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Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD.A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure.Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans.These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

Individuals who undergo multiplex direct-to-consumer (DTC) genomic testing receive genetic risk results for multiple conditions. To date, research has not investigated the influence of individual differences in disease perceptions among consumers on testing outcomes. A total of 2037 participants received DTC genomic testing and completed baseline and follow-up surveys assessing disease perceptions and health behaviors. Participants were asked to indicate their most feared disease of those tested. Perceived seriousness and controllability of the disease via lifestyle or medical intervention were assessed. Participants most frequently reported heart attack (19.1%) and Alzheimer's disease (18.6%) as their most feared disease. Perceived seriousness and control over the feared disease both influenced response to DTC genomic testing. Greater perceived seriousness and diminished perceived control were associated with higher, but not clinically significant levels of anxiety and distress. In some cases these associations were modified by genetic risk. No significant associations were observed for diet, exercise and screening behaviors. Individual differences in disease perceptions influence psychological outcomes following DTC genomic testing. Higher perceived seriousness may make a consumer more psychologically sensitive to test results and greater perceived control may protect against adverse psychological outcomes. Findings may inform development of educational and counseling services.

Objective To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM).

To describe consumers' perceptions of genetic counseling services in the context of direct-to-consumer personal genomic testing is the purpose of this research. Utilizing data from the Scripps Genomic Health Initiative, we assessed direct-to-consumer genomic test consumers' utilization and perceptions of genetic counseling services. At long-term follow-up, approximately 14 months post-testing, participants were asked to respond to several items gauging their interactions, if any, with a Navigenics genetic counselor, and their perceptions of those interactions. Out of 1325 individuals who completed long-term follow-up, 187 (14.1%) indicated that they had spoken with a genetic counselor. The most commonly given reason for not utilizing the counseling service was a lack of need due to the perception of already understanding one's results (55.6%). The most common reasons for utilizing the service included wanting to take advantage of a free service (43.9%) and wanting more information on risk calculations (42.2%). Among those who utilized the service, a large fraction reported that counseling improved their understanding of their results (54.5%) and genetics in general (43.9%). A relatively small proportion of participants utilized genetic counseling after direct-to-consumer personal genomic testing. Among those individuals who did utilize the service, however, a large fraction perceived it to be informative, and thus presumably beneficial.

The ongoing controversy surrounding direct-to-consumer (DTC) personal genomic tests intensified last year when the U.S. Government Accountability Office (GAO) released results of an undercover investigation of four companies that offer such testing. Among their findings, they reported that some of their donors received DNA-based predictions that conflicted with their actual medical histories. We aimed to more rigorously evaluate the relationship between DTC genomic risk estimates and self-reported disease by leveraging data from the Scripps Genomic Health Initiative (SGHI). We prospectively collected self-reported personal and family health history data for 3,416 individuals who went on to purchase a commercially available DTC genomic test. For 5 out of 15 total conditions studied, we found that risk estimates from the test were significantly associated with self-reported family and/or personal health history. The 5 conditions, included Graves’ disease, Type 2 Diabetes, Lupus, Alzheimer’s disease, and Restless Leg Syndrome. To further investigate these findings, we ranked each of the 15 conditions based on published heritability estimates and conducted post-hoc power analyses based on the number of individuals in our sample who reported significant histories of each condition. We found that high heritability, coupled with high prevalence in our sample and thus adequate statistical power, explained the pattern of associations observed. Our study represents one of the first evaluations of the relationship between risk estimates from a commercially available DTC personal genomic test and self-reported health histories in the consumers of that test.

Genome-wide association studies have separately identified four single nucleotide polymorphisms (SNPs) on chromosome 9p21 that confer susceptibility to coronary artery disease (CAD) and myocardial infarction (MI). This study presents the first analysis of these SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) in a premature, familial CAD/MI population (GeneQuest). We performed a case-control analysis of the GeneQuest Caucasian population with 310 cases with premature CAD and MI (average age at onset of 40.3 +/- 5.1) and 560 non-CAD controls to determine if these SNPs are associated with risk of CAD using both the population-based and family-based association study designs. The four SNPs are significantly associated with premature and familial MI and CAD in the GeneQuest Caucasian population (allelic P= 6.61 x 10(-7) to 1.87 x 10(-8)). Sib-TDT analysis showed that three of the four SNPs could confer significant susceptibility to premature CAD and MI. These results indicate that the four SNPs on chromosome 9p21 are also associated with premature, familial CAD.

The effects of beta blocker therapy in the settings of heart failure and coronary artery disease have been well described, although little data exist in patients presenting with acute coronary syndromes undergoing percutaneous coronary intervention. The current study will attempt to evaluate the efficacy of beta blocker therapy in this setting. Pooled data from five randomized, controlled trials of abciximab during coronary intervention were used to analyze the clinical efficacy of beta blocker therapy. The pooled analysis evaluated the end points of all-cause mortality, myocardial infarction, repeat revascularization, and the combined endpoint of death and myocardial infarction in 2,894 patients. At 30 days, death occurred in 12 of 1,939 (0.6%) patients receiving beta blocker therapy and in 19 of 955 (2.0%) patients not receiving beta blocker therapy, (P < 0.001). At 6 months, death occurred in 33 of 1,939 (1.7%) patients receiving beta blocker therapy and 35 of 955 (3.7%) not receiving beta blocker therapy, (P < 0.001). After creating a propensity model and adjusting for variables predictive of mortality in the multivariable analysis, beta blocker therapy continued to be associated with a significant reduction in mortality. The findings were similar to those shown for the effects of beta blocker therapy in separate subgroups of patients with unstable angina and acute myocardial infarction. This analysis demonstrates a lower short-term mortality in patients receiving beta blocker therapy who undergo percutaneous coronary intervention for unstable angina or acute myocardial infarction.

We analyzed vascular access site bleeding from the EPIC, EPILOG, and EPISTENT trials to quantify the decrease in vascular bleeding complications in these three trials, especially those attributable to abciximab. The incidence of combined major and minor vascular access site bleeding in nonabciximab (heparin plus placebo) patients progressively decreased from EPIC (8.2%) to EPILOG (2.9%) to EPISTENT (1.7%; P < 0.001). Combined major and minor vascular access site bleeding in abciximab (heparin plus abciximab) patients decreased from EPIC (20%) to EPILOG (5.8%) to EPISTENT (2.2%; P < 0.001). There were more major vascular access site bleeds with abciximab compared to placebo in EPIC (odds ration 3.2; P < 0.001) but not in EPILOG or EPISTENT. Modified abciximab and heparin dosing and improved vascular access site management strategies have decreased the risk of vascular access bleeding during coronary intervention and have essentially eliminated the excess access site bleeding associated with abciximab. Cathet Cardiovasc Intervent 2002;57:476–483. © 2002 Wiley-Liss, Inc.

Advanced age is associated with worse prognosis among patients with acute ST-elevation myocardial infarction. Many eligible elderly patients with acute ST-elevation myocardial infarction, however, do not receive any reperfusion therapy at all. The risk of intracranial hemorrhage complicating fibrinolytic therapy increases with age. Furthermore, routine adjunctive stenting has made coronary angioplasty safer. In total, primary percutaneous coronary intervention is the preferred reperfusion strategy among elderly patients with acute ST-elevation myocardial infarction, provided that it can be performed without excessive delay. The break-even incremental delay with primary percutaneous coronary intervention compared with fibrinolytic therapy is not clear at this point and will need to be elucidated by future investigation.

Expression of cell adhesion molecules (CAM) responsible for leukocyte-endothelium interactions plays a crucial role in inflammation and atherogenesis. Up-regulation of vascular CAM-1 (VCAM-1), intracellular CAM-1 (ICAM-1), and E-selectin expression promotes monocyte recruitment to sites of injury and is considered to be a critical step in atherosclerotic plaque development. Factors that trigger this initial response are not well understood. As platelet activation not only promotes thrombosis but also early stages of atherogenesis, we considered the role of thrombospondin-1 (TSP-1), a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, as a regulator of CAM expression. TSP-1 induced expression of VCAM-1 and ICAM-1 on endothelium of various origins, which in turn, resulted in a significant increase of monocyte attachment. This effect could be mimicked by a peptide derived from the C-terminal domain of TSP-1 and known to interact with CD47 on the cell surface. The essential role of CD47 in the cellular responses to TSP-1 was demonstrated further using inhibitory antibodies and knockdown of CD47 with small interfering RNA. Furthermore, we demonstrated that secretion of endogenous TSP-1 and its interaction with CD47 on the cell surface mediates endothelial response to the major proinflammatory agent, tumor necrosis factor alpha (TNF-alpha). Taken together, this study identifies a novel mechanism regulating CAM expression and subsequent monocyte binding to endothelium, which might influence the development of anti-atherosclerosis therapeutic strategies.

Coronary thrombosis leading to myocardial infarction is a complex process involving the interaction of the arterial wall, the coagulation cascade, and platelets. Increased understanding of the molecular biology of thrombosis has prompted an evolution in antithrombotic therapy, from the early use of warfarin following myocardial infarction to agents targeting specific receptors or modulators in the thrombotic process. The complexity of thrombosis allows for numerous sites of pharmacologic intervention; the multiple pathways leading to platelet aggregation and thrombin formation provide the opportunity for combined therapies. This review presents the current clinical data on antiplatelet, anticoagulant, and specific antithrombin therapies following myocardial infarction.

Beginning with its inception in 1985, the TAMI group performed randomized clinical trials in both academic: and nonacademic settings. The ten TAMI trials not only proved the viability of clinical research in a nontraditional environment, but also contributed significantly to the clinical investigation of acute myocardial infarction through small mechanistic trials. Despite having insufficient power to address overall survival and clinical outcome measures because of patient enrollments ranging from only 50–575 patients, the trials used similar entry criteria and follow-up measures, which permitted broader analyses of the prospectively collected dataset of randomized patients. This article reviews the history of the TAMI collaboration and discusses the findings of the individual trials as well as the contributions of larger analyses to our understanding of patient selection, prognosis, costs, and outcomes. (J Interven Cardiol 1996;9:89–115)

The clinical spectrum of ischaemic heart disease encompasses a variety of acute and chronic conditions including silent ischaemia, chronic stable angina, myocardial infarction, ischaemic cardiomyopathy and sudden cardiac death. Its pathogenesis and treatment is the subject of much ongoing research and debate. Keywords: atherosclerosis; myocardial infarction; congestive heart failure; coronary artery disease; thrombolysis

We report the immediate results and 6 month follow-up data of 494 consecutive patients who underwent coronary angioplasty in two or more major epicardial arteries. Clinical success was achieved in 95% of the 494 patients. The technical success rate of the 1,117 vessels dilated was 89%, defined as at least a 35% reduction (mean = 53%) of the initial percent diameter stenosis and a decrease in the transstenotic gradient to less than or equal to 15 mmHg (mean = 9 mmHg). Complications of the procedure included emergency bypass surgery (2.8%), myocardial infarction (3.0%), and hospital death (0.4%) inclusive. At least one of these complications (major cardiac event) occurred in 3.8% of patients. Prior to angioplasty, 46% of patients were in Canadian Cardiovascular Society Class II, 42% in Class III, and 12% in Class IV. Follow-up clinical evaluation (mean follow-up period of 16.9 months) showed 83% of patients in Class I, 14% in Class II, and 3% in Class III. Of the 286 successful patients who have reached 6 month follow-up plateau (mean follow-up period of 20.5 months), 164 (57%) have so far had repeat coronary angiography and exhibited three different patterns: all lesions patent (N = 54), some lesions restenosed (N = 60), and all lesions restenosed (N = 32). There were 18 patients with new vessel lesions (not previously dilated). Logistic regression analyses demonstrated that clinical factors including diabetes (P less than .05), hypercholesterolemia, (P less than .01), new onset angina (P less than .05), current smoking (P less than .01), and morphologic and technical factors such as preangioplasty diameter stenosis greater than 95% (P less than .05) and higher balloon inflation pressure (P less than .05) were predictive of increased risk of recurrence. Patients were classified into two groups based on the anatomy of the target lesions. In Group A (N = 217), patients had a single lesion in each of the vessels to be dilated; Group B (N = 277) patients had a complex lesion in at least one of the vessels dilated. Group B patients were more likely to develop recurrence (P less than .05). Of the original 494 patients, 488 (99%) are alive. Coronary angioplasty (either initially or with repeat PTCA) has been the definitive treatment in 453 of the 494 patients for an overall success of 92%.(ABSTRACT TRUNCATED AT 400 WORDS)

To test the utility and safety of percutaneous transluminal coronary angioplasty (PTCA) after recombinant tissue plasminogen activator (t-PA), we performed the procedure in all suitable candidates with acute myocardial infarction (MI) who had successful t-PA mediated coronary thrombolysis. Twenty consecutive patients with MI received t-PA after coronary angiographic conformation of total occlusion. Successful recanalization with t-PA was achieved in 13 patients, leaving a residual obstruction of 84 +/- 6% in the nine patients for whom PTCA was attempted at a mean of 21.6 h. Success was achieved in seven patients, leading to a residual lesion of 29 +/- 7%. In the two patients for whom PTCA was unsuccessful, total reocclusion occurred prior to the attempt despite therapy with heparin, aspirin, dipyridamole, and nifedipine. All PTCA procedures were uncomplicated. Serial two-dimensional echocardiography at 10 days, compared to admission, demonstrated infarct zone wall motion index improvement in the patients with successful PTCA (group A, 0.83 +/- 0.36 to 1.46 +/- 0.49) as compared to the 13 patients without thrombolysis or successful PTCA (group B, 0.61 +/- 0.26 to 0.66 +/- 0.39), (P less than 0.05). One patient of group A sustained a massive stroke at 2 weeks after hospital discharge. In the remaining six patients, follow-up exercise testing and/or coronary arteriography demonstrated a negative treadmill test and/or patent infarct vessel, respectively. After successful PTCA, no patient had clinical signs of reocclusion, reinfarction, postinfarction angina, or congestive heart failure. At 9.4 +/- 2 months, all six patients are asymptomatic and have returned to work. Thus, sequential PTCA after t-PA can be performed safely and successfully in patients with MI and this approach may be associated with improved regional function and a favorable post-MI course.

To determine the effect of thrombolytic therapy and/or immediate coronary angioplasty (PTCA) on left ventricularfunction. 129 patients with acute transmural myocardial infarction were retrospectively studied. Treatment strategies included thrombolytic therapy alone (n = 29), PTCA alone (n = 41), and combined thrombolytic therapy and PTCA (n = 59). Left ventricular ejection fraction (LVEF) and infarct zone regional wall motion (R WM) were determined from contrast ventriculography obtained acutely and at day 7-10. In the overall group, there was a 2 & 9% increase in LVEF (p < 0.02) and a 0.7 f 1.2 SD/chord increase in R WM (p < 0.0001) between day 1 and day 7-10. Patients with a patent infarct vessel at day 7-10 had a more significant change (A) in LVEF (3 f 8 vs -5 & 996, p = 0.0002) and RWM (0.8 f 1.2 vs 0.1 A 1.0 SD/chord, p < 0.02) than patients with .an occluded vessel. Patients with a residual stenosis < 70% at day 7-10 manifested a greater MVEF (3 f 8 vs -5 f 9%. p < 0.01) and ARWW (0.9 k 1.2 vs 0.1 1.0 SD/ chord, p < 0.05) than patients who were occluded. There was a negative correlation between residual