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Aims To evaluate outcomes of percutaneous left atrial appendage closure (LAAC) in patients with congestive heart failure (CHF) and non‐valvular atrial fibrillation (AF) in a consecutive, industry‐independent registry associated with periprocedural success and complications during long‐term follow‐up. Methods and results For this analysis, we included patients who underwent transcatheter LAAC from January 2014 to December 2019 at the University Heart Center in Lübeck, Germany, and compared patients with presence of CHF defined as patients with a reduced left ventricular ejection fraction (LVEF ≤ 40%), patients with a mid‐range LVEF (LVEF 41–49%), patients with diastolic dysfunction and preserved LVEF (LVEF ≥ 50%), and patients with right‐sided heart failure and impaired right ventricular function (tricuspid annular plane systolic excursion

Objectives To compare the Watchman™ versus Amulet™ left atrial appendage closure (LAAC) devices in a consecutive, industry-independent registry. Background Data reporting a head-to-head comparison between Amulet and Watchman devices are scarce. Methods Patients who underwent LAAC using Watchman or Amulet devices from January 2014 to December 2019 at the University Heart Center Lübeck, Lübeck, Germany were included in the present analysis. Primary endpoints included periprocedural complications (in-hospital death, pericardial tamponade, device embolization, stroke, major bleeding and vascular access complications), and complications during 2-year-follow-up (ischemic stroke, hemorrhagic stroke, thromboembolism, device thrombus, bleeding and death). Results After matching the patients for age (± 5 years), gender, CHA2DS2Vasc score (± 1) and HASBLED score (± 1), each of the Watchman and the Amulet groups included 113 patients. Patients in the Amulet group had significantly more periprocedural complications (2.7% vs 10.6%, p = 0.029; respectively) and more major bleeding complications (0% vs 5.3%, p = 0.029; respectively). During 2-year follow-up, the rate of events was comparable between the Watchman and Amulet groups (18.3% versus 20.8%, p = 0.729; respectively). Conclusion Amulet LAAC device was associated with increased periprocedural complications as compared to Watchman LAAC device. On 2-year follow-up, both devices showed comparable efficacy and safety.

Percutaneous edge-to-edge repair for mitral regurgitation (MR) is an established method to treat MR in patients not eligible for a surgical approach. Although the largest experience has been gathered with the MitraClip system (Abbott, Chicago, Illinois) ([1][1]), with the PASCAL (Edwards

Background The results of studies investigating the clinical benefit of a direct stenting (DS) strategy in ST-elevation myocardial infarction (STEMI) are inconsistent and data regarding cardiac magnetic resonance (CMR) parameters of myocardial injury are lacking. The aim of this study was to investigate the effect of DS on myocardial damage in comparison to a conventional stenting technique (CS) with predilation in patients with reperfused STEMI. Methods In a subanalysis of the randomized LIPSIA CONDITIONING trial ( NCT02158468 ), STEMI patients were stratified according to the percutaneous coronary intervention technique into the DS (n = 171) or CS (n = 171) group after matching the patients for age (±5 years), gender, and TIMI flow before coronary intervention. Patients underwent CMR imaging within one week after infarction. Clinical outcome (death, reinfarction, hospitalization for heart failure) was assessed within 6 months after the index event. Results Patients in the DS group had significantly lower infarct size (16 vs. 19% of left ventricular mass; p = 0.046) and microvascular obstruction with significant improvement of left ventricular parameters, which was associated with favorable clinical outcome with a lower incidence of heart failure hospitalizations (4% vs. 11%, p = 0.011) and mortality (5% vs. 12%, p = 0.034) as compared to patients with CS. In multivariate Cox regression analysis, DS was identified as an independent predictor of reduced mortality (HR 0.30, 95% CI 0.11–0.87, p = 0.026). Conclusion In patients with acute reperfused STEMI, DS is safe and feasible with a significant reduction of infarct size compared to CS and subsequent lower incidence of heart failure hospitalizations and mortality.

Background Intravenous morphine administration can adversely affect platelet inhibition induced by P2Y 12 receptor inhibitors after acute myocardial infarction. In contrast, some evidence suggests that opioid agonists may have cardioprotective effects on the myocardium. The aim of this prospective, randomized MonAMI (Impact of Morphine Treatment With and Without Metoclopramide Coadministration on Platelet Inhibition in Acute Myocardial Infarction) trial was, therefore, to investigate the impact of morphine with or without metoclopramide coadministration on myocardial and microvascular injury. Methods and Results Patients with acute myocardial infarction (n=138) were assigned in a 1:1:1 ratio to ticagrelor 180 mg plus: (1) intravenous morphine 5 mg (morphine group); (2) intravenous morphine 5 mg and metoclopramide 10 mg (morphine+metoclopramide group); or (3) intravenous placebo (control group) administered before primary percutaneous coronary intervention. Cardiac magnetic resonance imaging was performed in 104 patients on day 1 to 4 after the index event. Infarct size was significantly smaller in the morphine only group as compared with controls (percentage of left ventricular mass, 15.5 versus 17.9; P =0.047). Furthermore, the number of patients with microvascular obstruction was significantly lower after morphine administration (28% versus 54%; P =0.022) and the extent of microvascular obstruction was smaller (percentage of left ventricular mass, 0 versus 0.74; P =0.037). In multivariable regression analysis, morphine administration was independently associated with a reduced risk for the occurrence of microvascular obstruction (odds ratio, 0.37; 95% CI, 0.14–0.93 [ P =0.035]). There was no significant difference in infarct size ( P =0.491) and extent ( P =0.753) or presence ( P =0.914) of microvascular obstruction when comparing the morphine+metoclopramide group with the control group. Conclusions In this randomized study, intravenous administration of morphine before primary percutaneous coronary intervention resulted in a significant reduction of myocardial and microvascular damage following acute myocardial infarction. This effect was not observed in the morphine plus metoclopramide group. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02627950.

Background Left atrial appendage closure (LAAC) has emerged as an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation and may be especially attractive in patients with high risk or a history of bleeding. However, data of clinical benefit and incidence of post-procedural bleeding in patients with both high risk of bleeding and ischemic cerebral stroke after LAAC are lacking. Objectives This study sought to identify predictors and the prognostic impact of post-LAAC bleeding in patients at high risk and/or history of bleeding in the direct oral anticoagulant therapy (DOAC) era. Methods and results We retrospectively enrolled a total of 195 patients (75 ± 8.7 years, 38% female, 47% with previous major bleeding, mean CHA2DS2-VASc score 4.3 ± 1.6 and mean HAS-BLED score 2.7 ± 1.1) undergoing endocardial (91%) or epicardial (9%) LAAC during a mean follow-up of 339 ± 319 days. Twenty-three (11.9%) patients developed procedure-unrelated bleeding events after a median of 147 (43, 362) days after LAAC, in 12/23 (52%) patients under single antiplatelet therapy (SAPT), 6/23 (26%) dual antiplatelet therapy (DAPT), 1/23 (4%) DOAC, 1/23 (4%) VKA, 2/23 (9%) dual therapy (SAPT and DOAC/VKA) and 1/23 (4%) triple therapy (DAPT and DOAC/VKA). (Figure) Diabetes mellitus and previous major bleeding were identified as the independent predictors of post-LAAC bleeding (Odds ratio 2.65 [95% CI:1.04-6.73], p = 0.041, and 5.50 [95% confidence interval:1.72-17.5], p = 0.004). Post-LAAC bleeding was associated with all-cause death (9/23 [39%] vs 18/171 [11%], p = 0.001), but not ischemic stroke/TIA (1/23 [4%] vs 6/171 [4%], p = 0.593) nor device thrombus (2/23 [9%] vs 3/171 [2%], p = 0.108). Kaplan-Meier curve estimated that patients with post-LAAC bleeding had a worse mortality than those without post-LAAC bleeding (3-year mortality; 35.6% [95%CI; 11.6-61.0%] vs 68.7% [45.0-83.8], p = 0.029) Conclusions In AF patients with high bleeding risk or history of bleeding undergoing LAAC, bleeding events are common and may occur even after long-term duration after LAAC. Previous major bleeding history strongly predicts subsequent bleeding events following LAAC and is associated with unfavorable mortality. Further investigations are required to identify optimal post-procedural antithrombotic strategies for patients undergoing LAAC with previous major bleeding. Abstract Figure. The association between time to bleeding

Aims The aim of the current study was to investigate the impact of a chronic total occlusion (CTO) in a non-infarct-related coronary artery (non-IRA) on one-year mortality and occurrence of cardiac arrhythmia in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI). Methods and results In a retrospective sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II trial (IABP-SHOCK II) and its accompanying registry, 201 (26%) of 761 patients had a CTO in a non-IR major coronary artery. Mortality was significantly higher in the CTO group at day of admission (19% vs. 11%; p=0.005), 30 days (53% vs. 41%, p=0.002), and 12 months (63% vs. 51%, p=0.002). In the adjusted multivariate Cox regression analysis, a CTO in a non-IRA was an independent predictor of mortality at 12 months (hazard ratio 1.30, 95% confidence interval [CI]: 1.02-1.67, p=0.03). At 30-day follow-up, ventricular arrhythmias requiring defibrillation occurred more frequently in patients with non-IRA CTO in the univariate analysis (33% vs. 21%, odds ratio 1.83, 95% CI: 1.28-2.62, p=0.002). Conclusions In patients with CS complicating AMI, the presence of CTO in a non-IRA is associated with a higher incidence of ventricular arrhythmias and is an independent predictor of mortality at 12-month follow-up.

The most prominent procedure-related and thus modifiable risk factor for contrast-induced acute kidney injury is contrast media (CM) volume. The DyeVert™ system has been designed to reduce the amount of CM. The primary objective of this randomised controlled trial was thus to examine whether the novel DyeVert™ contrast reduction system (Osprey Medical Inc., Minnetonka, MN, USA) leads to a reduction in CM volume in patients undergoing diagnostic coronary angiography.Patients scheduled for a diagnostic coronary angiogram were randomised to angiography with or without the DyeVert™ system. The primary efficacy endpoint was mean CM volume. Image quality was evaluated by an independent reviewer blinded to treatment allocation.A total of 96 patients underwent randomisation. Baseline characteristics were well balanced between groups. Use of the DyeVert™ system resulted in a significant 41.0% reduction in CM volume (36.9±10.9mL versus 62.5±12.7mL, p0.001). Image quality using the DyeVert™ system was non-inferior compared to control (p=0.03). There were no device-related adverse events.The DyeVert™ system leads to significant reduction in CM volume in patients undergoing diagnostic coronary angiography, while maintaining image quality.

There is an ongoing debate on potential differences in outcome between ST-segment elevation myocardial infarction (STEMI) patients presenting outside of usual hospital working hours (“off-hours”) compared with patients presenting during classical working hours (“on-hours”) [(1,2)][1]. The

Background This study analyzed the effects on long‐term outcome of residual mitral regurgitation ( MR ) and mean mitral valve pressure gradient ( MVPG ) after percutaneous edge‐to‐edge mitral valve repair using the MitraClip system. Methods and Results Two hundred fifty‐five patients who underwent percutaneous edge‐to‐edge mitral valve repair were analyzed. Kaplan–Meier and Cox regression analyses were performed to evaluate the impact of residual MR and MVPG on clinical outcome. A combined clinical end point (all‐cause mortality, MV surgery, redo procedure, implantation of a left ventricular assist device) was used. After percutaneous edge‐to‐edge mitral valve repair, mean MVPG increased from 1.6±1.0 to 3.1±1.5 mm Hg ( P MR severity to ≤2+ postintervention was achieved in 98.4% of all patients. In the overall patient cohort, residual MR was predictive of the combined end point while elevated MVPG >4.4 mm Hg was not according to Kaplan–Meier and Cox regression analyses. We then analyzed the cohort with degenerative and that with functional MR separately to account for these different entities. In the cohort with degenerative MR , elevated MVPG was associated with increased occurrence of the primary end point, whereas this was not observed in the cohort with functional MR . Conclusions MVPG >4.4 mm Hg after MitraClip implantation was predictive of clinical outcome in the patient cohort with degenerative MR . In the patient cohort with functional MR , MVPG >4.4 mm Hg was not associated with increased clinical events.

Aims Patients with heart failure and severe mitral regurgitation (MR) have a poor prognosis and carry an increased risk for ventricular arrhythmias. The present study evaluates the impact of transcatheter mitral valve repair using the MitraClip on the potential reduction of ventricular arrhythmias. Methods and results Patients undergoing MitraClip implantation were prospectively enrolled into the present study and received 24 h Holter ECG assessment prior to and 6 months after the procedure. In addition, left ventricular dimensions and function were assessed at baseline and follow-up. A total of 50 patients with mainly functional MR (82%) were included. Non-sustained or sustained ventricular tachycardia (nsVT and/or sVT) occurred in 32% of patients and was reduced to 14% at follow-up (P = 0.01). Also, premature ventricular complex (PVC) burden ≥5% decreased from 16% to 4% (P = 0.04). Patients with persistent (n = 6) or new (n = 1) nsVT and/or sVT at follow-up showed a significant decrease in left ventricular ejection fraction from 38% (interquartile range 26–45%) to 33% (interquartile range 22–44%; P = 0.03). Conclusions In this prospective study, transcatheter mitral valve repair using MitraClip was associated with a reduced prevalence of ventricular arrhythmias. The subset of patients with persistent or new ventricular arrhythmias after MitraClip implantation showed progression of left ventricular dysfunction.

Background— Atrial fibrillation (AF) is frequently observed in patients with ST-segment–elevation myocardial infarction and associated with worse clinical outcome. However, the mechanisms for this increased risk are not fully understood. The purpose of this study was to investigate the relationship of the presence of AF to cardiac magnetic resonance (CMR) derived myocardial salvage and damage as well as clinical outcomes. Methods and Results— This multicenter CMR study enrolled 786 patients with ST-segment–elevation myocardial infarction. CMR parameters (infarct size, myocardial salvage index, microvascular obstruction, and myocardial function) were assessed 3 (interquartile range [IQR], 2–4) days post-ST-segment–elevation myocardial infarction and compared between patients with or without AF during hospitalization. Major adverse cardiac events were assessed as a composite of all-cause death, reinfarction, and new congestive heart failure at 12 months. AF was documented in 48 (6.1%) patients. There was no significant difference in infarct size (18 [IQR, 9–29]% versus 17 [IQR, 9–25]% of left ventricular mass; P =0.340), myocardial salvage index (51 [IQR, 34–69] versus 51 [IQR, 33–69]; P =0.830), or microvascular obstruction (0.6 [IQR, 0–2.0]% versus 0.0 [IQR, 0–1.8]% of left ventricular mass; P =0.340) between groups. Patients with AF had significantly lower left ventricular (47 [IQR, 34–54]% versus 51 [IQR, 44–58]%; P =0.003) and left atrial (42 [IQR, 17–57]% versus 53 [IQR, 45–59]%; P P =0.0120) or CMR prognosis markers (odds ratio, 3.77 [95% confidence interval, 1.83–7.79]; P =0.001). Conclusions— This CMR study found no major differences in myocardial salvage, infarct size, or microvascular damage in patients with ST-segment–elevation myocardial infarction or without AF. AF was, however, associated with cardiac dysfunction and independently related to major adverse cardiac events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00712101.

An 80-year-old male patient with permanent atrial fibrillation, CHA2DS2VASc score of 6, and HAS-BLED score of 5 was referred for implantation of a left atrial appendage occlusion device (LAAO) because of gastrointestinal bleeding under oral anticoagulation. After implantation of a 28-mm AMPLATZER

Background Antecedent hypertension is associated with poor outcome in patients with ST-elevation myocardial infarction (STEMI). Whether differences in myocardial salvage, infarct size and microvascular injury contribute to the adverse outcome is unknown. We investigated the association between antecedent hypertension and cardiovascular magnetic resonance (CMR) parameters of myocardial salvage and damage in a multicenter CMR substudy of the AIDA-STEMI trial (Abciximab Intracoronary versus intravenously Drug Application in ST-elevation myocardial infarction). Methods We analyzed 792 consecutive STEMI patients reperfused within 12 h after symptom onset. Patients underwent CMR imaging for assessment of myocardial salvage, infarct size and microvascular obstruction within 10 days after infarction. Major adverse cardiac events (MACE) were recorded at 12-month follow-up. Results Antecedent hypertension was present in 540 patients (68 %) and was associated with a significantly increased baseline risk profile (advanced age, higher body mass index, higher incidence of diabetes, hypercholesterolemia, previous angioplasty and multivessel disease, p 0.05). Conclusion Despite a higher rate of MACE in contemporary reperfused STEMI patients with antecedent hypertension, there was no difference in reperfusion efficacy, infarct size and reperfusion injury as visualized by CMR. Trial registration NCT00712101.

Objectives This study sought to examine and compare the incidence and progression of coronary artery calcium (CAC) among persons with metabolic syndrome (MetS) and diabetes mellitus (DM) versus those with neither condition. Background MetS and DM are associated with subclinical atherosclerosis as evidenced by CAC. Methods The MESA (Multiethnic Study of Atherosclerosis) included 6,814 African American, Asian, Caucasian, and Hispanic adults 45 to 84 years of age, who were free of cardiovascular disease at baseline. Of these, 5,662 subjects (51% women, mean age 61.0 ± 10.3 years) received baseline and follow-up (mean 2.4 years) cardiac computed tomography scans. We compared the incidence of CAC in 2,927 subjects without CAC at baseline and progression of CAC in 2,735 subjects with CAC at baseline in those with MetS without DM (25.2%), DM without MetS (3.5%), or both DM and MetS (9.0%) to incidence and progression in subjects with neither MetS nor DM (58%). Progression of CAC was also examined in relation to coronary heart disease events over an additional 4.9 years. Results Relative to those with neither MetS nor DM, adjusted relative risks (95% confidence intervals [CI]) for incident CAC were 1.7 (95% CI: 1.4 to 2.0), 1.9 (95% CI: 1.4 to 2.4), and 1.8 (95% CI: 1.4 to 2.2) (all p Conclusions Individuals with MetS and DM have a greater incidence and absolute progression of CAC compared with individuals without these conditions, with progression also predicting coronary heart disease events in those with MetS and DM.

Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score0 by computed tomography) in 6783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p0.01) for IL-6 and 1.18 (1.11-1.24; p0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.

In vivo insulin sensitivity can be assessed using "open loop" clamp or "closed loop" methods. Open loop clamp methods are static, and fix plasma glucose independently from plasma insulin. Closed loop methods are dynamic, and assess glucose disposal in response to a stable isotope labeled glucose tolerance test. Using PPARalpha(-/-) mice, open and closed loop assessments of insulin sensitivity/glucose disposal were compared. Indirect calorimetry done for the assessment of diurnal substrate utilization/metabolic flexibility showed that chow fed PPARalpha(-/-) mice had increased glucose utilization during the light (starved) cycle. Euglycemic clamps showed no differences in insulin stimulated glucose disposal, whether for chow or high fat diets, but did show differences in basal glucose clearance for chow fed PPARalpha(-/-) versus SV129J-wt mice. In contrast, the dynamic stable isotope labeled glucose tolerance tests reveal enhanced glucose disposal for PPARalpha(-/-) versus SV129J-wt, for chow and high fat diets. Area under the curve for plasma labeled and unlabeled glucose for PPARalpha(-/-) was approximately 1.7-fold lower, P0.01 during the stable isotope labeled glucose tolerance test for both diets. Area under the curve for plasma insulin was 5-fold less for the chow fed SV129J-wt (P0.01) but showed no difference on a high fat diet (0.30 +/- 0.1 for SV129J-wt vs. 0.13 +/- 0.10 for PPARalpha(-/-), P = 0.28). This study demonstrates that dynamic stable isotope labeled glucose tolerance test can assess "silent" metabolic phenotypes, not detectable by the static, "open loop", euglycemic or hyperglycemic clamps. Both open loop and closed loop methods may describe different aspects of metabolic inflexibility and insulin sensitivity.

Background Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. Methods Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. Results Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. Conclusions The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population. Copyright © 2009 John Wiley & Sons, Ltd.

Objective To describe the relationship of systemic inflammatory disease, complement factor H ( CFH ) Y402H (1277T→C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. Design Population-based, cross-sectional study. Participants We included 5887 persons aged 45 to 84 years with gradable AMD. Methods Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained. Main Outcome Measure Prevalence of AMD. Results While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ ln ] units, 2.34; 95% confidence interval [CI], 1.33–4.13) and interleukin-6 (OR per SD in ln , 2.06; 95% CI, 1.21–3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14–2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06–1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14–3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00–3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10–2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09–3.10), and large drusen area (OR, 1.66; 95% CI, 1.02–2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. Conclusions This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

Background— Use of 3-hydroxyl-3-methylglutaryl-3 coenzyme A reductase (HMGCR) inhibitors, or statins, reduces cardiovascular disease risk by lowering plasma low-density lipoprotein cholesterol (LDL-C) concentrations. However, LDL-C response is variable and influenced by many factors, including racial ancestry, with attenuated response in blacks compared with whites. We hypothesized that single nucleotide polymorphisms in the gene encoding HMGCR , a rate-limiting enzyme in cholesterol synthesis and the direct enzymatic target of statins, contribute to variation in statin response. Methods and Results— Genomic resequencing of HMGCR in 24 blacks and 23 whites identified 79 single nucleotide polymorphisms. Eleven single nucleotide polymorphisms were selected to tag common linkage disequilibrium clusters. These single nucleotide polymorphisms and the common haplotypes inferred from them were tested for association with plasma LDL-C and LDL-C response to simvastatin treatment (40 mg/d for 6 weeks) in 326 blacks and 596 whites. Black carriers of H7 and/or H2 had significantly lower baseline LDL-C ( P =0.0006) and significantly attenuated LDL-C response compared with black participants who did not carry either haplotype as measured by absolute response (−1.23±0.04 mmol/L, n=209, versus −1.45±0.06 mmol/L, n=117; P =0.0008) and percent response (−36.9±1.0% versus −40.6±1.3%; P =0.02), but no haplotype effect was observed in whites. Percent LDL-C response was lowest in carriers of both H2 and H7, all but one of whom were black (−28.2±4.9%, n=12 H2+H7 carriers, versus −41.5±0.5%, n=650 H2/H7 noncarriers; P =0.001). LDL-C responses in H7 and/or H2 noncarriers were indistinguishable between blacks and whites. Conclusions— HMGCR gene polymorphisms are associated with reduced plasma LDL-C and LDL-C response to simvastatin, and these effects are most evident in blacks.

The metabolic syndrome (MetS) is a cluster of abnormalities that increases cardiovascular risk. Two different current clinical definitions of MetS, World Health Organization (WHO) and National Cholesterol Education Program (NCEP) Adult Treatment Panel 3 (ATPIII) may differ in association with the atherosclerotic process. We quantified the agreement between the WHO and NCEP definitions and their association with subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).We analyzed 2601 Caucasian-Americans (C), 800 Chinese-Americans (Ch), 1864 African-Americans (A), and 1483 Hispanic-Americans (H) with complete data for MetS classification from the baseline of the population-based study MESA. Coronary artery calcification (CAC, Agatston score) was quantified by electron beam or helical computed tomography (CT), and intimal-medial thickness of internal and common carotid arteries (IIMT, CIMT) by B-mode ultrasound.The percentage positive agreement differed by ethnicity (Men: C, 65%; Ch, 58%; B, 67%; H, 74%. Women: C, 58%; Ch, 67%; A, 69%; H, 71%; P.001). Fasting insulin measurement added to the association of the NCEP definition with presence of CAC (P.001) and CIMT (P.001, men; P.002, women), while the waist-hip ratio metric of obesity adds to the association with CIMT (P.001, men; .003, women). The NCEP threshold for low HDL was associated with CIMT independent of the WHO definition (men, P = .035; women, P = .043). These independent associations did not differ by ethnicity.Metabolic risk factors that differ between the NCEP and WHO MetS definitions are useful in combination to assess the presence of subclinical atherosclerosis.

OBJECTIVE—To investigate the association of insulin resistance and clinically defined metabolic syndrome (MetS) with subclinical atherosclerosis and examine whether these relationships vary by race/ethnicity or sex. RESEARCH DESIGN AND METHODS—Subclinical atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-medial thickness (IMT) in 5,810 participants without diabetes in the Multi-Ethnic Study of Atherosclerosis, a cohort of adults aged 45–84 years without prior cardiovascular disease (CVD). Fasting insulin and glucose were utilized to estimate insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) index, and the revised National Cholesterol Education Program definition of MetS was utilized. Multivariable linear or relative risk regression was used to analyze the association between HOMA-IR and subclinical atherosclerosis and assess its independence from MetS components. RESULTS—HOMA-IR was associated with increased IMT after adjustment for demographics (age, site, and education), smoking, education, and LDL cholesterol in each ethnic group, except Hispanic subjects, and in both men and women. After further adjusting for nonglucose MetS components, HOMA-IR was not associated with increased IMT. Subjects in the highest quintile of HOMA-IR had an elevated prevalence of CAC in each ethnic group and both sexes, after adjustment for demographics, smoking, and LDL but not after further adjustment for nonglucose MetS components. Among those with detectable CAC, there was no significant relationship between HOMA-IR and the amount of CAC. CONCLUSIONS—Although HOMA-IR was associated with increased subclinical atherosclerosis, the association was not independent of the risk factors that comprise MetS. Determination of HOMA-IR is unlikely to contribute to improved determination of risk of subclinical CVD.

Background On average, angiotensin-converting enzyme inhibitors produce less office blood-pressure lowering in African Americans compared with Caucasians. Past studies did not compare daytime and nighttime ambulatory blood-pressure responses to angiotensin-converting enzyme inhibitors in African Americans and Caucasians. Methods We measured the office and ambulatory blood-pressure response to 8 weeks of a fixed dose of 10 mg daily of the angiotensin-converting enzyme inhibitor ramipril in a cohort of 72 African Americans and 89 Caucasians. Results Ramipril lowered age-adjusted daytime ambulatory systolic blood pressure 6 mm Hg and diastolic blood pressure 3 mm Hg less in African Americans compared with Caucasians (both P = .02). This difference persisted after adjusting for baseline blood pressure, body mass index, urine sodium and potassium, plasma aldosterone, and other covariates. Despite the difference in mean response, there was a 72% overlap in daytime blood-pressure response to ramipril between African Americans and Caucasians. Among Caucasians, ramipril lowered systolic blood pressure 2 mm Hg less during nighttime compared with daytime, whereas among African Americans, blood pressure lowering was equivalent during day and night. Nighttime blood-pressure response to ramipril did not differ significantly between African Americans and Caucasians. Conclusions Ramipril was more effective in lowering daytime blood pressure in Caucasians compared with African Americans, but appreciable differences in response did not persist at night. Despite the small difference in mean response between groups, the majority of African Americans and Caucasians had a similar blood-pressure response to a fixed dose of ramipril.

Context: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance have been reported, very little data are available from studies using detailed measures of insulin sensitivity (SI) and/or body fat distribution in ethnic groups at high risk for metabolic disease. Objective: The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans. Design: A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. SI was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration. Setting: A multicenter study using a family-based design was conducted. Participants: A total of 1636 nondiabetic Hispanic and African-American subjects participated. Main Outcome Measures: Circulating adiponectin concentration was measured. Results: Age, female gender, high-density lipoprotein, SAT, and SI were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics. Conclusion: Directly measured SI, VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.

Previous studies showing that smaller low-density lipoprotein (LDL) size is associated with greater atherosclerotic risk did not adequately control for small and large LDL particle correlation.We studied the association of lipoproteins measured by proton nuclear magnetic resonance spectroscopy with carotid intima-media thickness (IMT) in apparently healthy individuals (N = 5538, 38% White, 28% African American, 22% Hispanic, 12% Chinese). Small and large LDL particle concentrations (LDL-p) were inversely correlated (r = /-0.63, P0.0001). Controlling for risk factors but not for LDL subclass correlation, LDL size and small LDL-p separately were associated with IMT (-20.9 and 31.7 microm change in IMT per 1-S.D., respectively, both P0.001), but large LDL-p was not (4.9 microm, P = 0.27). When LDL subclasses were included in the same model, large and small LDL-p were both associated with IMT (36.6 and 52.2 microm higher IMT per 1-S.D., respectively, both P0.001; 17.7 and 11.6 microm per 100 nmol/L, respectively). LDL size was not significant after accounting for LDL subclasses and risk factors (P = 0.10).Both LDL subclasses were significantly associated with subclinical atherosclerosis, with small LDL confounding the association of large LDL with atherosclerosis. Future studies of LDL size should account for the strong inverse correlation of LDL subclasses.

Adiposity has been recognized as a risk factor for colorectal adenoma, but the influence of weight gain, adipose tissue distribution, and possible differences between ethnic/racial and gender groups remains unanswered. The aim of this prospective study was to examine the association between adiposity and weight change and colorectal adenoma risk. Over ∼10-year period, anthropometric measures and other risk factors were measured at three time points in the multicenter multiethnic Insulin Resistance Atherosclerosis Study cohort. Colonoscopies were then conducted on 600 cohort participants regardless of symptoms whose mean age at colonoscopy was 64 years. Multivariate logistic regression analyses were used to assess the association between colorectal adenomas and measures of adiposity and weight change over the ∼10-year period before colonoscopy. Obesity was positively associated with risk of colorectal adenomas at the time of colonoscopy [adjusted odds ratio (ORadj), 2.16; 95% confidence interval (95% CI), 1.13-4.14] and was stronger in women (ORadj, 4.42; 95% CI, 1.53-12.78) than in men (ORadj, 1.26; 95% CI, 0.52-3.07). The risk of adenomas increased among participants who gained weight compared with those who maintained weight over the ∼5 years (ORadj, 2.30; 95% CI, 1.25-4.22) and ∼10 years (ORadj, 2.12; 95% CI, 1.25-3.62). These associations were similar for both advanced and nonadvanced adenomas. These results suggest a positive association between obesity, weight gain, and colorectal adenoma risk. Stronger associations were observed when obesity was measured at the time of colonoscopy, suggesting that obesity may be a promoting factor in the growth of colorectal adenomas. (Cancer Epidemiol Biomarkers Prev 2007;16(3):526–31)

High blood pressure (BP) is associated with the presence and severity of subclinical disease. Less is known about associations between normal levels of BP and various measures of subclinical disease.The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled 6814 participants free of clinical cardiovascular disease (38% white, 28% African American, 22% Hispanic, and 12% Asian). The baseline examination included standardized measures of BP, common carotid intimal-medial thickness determined by ultrasonography, coronary artery calcium by computed tomography, and left ventricular mass by magnetic resonance imaging. Participants with treated hypertension (n = 2173) were excluded. Statistical methods included analysis of variance, linear regression, and chi(2) tests.Among the 4640 participants, BP was strongly related to age and African American ethnicity. Carotid intimal-medial thickness was directly associated with systolic BP (SBP) and inversely associated with diastolic BP (DBP, P.001 for both). For SBP in men, for instance, the adjusted regression coefficient was 0.058 mm per 1 SD (21 mm Hg; 95% CI, 0.045 to 0.070), and for SBP in women it was 0.043 (95% CI, 0.033 to 0.052). Left ventricular mass was directly related to SBP and DBP. The proportion with non-zero calcium scores increased with SBP but decreased with DBP.The range of BP examined in this study fell largely within the normal or prehypertension stage. In cross-sectional analysis of data from a population-based study, these untreated levels of BP were associated with a variety of measures of subclinical cardiovascular disease.

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polyporphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.

Purpose of review Automated insulin delivery using the subcutaneous site for both glucose sensing and insulin delivery, while not commercially available, is starting to be implemented in the research environment. Here, we review issues with glucose sensing and insulin delivery algorithms that need to be resolved in order to achieve a closed-loop system. Recent findings Glucose sensing technology is improving. New studies demonstrating minimal delay in the subcutaneous interstitial fluid glucose response are reviewed, together with early studies indicating longer delay. The pharmacokinetics/pharmacodynamics of subcutaneous insulin, which pose a significant obstacle to closing the delivery loop, are also reviewed, together with approaches being used to develop algorithms to overcome the delay in insulin absorption from this site. Closed-loop data using the Medtronic MiniMed external Physiologic Insulin Delivery system are presented. Summary Initial closed-loop data in both animals and humans suggest that a completely automated insulin delivery system is attainable, although substantial research remains to be conducted prior to such a system being available for home patient use.

Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and β-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (Si) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P < 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P < 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region.

Although statins are effective lipid-lowering agents, the phenotypic and demographic predictors of such lowering have been less well examined. We enrolled 944 African-American and white men and women who completed an open-label, 6-week pharmacogenetics trial of 40 mg of simvastatin. The phenotypic and demographic variables were examined as predictors of the change in lipids and lipoproteins using linear regression analysis. On average, treatment with simvastatin lowered low-density lipoprotein (LDL) cholesterol by 54 mg/dl and increased high-density lipoprotein (HDL) cholesterol by 2 mg/dl. Compared with African-Americans, whites had a 3-mg/dl greater LDL reduction and a 1-mg/dl higher HDL elevation, independent of other variables, including baseline lipoprotein levels (p

OBJECTIVE—Studies have demonstrated increased left ventricular mass (LVM) and diastolic dysfunction among diabetic patients without clinical cardiovascular disease (CVD), but few have assessed the potential contribution of subclinical CVD to ventricular abnormalities in diabetes. We examined whether diabetic cardiomyopathy is associated with subclinical atherosclerosis and if abnormalities are found with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS—LVM, end-diastolic volume (EDV), and stroke volume were measured by magnetic resonance imaging (MRI), and atherosclerosis was assessed by coronary artery calcium and carotid intima-media wall thickness in 4,991 participants in the Multi-Ethnic Study of Atherosclerosis, a cohort study of adults aged 45–84 without prior CVD. Multivariable linear regression was used to analyze the association between MRI measures and glucose status. RESULTS—Increased LVM was observed in white, black, and Hispanic participants with diabetes but not among Chinese participants. After adjustment for weight, height, CVD risk factors, and subclinical atherosclerosis, ethnicity-specific differences in ventricular parameters were present. Among whites and Chinese with diabetes, LVM was similar to that in normal subjects; EDV and stroke volume were reduced. In blacks with diabetes, EDV and stroke volume were reduced, and LVM was increased (+5.6 g, P < 0.05). Among Hispanics with diabetes, EDV and stroke volume were similar to normal, but LVM was increased (+5.5 g, P < 0.05). After adjustment, IFG was associated with a decrease in EDV and stroke volume in whites and blacks only; however, no significant differences in LVM were observed. CONCLUSIONS—Ethnicity-specific differences in LVM, EDV, and stroke volume are associated with abnormal glucose metabolism and are independent of subclinical CVD.

Objectives This study sought to test the hypothesis that reduced regional left ventricular (LV) function is associated with traditional risk factors including hypertension, hypercholesterolemia, and smoking in asymptomatic individuals. Background Coronary artery disease is the main etiology of congestive heart failure in the U.S. and Europe. However, the relationship between risk factors for coronary artery disease and decreased myocardial function has not been studied systematically in asymptomatic individuals. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study designed to investigate the nature of atherosclerosis in asymptomatic individuals. A total of 1,184 participants (45 to 84 years old) underwent tagged cardiac magnetic resonance imaging. Regional LV function was quantified by analyzing peak systolic circumferential strain (Ecc) in regions corresponding to the left anterior descending (LAD), circumflex (LCX), and right coronary (RCA) territories. The association between risk factors and strains was studied using multiple linear regression. Results Higher diastolic blood pressure (DBP) was associated with lower Ecc (p ≤ 0.002). The Ecc’s in the LAD territory of participants with DBP Conclusions Higher diastolic blood pressure and smoking are associated with decreased regional LV function in asymptomatic individuals.

To describe the prevalence of age-related macular degeneration (AMD) in 4 racial/ethnic groups (white, black, Hispanic, and Chinese) that participated in the second examination of the Multi-ethnic Study of Atherosclerosis (MESA).Prospective cohort study.Six thousand one hundred seventy-six 45- to 85-year-old subjects selected from 6 United States communities.Fundus images were taken using a 45 degrees digital camera through dark-adapted pupils and were graded for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System.Age-related macular degeneration.Prevalences of AMD were 2.4% (black), 4.2% (Hispanic), 4.6% (Chinese), to 5.4% (white) (P0.001 for any differences among groups). The highest prevalence of any AMD occurred in those 75 to 84 years old, varying from 7.4% in blacks to 15.8% in whites and Chinese (P = 0.03). Estimated prevalences of late AMD were 0.3% (black), 0.2% (Hispanic), 0.6% (white), and 1.0% (Chinese). These differences were marginally significant (age and gender adjusted, P = 0.08). The frequency of exudative AMD was highest in Chinese (age- and gender-adjusted odds ratio, 4.30; 95% confidence interval, 1.30-14.27) compared with whites. Differences in age, gender, pupil size, body mass index, smoking, alcohol drinking history, diabetes, and hypertension status did not explain the variability among the 4 racial/ethnic groups.Low prevalences of AMD were found in the MESA cohort in all groups. A lower prevalence of AMD was found in blacks compared with whites. The higher prevalence of exudative AMD in Chinese needs further study.

We examined the association between urine albumin excretion (UAE) and common and internal carotid artery intima-media thickness (IMT), end-diastolic left ventricular (LV) mass, and coronary artery calcification (CAC) scores using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults aged 45 to 85 years without clinical cardiovascular disease (CVD). The mean age of the MESA participants was 62.7 years, 47% were male, and 15% had diabetes mellitus (DM). Sex-specific spot urine albumin/creatinine ratios were used to define 4 UAE categories: normal, high normal, microalbuminuria, and macroalbuminuria. CAC scores were log-transformed after adding 1 to all scores. Mean values of subclinical CVD measures were computed by level of UAE after adjustment for blood pressure, DM, and other covariates. After adjustment for all covariates, geometric mean CAC scores were higher among participants with high normal UAE (8.8; P =0.07), microalbuminuria (9.9; P =0.002), and macroalbuminuria (13.1; P =0.02) compared with normal UAE (7.4), but only microalbuminuria reached statistical significance. Mean LV mass (g/m 2.7 ) was significantly higher in participants with high normal UAE (37.0; P =0.001), microalbuminuria (38.3; P ≤0.0001), and macroalbuminuria (42.3; P ≤0.0001) compared with normal UAE (36.0) after adjustment for all covariates. No significant difference in mean carotid IMT was found after adjustment for all covariates. Similar results were noted in MESA participants with and without DM. In conclusion, higher UAE, including levels below microalbuminuria, may reflect the presence of subclinical CVD among adults without established CVD.

The authors studied associations between ankle-brachial index (ABI) and subclinical atherosclerosis in the Multi-Ethnic Study of Atherosclerosis. Participants included 3,458 women (average age = 62.6 years) and 3,112 men (average age = 62.8 years) who were free of clinically evident cardiovascular disease. Measurements included ABI, carotid artery intima-media thickness, and coronary artery calcium assessed with computed tomography. Five ABI categories were defined: or =1.30 (high ABI). Compared with that in men with normal ABI, significantly higher internal carotid artery intima-media thickness was observed in men with definite PAD (1.58 vs. 1.09; p < 0.001), borderline ABI (1.33 vs. 1.09; p < 0.001), and low-normal ABI (1.18 vs. 1.09; p < 0.001) after adjustment for confounders. Fully adjusted odds ratios for a coronary artery calcium score greater than 20 decreased across progressively higher ABI categories in both women (2.85 (definite PAD), 1.27 (borderline ABI), 1.11 (low-normal ABI), 1.00 (normal ABI; referent), and 0.78 (high ABI); p for trend = 0.0002) and men (3.26 (definite PAD), 1.72 (borderline ABI), 1.14 (low-normal ABI), 1.00 (normal ABI; referent), and 1.43 (high ABI); p for trend = 0.0002). These findings indicate excess coronary and carotid atherosclerosis at ABI values below 1.10 (men) and 1.00 (women) and may imply increased risk of cardiovascular events in persons with borderline and low-normal ABI.

Background Albuminuria was shown to be heritable and to share common genetic determinants with blood pressure (BP) in individuals of white ethnicity. Our aim in this study was to examine the familial aggregation of albuminuria and its phenotypic, genetic, and environmental correlations with BP in nondiabetic individuals of Hispanic (HA) and African American (AA) ethnicity. Methods The study included 129 large HA and AA families, providing 1405 nondiabetic individuals; those on antihypertensive medications were excluded. The albumin/creatinine ratio (ACR) in a random urine sample was used as a measure of albuminuria. A variance component approach was used in the analysis. Results After adjusting for age, sex, and body mass index (BMI), the heritabilities of ACR, systolic BP (SBP) and diastolic BP (DBP) were 11%, 26%, and 28%. The phenotypic correlations between ACR and each of SBP and DBP in HA ( r = 0.17 and r = 0.16 respectively) and AA ( r = 0.26 and r = 0.16) were significant. When partitioned into genetic and environmental factors, the genetic correlations between ACR and each of SBP and DBP were significant in HA ( r g = 0.49 for each), whereas the environmental correlations were not. Conversely, the genetic correlations between ACR and SBP/DBP were not significant in AA (although with DBP it was not significantly different from that of HA), whereas a significant environmental correlation was observed between ACR and SBP ( r e = 0.28, P Conclusions Both albuminuria and BP exhibit familial aggregation in nondiabetic HA and AA. In HA, but not in AA, ACR and especially SBP share common genetic determinants. The mechanism of this ethnic heterogeneity is unclear but merits further investigation.

Introduction: This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications. Method: Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples. Results: Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used. Conclusions: Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.

Aim Cross-sectional studies have demonstrated a relationship between obesity and insulin sensitivity (S(I)); however, there is a lack of evidence from longitudinal studies. Methods The Insulin Resistance Atherosclerosis Study (IRAS) estimated S(I) (x10(-4)/min.microU/ml) directly using a frequently sampled intravenous glucose tolerance test with minimal model analysis in 504 normoglycaemic subjects. Partial correlation coefficients (r) were calculated to compare the relationship of change in S(I) from baseline to 5 years later (DeltaS(I)) with baseline waist circumference (waist) as a measure of abdominal obesity and body mass index (BMI) as a measure of overall obesity. Mean DeltaS(I) was -1.06 (SD = 1.85). Results Higher baseline waist (r = -0.16; p = 0.0005), but not BMI (r = -0.005; p = 0.91), was associated with (-) DeltaS(I) in models including sex, ethnicity, clinical centre and baseline S(I), BMI, waist, age and physical activity. The waist-DeltaS(I) relationship differed across the levels of baseline BMI, being significant only in normal weight (r = -0.21) and overweight subjects (r = -0.16), but not in obese subjects. DeltaS(I) was correlated with a 5-year change in either obesity measure (Deltawaist: r = -0.22 and DeltaBMI: r = -0.20; p = 0.0001). Conclusions Among non-diabetics, waist circumference was a strong predictor of declining S(I) among lean subjects, a modest predictor among overweight subjects, but was not predictive among obese individuals. Waist circumference should be considered, in addition to BMI, when identifying individuals at high risk of diabetes or the insulin resistance syndrome.

Background— There is substantial evidence that coronary calcification, a marker for the presence and quantity of coronary atherosclerosis, is higher in US whites than blacks; however, there have been no large population-based studies comparing coronary calcification among US ethnic groups. Methods and Results— Using computed tomography, we measured coronary calcification in 6814 white, black, Hispanic, and Chinese men and women aged 45 to 84 years with no clinical cardiovascular disease who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). The prevalence of coronary calcification (Agatston score >0) in these 4 ethnic groups was 70.4%, 52.1%, 56.5%, and 59.2%, respectively, in men ( P P 0 was greatest among whites, followed by Chinese (77% that of whites; 95% CI 62% to 96%), Hispanics (74%; 95% CI 61% to 90%), and blacks (69%; 95% CI 59% to 80%). Conclusions— We observed ethnic differences in the presence and quantity of coronary calcification that were not explained by coronary risk factors. Identification of the mechanism underlying these differences would further our understanding of the pathophysiology of coronary calcification and its clinical significance. Data on the predictive value of coronary calcium in different ethnic groups are needed.

Adipose tissue distribution (visceral vs subcutaneous) has been shown to be an important predictor of insulin resistance, diabetes and cardiovascular disease, independent of body mass index. The beta-2 adrenergic receptor is a major lipolytic receptor in human fat cells and the gene that codes for this protein is an important candidate gene for measures of adiposity and fat deposition. We examined whether two common polymorphisms in codons 16 (Arg16Gly) and 27 (Gln27Glu) are associated with measures of fat distribution in participants of the IRAS Family Study. We recruited African-American (AA) and Hispanic-American (HA) families from Los Angeles, CA, USA (18 pedigrees, 272 AA individuals), San Antonio, TX, USA (33 pedigrees, 448 HA individuals) and San Luis Valley, CO, USA (12 pedigrees, 272 HA individuals). We estimated adipose tissue distribution via computed tomography. To test for an association between adiposity measures and these polymorphisms, we used generalized estimating equations, adjusting for age, gender, clinical site (ethnicity), body mass index, and familial correlation. Of the 992 individuals genotyped for these polymorphisms, 57% were female and 15% had been diagnosed with type 2 diabetes mellitus. The mean age was 42.7±14.6 y. The Glu27 allele of the Gln27Glu polymorphism was positively associated with (P-value for recessive model): body mass index (0.025), visceral adipose tissue (

Plasma insulin and glucose concentrations are important quantitative phenotypes related to diabetes and the metabolic syndrome. Reports purporting to identify quantitative trait loci (QTLs) that contribute to the variation in fasting insulin and glucose concentrations are discrepant. As part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study, a genome scan was performed in African-American (n = 42) and Hispanic (n = 90) extended families to identify regions that may contain positional candidate genes for fasting insulin and fasting glucose (n = 1,604 subjects). There was significant evidence for linkage of fasting insulin to the short arm of chromosome 17 (logarithm of odds [LOD] = 3.30; 54 cM between D17S1294 and D17S1299, P = 1.0 × 10−4). The strongest evidence for linkage over all pedigrees for fasting glucose was also observed in this region (LOD = 1.44; 58 cM, P = 9.9 × 10−3). The results of this study provide impetus for future positional cloning of QTLs regulating insulin and glucose levels. Identifying genes in these regions should provide insight into the nature of genetic factors regulating plasma glucose and insulin concentrations.

To conduct linkage analysis for body mass index (BMI, kg/m2), waist-to-hip ratio (WHR), visceral adipose tissue mass (VAT, cm2) and subcutaneous adipose tissue mass (SAT, cm2) using a whole genome scan. Cross-sectional family study. African-American families from Los Angeles (AA, n=21 extended pedigrees) and Hispanic-American families (HA) from San Antonio, TX (HA-SA, n=33 extended pedigrees) and San Luis Valley, CO (HA-SLV, n=12 extended pedigrees), totaling 1049 individuals in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. VAT and SAT were measured using a computed tomography scan obtained at the fourth and fifth lumbar vertebrae. All phenotypes were adjusted for age, gender, and study center. VAT, SAT, and WHR were analyzed both unadjusted and adjusted for BMI. Significant linkage to BMI was found at D3S2387 (LOD=3.67) in African-Americans, and at D17S1290 in Hispanic-Americans (LOD=2.76). BMI-adjusted WHR was linked to 12q13–21 (D12S297 (LOD=2.67) and D12S1052 (LOD=2.60)) in Hispanic-Americans. The peak LOD score for BMI-adjusted VAT was found at D11S2006 (2.36) in Hispanic families from San Antonio. BMI-adjusted SAT was linked to D5S820 in Hispanic families (LOD=2.64). Evidence supporting linkage of WHR at D11S2006, VAT at D17S1290, and SAT at D1S1609, D3S2387, and D6S1056 was dependent on BMI, such that the LOD scores became nonsignificant after adjustment of these phenotypes for BMI. Our findings both replicate previous linkage regions and suggest novel regions in the genome that may harbor quantitative trait locis contributing to variation in measures of adiposity.