A comprehensive genetic association study of Alzheimer disease in African Americans.

OBJECTIVES: To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites. DESIGN: We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population. SUBJECTS: Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects. SETTING: Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study. RESULTS: Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P = .0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes. CONCLUSIONS: Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific.

Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance.

OBJECTIVES: Our purpose was to characterize the pattern and distribution of left ventricular (LV) hypertrophy by cardiovascular magnetic resonance (CMR) to more precisely define phenotypic expression and its clinical implications in hypertrophic cardiomyopathy (HCM). BACKGROUND: Based on prior pathologic and 2-dimensional echocardiographic studies, HCM has been regarded as a disease characterized by substantial LV wall thickening. METHODS: Cine and late gadolinium enhancement CMR were performed in 333 consecutive HCM patients (age 43 +/- 17 years). RESULTS: Basal anterior LV free wall and the contiguous anterior ventricular septum were the most commonly hypertrophied segments (n = 256; 77%). LV hypertrophy was focal (involving < or = 2 segments [< or = 12% of LV]) in 41 patients (12%), intermediate (3 to 7 segments [13% to 49% of LV]) in 112 patients (34%), and diffuse (> or = 8 segments [> or = 50% of LV]) in 180 patients (54%); 42 patients (13%) showed hypertrophied segments separated by regions of normal thickness. The number of hypertrophied segments was greater in patients with LV outflow tract obstruction (> or = 30 mm Hg) than without (10 +/- 4 vs. 8 +/- 4 per patient; p = 0.0001) and was associated with an advanced New York Heart Association functional class (p = 0.007). LV wall thickness was greater in segments with late gadolinium enhancement than without (20 +/- 6 mm vs. 16 +/- 6 mm; p < 0.001). We also identified 40 (12%) of HCM patients with segmental LV hypertrophy largely confined to the anterolateral free wall, posterior septum, or apex, which was underestimated or undetected by echocardiography. CONCLUSIONS: Although diverse, patterns of LV hypertrophy are usually not extensive in HCM, involving < or = 50% of the chamber in about one-half the patients, and are particularly limited in extent in an important minority. Contiguous portions of anterior free wall and septum constituted the predominant region of wall thickening, with implications for clinical diagnosis. These observations support an emerging role for CMR in the contemporary evaluation of patients with HCM.

Clinical profile and significance of delayed enhancement in hypertrophic cardiomyopathy.

BACKGROUND: Contrast-enhanced cardiovascular magnetic resonance with delayed enhancement (DE) can provide in vivo assessment of myocardial fibrosis. However, the clinical significance of DE in hypertrophic cardiomyopathy (HCM) remains unresolved. METHODS AND RESULTS: Cine and cardiovascular magnetic resonance with DE were performed in 202 HCM patients (mean age, 42+/-17 years; 71% male), DE was compared with clinical and demographic variables, and patients were followed up for 681+/-249 days for adverse disease events. DE was identified in 111 (55%) HCM patients, occupying 9%+/-11% of left ventricular myocardial volume, including >25% DE in 10% of patients. The presence of DE was related to occurrence of heart failure symptoms (P=0.05) and left ventricular systolic dysfunction (P=0.001). DE was present in all patients with ejection fraction < or =50% but also in 53% (102/192) of patients with preserved ejection fraction (P<0.001); %DE was both inversely related to (r=-0.3; P<0.001) and an independent predictor of ejection fraction (r=-0.4; P<0.001). DE (7%+/-7% of left ventricle) was present in 54 patients who were asymptomatic (and with normal ejection fraction). Over the follow-up period, the annualized adverse cardiovascular event rate in patients with DE exceeded that in patients without DE but did not achieve statistical significance (5.5% versus 3.3%; P=0.5). CONCLUSIONS: In a large HCM cohort, DE was an independent predictor of systolic dysfunction but with only a modest relationship to heart failure symptoms. These data suggest an important role for myocardial fibrosis in the clinical course of HCM patients but are not sufficient at this time to consider DE as an independent risk factor for adverse prognosis.

Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial.

BACKGROUND: Using a transcriptional profiling approach, we recently identified myeloid-related protein 8/14 (MRP-8/14) to be expressed by platelets during acute myocardial infarction (MI). Elevated concentrations of MRP-8/14 are associated with a higher risk for future cardiovascular events in apparently healthy individuals but have not been assessed with respect to prognosis in patients with acute coronary syndrome. METHODS: We performed a nested case-control study (n = 237 case-control pairs) among patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial (mean follow-up 24 months) to investigate the risk of cardiovascular death or MI associated with MRP-8/14 measured at 30 days after an acute coronary syndrome. RESULTS: Patients with cardiovascular death or MI after 30 days (cases) had higher median [25th, 75th percentile] MRP-8/14 levels than patients who remained free of recurrent events (5.6 [2.8, 13.5] mg/L vs 4.0 [1.9, 10.1] mg/L, P = .020). The risk of a recurrent cardiovascular event increased with each increasing quartile of MRP-8/14 (P-trend = 0.007) such that patients with the highest levels had a 2.0-fold increased odds (95% CI 1.1-3.6, P = .029) of a recurrent event after adjusting for standard risk indicators, randomized treatment, and C-reactive protein. Patients with elevated levels of MRP-8/14 and high-sensitivity C-reactive protein showed significantly increased risk of cardiovascular death or MI compared with patients with the lowest levels of both markers (adjusted odds ratio 2.1, 95% CI 1.2-3.8). CONCLUSIONS: Myeloid-related protein 8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.

Association of platelet counts on presentation and clinical outcomes in ST-elevation myocardial infarction (from the TIMI Trials).

Platelet activation and aggregation play pivotal roles in the thrombotic process of acute coronary syndromes. However, data regarding platelet count and its association with clinical outcomes in the setting of ST-elevation myocardial infarction (STEMI) are limited. We hypothesized that higher platelet counts on presentation would be associated with poorer clinical outcomes. Data from 10,793 patients with STEMI in the Thrombolysis In Myocardial Infarction (TIMI) trials database were analyzed. Mean platelet count on presentation was 254.8 x 10(3)/microl. Higher platelet counts were associated with higher rates of adverse clinical outcomes at 30 days. In a multivariable analysis that adjusted for confounders of platelet counts (age, gender, weight, diabetes, and smoking), higher platelet counts remained associated with an increased risk of the combined end point of death, reinfarction, and congestive heart failure. With a reference group of platelet counts <200 x 10(3)/microl, the multivariable odds ratios were 1.22 (95% confidence interval 1.05 to 1.42, p = 0.009) for platelet counts of 201 to 300 x 10(3)/microl, 1.37 (95% confidence interval 1.11 to 1.68, p = 0.002) for counts of 301 to 400 x 10(3)/microl, and 1.71 (95% confidence interval 1.16 to 2.51, p = 0.005) for counts >400 x 10(3)/microl. Further, a greater decrease in follow-up platelet counts (compared with baseline values) was independently associated with an increased risk of reinfarction at 30 days (odds ratio 1.44 for every decrease of 100 x 10(3)/microl unit of platelets, 95% confidence interval 1.13 to 1.82, p = 0.03). In conclusion, in STEMI, a higher platelet count on presentation was independently associated with adverse clinical outcomes, whereas a greater subsequent platelet count decrease was associated with an increased risk of reinfarction.

Administration of intracoronary eptifibatide during ST-elevation myocardial infarction.

Distal embolization of atherothrombotic material during primary percutaneous coronary intervention (PCI) is associated with impaired myocardial perfusion, abnormal left ventricular function, and higher mortality. At high local concentrations, glycoprotein IIb/IIIa receptor antagonists have been demonstrated to promote clot disaggregation in vitro. Intracoronary administration of eptifibatide in vivo may increase local drug concentration by several orders of magnitude and promote clot disaggregation with a minimal increase in systemic drug concentrations. We hypothesized that intracoronary administration of eptifibatide before primary PCI for ST-elevation myocardial infarction would be safe and would be associated with high rates of normal myocardial perfusion. Clinical and angiographic data were pooled from patients who underwent primary PCI and received intracoronary eptifibatide as part of clinical practice. In-hospital adverse events were collected retrospectively. No deaths, urgent revascularizations, or reinfarctions were observed among the 59 patients who were treated with intracoronary eptifibatide. There were no Thrombolysis In Myocardial Infarction (TIMI) major bleeding events. Two TIMI minor bleeding events were noted. Normal TIMI myocardial perfusion grade 3 flow after PCI was noted in 54.4% of patients. No adverse events. including arrhythmias, were noted during intracoronary eptifibatide administration. In conclusion, intracoronary eptifibatide can be administered safely during primary PCI and is associated with few adverse events. Relatively high rates of normal myocardial perfusion were observed after primary PCI with adjunctive intracoronary eptifibatide. Further prospective randomized trials are warranted to evaluate the efficacy and safety of intracoronary eptifibatide.

Angiographic and clinical outcomes associated with direct versus conventional stenting among patients treated with fibrinolytic therapy for ST-elevation acute myocardial infarction.

The present study reports outcomes of direct stenting versus conventional stenting, which was performed during adjunctive/rescue percutaneous coronary intervention (n = 556) in the Integrilin and Tenecteplase in Acute Myocardial Infarction trial, the Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction-Thrombolysis in Myocardial Infarction 23 trial, and the Fibrinolytic and Aggrastat ST-Elevation Resolution trial of fibrinolytic therapy in ST-elevation myocardial infarction. Direct stenting was associated with a lower rate of death, myocardial infarction, or congestive heart failure during hospitalization and at 30 days and was independently associated with improved in-hospital outcomes (odds ratio 0.44, 95% confidence interval 0.23 to 0.85, p = 0.014).