Epigenetic modifications: basic mechanisms and role in cardiovascular disease (2013 Grover Conference series)

Abstract Epigenetics refers to heritable traits that are not a consequence of DNA sequence. Three classes of epigenetic regulation exist: DNA methylation, histone modification, and noncoding RNA action. In the cardiovascular system, epigenetic regulation affects development, differentiation, and disease propensity or expression. Defining the determinants of epigenetic regulation offers opportunities for novel strategies for disease prevention and treatment

Joseph A. Vita, MD, 1956-2014

On November 2, 2014, our friend and colleague, Joseph Vita, died after a short but gallant struggle with lung cancer at the age of 58. Joe was never a smoker and typically appeared 10 years younger than his age; thus, it was particularly shocking to many when he became ill so suddenly and in his prime. He will be sorely missed; his contributions to cardiovascular medicine were many and diverse. He was a brilliant investigator, a superb clinician, an outstanding mentor, and an expert journal editor

Lipid Levels After Acute Coronary Syndromes

ObjectivesThis analysis from the LUNAR (Limiting UNdertreatment of lipids in ACS with Rosuvastatin) study assessed lipid changes 1 to 4 days after onset of acute coronary syndromes (ACS), before initiation of study treatment.BackgroundEarly studies indicated that cholesterol levels decrease significantly after ACS. However, most studies were small or did not measure low-density lipoprotein cholesterol (LDL-C) directly, and many used nonfasting or retrospective data. More recent studies suggest less pronounced changes in cholesterol levels after ACS.MethodsThe LUNAR trial is a prospective, multicenter, randomized, open-label study in adults hospitalized for acute ST-segment elevation myocardial infarction (STEMI), non-STEMI, or unstable angina (UA). Blood samples were taken at median times after onset of ACS symptoms of 26 h (Day 1, fasting or nonfasting sample), 43 h (Day 2, fasting sample), and 84 h (Day 4, fasting sample) for direct measurement of serum lipid levels before study treatments were started.ResultsOf 507 patients available for analysis, 212 were admitted for STEMI, 176 for non-STEMI, and 119 for UA. The LDL-C levels decreased in the 24 h after admission (from 136.2 to 133.5 mg/dl), followed by an increase over the subsequent 2 days (to 141.8 mg/dl). These changes did not seem to be clinically meaningful. Similar changes were observed for total cholesterol and smaller changes for high-density lipoprotein cholesterol; fasting triglyceride levels did not change.ConclusionsMean lipid levels vary relatively little in the 4 days after an ACS and can be used to guide selection of lipid-lowering medication. (LUNAR Phase IIIb Study Comparing Rosuvastatin and Atorvastatin in Subjects With Acute Coronary Syndromes; NCT00214630

407-3 Glutathione Peroxidase Prevents the Inactivation of Nitric Oxide and Restores the Inhibition of Platelet Function by S-Nitrosothiols

The interaction of nitric oxide (NO) with reactive oxygen species in the vasculature can inactivate NO leading to potentially adverse vascular consequences. Glutathione peroxidases (GSH-Px), a family of antioxidant enzymes present at reduced concentrations in plasma and platelets of patients with coronary artery disease, catalyze the reduction of hydrogen peroxide and lipid hydroperoxides (LOOH) by glutathione. Given the role of LOOH in platelet eicosanoid metabolism and their presence in atherosclerotic plaque, we investigated the effect of GSH-Px on the inhibition of platelet function by the naturally occurring NO donor, S-nitroso-glutathione (SNO-Glu). Subthreshold inhibitory concentrations of SNO-Glu were added to platelet-rich plasma, and aggregation was induced by arachidonate. The addition of GSHPx (0.2–20U/ml) to this system led to a dose-dependent inhibition of platelet aggregation with an IC50= 0.6U/ml GSH-Px (p < 0.05 by ANOVA). Superoxide dismutase (0.1–200U/ml), catalase (0.1–200U/ml), or GSH-Px without SNO-Glu did not alter platelet aggregation responses. The addi ion of GSH-Px to a subthreshold inhibitory concentration of sodium nitroprusside also did not affect platelet aggregation responses. LOOH increased platelet aggregation in the presence of SNO-Glu, an effect reversed by GSH-Px. Levels of cGMP were measured after platelets were incubated with SNO-Glu, exogenous LOOH, and GSH-Px. SNO-Glu alone increased cGMP levels, and this effect was attenuated by LOOH but restored by the addition of GSH-Px. GSH-Px activity was equivalent with either SNO-Glu or glutathione as cosubstrate. Incubation of SNO-Glu with GSH-Px led to a 48.5% decrease in the concentration of SNO-Glu as determined by HPLC-electrochemical detection. Incubation of SNO-Glu with albumin in the presence of GSH-Px led to increased formation of S-nitroso-albumin, a prevalent reservoir of EDRF in plasma. These results show that GSH-Px, at physiologically relevant concentrations, has a potent effect on NO-induced inhibition of platelet aggregation and that this enzyme may have two functions: (i) metabolism of LOOH, thereby preventing its inactivation of NO; and (ii) metabolism of SNO-Glu, thereby liberating NO and/or supporting further transnitrosation reactions These findings suggest that GSH-Px, in addition to its antioxidant functions, regulates the availability of NO in the vasculature and possibly alters plateletdependent thrombotic events

Human disease classification in the postgenomic era: A complex systems approach to human pathobiology

Contemporary classification of human disease derives from observational correlation between pathological analysis and clinical syndromes. Characterizing disease in this way established a nosology that has served clinicians well to the current time, and depends on observational skills and simple laboratory tools to define the syndromic phenotype. Yet, this time-honored diagnostic strategy has significant shortcomings that reflect both a lack of sensitivity in identifying preclinical disease, and a lack of specificity in defining disease unequivocally. In this paper, we focus on the latter limitation, viewing it as a reflection both of the different clinical presentations of many diseases (variable phenotypic expression), and of the excessive reliance on Cartesian reductionism in establishing diagnoses. The purpose of this perspective is to provide a logical basis for a new approach to classifying human disease that uses conventional reductionism and incorporates the non-reductionist approach of systems biomedicine

A perspective on the potential problems with aspirin as an antithrombotic agent: a comparison of studies in an animal model with clinical trials

AbstractAspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials