Role of adenylate cyclase 9 in the pharmacogenomic response to dalcetrapib clinical paradigm and molecular mechanisms in precision cardiovascular medicine

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.Cardiolog

Rationale, design and methodology of a double-blind, randomized, placebo-controlled study of escitalopram in prevention of Depression in Acute Coronary Syndrome (DECARD)

<p>Abstract</p> <p>Background</p> <p>The prevalence of depression in patients with acute coronary syndrome, i.e. myocardial infarction and unstable angina, is higher than in the general population. The prevalence of anxiety is higher as well. Both depression and anxiety are associated with poor cardiac outcomes and higher mortality. Comorbid depression in patients with acute coronary syndrome often goes undiagnosed, and it is therefore a challenging task to prevent this risk factor. The study of DEpression in Coronary ARtery Disease (DECARD) is designed to examine if it is possible to prevent depression in patients with acute coronary syndrome.</p> <p>Methods</p> <p>Two hundred forty non-depressed patients with acute coronary syndrome are randomized to treatment with either escitalopram or placebo for 1 year. Psychiatric and cardiac assessment of patients is performed to evaluate the possibility of preventing depression. Diagnosis of depression and Hamilton Depression Scale are the primary outcome measures.</p> <p>Discussion</p> <p>This is the first study of prevention of depression in patients after acute coronary syndrome with a selective serotonin reuptake inhibitor.</p> <p>Trial Registration</p> <p><url>http://www.ClinicalTrials.gov.</url> Identifier: NCT00140257</p

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

Dalcetrapib reduces risk of new-onset diabetes in patients with coronary heart disease

OBJECTIVE:Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS:In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib, 600 mg daily, or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS:At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS:In patients with a recent acute coronary syndrome, incident diabetes is common, and is reduced substantially by treatment with dalcetrapib.Gregory G. Schwartz, Lawrence A. Leiter, Christie M. Ballantyne, Philip J. Barter, Donald M. Black ... Stephen Nicholls ... et al