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recommended a 2-step screening method, consisting of the 2-item Patient Health Questionnaire (PHQ-2) followed by the 9-item Patient Health Questionnaire (PHQ-9), for identifying depression in cardiovascular patients. The accuracy and prognostic value of this screening method have not been evaluated. Methods and Results-We administered the 2-step AHA-recommended screening algorithm to 1024 patients with stable coronary heart disease and calculated sensitivity and specificity against a gold standard interview for major depressive disorder. Subsequent cardiovascular events (myocardial infarction, stroke, transient ischemic attack, heart failure, or death) were determined during a mean of 6.27Ϯ2.11 years of follow-up. The AHA-recommended screening method had high specificity (0.91; 95% confidence interval, 0.89 to 0.93) but low sensitivity (0.52; 95% confidence interval, 0.46 to 0.59) for a diagnosis of major depressive disorder. Participants who screened positive on the AHA depression protocol had a 55% greater risk of events than those who screened negative (age-adjusted hazard ratio, 1.55; 95% confidence interval, 1.21 to 1.97; Pϭ0.0005). After adjustment for age, sex, body mass index, history of myocardial infarction, hypertension, diabetes, heart failure, and high-density lipoprotein levels, screening positive remained associated with a 41% greater rate of cardiovascular events (hazard ratio, 1.41; 95% confidence interval, 1.10 to 1.81; Pϭ0.008). Conclusions-Among outpatients with stable coronary heart disease, the AHA-recommended depression screening protocol is highly specific for depression and identifies patients at risk for adverse cardiovascular outcomes. (Circ Cardiovasc Qual Outcomes. 2011;4:533-540.)

Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their pharmacogenetic analysis with population sizes often inadequate for sufficiently powered studies. Grouping rare mutations by functional phenotype rather than mutation site can potentially increase sample size. Using human population-based studies (n ‫؍‬ 1,761) to search for dysfunctional human prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all with frequencies less than 2% in our study cohort. Eight of the 18 had defects in binding, activation, and/or protein stability/folding. Mutations (M113T, L104R, and R279C) in three highly conserved positions demonstrated severe misfolding manifested by impaired binding and activation of cell surface receptors. To assess for association with coronary artery disease, we performed a case-control study comparing coronary angiographic results from patients with reduced cAMP production arising from the non-synonymous mutations (n ‫؍‬ 23) with patients with non-synonymous mutations that had no reduction in cAMP (n ‫؍‬ 17). Major coronary artery obstruction was significantly increased in the dysfunctional mutation group in comparison with the silent mutations. We then compared the 23 dysfunctional receptor patients with 69 age-and risk factor-matched controls (1:3). This verified the significantly increased coronary disease in the non-synonymous dysfunctional variant cohort. This study demonstrates the potential utility of in vitro functional characterization in predicting clinical phenotypes and represents the most comprehensive characterization of human prostacyclin receptor genetic variants to date. Single nucleotide polymorphisms (SNPs)3 occurring in DNA coding regions are sequence changes that result in either synonymous (i.e. no change in amino acid sequence) or non-synonymous (change in amino acid sequence) mutations. They are implicated in the pathogenesis of diseases (1), in the efficacy of drugs, and in drug-to-drug interactions (2-4). It is now generally believed that greater than 80% of the observed variability between individuals is the result of genetic variants (5). Numerous databases, including the National Center for Biotechnology Information SNP database, have accumulated millions of SNPs, and a growing list of clinical trials seeks to address the role of SNPs in pathophysiology and treatment response (6 -8). Despite the rapid accumulation of data, surprisingly little has entered clinical practice. This may be in part due to the requirement for very large cohorts to perform an adequately powered study for the rarer mutations. Detailed genetic variant functional analysis in biochemical systems may provide a possible solution.The human prostacyclin receptor gene (PTGIR) spans ϳ7,000 bases along chromosome 19 (locus 19q13.3) and comprises three exons separated by two introns: one intron lies upstream from the ATG start codon, and the other lies at the end of the sixth transmembrane helix (9). The human prostacycli...

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Accuracy and prognostic value of AHA-recommended depression screening in patients with coronary heart disease from the Heart & Soul Study Background- In 2008, the American Heart Association (AHA) recommended a two-step screening method, consisting of the two-item Patient Health Questionnaire (PHQ-2) followed by the nine-item Patient Health Questionnaire (PHQ-9), for identifying depression in cardiovascular patients. The accuracy and prognostic value of this screening method have not been evaluated. Methods and Results- We administered the two-step AHA-recommended screening algorithm to 1024 patients with stable CHD and calculated sensitivity and specificity against a gold standard interview for major depressive disorder (MDD). Subsequent cardiovascular events (myocardial infarction, stroke, transient ischemic attack, heart failure or death) were determined during a mean of 6.27 ± 2.11 years follow-up. The AHA-recommended screening method had high specificity (0.91, 95% CI 0.46-0.59), but low sensitivity (0.52, 95% CI 0.89-0.93) for a diagnosis of MDD. Participants who screened positive on the AHA depression protocol had a 55% greater risk of events than those who screened negative (age-adjusted HR 1.55, 95% CI 1.21-1.97; p=0.0005). After adjustment for sex, body mass index, history of myocardial infarction, hypertension, diabetes, heart failure and HDL levels, screening positive remained associated with a 41% greater rate of cardiovascular events (HR 1.41, 95% CI, 1.10-1.81; p=0.008). Conclusions- Among outpatients with stable CHD, the AHA-recommended depression screening protocol is highly specific for depression and identifies patients at risk for adverse cardiovascular outcomes.

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