N. West

Association Between IVUS Findings and Adverse Outcomes in Patients With Coronary Artery Disease The VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study

OBJECTIVES The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac events (MACE) on individual plaque or whole patient analysis. BACKGROUND Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies. METHODS One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization. RESULTS In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio [HR]: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004). CONCLUSIONS VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.

Functional Effect of the C242T Polymorphism in the NAD(P)H Oxidase p22phox Gene on Vascular Superoxide Production in Atherosclerosis

BackgroundIncreased superoxide anion production increases oxidative stress and reduces nitric oxide bioactivity in vascular disease states. NAD(P)H oxidase is an important source of superoxide in human blood vessels, and some studies suggest a possible association between polymorphisms in the NAD(P)H oxidase CYBA gene and atherosclerosis; however, no functional data address this hypothesis. We examined the relationships between the CYBA C242T polymorphism and direct measurements of superoxide production in human blood vessels. Methods and ResultsVascular NAD(P)H oxidase activity was determined in human saphenous veins obtained from 110 patients with coronary artery disease and identified risk factors. Immunoblotting, reverse-transcription polymerase chain reaction, and DNA sequencing showed that p22phox protein, mRNA, and 242C/T allelic variants are expressed in human blood vessels. Vascular superoxide production, both basal and NADH-stimulated, was highly variable between patients, but the presence of the CYBA 242T allele was associated with significantly reduced vascular NAD(P)H oxidase activity, independent of other clinical risk factors for atherosclerosis. ConclusionsAssociation of the CYBA 242T allele with reduced NAD(P)H oxidase activity in human blood vessels suggests that genetic variation in NAD(P)H oxidase components may play a significant role in modulating superoxide production in human atherosclerosis.

Nitric oxide modulates superoxide release and peroxynitrite formation in human blood vessels.

Nitric oxide and superoxide have important roles as vascular signaling molecules. Nitric oxide (NO) reacts rapidly with superoxide, producing peroxynitrite. The relative balance between these radicals has important implications for vascular pathophysiology in hypertension and other vascular disease states. However, the relationships between superoxide, NO, and peroxynitrite formation in human blood vessels remain unclear. Accordingly, we systematically measured NO, superoxide, and peroxynitrite production from human internal mammary arteries, radial arteries, and saphenous veins from 78 patients undergoing coronary bypass surgery. Basal superoxide release was detected in all vessels at similar levels. However, endothelial removal or nitric oxide synthase inhibition increased mean superoxide release, with a corresponding reduction in peroxynitrite formation. Conversely, NO donors and superoxide scavengers both reduced superoxide release, whereas only NO donors increased peroxynitrite formation. These changes were much larger in arteries that in veins, but there were striking correlations between superoxide production, NO bioavailability, and peroxynitrite formation between the vessel types. Our findings provide direct evidence for coordinated vascular signaling mediated by interactions between NO, superoxide, and peroxynitrite and have important implications for studies of the functional effects of these radicals in human blood vessels.

The Atmospheric Neutrino Flavor Ratio from a 3.9 Fiducial Kiloton-Year Exposure of Soudan 2

Abstract We report a measurement of the atmospheric neutrino flavor ratio, R, using a sample of quasi-elastic neutrino interactions occurring in an iron medium. The flavor ratio (tracks/showers) of atmospheric neutrinos in a 3.9 fiducial kiloton-year exposure of Soudan 2 is 0.64±0.11(stat.)±0.06(syst.) of that expected. Important aspects of our main analysis have been checked by carrying out two independent, alternative analyses; one is based upon automated scanning, the other uses a multivariate approach for background subtraction. Similar results are found by all three approaches.

Measurement of the atmospheric neutrino flavour composition in Soudan 2

Abstract The atmospheric neutrino flavour ratio measured using a 1.52 kton-year exposure of Soudan 2 is found to be 0.72 ± 0.19−0.07+0.05 relative to the expected value from a Monte Carlo calculation. The possible background of interactions of neutrons and photons produced in muon interactions in the rock surrounding the detector has been investigated and is shown not to produce low values of the ratio.

Clinical and Angiographic Predictors of Restenosis After Stent Deployment in Diabetic Patients

Background—Restenosis and consequent adverse cardiac events are increased in diabetics undergoing percutaneous coronary intervention. Use of intracoronary stents may ameliorate such risks; however, factors influencing the likelihood of restenosis after stent deployment in this high-risk patient subgroup are unknown. Methods and Results—We retrospectively analyzed all stented diabetic patients in 16 studies of percutaneous coronary intervention, all of which underwent core angiographic analysis at Cardialysis, Rotterdam. Univariate and multivariate analyses, with 37 clinical and angiographic variables, compared those with and without restenosis and predicted restenosis rates calculated through the use of reference charts derived from angiographic data. Within the studies, 418 of 3090 (14%) stented patients with 6-month angiographic follow-up had diabetes. Restenosis (≥50% diameter stenosis at follow-up) occurred in 550 of 2672 (20.6%) nondiabetic and 130 of 418 (31.1%) diabetic patients (P <0.001). Univariate predictors of restenosis in diabetics were smaller vessel reference diameter (RD) (P <0.001), smaller minimal luminal diameter before stenting (P =0.01), smaller minimal luminal diameter and percent diameter stenosis after stenting (P <0.001, P =0.04), greater stented length of vessel (P <0.001), and reduced body mass index (BMI) (P =0.04). With the use of multivariate analysis, only smaller RD (P =0.003), greater stented length of vessel (P =0.04), and reduced BMI (P =0.04) were associated with restenosis. Reference charts demonstrated an incremental risk of restenosis that appears solely dependent on vessel RD. Conclusions—Restenosis after stent deployment is significantly increased in diabetic patients. Vessel caliber, stented length of vessel, and lower BMI are predictors of in-stent restenosis in patients with diabetes. Furthermore, vessel caliber affected the predicted risk of restenosis incrementally.

Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice.

(6 R)-5,6,7,8-Tetrahydro-biopterin (H4B) is essential for the catalytic activity of all NO synthases. The hyperphenylalaninemic mouse mutant (hph-1) displays 90% deficiency of the GTP cyclohydrolase I, the rate-limiting enzyme in H4B synthesis. A relative shortage of H4B may shift the balance between endothelial NO synthase (eNOS)-catalyzed generation of NO and reactive oxygen species. Therefore, the hph-1 mouse represents a unique model to assess the effect of chronic H4B deficiency on endothelial function. Aortas from 8-week-old hph-1 and wild-type mice (C57BL×CBA) were compared. H4B levels were determined by high-performance liquid chromatography and NO synthase activity by [3H]citrulline assay in homogenized tissue. Superoxide production by the chemiluminescence method was measured. Isometric tension was continuously recorded. The intracellular levels of H4B as well as constitutive NO synthase activity were significantly lower in hph-1 compared with wild-type mice. Systolic blood pressure was increased in hph-1 mice. However, endothelium-dependent relaxations to acetylcholine were present in both groups and abolished by inhibition of NO synthase with NG-nitro-l-arginine methyl ester as well. Only in hph-1 mice were the relaxations inhibited by catalase and enhanced by superoxide dismutase. After incubation with exogenous H4B, the differences between the 2 groups disappeared. Our findings demonstrate that H4B deficiency leads to eNOS dysfunction with the formation of reactive oxygen species, which become mediators of endothelium-dependent relaxations. A decreased availability of H4B may favor an impaired activity of eNOS and thus contribute to the development of vascular diseases.

Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention The CRISP Stent Trial Long-term Follow-up

Background—Postprocedural myocardial infarction (type 4a) has been shown to be an adverse prognostic indicator after elective percutaneous coronary intervention (PCI). The Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study demonstrated that remote ischemic preconditioning reduced procedural symptoms, ECG ST-segment deviation, and cardiac troponin I release after elective PCI and reduced the major adverse cardiac and cerebral event (MACCE) rate at 6 months. We were interested to confirm if this early benefit in MACCE rate in the remote ischemic preconditioning group was sustained long-term. Methods and Results—Patients were telephoned by researchers blinded to the randomization details. MACCE, defined as all-cause mortality, nonfatal myocardial infarction, transient ischemic attack or stroke, and heart failure requiring hospital admission, were adjudicated by case note and national database review. One hundred ninety-two (89.3%) of the 225 patients with elective PCI randomized in the original study were available for long-term follow-up (mean time to event or last follow-up: 1579.7±603.6 days). There were a total of 59 (30.7%) MACCEs. Patients with an MACCE had a higher mean cardiac troponin I after PCI (±SD): 2.07±6.99 versus 0.91±2.07 ng/mL (P=0.05). The MACCE rate at 6 years remained lower in the remote ischemic preconditioning group (hazard ratio, 0.58; 95% confidence interval, 0.35–0.97; P=0.039; absolute risk reduction=0.13 and number needed to treat=8 to prevent the MACCE at 6 years). Conclusions—Remote ischemic preconditioning reduces the incidence of postprocedural cardiac troponin I after elective PCI and confers an MACCE-free survival benefit at both short- and long-term follow-up. Clinical Trial Registration—URL: http://www.ukcrn.org.uk. Unique identifier: UKCRN 4074

Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans

Background— Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species. Methods and Results— mtDNA damage occurred early in the vessel wall in apolipoprotein E–null (ApoE−/−) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE−/− mice deficient for mitochondrial polymerase-&ggr; proofreading activity (polG−/−/ApoE−/−). polG−/−/ApoE−/− mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG−/−/ApoE−/− mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG−/−/ApoE−/− bone marrow increased the features of plaque vulnerability, and polG−/−/ApoE−/− monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. Conclusions— We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.

A Pilot Study to Assess Whether Glucagon-Like Peptide-1 Protects the Heart From Ischemic Dysfunction and Attenuates Stunning After Coronary Balloon Occlusion in Humans

Background— The incretin hormone glucagon-like peptide-1 (GLP-1) has been shown to have cardioprotective properties in animal models of ischemia and infarction due to promotion of myocardial glucose uptake and suppression of apoptosis. We investigated whether GLP-1 protected the heart from dysfunction caused by supply ischemia during percutaneous coronary intervention (PCI). Methods and Results— Twenty patients with normal left ventricular (LV) function and single-vessel coronary disease within the left anterior descending artery undergoing elective PCI were studied. A conductance catheter was placed into the LV through the femoral artery, and pressure-volume loops were recorded at baseline and during a 1-minute low-pressure balloon occlusion at the site of the stenosis. The patients were randomized to receive an infusion of either GLP-1(7–36) amide at 1.2 pmol/kg per minute or saline immediately after the first balloon occlusion. Coronary balloon occlusion caused LV stunning in the control group with cumulative LV dysfunction on subsequent occlusion that was not seen in the GLP-1 group. GLP-1 improved recovery of LV systolic and diastolic function at 30 minutes after balloon occlusion compared with control (delta dP/dtmax from baseline, −1.6% versus −12.2%; P=0.02) and reduced the LV dysfunction after the second balloon occlusion (delta dP/dtmax, −13.1% versus −25.3%; P=0.01). Conclusions— In this pilot study, infusion of GLP-1 has been demonstrated to reduce ischemic LV dysfunction after supply ischemia during coronary balloon occlusion in humans and mitigates stunning. The findings require confirmation in a larger scale clinical trial. Clinical Trial Registration— URL: http://www.isrctn.org. Unique identifier: ISRCTN 77442023.