Methods and Results— SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death.

Conclusions— ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components.

Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000609.

Methods and Results— Data were collated from 40 long-term prospective studies involving a total of 87 474 participants and 10 625 incident CVD outcomes. In a comparison of individuals in the top third with those in the bottom third of baseline values of natriuretic peptides, the combined risk ratio (RR), adjusted for several conventional risk factors, was 2.82 (95% confidence interval [CI], 2.40 to 3.33) for CVD. Analysis of the 6 studies with at least 250 CVD outcomes (which should be less prone to selective reporting than are smaller studies) yielded an adjusted RR of 1.94 (95% CI, 1.57 to 2.39). RRs were broadly similar with BNP or NT-proBNP (RR, 2.89 [95% CI, 1.91 to 4.38] and 2.82 [95% CI, 2.35 to 3.38], respectively) and by different baseline vascular risk (RR, 2.68 [95% CI, 2.07 to 3.47] in approximately general populations; RR, 3.35 [95% CI, 2.38 to 4.72] in people with elevated vascular risk factors; RR, 2.60 [95% CI, 1.99 to 3.38] in patients with stable CVD). Assay of BNP or NT-proBNP in addition to measurement of conventional CVD risk factors yielded generally modest improvements in risk discrimination.

Conclusions— Available prospective studies indicate strong associations between circulating concentration of natriuretic peptides and CVD risk under a range of different circumstances. Further investigation is warranted, particularly in large general population studies, to clarify any predictive utility of these markers and to better control for publication bias.

Methods and Results— We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or ≥2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was –6% in the low hs-CRP group (27% with placebo) and –33.3% in the high hs-CRP group (–11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026).

Conclusion— In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP ≥2.0 mg/L.

Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Methods and Results— We followed up 5200 elderly patients (41% exercise) after dual-isotope MPS over 2.8±1.7 years (362 cardiac deaths [CDs], 7.0%, 2.6%/y) and a subset with extended follow-up (684 patients for 6.2±2.9 years; 320 all-cause deaths). Survival modeling of CD revealed that both MPS-measured ischemia and fixed defect added incrementally to pre-MPS data in both adenosine and exercise stress patients. Modeling a subset with gated MPS (n=2472) revealed that ejection fraction and perfusion data added incrementally to each other, further enhancing risk stratification. Unadjusted, annualized post–normal MPS CD rate was 1.3% but <1% in patients with normal rest ECG, exercise stress, or age of 75 to 84 years and was 2.3% to 3.7% in patients ≥85 years of age or undergoing pharmacological stress. However, compared with age-matched US population CD rates (75 to 84 years of age, 1.5%; ≥85 years, 4.8%), normal MPS CD rates were approximately one-third lower than the baseline risk of US individuals (both P<0.05). Modeling of all-cause death in 684 patients with extended follow-up revealed that after risk adjustment, an interaction between early treatment and ischemia was present; increasing ischemia was associated with increasing survival with early revascularization, whereas in the setting of little or no ischemia, medical therapy had improved outcomes.

Conclusions— Stress MPS effectively stratifies CD risk in elderly patients and may identify optimal post-MPS therapy. CD rates after normal MPS are low in all subsets in relative terms compared with the age-matched US population.

Methods and Results— One hundred three patients referred for investigation of suspected angina underwent MRMPI with a 1.5-T scanner. The stress agent was intravenous adenosine (140 µg · kg^–1 · min^–1), and the first-pass bolus contained 0.1 mmol/kg gadolinium. In the following week, coronary angiography with pressure wire studies was performed. FFR was recorded in all patent major epicardial coronary arteries, with a value <0.75 denoting significant stenosis. MRMPI scans, analyzed by 2 blinded observers, identified perfusion defects in 121 of 300 coronary artery segments (40%), of which 110 had an FFR <0.75. We also found that 168 of 179 normally perfused segments had an FFR ≥0.75. The sensitivity and specificity of MRMPI for the detection of functionally significant coronary heart disease were 91% and 94%, respectively, with positive and negative predictive values of 91% and 94%.

Conclusion— MRMPI can detect functionally significant coronary heart disease with excellent sensitivity, specificity, and positive and negative predictive values compared with FFR.

Methods and Results— Consecutive patients who underwent percutaneous coronary intervention for ULMD had prospective platelet reactivity assessment by light transmittance aggregometry after a loading dose of 600 mg of clopidogrel. The primary end point of the study was cardiac mortality, and the secondary end point was stent thrombosis. From January 2005 to September 2008, 215 consecutive patients were treated with DES for ULMD. The incidence of HRPR after clopidogrel loading was 18.6%. The median follow-up was 19.3 months. The overall estimated 1-, 2- and 3-year cardiac mortality rate was 3.9±1.3%, 7.5±2.2%, and 12.2±3.4%, respectively. The 3-year cardiac mortality rate was 8.0±3.1% in the low residual platelet reactivity (LRPR) group and 28.3±10.4% in the HRPR group (P=0.005). The 3-year stent thrombosis rate was 4.2±1.8% in the low residual platelet reactivity group and 16.0±7.3% in the HRPR group (P=0.021). By forward stepwise regression analysis, HRPR after clopidogrel loading was the only independent predictor of cardiac death (hazard ratio, 3.82; 95% confidence interval,1.38 to 10.54; P=0.010) and stent thrombosis (hazard ratio, 3.69; 95% confidence interval, 1.12 to 12.09; P=0.031).

Conclusions— HRPR after 600-mg clopidogrel loading is a strong marker of increased risk of cardiac death and DES thrombosis in patients receiving DES stenting for ULMD. Routine assessment of in vitro residual platelet reactivity after clopidogrel loading in patients with ULMD potentially suitable for DES-supported percutaneous coronary intervention should be considered to guide patient care decisions.

Methods and Results— By using the LoxP/Cre approach, we generated the endo-DDAH1^–/– mice. The endo-DDAH1^–/– mice had no apparent defect in growth or development compared with wild-type littermates. DDAH1 expression was greatly reduced in kidney, lung, brain, and liver, indicating that in these organs DDAH1 is distributed mainly in vascular endothelial cells. The endo-DDAH1^–/– mice showed a significant increase of asymmetric dimethylarginine concentration in plasma (1.41 µmol/L in the endo-DDAH1^–/– versus 0.69 µmol/L in the control mice), kidney, lung, and liver, which was associated with significantly increased systolic blood pressure (132 mm Hg versus 113 mm Hg in wild-type). The endo-DDAH1^–/– mice also exhibited significantly attenuated acetylcholine-induced NO production and vessel relaxation in isolated aortic rings.

Conclusions— Our study demonstrates that DDAH1 is highly expressed in vascular endothelium and that endothelial DDAH1 plays an important role in regulating blood pressure. In the context that asymmetric methylarginines are broadly produced by many type of cells, the strong DDAH1 expression in vascular endothelium demonstrates for the first time that vascular endothelium can be an important site to actively dispose of toxic biochemical molecules produced by other types of cells.

Methods and Results— Cultured on fibronectin in conditioned media, human peripheral blood mononuclear cells differentiated, within 10 days of culture, into EPCs, which uptake acetylated low-density lipoprotein, bind ulex-lectin, lack monocyte/leukocyte markers (CD14, P-selectin glycoprotein ligand-1, L-selectin), express progenitor/endothelial markers (CD34, vascular endothelial growth factor receptor-2, von Willebrand factor, and vascular endothelial cadherin), and proliferate in culture. These EPCs bound activated platelets via CD62P and inhibited its translocation, glycoprotein IIb/IIIa activation, aggregation, and adhesion to collagen, mainly via prostacyclin secretion. Indeed, this was associated with upregulation of cyclooxygenase-2 and inducible nitric oxide synthase. However, the effects on platelets in vitro were reversed by cyclooxygenase and cyclooxygenase-2 inhibition but not by nitric oxide or inducible nitric oxide synthase inhibition. Moreover, in a ferric chloride–induced murine arterial thrombosis model, injection of EPCs led to their incorporation into sites of injury and impaired thrombus formation, leading to an incomplete occlusion with 50% residual flow.

Conclusions— Peripheral blood mononuclear cell–derived EPCs bind platelets via CD62P and inhibit platelet activation, aggregation, adhesion to collagen, and thrombus formation, predominantly via upregulation of cyclooxygenase-2 and secretion of prostacyclin. These findings add new insights into the biology of EPCs and define their potential roles in regulating platelet function and thrombosis.

Methods and Results— The expression of Tie2, the Ang1 receptor, was significantly higher in ^mobPBSCs than naïve peripheral blood mononuclear cells (19.2±3.0% versus 1.2±0.8% versus 1.2±0.2%; P<0.001 for ^mobPBSCs from acute myocardial infarction (AMI) patients with granulocyte colony-stimulating factor treatment for 3 days versus peripheral blood mononuclear cells from AMI patients versus peripheral blood mononuclear cells from stable angina patients). After 4 hours of cartilage oligomeric matrix protein (COMP)-Ang1 stimulation, ^mobPBSCs committed to the endothelial lineage with the induction of CD31 and VE-cadherin expression, mediated by Tie2/Ets-1 pathway. Priming of ^mobPBSCs with COMP-Ang1 induced the expression of 4β1 and 5β1 integrins, which are also Ets-1 downstream molecules, leading to enhanced adhesion to endothelial cells or fibronectin. In a rabbit ear ischemia/reperfusion model, priming of ^mobPBSCs with COMP-Ang1 improved first-pass engraftment to the distal vascular bed after intraarterial delivery. In a murine ischemic hind-limb model, intravascular delivery of primed ^mobPBSCs enhanced both engraftment and neovascularization.

Conclusions— The short-term priming with COMP-Ang1 may be a feasible and promising option to activate ^mobPBSCs by enhancing differentiation and adhesiveness and to improve the efficacy of cell therapy for ischemic diseases.

Methods and Results— Seven sixth-grade classes (182 children, aged 11.1±0.7 years) were randomized to an intervention group (4 classes with 109 students) with daily school exercise lessons for 1 year and a control group (3 classes with 73 students) with regular school sports twice weekly. The significant effects of intervention estimated from ANCOVA adjusted for intraclass correlation were the following: increase of peak Vo₂ (3.7 mL/kg per minute; 95% confidence interval, 0.3 to 7.2) and increase of circulating progenitor cells evaluated by flow cytometry (97 cells per 1x10⁶ leukocytes; 95% confidence interval, 13 to 181). No significant difference was seen for body mass index–standard deviation score (–0.08; 95% confidence interval, –0.28 to 0.13); however, there was a trend to reduction of the prevalence of overweight and obese children in the intervention group (from 12.8% to 7.3%). No treatment effect was seen for motor and coordinative abilities (4; 95% confidence interval, –1 to 8) and high-density lipoprotein cholesterol (0.03 mmol/L; 95% confidence interval, –0.08 to 0.14).

Conclusions— Regular physical activity by means of daily school exercise lessons has a significant positive effect on physical fitness (Vo₂max). Furthermore, the number of circulating progenitor cells can be increased, and there is a positive trend in body mass index–standard deviation score reduction and motor ability improvement. Therefore, we conclude that primary prevention by means of increasing physical activity should start in childhood.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Identifier: NCT00176371.

Methods and Results— The Inhibition of Unnecessary RV Pacing With AV Search Hysteresis in ICDs (INTRINSIC RV) trial included 1530 patients undergoing ICD implantation. After implantation of a dual-chamber ICD, patients were followed for a mean of 10.4 months. The mean HR for 1436 patients over the follow-up period was determined from device histograms. Patients were grouped into strata by mean HR, and the relationship between the primary end point and mean HR was analyzed with Mantel-Haenszel ordinal ² tests. Higher intrinsic (unpaced) HR was associated with greater risk of achieving the primary end point of death or heart failure hospitalization (P<0.001). Of patients with a mean HR <75 bpm, 5.8% died or were hospitalized for heart failure, whereas 20.9% with a mean HR >90 bpm achieved the same end point, a 3.6-fold difference (P<0.0001). In a multivariate model with the use of Cox regression, HR was a significant predictor with a hazard ratio of 1.34 (P=0.0001; 95% confidence interval, 1.19 to 1.50), as were age, New York Heart Association functional class, and percent right ventricular pacing, but it was independent of gender and β-blocker dosing. When considered as continuous or discrete variables grouped by 5-bpm increments, HR remained a significant predictor.

Conclusions— In this ICD population, the mean intrinsic HR was strongly associated with outcomes.

Clinical Trial Registration— http://www.clinicaltrials.gov. Identifier: NCT00148967.

Methods and Results— Among 357 consecutive patients with type A acute aortic syndrome, 101 (28.3%) had IMH and 256 had AD. Urgent operations were performed in 224 patients with AD (87.5%) and 16 with unstable IMH (15.8%; P<0.001). The remaining 85 stable IMH patients received initial medical treatment, and adverse clinical events developed in 31 patients (36.5%) within 6 months, which included development of AD (n=25), delayed surgery (n=25), or death (n=6). Initial aorta diameter and hematoma thickness were independent predictors for development of these events, and the best cutoff values were 55 and 16 mm, respectively. The overall hospital mortality was lower in IMH patients than in AD patients (7.9% [8/101] versus 17.2% [44/256]; P=0.0296) and was comparable to that of surgically treated AD patients (7.9% versus 10.7% [24/224]; P=0.56). The 1-, 2-, and 3-year survival rates of IMH patients were 87.6±3.6%, 84.9±3.7%, and 83.1±4.1%, respectively. There was no statistical difference of overall survival rates between patients with IMH and surgically treated AD patients (P=0.787).

Conclusions— The clinical outcome of IMH patients receiving treatment by our policy was comparable to that of surgically treated AD patients. However, adverse clinical events were not uncommon with medical treatment alone, and initial aorta diameter and hematoma thickness may identify patients who might benefit from urgent surgery.

Methods and Results— This prospective cohort study included 6880 representative unselected patients ≥65 years of age with monitored follow-up over 5 years. According to physician diagnosis, 5392 patients had no PAD, 836 had asymptomatic PAD (ankle brachial index <0.9 without symptoms), and 593 had symptomatic PAD (lower-extremity peripheral revascularization, amputation as a result of PAD, or intermittent claudication symptoms regardless of ankle brachial index). The risk of symptomatic compared with asymptomatic PAD patients was significantly increased for the composite of all-cause death or severe vascular event (myocardial infarction, coronary revascularization, stroke, carotid revascularization, or lower-extremity peripheral vascular events; hazard ratio, 1.48; 95% confidence interval, 1.21 to 1.80) but not for all-cause death alone (hazard ratio, 1.13; 95% confidence interval, 0.89 to 1.43), all-cause death/myocardial infarction/stroke (excluding lower-extremity peripheral vascular events and any revascularizations; hazard ratio, 1.18; 95% confidence interval, 0.92 to 1.52), cardiovascular events alone (hazard ratio, 1.20; 95% confidence interval, 0.89 to 1.60), or cerebrovascular events alone (hazard ratio, 1.33; 95% confidence interval, 0.80 to 2.20). Lower ankle brachial index categories were associated with increased risk. PAD was a strong factor for the prediction of the composite end point in an adjusted model.

Conclusions— Asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and/or vascular event risk. Notably, the risk of mortality was similar in symptomatic and asymptomatic patients with PAD and was significantly higher than in those without PAD. In the primary care setting, the diagnosis of PAD has important prognostic value.

Methods and Results— This was a prospective, nested, case-control analysis among individuals of European ancestry enrolled in 6 prospective cohort studies. Study subjects were followed up for development of SCD, and genotypes for rs10757274 were determined for 492 sudden and/or arrhythmic deaths and 1460 controls matched for age, sex, cohort, history of cardiovascular disease, and follow-up time. Conditional logistic regression with fixed-effects meta-analysis assuming an additive model was used to test for associations. When individual study results were combined in the meta-analysis, each increasing copy of the G allele at rs10757274 conferred a significantly elevated age-adjusted odds ratio for SCD of 1.21 (95% confidence interval, 1.04 to 1.40; P=0.01). Controlling for cardiovascular and lifestyle risk factors strengthened these relationships (odds ratio, 1.29 per G-allele copy; 95% confidence interval, 1.09 to 1.53; P=0.003). These results were not materially altered in sensitivity analyses limited to definite SCD, in models that further controlled for the development of interim cardiovascular disease, or when the highly correlated variant rs2383207 was tested.

Conclusions— The major allele of a single-nucleotide polymorphism previously associated with increased risk of coronary artery disease events is associated with increased risk of SCD in individuals of European ancestry. Study of the mechanism underlying this association may improve our understanding of lethal cardiovascular disease.

Methods and Results— The medical records of 857 consecutive patients who had complete cine and DE-MRI evaluation at a tertiary care center were reviewed regardless of whether the patients had coronary artery disease. The presence and extent of myocardial scar were evaluated qualitatively by a single experienced observer. The primary, composite end point was all-cause mortality or cardiac transplantation. Survival data were obtained from the Social Security Death Index. The median follow-up was 4.4 years; 252 patients (29%) reached one of the end points. Independent predictors of mortality or transplantation included congestive heart failure, ejection fraction, and age (P<0.0001 for each), as well as scar index (hazard ratio, 1.26; 95% confidence interval, 1.02 to 1.55; P=0.033). Similarly, in subsets of patients with or without coronary artery disease, scar index also independently predicted mortality or transplantation (hazard ratio, 1.33; 95% confidence interval, 1.05 to 1.68; P=0.018; and hazard ratio, 5.65; 95% confidence interval, 1.74 to 18.3; P=0.004, respectively). Cox regression analysis showed worse outcome in patients with any DE in addition to depressed left ventricular ejection fraction (<50%).

Conclusion— The degree of DE detected by DE-MRI appears to strongly predict all-cause mortality or cardiac transplantation after adjustment for traditional, well-known prognosticators.

Methods and Results— Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit⁺ cells, and increased vasculature in the damaged region.

Conclusions— Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell–based therapeutic approaches.

Methods and Results— We generated 2 lines of transgenic (Tg) rabbits expressing human CRP (hCRP). The plasma levels of hCRP in hCRP-Tg-1 and hCRP-Tg-2 rabbits were 0.4±0.13 (n=14) and 57.8±20.6 mg/L (n=12), respectively. In addition, hCRP isolated from Tg rabbit plasma exhibited the ability to activate the rabbit complement. To define the role of hCRP in atherosclerosis, we compared the susceptibility of hCRP-Tg rabbits to cholesterol-rich diet-induced aortic and coronary atherosclerosis with that of non-Tg rabbits. After being fed with a cholesterol-rich diet for 16 weeks, Tg and non-Tg rabbits developed similar hypercholesterolemia and lesion sizes in both aortic and coronary arteries. Immunohistochemical staining and Western blotting revealed that hCRP was indeed present in the lesions but did not affect macrophage accumulation and smooth muscle cell proliferation of the lesions.

Conclusions— Neither high nor low plasma concentrations of hCRP affected aortic or coronary atherosclerosis lesion formation in hCRP-Tg rabbits.

Methods and Results— Individuals with type 2 diabetes mellitus were infused with placebo or rHDL (CSL-111; 20 mg · kg^–1 · h^–1) for 4 hours, resulting in an 1.4-fold increase in plasma HDL cholesterol levels. rHDL infusion was associated with a >50% reduction in the ex vivo platelet aggregation response to multiple agonists, an effect that persisted in washed platelets. In vitro studies in platelets from healthy individuals revealed that the inhibitory effects of rHDL on platelet function were time and dose dependent and resulted in a widespread attenuation of platelet function and a 50% reduction in thrombus formation under flow. These effects could be recapitulated, in part, by the isolated phospholipid component of rHDL, which enhanced efflux of cholesterol from platelets and reduced lipid raft assembly. In contrast, the apolipoprotein AI component of rHDL had minimal effect on platelet function, cholesterol efflux, or lipid raft assembly.

Conclusion— These findings suggest that rHDL therapy is highly effective at inhibiting the heightened reactivity of diabetic platelets, partly through reducing the cholesterol content of platelet membranes. These properties, combined with the known short-term beneficial effects of rHDL on atherosclerotic lesions, suggest that rHDL infusions may be an effective approach to reduce atherothrombotic complications in diabetic individuals.

Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00395148.

Methods and Results— Using data from 3078 participants from the Framingham Offspring Study (a cohort study) who attended examinations 4 (1987), 5 (1991), and 6 (1995), we evaluated the progression of MetS and its components. MetS was defined according to the Adult Treatment Panel III criteria. Using logistic regression, we evaluated the predictive ability of the presence of each component of the MetS on the subsequent development of MetS. Additionally, we examined the probability of developing cardiovascular disease or mortality (until 2007) by having specific combinations of 3 that diagnose MetS. The prevalence of MetS almost doubled in 10 years of follow-up. Hyperglycemia and central obesity experienced the highest increase. High blood pressure was most frequently present when a diagnosis of MetS occurred (77.3%), and the presence of central obesity conferred the highest risk of developing MetS (odds ratio, 4.75; 95% confidence interval, 3.78 to 5.98). Participants who entered the MetS having a combination of central obesity, high blood pressure, and hyperglycemia had a 2.36-fold (hazard ratio, 2.36; 95% confidence interval, 1.54 to 3.61) increase of incident cardiovascular events and a 3-fold (hazard ratio, 3.09, 95% confidence interval, 1.93 to 4.94) increased risk of mortality.

Conclusions— Particular trajectories and combinations of factors on entering the MetS confer higher risks of incident cardiovascular disease and mortality in the general population and among those with MetS. Intense efforts are required to identify populations with these particular combinations and to provide them with adequate treatment at early stages of disease.

Methods and Results— A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload.

Conclusion— These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.

Methods and Results— We analyzed cardiac and liver T2* magnetic resonance and serum ferritin in 652 thalassemia major patients from 21 UK centers with 1442 magnetic resonance scans. The relative risk for heart failure with cardiac T2* values <10 ms (compared with >10 ms) was 160 (95% confidence interval, 39 to 653). Heart failure occurred in 47% of patients within 1 year of a cardiac T2* <6 ms with a relative risk of 270 (95% confidence interval, 64 to 1129). The area under the receiver-operating characteristic curve for predicting heart failure was significantly greater for cardiac T2* (0.948) than for liver T2* (0.589; P<0.001) or serum ferritin (0.629; P<0.001). Cardiac T2* was <10 ms in 98% of scans in patients who developed heart failure. The relative risk for arrhythmia with cardiac T2* values <20 ms (compared with >20 ms) was 4.6 (95% confidence interval, 2.66 to 7.95). Arrhythmia occurred in 14% of patients within 1 year of a cardiac T2* of <6 ms. The area under the receiver-operating characteristic curve for predicting arrhythmia was significantly greater for cardiac T2* (0.747) than for liver T2* (0.514; P<0.001) or serum ferritin (0.518; P<0.001). The cardiac T2* was <20 ms in 83% of scans in patients who developed arrhythmia.

Conclusions— Cardiac T2* magnetic resonance identifies patients at high risk of heart failure and arrhythmia from myocardial siderosis in thalassemia major and is superior to serum ferritin and liver iron. Using cardiac T2* for the early identification and treatment of patients at risk is a logical means of reducing the high burden of cardiac mortality in myocardial siderosis.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00520559.

Methods and Results— Eighty-one consecutive patients with biopsy-proven extracardiac sarcoidosis were prospectively recruited for a parallel and masked comparison of cardiac involvement between (1) DE-CMR and (2) standard clinical evaluation with the use of consensus criteria (modified Japanese Ministry of Health [JMH] guidelines). Standard evaluation included 12-lead ECG and at least 1 dedicated non-CMR cardiac study (echocardiography, radionuclide scintigraphy, or cardiac catheterization). Patients were followed for 21±8 months for major adverse events (death, defibrillator shock, or pacemaker requirement). Patients were predominantly middle-aged (46±11 years), female (62%), and black (73%) and had chronic sarcoidosis (median, 7 years) and preserved left ventricular ejection fraction (median, 56%). DE-CMR identified cardiac involvement in 21 patients (26%) and JMH criteria in 10 (12%, 8 overlapping), a >2-fold higher rate for DE-CMR (P=0.005). All patients with myocardial damage on DE-CMR had coronary disease excluded by x-ray angiography. Pathology evaluation in 15 patients (19%) identified 4 with cardiac sarcoidosis; all 4 were positive by DE-CMR, whereas 2 were JMH positive. On follow-up, 8 had adverse events, including 5 cardiac deaths. Patients with myocardial damage on DE-CMR had a 9-fold higher rate of adverse events and an 11.5-fold higher rate of cardiac death than patients without damage.

Conclusions— In patients with sarcoidosis, DE-CMR is more than twice as sensitive for cardiac involvement as current consensus criteria. Myocardial damage detected by DE-CMR appears to be associated with future adverse events including cardiac death, but events were few, and this needs confirmation in a larger cohort.

Methods and Results— Patients with at least 1 moderate SVG lesion (30% to 60% diameter stenosis) were randomized either to stenting the moderate SVG lesion with a PES (n=30, PES group) or to medical treatment alone (n=27, medical treatment group). Patients had an angiographic and intravascular ultrasound evaluation of the SVG at baseline and at 12-month follow-up. The primary end points were (1) the ultrasound SVG minimal lumen area at follow-up and (2) the changes in ultrasound atheroma volume in an angiographically nondiseased SVG segment. Mean time from coronary artery bypass grafting was 12±6 years, and mean low-density lipoprotein cholesterol level was 73±31 mg/dL. A total of 70 moderate SVG lesions (39±7% diameter stenosis) were evaluated. Significant disease progression occurred in the medical treatment group at the level of the moderate SVG lesion (decrease in minimal lumen area from 6.3±3.0 to 5.6±3.1 mm²; P<0.001), leading to a severe flow-limiting lesion or SVG occlusion in 22% of the patients compared with none in the PES group (P=0.014). In the PES group, mean minimal lumen area increased (P<0.001) from 6.1±2.2 to 8.6±2.9 mm² at follow-up (P=0.001 compared with the medical treatment group at 12 months). There were no cases of restenosis or stent thrombosis. No significant atherosclerosis progression occurred at the nonstented SVG segments. At 12-month follow-up, the cumulative incidence of major adverse cardiac events related to the target SVG was 19% in the medical treatment group versus 3% in the PES group (P=0.091).

Conclusions— Stenting moderate nonsignificant lesions in old SVGs with PES was associated with a lower rate of SVG disease progression and a trend toward a lower incidence of major adverse cardiac events at 1-year follow-up compared with medical treatment alone, despite very low low-density lipoprotein cholesterol values. This pilot study supports further investigation into the role of plaque sealing in SVGs.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT002289835.

Methods and Results— We prospectively evaluated 2691 patients treated with drug-eluting stents who had a baseline CRP measurement. The primary outcome was stent thrombosis; secondary outcomes were death, myocardial infarction (MI), death or MI, and target vessel revascularization. During follow-up (median, 3.9 years), 32 patients had definite or probable stent thrombosis, 137 patients died, 227 had an MI, and 195 underwent target vessel revascularization. In multivariable Cox proportional-hazards models, elevated levels of CRP were significantly associated with increased risk of stent thrombosis (hazard ratio, 3.86; 95% confidence interval, 1.82 to 8.18; P<0.001). Elevated CRP levels also significantly predicted the risks of death (hazard ratio, 1.61; 95% confidence interval, 1.13 to 2.28; P=0.008), MI (hazard ratio, 1.63; 95% confidence interval, 1.25 to 2.12; P=0.001), and death or MI (hazard ratio, 1.61; 95% confidence interval, 1.29 to 2.00; P<0.001) but not target vessel revascularization (hazard ratio, 1.20; 95% confidence interval, 0.90 to 1.61; P=0.21). The incorporation of CRP into a model with patient, lesion, and procedural factors resulted in a significant increase in the C statistic for the prediction of stent thrombosis, MI, and the composite of death or MI.

Conclusions— Elevated CRP levels were significantly associated with increased risks of stent thrombosis, death, and MI in patients receiving drug-eluting stents, suggesting the usefulness of inflammatory risk assessment with CRP. Given the relatively infrequent occurrence of stent thrombosis, death, and MI, larger studies with longer-term follow-up are required to confirm the novel relationship.

Methods and Results— Six-week-old apolipoprotein E–deficient mice on a standard diet were orally given anti-CD3 antibody or control immunoglobulin G on 5 consecutive days, and atherosclerosis was assessed at age 16 weeks. Oral administration of anti-CD3 antibody significantly reduced atherosclerotic lesion formation and accumulations of macrophages and CD4⁺ T cells in the plaques compared with controls. We observed a significant increase in LAP⁺ cells and CD25⁺Foxp3⁺ cells in the CD4⁺ T-cell population in anti-CD3–treated mice, in association with increased production of the antiinflammatory cytokine transforming growth factor-β and suppressed T-helper type 1 and type 2 immune responses. Neutralization of transforming growth factor-β in vivo abrogated the preventive effect of oral anti-CD3 antibody.

Conclusions— Our findings indicate the atheroprotective role of oral anti-CD3 antibody treatment in mice via induction of a regulatory T-cell response. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis.

Methods and Results— Using Cox proportional hazards modeling, we examined the association between major bleeding and death at 30 days using pooled individual patient data from 8 large randomized controlled trials (n=13 085) comparing fondaparinux with control (low-molecular-weight heparin or placebo) for the prophylaxis of venous thromboembolism in hospitalized surgical or medical patients. Patients who developed major bleeding were older, were more likely to be male, had a lower body weight and lower creatinine clearance, and were more likely to be receiving fondaparinux. At 30 days, the risk of death was 7-fold higher among patients with a major bleeding event (8.6% versus 1.7%; adjusted hazard ratio, 6.96; 95% confidence interval, 4.60 to 10.51). There was a consistent pattern of reduced mortality in patients treated with fondaparinux irrespective of whether patients experienced major bleeding (6.8% versus 11.4%; hazard ratio, 0.58; 95% confidence interval, 0.27 to 1.23) or no major bleeding (1.5% versus 1.9%; hazard ratio, 0.77; 95% confidence interval, 0.59 to 1.02; P for heterogeneity=0.47).

Conclusions— Major bleeding in hospitalized surgical and medical patients participating in venous thromboembolism prevention trials is a strong predictor of mortality.

Methods and Results— From 1993 to 1997, 27 178 men and 29 876 women 50 to 64 years of age were recruited into a Danish prospective study (Diet, Cancer, and Health). During 10 years of follow-up, the outcome of VTE events was identified in the Danish National Patient Registry and verified by review of medical records. Body weight, body mass index, waist circumference, hip circumference, and total body fat were measured at baseline. We used Cox proportional hazard models to assess the association between anthropometry and VTE. Age was used as a time axis, with further adjustment for smoking, physical activity, height, hypertension, diabetes mellitus, cholesterol, and, among women, use of hormone replacement therapy. We verified 641 incident VTE events and found monotonic dose-response relationships between VTE and all anthropometric measurements in both sexes. In mutually adjusted analyses of waist and hip circumference, we found that hip circumference was positively associated with VTE in women but not in men, whereas waist circumference was positively associated with VTE in men but not in women.

Conclusions— All measurements of obesity are predictors of the risk for VTE. Positive associations were found between VTE and body weight, body mass index, waist circumference, hip circumference, and total body fat mass.

Methods and Results— Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration ≥120 ms, LV end-diastolic dimension ≥55 mm, and LV ejection fraction ≤40% were randomized to active therapy (CRT on; n=419) or control (CRT off; n=191) for 12 months. Doppler echocardiograms were recorded at baseline, before hospital discharge, and at 6 and 12 months. When CRT was turned on initially, immediate changes occurred in LV volumes and ejection fraction; however, these changes did not correlate with the long-term changes (12 months) in LV end-systolic (r=0.11, P=0.31) or end-diastolic (r=0.10, P=0.38) volume indexes or LV ejection fraction (r=0.07, P=0.72). LV end-diastolic and end-systolic volume indexes decreased in patients with CRT turned on (both P<0.001 compared with CRT off), whereas LV ejection fraction in CRT-on patients increased (P<0.0001 compared with CRT off) from baseline through 12 months. LV mass, mitral regurgitation, and LV diastolic function did not change in either group by 12 months; however, there was a 3-fold greater reduction in LV end-diastolic and end-systolic volume indexes and a 3-fold greater increase in LV ejection fraction in patients with nonischemic causes of heart failure.

Conclusions— CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year, with the greatest changes occurring in patients with a nonischemic cause of heart failure. CRT may interrupt the natural disease progression in these patients.

Clinical Trial Registration— Clinicaltrials.gov Identifier: NCT00271154.

Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261).

Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

Methods and Results— A formal intravascular ultrasound substudy enrolled 464 patients with baseline and 13-month follow-up imaging at 36 centers. Overall, 446 lesions in 402 patients were suitable for standard qualitative and quantitative analyses, which were performed at an independent blinded core laboratory. The primary prespecified end point was the in-stent percent net volume obstruction at follow-up. Median stent length measured 23.4 mm (first and third quartiles, 18.5 and 31.9 mm). PES compared with BMS significantly reduced 13-month percent net volume obstruction (6.5% [first and third quartiles, 2.2% and 10.8%] versus 15.6% [first and third quartiles, 7.2% and 28.8%]; P<0.0001). PES compared with BMS also resulted in more late-acquired stent malapposition (29.6% versus 7.9%; P=0.0005) resulting from positive vessel remodeling. Plaque and/or thrombus protrusion through stent struts was initially present in 70.4% of PES and 64.8% of BMS; all resolved during follow-up. New aneurysm formation, stent fracture, and subclinical thrombus were uncommon, although seen only in PES.

Conclusions— PES compared with BMS significantly reduce neointimal hyperplasia in patients with ST-segment elevation myocardial infarction but also result in a high frequency of late-acquired stent malapposition as a result of positive vessel remodeling. Ongoing long-term follow-up is required to establish the clinical significance of these findings.

Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Methods and Results— Differentiation of embryonic stem cells into endothelial cells in an in vitro embryoid body is paralleled by an amplification of heparan sulfate glycosaminoglycan sulfation, which correlates with the levels of the enzyme N-deacetylase/N-sulfotransferase 1 (NDST1). Small hairpin RNA–mediated knockdown of NDST1 or modification of heparan sulfate glycosaminoglycans in embryonic stem cells with heparinases or sodium chlorate inhibited differentiation of embryonic stem cells into endothelial cells. This was translated to an in vivo zebrafish embryo model, in which the genetic knockdown of NDST1 resulted in impaired vascularization characterized by a concentration-dependent decrease in intersegmental vessel lumen and a large tail-vessel configuration, which could be rescued by use of exogenous sulfated heparan sulfate glycosaminoglycans. To explore the cross talk between the glycome and the transcriptome during vasculogenesis, we identified by microarray and then validated wild-type and NDST1 knockdown–associated gene-expression patterns in zebrafish embryos. Temporal analysis at 3 developmental stages critical for vasculogenesis revealed a cascade of pathways that may mediate glycocalyx regulation of vasculogenesis. These pathways were intimately connected to cell signaling, cell survival, and cell fate determination. Specifically, we demonstrated that forkhead box O3A/5 proteins and insulin-like growth factor were key downstream signals in this process.

Conclusions— The present study for the first time implicates interplay between the glycome and the transcriptome during vasculogenesis, revealing the possibility of harnessing specific cellular glyco-microenvironments for therapeutic vascularization.

Methods and Results— We established a novel atherosclerosis-susceptible mouse model with both severe HHcy and hypercholesterolemia in which the mouse cystathionine β-synthase (CBS) and apolipoprotein E (apoE) genes are deficient and an inducible human CBS transgene is introduced to circumvent the neonatal lethality of the CBS deficiency (Tg-hCBS apoE^–/– Cbs^–/– mice). Severe HHcy accelerated atherosclerosis and inflammatory monocyte/macrophage accumulation in lesions and increased plasma tumor necrosis factor- and monocyte chemoattractant protein-1 levels in Tg-hCBS apoE^–/– Cbs^–/– mice fed a high-fat diet. Furthermore, we characterized monocyte heterogeneity in Tg-hCBS apoE^–/– Cbs^–/– mice and another severe HHcy mouse model (Tg-S466L Cbs^–/–) with a disease-relevant mutation (Tg-S466L) that lacks hyperlipidemia. HHcy increased monocyte population and selective expansion of inflammatory Ly-6C^hi and Ly-6C^mid monocyte subsets in blood, spleen, and bone marrow of Tg-S466L Cbs^–/– and Tg-hCBS apoE^–/– Cbs^–/– mice. These changes were exacerbated in Tg-S466L Cbs^–/– mice with aging. Addition of l-homocysteine (100 to 500 µmol/L), but not l-cysteine, maintained the Ly-6C^hi subset and induced the Ly-6C^mid subset in cultured mouse primary splenocytes. Homocysteine-induced differentiation of the Ly-6C^mid subset was prevented by catalase plus superoxide dismutase and the NAD(P)H oxidase inhibitor apocynin.

Conclusion— HHcy promotes differentiation of inflammatory monocyte subsets and their accumulation in atherosclerotic lesions via NAD(P)H oxidase–mediated oxidant stress.

Methods and Results— In 49 pediatric patients (median age, 0.75 years) with congenital heart disease who underwent cardiac catheterization procedures, blood samples were taken before and shortly after the procedure. -H2AX foci were determined in peripheral blood T lymphocytes. In each patient, a net increase in -H2AX foci, representing DNA double-strand breaks induced by interventional x-rays, was observed. In addition, a patient-specific Monte Carlo simulation of the procedure was performed, resulting in individual blood, organ, and tissue doses. Plotting of -H2AX foci versus blood dose indicated a low-dose hypersensitivity. Median effective doses calculated according to the International Commission on Radiological Protection 60 and 103 publications are 5.6 and 6.4 mSv, respectively. The lifetime-attributable risk of cancer mortality was calculated from the linear-no-threshold model and the -H2AX foci data. This resulted in lifetime-attributable risk values of 1% and 4%, respectively, for the patient population under study.

Conclusions— -H2AX foci as a biomarker for DNA damage indicate that radiation risk estimates according to the linear-no-threshold hypothesis are possibly underestimates. Great care should be taken to minimize and optimize patient radiation exposure.

Methods and Results— When transgenic mice with green fluorescent protein (GFP) expressed downstream of the Tie2 promoter were injected with Ac-LDL, Ac-LDL was specifically endocytosed by sinusoids, and Tie2 expression was more pronounced in the arteries, arterioles, and transitional capillaries. Combining these 2 functional endothelial markers and using confocal microscopy to obtain 3-dimensional images, we identified transitional zones where arterioles emptied into the sinusoids. Alternatively, coinjection of lectin with DiI-Ac-LDL has a similar result in normal mice, as seen in Tie2/GFP mice, and can be used to differentiate vessel types in nontransgenic mice.

Conclusions— These results demonstrate that bone marrow vasculature is functionally heterogeneous. Methods to study changes in the marrow vasculature using microvascular density or quantifying changes in the vascular niche need to take this heterogeneity into account.