The impact of PCI on the long-term prognosis of patients with stable coronary artery disease has not been established.

We identified 17 randomized trials comparing a PCI-based invasive treatment strategy with medical treatment in 7,513 patients with symptoms or signs of myocardial ischemia but no acute coronary syndrome. Of these patients, 3,675 were assigned to the PCI group and 3,838 to the medical treatment group. The primary end point was all-cause death. The length of follow-up was in the range between 12 and 122 months, 51 months on average.

In the PCI group, 271 patients died compared with 335 patients in the medical treatment group, which corresponds to a 20% reduction in the odds ratio (OR) of all-cause death (OR: 0.80; 95% confidence interval [CI]: 0.64 to 0.99, p = 0.263 for heterogeneity across the trials). Allocation to the PCI group was associated with a nonsignificant 26% reduction in the OR of cardiac death (OR: 0.74, 95% CI: 0.51 to 1.06). In the PCI group, 319 patients had a nonfatal myocardial infarction after randomization compared with 357 patients in the medical treatment group (OR: 0.90, 95% CI: 0.66 to 1.23).

These findings suggest that a PCI-based invasive strategy may improve long-term survival compared with a medical treatment-only strategy in patients with stable coronary artery disease.

Apelin is the endogenous ligand for the previously orphaned G-protein–coupled receptor, APJ. This novel pathway is widely expressed in the cardiovascular system and is emerging as an important mediator of cardiovascular homeostasis. In pre-clinical models, apelin causes venous and arterial vasodilation.

Vascular effects of apelin were assessed in 24 healthy volunteers. Dorsal hand vein diameter was measured by the Aellig technique during local intravenous infusions (0.1 to 3 nmol/min) of apelin-36, (Pyr¹)apelin-13, and sodium nitroprusside (0.6 nmol/min). Forearm blood flow was measured by venous occlusion plethysmography during intrabrachial infusions of apelin-36 and (Pyr¹)apelin-13 (0.1 to 30 nmol/min) and subsequently in the presence or absence of a "nitric oxide clamp" (nitric oxide synthase inhibitor, L-N ^G-monomethylarginine [8 µmol/min], coinfused with nitric oxide donor, sodium nitroprusside [90 to 900 ng/min]), or a single oral dose of aspirin (600 mg) or matched placebo.

Although sodium nitroprusside caused venodilation (p < 0.0001), apelin-36 and (Pyr¹)apelin-13 had no effect on dorsal hand vein diameter (p = 0.2). Both apelin isoforms caused reproducible vasodilation in forearm resistance vessels (p < 0.0001). (Pyr¹)apelin-13–mediated vasodilation was attenuated by the nitric oxide clamp (p = 0.004) but unaffected by aspirin (p = 0.7).

Although having no apparent effect on venous tone, apelin causes nitric oxide–dependent arterial vasodilation in vivo in man. The apelin-APJ system merits further clinical investigation to determine its role in cardiovascular homeostasis.

Aggressive LDL-C reduction with statins improves cardiovascular outcomes in acute and chronic coronary heart disease (CHD). The importance of baseline LDL-C is unclear.

We compared 2-year composites of death, myocardial infarction (MI), unstable angina, revascularization >30 days, and stroke (primary end point), and CHD death, MI, and revascularization >30 days (secondary end point) in 2,986 statin-naïve patients with recent acute coronary syndrome (ACS) randomized to atorvastatin 80 mg versus pravastatin 40 mg in the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) study stratified by quartiles of baseline LDL-C. Multivariable models assessed whether the treatment benefit was dependent on baseline LDL-C.

A significant reduction in the hazards of the primary (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.47 to 0.85, p = 0.002) and secondary (HR: 0.57, 95% CI: 0.42 to 0.79, p = 0.001) end points occurred in patients within the highest quartile (>132 mg/dl) of baseline LDL-C treated with atorvastatin 80 mg. The benefit of intensive therapy progressively declined as baseline LDL-C decreased. The lowest quartile (LDL-C ≤92 mg/dl) experienced similar rates of the primary (HR: 0.93, 95% CI: 0.69 to 1.25, p = 0.63) and secondary (HR: 0.98, 95% CI: 0.71 to 1.35, p = 0.89) end points. Adjusted interaction tests between treatment and highest versus lowest baseline LDL-C quartile were significant for the primary and secondary end points (p = 0.03 and p = 0.007, respectively). Analyzing baseline LDL-C as a continuous variable, atorvastatin 80 mg was associated with improved outcomes provided the baseline LDL-C was >66 mg/dl.

A progressive reduction in the benefit of intensive LLT with atorvastatin 80 mg over pravastatin 40 mg occurred in statin-naïve ACS patients as baseline LDL-C declined. (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 [PROVE IT–TIMI 22]; NCT00382460)

Atrial fibrillation is a risk factor for stroke, with 90% of clots occurring in the LAA. Several surgical techniques of LAA closure are used to theoretically reduce the stroke risk, with varying success rates.

A total of 137 of 2,546 patients who underwent surgical LAA closure from 1993 to 2004 had a TEE after surgery. Techniques consisted of either excision or exclusion by sutures or stapling. The TEE measurements included color Doppler flow in the LAA and interrogation for thrombus. Patent LAA, remnant LAA (residual stump >1 cm), or excluded LAA with persistent flow into the LAA were identified as unsuccessful closure.

Of the 137 patients, 52 (38%) underwent excision and 85 (62%) underwent exclusion (73 suture and 12 stapler). Only 55 of 137 (40%) of closures were successful. Successful LAA closure occurred more often with excision (73%) than suture exclusion (23%) and stapler exclusion (0%) (p < 0.001). We found LAA thrombus to be present in 28 of 68 patients (41%) with unsuccessful LAA exclusion versus none with excision. At time of TEE, 6 patients with successful LAA closure (11%) and 12 with unsuccessful closure (15%) had evidence of stroke/transient ischemic attack (p = 0.61).

There is a high occurrence of unsuccessful surgical LAA closure. Of the various techniques, excision appears to be the most successful.

A high prevalence of MetS has been reported in adolescents.

Four hundred forty-six nondiabetic American Indian adolescents (age 14 to 20 years, 238 girls) underwent clinical evaluation, laboratory testing, and Doppler echocardiography. Age- and gender-specific partition values were used to define obesity and hypertension. Metabolic syndrome was defined according to Adult Treatment Panel III criteria, modified for adolescents. Left ventricular (LV) hypertrophy and left atrial (LA) dilation were identified using age- and gender-specific partition values.

One hundred eleven participants met criteria for MetS. They had a similar age and gender distribution as non-MetS participants. Analysis of covariance, controlling for relevant confounders, demonstrated that participants with MetS had higher LV, LA, and aortic root diameters, higher LV relative wall thickness, and greater LV mass index. Accordingly, MetS participants showed higher prevalences of LV hypertrophy (43.2% vs. 11.7%) and LA dilation (63.1% vs. 21.9%, both p < 0.001) compared with non-MetS participants. In addition, MetS was associated with a reduction in midwall shortening, lower transmitral mitral early to atrial peak velocity ratio, and mildly prolonged mitral early deceleration time (all p < 0.05). In multiple regression analysis, independently of demographics, obesity, blood pressure, and single metabolic components of MetS, clustered MetS was associated with a 2.6-fold higher likelihood of LV hypertrophy and a 2.3-fold higher likelihood of LA dilation (both p ≤ 0.02).

In a population sample of adolescents, MetS is associated with higher prevalences of LV hypertrophy and LA dilation and with reduced LV systolic and diastolic function, independently of individual MetS components.

The mechanisms regulating fibrinogen levels are not fully understood, and they are likely to be regulated by complex gene–environment interactions.

In the AIRGENE study, 895 survivors of myocardial infarction from 5 European cities were followed prospectively for 6 to 8 months, and plasma fibrinogen, interleukin (IL)-6, and C-reactive protein levels were determined monthly. We analyzed 21 SNPs and the corresponding haplotypes in the 3 fibrinogen genes.

Eight SNPs in FGA and FGB were significantly associated with fibrinogen levels. Similarly, 2 different haplotypes in FGA and 3 in FGB were also associated with mean fibrinogen levels. The IL-6 levels had a significant impact on the associations between SNPs/haplotypes in FGA/FGB and fibrinogen levels. We also identified SNPs and haplotypes in FGA and FGB with strong impact on the intraindividual variability of fibrinogen during the follow-up period.

We identified common SNPs and haplotypes on FGA/FGB genes, explaining the interindividual and intraindividual variability of fibrinogen levels, in patients with a history of myocardial infarction. We have also identified for the first time, SNPs/haplotypes on FGA/FGB whose effects on fibrinogen expression are modified by the underlying IL-6 levels. These findings may have an impact on risk stratification and the design of genetically guided therapeutic approaches in patients with advanced atherosclerosis.

In animal models, CGRP contributes to the cardiovascular effects of GTN. The enzyme principally responsible for GTN bioactivation is ALDH2. The common ALDH2*2 polymorphism is associated with a lack of GTN efficacy.

In 18 ALDH2*2-genotyped Chinese volunteers, we observed the changes in plasma concentrations of CGRP after sublingual GTN administration and its correlation with GTN response, and assessed the expression of CGRP messenger ribonucleic acid (mRNA) in cultured peripheral blood mononuclear cells (PBMCs) pre-treated with 10^–5 mol/l GTN.

In contrast to carriers of the ALDH2*2 allele, ALDH2*1/*1 homozygotes showed a significantly higher extent of absolute changes in both systolic blood pressure (SBP) and HR (HR) at several time points after GTN administration. Plasma concentrations of CGRP were increased significantly 12 min after GTN administration, the percentage increase in plasma concentrations of CGRP correlated positively with both SBP and HR, and percentage increase in plasma concentrations of CGRP was significantly higher in ALDH2*1/*1 homozygotes. In addition, PBMCs from ALDH2*1/*1 homozygotes showed a higher-fold increase in both CGRP I and CGRP II mRNA after GTN stimulation, and the GTN-induced increase in CGRP mRNA expression in PBMCs from ALDH2*1/*1 homozygotes was inhibited by the ALDH2 inhibitor chloral hydrate.

We found that CGRP is associated with the cardiovascular effect of GTN through an ALDH2-dependent pathway in humans.

The ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial demonstrated that in moderate- and high-risk ACS patients undergoing PCI, bivalirudin alone compared to unfractionated heparin (UFH) or enoxaparin plus a glycoprotein (GP) IIb/IIIa inhibitor resulted in less major bleeding and similar ischemic outcomes at 30 days. The impact of bivalirudin on 1-year outcomes in ACS patients undergoing PCI is unknown.

In the ACUITY trial, 13,819 patients were enrolled, and 7,789 (56.4%) patients had PCI. Composite ischemia (death, myocardial infarction, or unplanned revascularization) and mortality at 1 year were assessed.

Among patients undergoing PCI, 2,561, 2,609, and 2,619 were randomized to UFH or enoxaparin plus a GP IIb/IIIa inhibitor, bivalirudin plus a GP IIb/IIIa inhibitor, and bivalirudin monotherapy, respectively. At 1 year, there were no differences in composite ischemia (17.8% vs. 19.4% vs. 19.2%, p = NS) or mortality (3.2% vs. 3.3% vs. 3.1%, p = NS) among the 3 groups, respectively.

Bivalirudin compared with UFH or enoxaparin plus a GP IIb/IIIa inhibitor results in similar rates of composite ischemia and mortality at 1 year in moderate- and high-risk ACS patients undergoing PCI.

Although numerous trials have compared coronary angioplasty with bypass surgery, none assessed the clinical evaluation in the long term.

We evaluated the 10-year clinical outcome in the SIMA (Stent versus Internal Mammary Artery grafting) trial. Patients were randomly assigned to stent implantation versus CABG.

Of 123 randomized patients, 59 underwent CABG and 62 received a stent (2 patients were excluded). Follow-up after 10 years was obtained for 98% of the randomized patients. Twenty-six patients (42%) in the percutaneous coronary intervention group and 10 patients (17%) in the CABG group reached an end point (p < 0.001). This difference was due to a higher need for additional revascularization. The incidences of death and myocardial infarction were identical at 10%. Progression of the disease requiring additional revascularization was rare (5%) and was similar for the 2 groups. Stent thrombosis occurred in 2 patients (3%). Angina functional class showed no significant differences between the 2 groups.

Both stent implantation and CABG are safe and highly effective in relieving symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Stenting with bare-metal stents is associated with a higher need for repeat interventions. The long-term prognosis for these patients is excellent with either mode of revascularization.

Anemia is frequently observed in patients with CHF, and evidence suggests that anemia might be associated with an increased mortality.

A systematic literature search in MEDLINE (through November 2007) for English language articles was performed. In addition, a manual search was performed. We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between anemia and mortality in CHF. Of a total of 1,327 initial studies, we included 34 studies, comprising 153,180 patients. Information on study design, patient characteristics, outcome, and potential confounders were extracted.

Anemia was defined by criteria used in the original articles. Of the 153,180 CHF patients, 37.2% were anemic. After a minimal follow-up of 6 months, 46.8% of anemic patients died compared with 29.5% of nonanemic patients. Crude mortality risk of anemia was odds ratio 1.96 (95% confidence interval: 1.74 to 2.21, p < 0.001). Lower baseline hemoglobin values were associated with increased crude mortality rates (r = –0.396, p = 0.025). Adjusted hazard ratios showed an increased adjusted risk for anemia (hazard ratio 1.46 [95% confidence interval: 1.26 to 1.69, p < 0.001]). Subgroup analysis showed no significant difference between mortality risk of anemia in diastolic or systolic CHF.

Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF. Anemia should, therefore, be considered as a useful prognosticator, and therapeutic strategies aimed to increase hemoglobin levels in CHF should be investigated.

The mechanism by which BW shocks have a higher defibrillation efficacy than MW shocks remains unclear.

We simultaneously mapped epicardial membrane potential (Vm) and Ca_i during 6-ms MW and 3-ms/3-ms BW shocks in 19 Langendorff-perfused rabbit ventricles. After shock, the percentage of depolarized area was plotted over time. The maximum (peak) post-shock values (VmP and Ca_iP, respectively) were used to measure heterogeneity. Higher VmP and Ca_iP imply less heterogeneity.

The defibrillation thresholds for BW and MW shocks were 288 ± 99 V and 399 ± 155 V, respectively (p = 0.0005). Successful BW shocks had higher VmP (88 ± 9%) and Ca_iP (70 ± 13%) than unsuccessful MW shocks (VmP 76 ± 10%, p < 0.001; Ca_iP 57 ± 8%, p < 0.001) of the same shock strength. In contrast, for unsuccessful BW and MW shocks of the same shock strengths, the VmP and Ca_iP were not significantly different. The MW shocks more frequently created regions of low Ca_i surrounded by regions of high Ca_i (post-shock Ca_i sinkholes). The defibrillation threshold for MW and BW shocks became similar after disabling the sarcoplasmic reticulum (SR) with thapsigargin and ryanodine.

The greater efficacy of BW shocks is directly related to their less heterogeneous effects on shock-induced SR Ca release and Ca_i transients. Less heterogeneous Ca_i transients reduces the probability of Ca_i sinkhole formation, thereby preventing the post-shock reinitiation of ventricular fibrillation.

Electroanatomic substrate mapping is an important step in the post-infarct ventricular tachycardia (VT) ablation strategy, but this technique has not yet been compared with a gold-standard noninvasive tool informing on the topography and transmural extent of myocardial scars in humans.

Ten patients (9 men, age 71 ± 10 years) admitted for post-infarct VT ablation underwent both a left ventricle DCE MRI and a sinus-rhythm 3-dimensional (3D) (CARTO) EAM (Biosense Webster, Johnson & Johnson, Diamond Bar, California). A 3D color-coded MRI-reconstructed left ventricular endocardial shell was generated to display scar data (intramural location and transmural extent). A matching process allocated any CARTO point to its corresponding position on the MRI map. Electrogram (EGM) characteristics were then evaluated in relation to scar data.

A spiky EGM morphology, a reduced unipolar or bipolar EGM voltage amplitude (<6.52 and <1.54 mV, respectively), as well as a longer bipolar EGM duration (>56 ms) independently correlated with the presence of scar whatever its intramural position. Endocardial scars had a larger degree of signal reduction than intramural or epicardial scars. None of the parameters was correlated with transmural scar depth. A clear mismatch in infarct surface between CARTO and MRI maps was observed in one-third of infarct zones.

Sinus-rhythm EAM helps identify the limits of post-infarct scars. However, the accuracy of EAM for precise scar delineation is limited. This limit might be circumvented using anatomical information provided by 3D MRI data.

Oxidative stress is increased in atherosclerotic lesions and might play an important role in plaque progression and calcification. The role of oxidative stress in valve disease is not clear.

Superoxide (dihydroethidium fluorescence and lucigenin-enhanced chemiluminescence), hydrogen peroxide (H₂O₂) (dichlorofluorescein fluorescence), and expression and activity of pro- and anti-oxidant enzymes were measured in normal valves from hearts not suitable for transplantation and stenotic aortic valves that were removed during surgical replacement of the valve.

In normal valves, superoxide levels were relatively low and distributed homogeneously throughout the valve. In stenotic valves, superoxide levels were increased 2-fold near the calcified regions of the valve (p < 0.05); noncalcified regions did not differ significantly from normal valves. Hydrogen peroxide levels were also markedly elevated in calcified regions of stenotic valves. Nicotinamide adenine dinucleotide phosphate oxidase activity was not increased in calcified regions of stenotic valves. Superoxide levels in stenotic valves were significantly reduced by inhibition of nitric oxide synthases (NOS), which suggests uncoupling of the enzyme. Antioxidant mechanisms were reduced in calcified regions of the aortic valve, because total superoxide dismutase (SOD) activity and expression of all 3 SOD isoforms was significantly decreased. Catalase expression also was reduced in pericalcific regions.

This study provides the first evidence that oxidative stress is increased in calcified regions of stenotic aortic valves from humans. Increased oxidative stress is due at least in part to reduction in expression and activity of antioxidant enzymes and perhaps to uncoupled NOS activity. Thus, mechanisms of oxidative stress differ greatly between stenotic aortic valves and atherosclerotic arteries.

Atherosclerotic plaques in the aortic arch are a risk factor for ischemic stroke. Their relationship with blood hypercoagulability, which might enhance their embolic potential and affect treatment and prevention, is not known.

We performed transesophageal echocardiography in 255 patients with first acute ischemic stroke and in 209 control subjects matched by age, gender, and race/ethnicity. The association between arch plaques and hypercoagulability, and its effect on the stroke risk, was assessed with a case-control design. Stroke patients were then followed prospectively to assess recurrent stroke and death.

Large (≥4 mm) arch plaques were associated with increased stroke risk (adjusted odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.3 to 4.6), especially when ulcerations or superimposed thrombus were present (adjusted OR: 3.3, 95% CI: 1.4 to 8.2). Prothrombin fragment F 1.2, an indicator of thrombin generation, was associated with large plaques in stroke patients (p = 0.02), but not in control subjects. Over a mean follow-up of 55.1 ± 37.2 months, stroke patients with large plaques and F 1.2 over the median value had a significantly higher risk of recurrent stroke and death than those with large plaques but lower F 1.2 levels (230 events per 1,000 person-years vs. 85 events per 1,000 person-years; p = 0.05).

In patients presenting with acute ischemic stroke, large aortic plaques are associated with blood hypercoagulability, suggesting a role for coagulation activation in the stroke mechanism. Coexistence of large aortic plaques and blood hypercoagulability is associated with an increased risk of recurrent stroke and death.

The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPAR agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPAR but not PPAR agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPAR activation, we studied pioglitazone's effects via PPAR.

Pioglitazone effects on known PPAR responses—ligand binding domain activation and PPAR target gene expression—were tested in vitro and in vivo, including in wild-type and PPAR-deficient cells and mice, and compared with the effects of other PPAR (rosiglitazone) and PPAR (WY14643) agonists.

Pioglitazone repressed endothelial TNF-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IB in a manner dependent on both pioglitazone exposure and PPAR expression. Pioglitazone also activated the PPAR ligand binding domain and induced PPAR target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IB expression in wild-type but not PPAR-deficient mice.

Pioglitazone regulates inflammatory target genes in hepatic (IB) and endothelial (VCAM-1) settings in a PPAR-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Drug-eluting stent implantation significantly improved the angiographic and clinical outcomes compared with bare-metal stent implantation in diabetic patients. However, comparison of SES with PES in diabetic patients has not been sufficiently evaluated.

This prospective, multicenter, randomized study compared SES (n = 200) and PES implantation (n = 200) for diabetic patients (n = 400). The primary end point was in-segment restenosis at 6 months according to intention-to-treat principle.

The 2 groups had similar baseline clinical and angiographic characteristics. Six-month in-stent (3.4% vs. 18.2%, p < 0.001) and in-segment restenosis (4.0% vs. 20.8%, p < 0.001) and 9-month target lesion revascularization (2.0% vs. 7.5%, p = 0.017) were significantly lower in the SES versus the PES group. The incidence of death (0% in SES vs. 0.5% in PES, p = 0.999) or myocardial infarction (0.5% in SES vs. 0.5% in PES, p = 0.999) at 9-month follow-up was not statistically different between the 2 groups. Major adverse cardiac events including death, myocardial infarction, and target lesion revascularization at 9 months (2.0% vs. 8.0%, p = 0.010) were lower in the SES versus the PES group.

Sirolimus-eluting stent implantation is superior in reducing angiographic restenosis and improving 9-month clinical outcomes in patients with DM and coronary artery disease compared with PES implantation.

Nonresponsiveness to clopidogrel is a predictor of DES thrombosis. No prospective data exist about the possible association of dual nonresponsiveness to clopidogrel and aspirin with DES thrombosis.

Platelet function was assessed after a loading dose of 600 mg clopidogrel in 746 patients who had successful DES implantation followed by 6-month dual-antiplatelet therapy. Platelet reactivity was assessed by light transmittance aggregometry using adenosine 5'-diphosphate, arachidonic acid, and collagen. The primary end point was definite/probable DES thrombosis at 6 months. The secondary end point was the composite of cardiac mortality and DES thrombosis.

The incidence of dual nonresponsiveness to aspirin and clopidogrel was 6%. Definite/probable DES thrombosis was significantly higher in dual aspirin and clopidogrel nonresponders (11.1%) than in clopidogrel and aspirin responders (2.1%, p < 0.001), isolated clopidogrel nonresponders (2.2%, p < 0.05), or aspirin nonresponders (2.3%, p < 0.05). The incidence of the secondary end point was 4.4% in isolated clopidogrel nonresponders, 2.3% in isolated aspirin nonresponders, and 13.3% in dual aspirin and clopidogrel nonresponders. Dual clopidogrel and aspirin nonresponsiveness was an independent predictor of DES thrombosis (hazard ratio: 3.18, 95% confidence interval: 1.14 to 8.83, p = 0.027) and the composite of cardiac mortality and DES thrombosis (hazard ratio: 2.94, 95% confidence interval: 1.16 to 7.41, p = 0.022).

Dual nonresponsiveness to aspirin and clopidogrel is a relatively infrequent condition that identifies patients at a very high risk of DES thrombosis or death.

Reticulated platelets are young platelets that are larger and possibly more active than non-RPs.

Flow cytometry was used to measure RPs after staining with thiazole orange and to define the upper 20% and lower 20% of platelets by size. Platelet aggregation was measured with light transmission aggregometry (LTA); platelet activation was assessed by measuring activated platelet surface expression of P-selectin and glycoprotein (GP) IIb/IIIa.

Ninety patients were recruited and stratified into tertiles of %RPs. Patients in the upper tertile displayed greater platelet aggregation to 5-µmol/l adenosine diphosphate (ADP) (50.7 ± 16.4% vs. 34.2 ± 17.3%, p < 0.001), 1.5-mmol/l arachidonic acid (AA) (27.3 ± 16.9% vs. 11.7 ± 9.3%, p < 0.001), and 1-µg/ml collagen (18 ± 11.6% vs. 12.1 ± 8.7%, p < 0.05) and greater expression of GP IIb/IIIa (4.7 ± 1.8% vs. 3.1 ± 2.2%, p < 0.001). Frequency of low response to aspirin (AA LTA >20%) was higher in the upper tertile (53% vs. 17%, p < 0.001) compared with the lower tertile; low response to clopidogrel (ADP LTA >50%) was also elevated in the upper tertile (50% vs. 13%, p = 0.003). The larger platelet gate had a higher % of RPs compared with the smaller gate (15.4 ± 16.7% vs. 1.7 ± 2.3%, p < 0.001) and greater GP IIb/IIIa (5.7 ± 3.1 vs. 2.1 ± 1.2, p < 0.001) and P-selectin expression (7.8 ± 4.9 vs. 4.6 ± 2.7, p < 0.001).

The proportion of circulating RPs strongly correlates with response to antiplatelet therapy in patients with stable CAD. Large platelets exhibit increased reactivity despite dual antiplatelet therapy, compared with smaller platelets.

Angiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans.

We developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF.

Increasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction.

Soluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF.

Histological studies have demonstrated a potential role of inflammation and neoangiogenesis in AVS.

We examined 96 leaflets scheduled for aortic valve replacement. Twenty-five patients had AVS, and 7 had aortic valve insufficiency (AVI). Temperature measurements were performed right before hypothermic cardioplegia. Temperature difference (T) was assigned as the mean temperature of each leaflet minus the temperature of the aortic wall. Histological, immunohistological analysis, and vascular endothelial growth factor (VEGF) immunoreactivity was performed.

Significant thermal heterogeneity was recorded within the leaflets of AVS, compared with AVI (1.52 ± 1.35°C vs. 0.13 ± 0.11°C, p < 0.01). In AVS T was greater in all leaflets compared with the AVI group (p < 0.01). Leaflets of AVS had increased inflammatory cell infiltration, calcium deposit, and anti-VEGF expression compared with AVI (p < 0.01).

Thermal heterogeneity is increased in AVS and correlates with inflammatory mononuclear cell infiltration, expression of pro-inflammatory cytokines and neoangiogenic factors.

Using PISA provides measures of MRFR, but calculating MRSV is challenging because of dynamic variations in the flow profile dependent on the underlying mechanism of mitral regurgitation (MR). Although various single-point and time-integral approaches have been described to overcome this limitation, uncertainty exists about the accuracy and feasibility of these methods in routine clinical practice.

In 73 patients with MR of different etiologies, MRSV was calculated from an apical 4-chamber view using the following 4 hemispheric PISA methods: 1) PISA-velocity–time integral (VTI) = midsystolic MRFR by PISA x regurgitant flow VTI/peak velocity; 2) simplified PISA = midsystolic MRFR/3.25; 3) serial PISA = sum of instantaneous MRFRs over serial 2-dimensional frames; and 4) M-mode PISA = time-integral of MRFRs from color M-mode. The MRSV by MRI was calculated from mitral inflow minus aortic outflow.

Single-point PISA methods yielded greater underestimation of MRSV (mean error: –13.3 ± 10.2 ml [PISA-VTI]; –13.5 ± 10.3 ml [simplified PISA]), particularly in functional MR, compared with time-integral PISA methods accounting for variations of MRFR and EROA over time (mean error: –8.0 ± 6.4 ml [M-mode PISA]; –8.7 ± 7.4 ml [serial PISA]).

Depending on the underlying mechanism of MR, dynamic variations of MRFR and EROA revealed important limitations of MRSV calculation using single-point and time-integral PISA methods.

Exercise intolerance is a major determinant of quality of life in patients with chronic heart failure. One of the major goals of the treatment for chronic heart failure is to improve quality of life.

Four weeks after left coronary ligation, we transplanted bone marrow cells isolated from the transgenic mice expressing a hemoglobin variant with low oxygen affinity, Presbyterian, into the lethally irradiated mice with heart failure or administered a synthetic allosteric modifier of hemoglobin. The mice were then exercised on a treadmill.

Four weeks after the left coronary artery ligation, mice showed cardiac dysfunction and chamber dilation, which were characteristics of heart failure. The transplantation led to a reduction in hemoglobin–oxygen affinity and an increase in oxygen supply for skeletal muscle without changes in muscle properties. The transplanted mice showed improved running performance on a treadmill despite impaired cardiac contractility. Furthermore, administration of the synthetic allosteric modifier of hemoglobin showed a similar effect.

Allosteric modification of hemoglobin represents a therapeutic option for improving exercise capacity in patients with chronic heart failure. One mechanism of improvement in exercise capacity is enhanced oxygen delivery in the skeletal muscle.

Contrast-induced nephropathy accounts for more than 10% of hospital-acquired renal failure. Recent studies suggest that hydration with sodium bicarbonate is more protective than isotonic saline in the prevention of CIN.

The prospective, single center study included 502 patients with estimated creatinine clearance <60 ml/min, randomized to receive infusion of either saline or sodium bicarbonate before and after iso-osmolar contrast medium administration. All patients received oral NAC 600 mg twice a day. Contrast-induced nephropathy was defined as an absolute increase of serum creatinine ≥0.5 mg/dl measured within 5 days.

Contrast-induced nephropathy occurred in 54 patients (10.8%); 25 (10%) were treated with sodium bicarbonate and 29 (11.5%) with saline (p = 0.60). In patients with CIN, the mean increase in creatinine was not significantly different in the 2 study groups (0.9 ± 0.6 mg/dl vs. 0.7 ± 0.2 mg/dl, respectively; p = 0.15). Only 2 patients needed temporary hemofiltration.

Hydration with sodium bicarbonate plus NAC before contrast medium exposure is not more effective than hydration with isotonic saline plus NAC for prophylaxis of CIN in patients with moderate-to-severe renal dysfunction. (Sodium Bicarbonate Versus Saline for the Prevention of Contrast-Induced Nephropathy; NCT00606827)

Controversy exists regarding the optimal approach to measure adiposity, and the utility of body mass index has been questioned.

Participants included 16,332 men in the Physicians' Health Study (mean age 61 years in 1991) and 32,700 women in the Women's Health Study (mean age 61 years in 1999). We used Cox proportional hazards models to determine relative risks and 95% confidence intervals (CIs) for developing CVD according to self-reported anthropometric indexes.

A total of 1,505 CVD cases occurred in men and 414 occurred in women (median follow-up 14.2 and 5.5 years, respectively). Although WHtR demonstrated statistically the strongest associations with CVD and best model fit, CVD risk increased linearly and significantly with higher levels of all indexes. Adjusting for confounders, the relative risk for CVD was 0.58 (95% CI: 0.32 to 1.05) for men with the lowest WHtR (<0.45) and 2.36 (95% CI: 1.61 to 3.47) for the highest WHtR (≥0.69; vs. WHtR 0.49 to <0.53). Among women, the relative risk was 0.65 (95% CI: 0.33 to 1.31) for those with the lowest WHtR (<0.42) and 2.33 (95% CI: 1.66 to 3.28) for the highest WHtR (≥0.68; vs. WHtR 0.47 to <0.52).

The WHtR demonstrated statistically the best model fit and strongest associations with CVD. However, compared with body mass index, differences in cardiovascular risk assessment using other indexes were small and likely not clinically consequential. Our findings emphasize that higher levels of adiposity, however measured, confer increased risk of CVD.

Obesity is a major risk factor for developing coronary heart disease. Whether obesity accelerates disease progression after CABG is unclear.

We examined how body mass index (BMI) related to atherosclerotic graft progression and a clinical composite outcome of death, nonfatal myocardial infarction, stroke, CABG surgery, or angioplasty among 1,314 participants in the Post CABG trial. Participants who had undergone CABG surgery were randomly assigned in a 2 x 2 factorial design to warfarin versus placebo and aggressive low-density lipoprotein cholesterol (LDL-C) lowering with lovastatin 40 to 80 mg/day (to achieve LDL-C of 60 to 85 mg/dl) versus moderate LDL-C lowering with lovastatin 2.5 to 5 mg/day (to achieve LDL-C of 130 to 140 mg/dl). Angiographic progression was assessed by coronary angiography at 4 to 5 years.

Higher BMI was associated with a higher likelihood of angiographic progression (p trend = 0.003) after adjustment for demographic factors, treatment assignment, smoking status, and years since CABG surgery, but not with clinical events (p trend = 0.81). In stratified analyses, higher BMI was associated with angiographic progression in the low-dose lovastatin group (p trend <0.001) but not in the high-dose group (p = 0.03 for test for interaction of BMI and statin treatment). In the high-dose lovastatin group, higher BMI appeared to be protective against clinical events (p trend = 0.06, test of interaction: 0.02).

Higher BMI is strongly associated with atherogenic progression after CABG surgery. Aggressive statin therapy may be protective against obesity-related acceleration of coronary heart disease.

Reducing LDL-C to a pre-determined goal may still leave an excess of atherogenic lipoproteins, as reflected in apoB levels.

The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial examined the effects of statin treatment in patients with high coronary heart disease (CHD) risk, LDL-C ≥130 and <250 mg/dl, and triglycerides <400 mg/dl. Therapy consisted of rosuvastatin (10 or 20 mg), atorvastatin (10 or 20 mg), or simvastatin (20 or 40 mg). The apoB and LDL-C or non–HDL-C at baseline and after 16 weeks of therapy were compared using linear regression.

In untreated patients, the apoB target of <90 mg/dl was roughly equivalent to an LDL-C level <100 mg/dl and a non–HDL-C level <130 mg/dl, which is consistent with existing apoB and lipoprotein guidelines. However, during statin therapy, to reach an apoB target of <90 mg/dl it was necessary to reduce non–HDL-C to <100 mg/dl or to reduce LDL-C to <70 mg/dl (in high-triglyceride patients) or <80 mg/dl (in lower-triglyceride patients). The tight correlation seen for non–HDL-C with apoB while on statin therapy (R² = 0.92) implies that non–HDL-C may be an acceptable surrogate for direct apoB measurement.

These data are consistent with the more aggressive cholesterol goals sugges