors.nnnMETHODSnUsing weighted sampling in the largest inpatient health database in the United States (National Inpatient Sample), we evaluated data from patients with a primary procedure of CIED implantation from 1998 to 2013 who had at least 1 new vascular access (new or upgrade of prior CIED). The unadjusted and adjusted associations of PTX with mortality and other parameters were examined.nnnRESULTSnAmong 3,764,703 CIED procedures, PTX occurred in 47,839 cases (1.3%). The apparent incidence of PTX peaked at 1.6% in 2012 and 2013, although this result may have been affected by a concomitant decrease of inpatient (vs outpatient) CIED. PTX was significantly associated with pulmonary complications, chest tube insertion, length of stay, and costs. Mortality was statistically higher in patients with PTX (1.2% vs 0.7%; P <.001), a relationship that remained significant in a multivariate logistic regression analysis (odds ratio 1.50, 95% confidence interval 1.36-1.65; P <.001). Age >80 years, female gender, Caucasian race, chronic obstructive pulmonary disease, and dual-chamber (vs single-chamber) device were all associated with higher odds for PTX occurrence. Placement of a chest tube was a major determinant of worse outcomes and higher costs.nnnCONCLUSIONnPTX remains an important complication of CIED procedures and is associated with increased morbidity, mortality, and costs.

Spontaneous coronary thrombosis following thrombolytic therapy for acute cardiovascular accident and stroke: a case study.

Cardiac complications following stroke or acute cerebrovascular accidents (CVA) are common; however, many of these complications are asymptomatic and do not cause adverse cardiac effects. Symptomatic events (such as acute myocardial infarction after CVA) rarely occur and are often the result of an underlying cardiac embolic source, such as a left ventricular thrombus. We report a case of spontaneous coronary thrombosis following thrombolytic therapy for acute CVA, and discuss the implication that an underlying systemic pro-thrombotic state may predispose individuals to thrombosis in disparate vascular beds.

Thromboinflammatory response and predictors of outcomes in patients undergoing transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) has been increasingly used to treat patients with symptomatic aortic stenosis. Despite improvements in valve deployment, patients that have undergone TAVR are at high risk for major adverse events following the procedure. Blood cell numbers, platelet function, and biomarkers of systemic inflammation were analyzed in 58 patients undergoing TAVR with the Edward’s SAPIEN valve. Following valve deployment, platelet count and agonist-induced platelet activity declined and plasma markers of systemic inflammation (interleukin-6 and S100A8/A9) increased. Baseline platelet activity prior to TAVR correlated with perioperative changes plasma interleukin-6 levels. Moreover, perioperative changes in plasma inflammatory markers predicted the decline in platelet count in the days following the TAVR procedure. Additionally, a significant effect of gender on platelet count following TAVR and was observed. Finally, post-procedural mortality was associated with sustained thrombocytopenia after TAVR. Our findings suggest that TAVR elicits a thromboinflammatory state that may contribute to post-procedural thrombocytopenia. Importantly, our results add to the growing body of literature that suggests the thromboinflammatory changes that occur early after TAVR may predict long-term outcomes.

Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice

INTRODUCTIONnThe multifunctional serine protease thrombin exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling. This study was designed to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure.nnnMATERIAL AND METHODSnTransverse aortic constriction (TAC) surgery was performed on C57Bl/6J male mice to elicit cardiac hypertrophy. TAC, or sham, mice were randomly assigned to receive chow supplemented with the oral anticoagulant, dabigatran etexilate, or placebo.nnnRESULTSnDabigatran did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia length, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran reduced perivascular fibrosis by 25%, interstitial fibrosis by 54%, and the expression of myocardial fibrosis markers collagen I & III, MMP9, SMA, and PAR-1. These changes were associated with significant improvement in both coronary flow reserve and global left ventricular function. In cultured cardiac fibroblasts, dabigatran decreased thrombin and PAR-1-mediated collagen deposition by 30% and 37%, respectively.nnnCONCLUSIONSnDabigatran attenuates cardiac fibrosis in the setting of pressure overload and improves coronary flow reserve and global cardiac function possibly by inhibiting thrombin activity and down-regulating PAR-1 expression in the absence of an effect on cardiomyocyte hypertrophy.

Comparison of Outcomes in Patients Having Acute Myocardial Infarction With Versus Without Sickle-Cell Anemia

Sickle-cell disease (SCD) affects millions worldwide. Sickle-cell anemia (SCA), the most severe form of this disease, is the most common inherited blood disorder in the United States. There are limited data on the incidence, clinical characteristics, and outcomes of acute myocardial infarction (AMI) in these patients. Using data from the National Inpatient Sample database, we matched cases (AMI with SCA) with controls (AMI without SCA) in a 1:1 ratio for age, gender, race, and year of admission. We compared both groups in terms of clinical characteristics and inpatient outcomes and performed a logistic regression with mortality as the primary outcome. Using weighted samples, we also described trends of SCA in the general population of patients with AMI. Of the 2,386,657 admissions with AMI, SCA was reported in 501 (0.02%) patients, and 495 were successfully matched to controls. Patients with SCA were less likely to have risk factors for coronary artery disease than those without SCA. Patients with SCA were more likely to develop pneumonia, respiratory failure, and acute renal failure, and require mechanical ventilation, hemodialysis for acute renal failure and blood transfusion. In-hospital mortality was significantly higher in patients with SCA. In a multivariate analysis, SCA was an independent predictor of mortality (odds ratio 3.49; 95% confidence interval 1.99 to 6.12; pu2009=u2009<u2009.001). In conclusion, myocardial infarction occurs in patients with SCA at a relatively early age. These patients do not typically have the traditional risk factors for the acute coronary syndrome. Mortality in these patients is significantly higher in age-, gender-, and race-matched controls.

Acute Effects of Implantable Cardioverter-Defibrillator Shocks on Biomarkers of Myocardial Injury, Apoptosis, Heart Failure, and Systemic Inflammation.

Implantable cardioverter‐defibrillator (ICD) shocks are potentially associated with myocardial injury, altered hemodynamics, apoptosis, and inflammatory signaling. Their precise cellular impact can be explored after defibrillation testing (DFT) via biomarkers. We evaluated changes in biomarkers after ICD shocks during DFT.

Predictors, Morbidity, and Costs Associated with Pneumothorax during Electronic Cardiac Device Implantation.

Pneumothorax (PTX) is a major cause of morbidity associated with cardiac implantable electronic devices (CIEDs). We sought to evaluate predictors of PTX at our centers during CIED implantations, including the venous access technique utilized, as well as to determine morbidity and costs associated with PTX.