Real-time magnetic resonance imaging-guided endovascular recanalization of chronic total arterial occlusion in a swine model.

BACKGROUND: Endovascular recanalization (guidewire traversal) of peripheral artery chronic total occlusion (CTO) can be challenging. X-ray angiography resolves CTO poorly. Virtually "blind" device advancement during x-ray-guided interventions can lead to procedure failure, perforation, and hemorrhage. Alternatively, MRI may delineate the artery within the occluded segment to enhance procedural safety and success. We hypothesized that real-time MRI (rtMRI)-guided CTO recanalization can be accomplished in an animal model. METHODS AND RESULTS: Carotid artery CTO was created by balloon injury in 19 lipid-overfed swine. After 6 to 8 weeks, 2 underwent direct necropsy analysis for histology, 3 underwent primary x-ray-guided CTO recanalization attempts, and the remaining 14 underwent rtMRI-guided recanalization attempts in a 1.5-T interventional MRI system. Real-time MRI intervention used custom CTO catheters and guidewires that incorporated MRI receiver antennae to enhance device visibility. The mean length of the occluded segments was 13.3+/-1.6 cm. The rtMRI-guided CTO recanalization was successful in 11 of 14 swine and in only 1 of 3 swine with the use of x-ray alone. After unsuccessful rtMRI (n=3), x-ray-guided attempts were also unsuccessful. CONCLUSIONS: Recanalization of long CTO is entirely feasible with the use of rtMRI guidance. Low-profile clinical-grade devices will be required to translate this experience to humans.

Prognostic value of myeloperoxidase in patients with chest pain.

BACKGROUND: Inflammation is linked to adverse outcomes in acute coronary syndromes. Myeloperoxidase, an abundant leukocyte enzyme, is elevated in culprit lesions that have fissured or ruptured in patients with sudden death from cardiac causes. Numerous lines of evidence suggest mechanistic links between myeloperoxidase and both inflammation and cardiovascular disease. METHODS: We assessed the value of plasma levels of myeloperoxidase as a predictor of the risk of cardiovascular events in 604 sequential patients presenting to the emergency department with chest pain. RESULTS: Initial plasma myeloperoxidase levels predicted the risk of myocardial infarction, even in patients who are negative for troponin T (<0.1 ng per milliliter) at base line (P<0.001). Myeloperoxidase levels at presentation also predicted the risk of major adverse cardiac events (myocardial infarction, the need for revascularization, or death) within 30 days and 6 months after presentation (P<0.001). In patients without evidence of myocardial necrosis (defined as those who were negative for troponin T), the base-line myeloperoxidase levels independently predicted the risk of major adverse coronary events at 30 days (unadjusted 2nd, 3rd, and 4th quartile odds ratios, 2.2 [95 percent confidence interval, 1.1 to 4.6], 4.2 [95 percent confidence interval, 2.1 to 8.4], and 4.1 [95 percent confidence interval, 2.0 to 8.4], respectively) and at 6 months. CONCLUSIONS: A single initial measurement of plasma myeloperoxidase independently predicts the early risk of myocardial infarction, as well as the risk of major adverse cardiac events in the ensuing 30-day and 6-month periods. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis, highlighting its potential usefulness for risk stratification among patients who present with chest pain.

Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction.

BACKGROUND: Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney. METHODS: We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days. RESULTS: Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function. CONCLUSIONS: Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance.

Real-time magnetic resonance imaging-guided stenting of aortic coarctation with commercially available catheter devices in Swine.

BACKGROUND: Real-time MR imaging (rtMRI) is now technically capable of guiding catheter-based cardiovascular interventions. Compared with x-ray, rtMRI offers superior tissue imaging in any orientation without ionizing radiation. Translation to clinical trials has awaited the availability of clinical-grade catheter devices that are both MRI visible and safe. We report a preclinical safety and feasibility study of rtMRI-guided stenting in a porcine model of aortic coarctation using only commercially available catheter devices. METHOD AND RESULTS: Coarctation stenting was performed wholly under rtMRI guidance in 13 swine. rtMRI permitted procedure planning, device tracking, and accurate stent deployment. "Active" guidewires, incorporating MRI antennas, improved device visualization compared with unmodified "passive" nitinol guidewires and shortened procedure time (26+/-11 versus 106+/-42 minutes; P=0.008). Follow-up catheterization and necropsy showed accurate stent deployment, durable gradient reduction, and appropriate neointimal formation. MRI immediately identified aortic rupture when oversized devices were tested. CONCLUSIONS: This experience demonstrates preclinical safety and feasibility of rtMRI-guided aortic coarctation stenting using commercially available catheter devices. Patients may benefit from rtMRI in the future because of combined device and tissue imaging, freedom from ionizing radiation, and the ability to identify serious complications promptly.

Real-time magnetic resonance-guided endovascular repair of experimental abdominal aortic aneurysm in swine.

OBJECTIVES: This study tested the hypotheses that endografts can be visualized and navigated in vivo solely under real-time magnetic resonance imaging (rtMRI) guidance to repair experimental abdominal aortic aneurysms (AAA) in swine, and that MRI can provide immediate assessment of endograft apposition and aneurysm exclusion. BACKGROUND: Endovascular repair for AAA is limited by endoleak caused by inflow or outflow malapposition. The ability of rtMRI to image soft tissue and flow may improve on X-ray guidance of this procedure. METHODS: Infrarenal AAA was created in swine by balloon overstretch. We used one passive commercial endograft, imaged based on metal-induced MRI artifacts, and several types of homemade active endografts, incorporating MRI receiver coils (antennae). Custom interactive rtMRI features included color coding the catheter-antenna signals individually, simultaneous multislice imaging, and real-time three-dimensional rendering. RESULTS: Eleven repairs were performed solely using rtMRI, simultaneously depicting the device and soft-tissue pathology during endograft deployment. Active devices proved most useful. Intraprocedural MRI provided anatomic confirmation of stent strut apposition and functional corroboration of aneurysm exclusion and restoration of laminar flow in successful cases. In two cases, there was clear evidence of contrast accumulation in the aneurysm sac, denoting endoleak. CONCLUSIONS: Endovascular AAA repair is feasible under rtMRI guidance. Active endografts facilitate device visualization and complement the soft tissue contrast afforded by MRI for precise positioning and deployment. Magnetic resonance imaging also permits immediate post-procedural anatomic and functional evaluation of successful aneurysm exclusion.

Statins promote potent systemic antioxidant effects through specific inflammatory pathways.

BACKGROUND: The pleiotropic actions of hydroxymethylglutaryl CoA reductase inhibitors (statins) include antiinflammatory and antioxidant actions. We recently reported that statins induce reductions in plasma protein levels of nitrotyrosine (NO2Tyr), a modification generated by nitric oxide-derived oxidants. Whether alternative oxidative pathways are suppressed in vivo after statin administration has not yet been reported. METHODS AND RESULTS: As an extension of our prior study, hypercholesterolemic subjects with no known coronary artery disease were evaluated at baseline and after 12 weeks of atorvastatin therapy (10 mg/d). Plasma levels of protein-bound chlorotyrosine, NO2Tyr, dityrosine, and orthotyrosine, specific molecular fingerprints for distinct oxidative pathways upregulated in atheroma, were determined by mass spectrometry. In parallel, alterations in lipoproteins and C-reactive protein were determined. Statin therapy caused significant reductions in chlorotyrosine, NO2Tyr, and dityrosine (30%, 25%, and 32%, respectively; P<0.02 each) that were similar in magnitude to reductions in total cholesterol and apolipoprotein B-100 (25% and 29%, P<0.001 each). Nonsignificant decreases in orthotyrosine and C-reactive protein levels were observed (9% and 11%, respectively; P>0.10 each). Statin-induced reductions in oxidation markers were independent of decreases in lipids and lipoproteins. CONCLUSIONS: Statins promote potent systemic antioxidant effects through suppression of distinct oxidation pathways. The major pathways inhibited include formation of myeloperoxidase-derived and nitric oxide-derived oxidants, species implicated in atherogenesis. The present results suggest potential mechanisms that may contribute to the beneficial actions of statins. They also have important implications for monitoring the antiinflammatory and antioxidant actions of these agents.

Inflammation as a risk factor for atrial fibrillation.

BACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort. METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001). CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

Advances in cardiac biomarkers.

The diagnostic and prognostic roles of new and established cardiac biomarkers are continually changing. This update article discusses clinical diagnosis as a framework for directing biomarker testing. Markers are reviewed in the settings of acute coronary syndromes, decompensated heart failure, and noncardiac clinical scenarios.

A randomized, double-blinded, placebo-controlled, dose-ranging study measuring the effect of an adenosine agonist on infarct size reduction in patients undergoing primary percutaneous transluminal coronary angioplasty: the ADMIRE (AmP579 Delivery for Myocardial Infarction REduction) study.

BACKGROUND: Evidence suggests that myocardial ischemic preconditioning and reperfusion injury may be mediated by adenosine A1 and A2 receptors. AMP579 is a mixed adenosine agonist with both A1 and A2 effects. In animal models of acute myocardial infarction (MI), AMP579 reduced infarct size at serum levels of 15 to 24 ng/mL. METHODS: The AMP579 Delivery for Myocardial Infarction REduction study evaluated AMP579 in a double-blind, multicenter, placebo-controlled trial of 311 patients undergoing primary percutaneous transluminal coronary angioplasty (PTCA) after acute ST-segment elevation MI. Patients were randomly assigned to placebo or to 3 different doses of AMP579 continuously infused over 6 hours. The primary end point was final MI size measured by technetium Tc-99m sestamibi scanning at 120 to 216 hours after PTCA. Secondary end points included myocardial salvage and salvage index at the same time interval (in a subset of patients who underwent baseline technetium Tc-99m sestamibi scan), left ventricular ejection fraction and heart failure at 4 to 6 weeks, duration of hospitalization, and cardiac events at 4 weeks and 6 months. RESULTS: Final infarct size did not differ among the placebo group and the active treatment groups for either anterior MI or nonanterior MI. In patients with anterior MI, median myocardial salvage was increasingly higher in the groups receiving ascending dosages of AMP579 plus PTCA. Serum levels approaching levels shown to reduce infarct size in animal models were achieved only in the 60-mcg/kg treatment group. CONCLUSION: AMP579 was safe at the doses tested, but it did not reduce infarct size. There was a trend toward greater myocardial salvage in treated patients with anterior MI.

Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2).

Therapeutic angiogenesis represents an attempt to relieve inadequate blood flow by the directed growth and proliferation of blood vessels. Neovascularization is a complex process involving multiple growth factors, receptors, extracellular matrix glycoproteins, intracellular and extracellular signaling pathways, and local and bone-marrow-derived constituent cells, all responding to a symphonic arrangement of temporal and spatial cues. In cardiovascular disease, patients with refractory angina and lower extremity intermittent claudication seem most amenable to early tests of therapeutic angiogenesis. Monotherapy with the recombinant protein basic fibroblast growth factor (FGF-2) has been tested in six human trials. These have shown provisional safety, and two have provided 'proof of concept' for the strategy of therapeutic angiogenesis. One large randomized phase II trial failed to show significant efficacy in coronary artery disease. Another showed significant efficacy in peripheral artery disease, although the magnitude of benefit was disappointing at the dose tested. This overview details the suitable clinical trial design and further steps toward the clinical development of FGF-2.

Cardiac amyloidosis presenting with elevations of cardiac troponin I and angina pectoris.

We present the case of a 43-year-old male who was initially evaluated for angina pectoris and dyspnea. His CK, CK-MB, and cTnI were all elevated following a blood transfusion and he underwent coronary arteriography, which demonstrated no luminal obstructions. After several months, he was transferred to Mayo Clinic where diagnoses of fulminant cardiac amyloidosis and systemic multiple myeloma were established. The cTnI remained elevated despite normalization of the CK and CK-MB. Despite aggressive treatment, the patient died. Postmortem analysis demonstrated amyloid cardiac deposition including involvement of the coronary microvasculature. Electron microscopy revealed myocyte compression injury from amyloid infiltration. We believe this is the first report of elevated troponin I in a patient with cardiac amyloidosis. The electron microscopy in our case confirms cardiac damage as the mechanism for cTnI elevation. This observation strengthens our knowledge about the specificity of cTnI for the detection of cardiac injury.

Usefulness of myeloperoxidase levels in healthy elderly subjects to predict risk of developing heart failure.

Increased systemic myeloperoxidase (MPO) has been associated with both the presence and severity of heart failure (HF). This study tested the hypothesis that increased systemic MPO in apparently healthy elderly subjects may predict increased risk of developing HF. Systemic MPO was measured in all available samples from the 1992 to 1993 visit of the Cardiovascular Health Study (CHS). After excluding subjects without available blood samples or with a history of prevalent HF, myocardial infarction (MI), or stroke, 3,733 subjects were included. A total of 569 subjects developed incident HF during 7.2 +/- 2.3 years of follow-up. Patients in the highest MPO quartile (>432 pmol/L) showed higher risk of developing incident HF after adjusting for MI, age, gender, systolic blood pressure, smoking, low-density lipoprotein cholesterol, diabetes mellitus, and any subclinical cardiovascular disease (hazard ratio 1.34, 95% confidence interval 1.06 to 1.72, p = 0.013). However, the relation was more apparent after censoring subjects with incident MI before incident HF, even when adjusted for C-reactive protein and cystatin C (hazard ratio 1.46, 95% confidence interval 1.08 to 1.97, p = 0.02). Interestingly, stratified analyses showed that the relation between increased MPO and HF risk was stronger in subjects without traditional cardiovascular risk factors (

Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study.

OBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort. BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis. METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis. RESULTS: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092). CONCLUSIONS: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.

Technology preview: X-ray fused with magnetic resonance during invasive cardiovascular procedures.

BACKGROUND: We have developed and validated a system for real-time X-ray fused with magnetic resonance imaging, MRI (XFM), to guide catheter procedures with high spatial precision. Our implementation overlays roadmaps-MRI-derived soft-tissue features of interest-onto conventional X-ray fluoroscopy. We report our initial clinical experience applying XFM, using external fiducial markers, electrocardiogram (ECG)- gating, and automated real-time correction for gantry and table movement. METHODS: This prospective case series for technical development was approved by the NHLBI Institutional Review Board and included 19 subjects. Multimodality external fiducial markers were affixed to patients' skin before MRI, which included contrast-enhanced, 3D T1-weighted, or breath-held and ECG-gated 2D steady state free precession imaging at 1.5T. MRI-derived roadmaps were manually segmented while patients were transferred to a calibrated X-ray fluoroscopy system. Image spaces were registered using the fiducial markers and thereafter permitted unrestricted gantry rotation, table panning, and magnification changes. Static and ECG-gated MRI data were transformed from 3D to 2D to correspond with gantry and table position and combined with live X-ray images. RESULTS: Clinical procedures included graft coronary arteriography, right ventricular free-wall biopsy, and iliac and femoral artery recanalization and stenting. MRI roadmaps improved operator confidence, and in the biopsy cases, outperformed the best available alternative imaging modality. Registration errors were increased when external fiducial markers were affixed to more mobile skin positions, such as over the abdomen. CONCLUSION: XFM using external fiducial markers is feasible during X-ray guided catheter treatments. Multimodality image fusion may prove a useful adjunct to invasive cardiovascular procedures.

Real-time MRI guided atrial septal puncture and balloon septostomy in swine.

Cardiac perforation during atrial septal puncture (ASP) might be avoided by improved image guidance. X-ray fluoroscopy (XRF), which guides ASP, visualizes tissue poorly and does not convey depth information. Ultrasound is limited by device shadows and constrained imaging windows. Alternatively, real-time MRI (rtMRI) provides excellent tissue contrast in any orientation and may enable ASP and balloon atrial septostomy (BAS) in swine. Custom MRI catheters incorporated "active" (receiver antenna) and "passive" (iron or gadolinium) elements. Wholly rtMRI-guided transfemoral ASP and BAS were performed in 10 swine in a 1.5T interventional suite. Hemodynamic results were measured with catheters and velocity encoded MRI. Successful ASP was performed in all 10 animals. Necropsy confirmed septostomy confined within the fossa ovalis in all. BAS was successful in 9/10 animals. Antenna failure in a re-used needle led to inadvertent vena cava tear prior to BAS in 1 animal. ASP in the same animal was easily performed using a new needle. rtMRI illustrated clear device-tissue-lumen relationships in multiple orientations, and facilitated simple ASP and BAS. The mean procedure time was 19 +/- 10 minutes. Septostomy achieved a mean left to right shunt ratio of 1.3:1 in these healthy animals. Interactive rtMRI permits rapid transcatheter ASP and BAS in swine. Further technical development may enable novel applications.

Measurement of skeletal muscle perfusion during postischemic reactive hyperemia using contrast-enhanced MRI with a step-input function.

The regional distribution of skeletal muscle blood flow was measured during postischemic reactive hyperemia using Gd-DTPA contrast-enhanced (CE) MRI. The release of an occlusive thigh cuff was used to deliver a step-input of contrast concentration that was coincident with the onset of reactive hyperemia. A first-order tracer kinetic equation was used to estimate the unidirectional influx constant, Ki (ml/100 g/min), and the distribution volume of Gd-DTPA in the tissue, v(e), from T1-weighted images acquired with saturation recovery (SR) steady-state free precession (SSFP) and spoiled gradient-echo (SPGR) protocols. The capillary permeability surface (PS) area increased significantly during reactive hyperemia, which facilitated rapid extraction of Gd-DTPA during the first pass. Regional muscle group studies from 11 normal volunteers yielded blood flow (Ki) values of 108.3 +/- 34.1 ml/100 g/min in the gastrocnemius, 184.3 +/- 41.3 ml/100 g/min in the soleus, and 122.4 +/- 34.4 ml/100 g/min in the tibialis anterior. The distribution volumes (v(e)) in the corresponding muscle groups were respectively 8.3% +/- 2.1%, 9.3% +/- 1.9%, and 7.9% +/- 1.8% from the kinetic model, and 8.8% +/- 2.4%, 9.1% +/- 1.9%, and 7.2% +/- 1.4% from tissue relaxometry studies. Bulk blood flow studies in the same volunteers using phase-contrast velocimetry (popliteal artery) yielded significantly lower flow values, but with a correlation coefficient R2 = 0.62 and P = 0.004.

Antiplatelet therapies in combination for the treatment of patients with stable and unstable coronary artery disease.

There have been several recent trials of antiplatelet therapy that are relevant to the management of patients with coronary artery disease. The CURE, PCI-CURE, ESPRIT, TACTICS-TIMI 18, and TARGET studies were all major randomized clinical trials that have advanced the field of cardiovascular medicine tremendously. Additionally, the CREDO trial will soon be presented. It is evident from these trials that clopidogrel therapy improves upon the results seen with aspirin alone in patients with acute coronary syndromes. This is true even of patients undergoing an invasive approach, which is clearly the preferred strategy in moderate and high risk patients with acute coronary syndromes. It is imperative that this invasive approach be coupled with intravenous blockade of the glycoprotein IIb/IIIa receptor. The benefits of clopidogrel and glycoprotein IIb/IIIa inhibitors appear complementary. Questions remain about the optimal duration of clopidogrel treatment after elective stenting and of the particular choice of glycoprotein IIb/IIIa inhibitor both in acute and elective settings.

Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy.

CONTEXT: Formation of nitric oxide-derived oxidants may serve as a mechanism linking inflammation to development of atherosclerosis. Nitrotyrosine, a specific marker for protein modification by nitric oxide-derived oxidants, is enriched in human atherosclerotic lesions and low-density lipoprotein (LDL) recovered from human atheroma. OBJECTIVES: To determine whether systemic levels of nitrotyrosine are associated with the prevalence of coronary artery disease (CAD) and are modulated by hydroxymethylglutaryl coenzyme-A reductase inhibitor (statin) therapy. DESIGN, SETTING, AND PATIENTS: A case-control and interventional study at 2 urban tertiary-care referral centers; recruitment for each was from June 1, 2001, until January 1, 2002. For the case-control study, 100 case-patients with established CAD and 108 patients with no clinically evident CAD were recruited consecutively. In the interventional study, participants aged 21 years or older with hypercholesterolemia (LDL cholesterol > or =130 mg/dL [> or =3.5 mmol/L]) underwent nutrition and exercise counseling. Those whose levels did not decrease with 6 to 8 weeks were enrolled in the study (n = 35). For 12 weeks, they received 10 mg/d of oral atorvastatin therapy. MAIN OUTCOME MEASURES: In the case-control study, the association between systemic levels of protein-bound nitrotyrosine, CAD risk, and presence of CAD. In the interventional study, the change in nitrotyrosine, lipoprotein, and C-reactive protein (CRP) levels. RESULTS: Nitrotyrosine levels were significantly higher among patients with CAD (median 9.1 micromol/mol [interquartile range, 4.8-13.8 micromol/mol] tyrosine vs 5.2 micromol/mol [interquartile range, 2.2-8.4 micromol/mol]; P<.001). Patients in the upper quartile of nitrotyrosine (29%; P<.001) had a higher odds of CAD compared with those in the lowest quartile (unadjusted odds ratio, 6.1; 95% confidence interval, 2.6-14.0; P<.001). In multivariate models adjusting for Framingham Global Risk Score and CRP, upper quartiles of nitrotyrosine remained associated with CAD (odds ratio, 4.4; 95% confidence interval, 1.8-10.6; P<.001). Statin therapy reduced nitrotyrosine levels significantly (25%; P<.02) with a magnitude similar to reductions in total cholesterol levels (25%; P<.001) and LDL particle number (29%; P<.001) yet were independent of alterations in lipoproteins and inflammatory markers like CRP. CONCLUSIONS: The findings from this preliminary study indicate that nitrotyrosine levels are associated with the presence of CAD and appear to be modulated by statin therapy. These results suggest a potential role for nitric oxide-derived oxidants as inflammatory mediators in CAD and may have implications for atherosclerosis risk assessment and monitoring of anti-inflammatory actions of statins.