Issam Zineh

Adverse Cardiovascular Outcomes in Women With Nonobstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project

BACKGROUND Women with clinical findings suggestive of ischemia but without findings of obstructive coronary artery disease (CAD) on angiography represent a frequent clinical problem; predicting prognosis is challenging. METHODS The Womens Ischemia Syndrome Evaluation (WISE) study examined symptomatic women referred for clinically indicated coronary angiography and followed up for a mean 5.2 years. The St James Women Take Heart (WTH) Project enrolled asymptomatic, community-based women with no history of heart disease who were followed up for 10 years. We compared cardiovascular events (ie, myocardial infarction, stroke, and hospitalization for heart failure) and death in 540 WISE women with suspected ischemia but no angiographic evidence of obstructive CAD with those from a cohort of 1000 age- and race-matched WTH women. RESULTS Compared with the WISE women, asymptomatic WTH women had a lower prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus (P < .001). Five-year annualized event rates for cardiovascular events were 16.0% in WISE women with nonobstructive CAD (stenosis in any coronary artery of 1%-49%), 7.9% in WISE women with normal coronary arteries (stenosis of 0% in all coronary arteries), and 2.4% in asymptomatic WTH women (P < or = .002), after adjusting for baseline CAD risk factors. The cardiovascular events were most frequent in women with 4 or more cardiac risk factors, with the 5-year annualized cardiovascular event rate being 25.3% in women with nonobstructive CAD, 13.9% in WISE women with normal coronary arteries, and 6.5% in asymptomatic women (P = .003). CONCLUSION Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women.

β1‐Adrenergic Receptor Polymorphisms and Antihypertensive Response to Metoprolol

Marked interpatient variability exists in blood pressure response to β‐blocker monotherapy. We tested the hypothesis that 2 common polymorphisms in the gene for β1‐adrenergic receptor are associated with antihypertensive response to metoprolol in patients with uncomplicated hypertension.

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges

Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drugs pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered.

The Pharmacogenetics Research Network: From SNP Discovery to Clinical Drug Response

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug‐metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

DNA, drugs and chariots: on a decade of pharmacogenomics at the US FDA

Over the past 10 years, the US FDA has become a strong pharmacogenomics advocate as part of its mission to both protect and advance public health by enabling innovations that make medicines safer to use and more effective. The agency has evolved its advocacy cautiously on a foundation of science-based information from novel programs, such as the Voluntary Genomics Data Submission initiative, and on careful regulatory assessment of the extraordinary advances in clinical pharmacogenomics that have supported the update of drug labels with genetic information. This commentary goes into detail on the evolution of these achievements. However, many challenges remain for pharmacogenomics, and they will continue to evolve, and all stakeholders must work together. As the decade draws to a close, we have presented four major areas that need to be addressed collectively to assure that pharmacogenomics continues to mature over the next 10 years into a science that is essential to the practice of medicine.

High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering.

Allopurinol pharmacogenetics: assessment of potential clinical usefulness

Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics.

The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women's Ischemia Syndrome Evaluation (WISE).

UNLABELLED High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women. METHODS We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Womens Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. RESULTS Mean age was 57 +/- 11 years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% CI 1.05-3.64, P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% CI 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but became nonsignificant when angiographic results were included. CONCLUSION Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events.

Pharmacogenomics of antihypertensive drugs : Rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study

BACKGROUND Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise. TRIAL DESIGN The objective of this trial is to identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a beta-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created. CONCLUSIONS Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes.

The ICD shock and stress management program: A randomized trial of psychosocial treatment to optimize quality of life in ICD patients

Background: Implantable cardioverter defibrillator (ICD) patients potentially face significant psychological distress because of their risk for life‐threatening arrhythmias and the occurrence of ICD shock.