Ahmed Hasan

Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.

BACKGROUND Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. DESIGN The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. SUMMARY CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.

Cardiovascular Pharmacogenomics: Current Status and Future Directions—Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular

Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery

Dual antiplatelet therapy (DAPT) is prescribed to millions of patients worldwide following coronary stenting. DAPT is indicated to lower the risk of ischemic events, such as myocardial infarction, including stent thrombosis, ischemic stroke, or death from cardiovascular causes. A significant number of these patients undergo noncardiac surgery and may require DAPT interruption. This poses a significant clinical dilemma because DAPT interruption exposes patients to the potential risk of stent thrombosis, perioperative myocardial infarction, or both. Conversely, continuing DAPT may be associated with excess bleeding complications. Observational data in this area are conflicting, and there are no randomized clinical trials to guide practitioner decision making. On the basis of predominantly consensus recommendations, various strategies for managing DAPT during the perioperative period have been proposed. This review presents 3 commonly encountered clinical scenarios that lead into an evidence-based discussion of practical strategies for managing perioperative antiplatelet therapy in patients following percutaneous coronary intervention.

Functional Assays to Screen and Dissect Genomic Hits: Doubling Down on the National Investment in Genomic Research

The National Institutes of Health have made substantial investments in genomic studies and technologies to identify DNA sequence variants associated with human disease phenotypes. The National Heart, Lung, and Blood Institute has been at the forefront of these commitments to ascertain genetic variation associated with heart, lung, blood, and sleep diseases and related clinical traits. Genome-wide association studies, exome- and genome-sequencing studies, and exome-genotyping studies of the National Heart, Lung, and Blood Institute-funded epidemiological and clinical case-control studies are identifying large numbers of genetic variants associated with heart, lung, blood, and sleep phenotypes. However, investigators face challenges in identification of genomic variants that are functionally disruptive among the myriad of computationally implicated variants. Studies to define mechanisms of genetic disruption encoded by computationally identified genomic variants require reproducible, adaptable, and inexpensive methods to screen candidate variant and gene function. High-throughput strategies will permit a tiered variant discovery and genetic mechanism approach that begins with rapid functional screening of a large number of computationally implicated variants and genes for discovery of those that merit mechanistic investigation. As such, improved variant-to-gene and gene-to-function screens-and adequate support for such studies-are critical to accelerating the translation of genomic findings. In this White Paper, we outline the variety of novel technologies, assays, and model systems that are making such screens faster, cheaper, and more accurate, referencing published work and ongoing work supported by the National Heart, Lung, and Blood Institutes R21/R33 Functional Assays to Screen Genomic Hits program. We discuss priorities that can accelerate the impressive but incomplete progress represented by big data genomic research.