Circadian body temperature variability is an indicator of poor prognosis in cardiomyopathic hamsters.

BACKGROUND: Low body temperature is an independent predictor of poor prognosis in patients with congestive heart failure. The cardiomyopathic hamster develops progressive biventricular dysfunction, resulting in heart failure death at 9 months to 1 year of life. Our goal was to use cardiomyopathic hamsters to examine the relationship between body temperature and heart failure decompensation and death. METHODS AND RESULTS: To this end, we implanted temperature and activity transducers with telemetry into the peritoneal space of 46 male Bio-TO-2 Syrian cardiomyopathic hamsters. Multiple techniques, including computing mean temperature, frequency domain analysis, and nonlinear analysis, were used to determine the most useful method for predicting poor prognosis. Data from 44 hamsters were included in our final analysis. We detected a decline in core body temperature in 98% of the hamsters 8+/-4 days before death (P < .001). We examined the dominant frequency of temperature variation (ie, the circadian rhythm) by using cosinor analysis, which revealed a significant decrease in the amplitude of the body temperature circadian rhythm 8 weeks before death (0.28 degrees C; 95% CI, 0.26-0.31) compared to baseline (0.36 degrees C; 95% CI, 0.34-0.39; P=.005). The decline in the circadian temperature variation preceded all other evidence of decompensation. CONCLUSIONS: We conclude that a decrease in the amplitude of the body temperature circadian rhythm precedes fatal decompensation in cardiomyopathic hamsters. Continuous temperature monitoring may be useful in predicting preclinical decompensation in patients with heart failure and in identifying opportunities for therapeutic intervention.

Americans on health care reform: results from polls conducted with Zogby International, Inc.

During a time of uncertainty regarding the future of the American health care system, an assessment, over time, of Americans' opinion on different legislative or health policy directions is a valuable asset to decision makers. After polling over 10,000 Americans via three polls on these topics over four months, a few distinct trends have emerged. When it comes to health care reform, Americans want a "tune-up," not a "trade-in" of their health care system by implementing reforms that allow the system to work more efficiently for the largest number of people possible, paying for it through savings found by reducing extraneous and wasteful spending and by increasing the quality of care. A clear sense of equity is also evident, as a majority do not agree with insurance companies using pre-existing health conditions as a metric in determining eligibility and believe in mandating that those who are employed, except for the smallest companies, should be covered.

Utilizing a trauma systems approach to benchmark and improve combat casualty care.

BACKGROUND: Derived from the necessity to improve the outcomes of soldiers injured on the battlefield, the U.S. military forces developed and implemented the Joint Theater Trauma System (JTTS) and the Joint Theater Trauma Registry based on U.S. civilian trauma system models. The purpose of this analysis was to develop battlefield injury outcome benchmark metrics and to evaluate the impact of JTTS-driven performance improvement interventions. METHODS: To quantify these achievements, the Joint Theater Trauma Registry captured mechanistic, physiologic, diagnostic, therapeutic, and outcome data on 18,377 injured patients from January 2004 to May 2008 for analysis. Benchmarks were developed and statistically validated by using control chart methodology. RESULTS: The majority (66.4%) of battlefield wounds were penetrating mechanism, 23.3% of all patients had an Injury Severity Score of > or = 16, 21.8% had a base deficit of > or = 5, 30.5% of patients required blood, and 6.8% required massive transfusion (> or = 10 units red blood cell per 24 hours). In this severely injured population from the battlefield, the JTTS developed several pertinent benchmark metrics to assess quality of care associated with postinjury complications and mortality. The implementation of 27 JTTS-developed evidenced-based clinical practice guidelines and an improved information dissemination process was associated with a decrease in aggregate postinjury complications by 54%. CONCLUSIONS: Despite the numerous challenges of a global trauma system, the JTTS has set the standard for trauma care on the modern battlefield utilizing evidence-based medicine. The development of injury care benchmarks enhanced the evolution of the combat casualty care performance improvement process within the trauma system.

Temporal trends in anti-diabetes drug use in TRICARE following safety warnings in 2007 about rosiglitazone.

PURPOSE: To describe utilization patterns for anti-diabetes medications among a cohort of diabetes patients in the Military Health System (MHS) before and after warnings about rosiglitazone issued in May 2007. METHODS: We used segmented regression analysis to compare changes in the level and trend of rosiglitazone utilization and use of other anti-diabetes therapies in the period prior to the drug warnings (between April 2006 and May 2007) and the period after the warnings were issued (between October 2007 and May 2008). RESULTS: The level and trend of rosiglitazone use changed after the highly publicized warnings. The number of prescriptions filled fell by almost 7000 after the warning (p < 0.001). The number of prescriptions filled for pioglitazone, sulfonylureas, and other diabetes drugs increased significantly after the warnings (p < 0.05 in all models). Overall, the level and trend of filled prescriptions per month for all anti-diabetic drugs did not significantly change after the warnings. CONCLUSIONS: Utilization patterns changed in response to warnings about rosiglitazone. While overall utilization of anti-diabetic drugs did not change, further study is needed to determine the associated health outcomes.

An iodinated liposomal computed tomographic contrast agent prepared from a diiodophosphatidylcholine lipid.

Herein we report a novel vesicle-forming iodinated contrast agent for applications in computed tomographic (CT) imaging and drug delivery. Specifically, we have chemically modified a phosphatidylcholine lipid that is commonly used in liposome formation to create an iodinated lipid that self-assembles into approximately 50-150 nm iodoliposomes possessing as-prepared imaging contrast functionality. These iodoliposomes are structurally organized such that the iodinated moieties are contained within the vesicle's bilayer, leaving the liposomal interior unoccupied and thus available for encapsulating drugs. The iodoliposomes were characterized using electron microscopy and dynamic light scattering. We also calculated the iodoliposomes' iodine encapsulation efficiency, which was sufficient for use in current CT imaging protocols. These iodinated liposomes could also serve as multifunctional carriers upon the encapsulation of pharmaceutical agents, permitting simultaneous CT imaging and therapeutic treatment. Alternatively, the commercially available iodinated contrast agent iohexol could be encapsulated inside the iodoliposomes' aqueous core to further enchance their imaging contrast.

Racial and ethnic health disparities in TRICARE.

BACKGROUND: As a major provider of health care for racial and ethnic minority groups, the federal government has affirmed its commitment to the elimination of health disparities. Although numerous studies have examined health care disparities in various federal systems of care, few have examined these issues within TRICARE, the Department of Defense (DoDJ's program for providing health care coverage to members of the uniformed services and their dependents. METHODS: This study provides an exploratory analysis examining apparent disparities in health status, access to and satisfaction with care, and use of preventive care using the 2007 Health Care Survey of DoD Beneficiaries. Analyses compare outcomes by race/ethnicity and between TRICARE beneficiaries and national norms derived from the National Consumer Assessment of Health Plans Study Benchmarking Database and the National Healthcare Disparities Report, and are stratified by duty status. RESULTS: Compared to black non-Hispanics, a higher proportion of white non-Hispanic active-duty and retiree TRICARE beneficiaries reported good to excellent health status. However, on most measures, we found no differences between white non-Hispanic beneficiaries and members of racial/ethnic groups. When differences did exist, minority populations were likely to report better access to and use of services than whites. CONCLUSIONS: Although health disparities exist in health status and some measures of preventive care, black non-Hispanics and Hispanics often receive more equitable care under TRICARE than in the nation as a whole. These findings suggest the need to explore the characteristics of TRICARE that may be associated with more-favorable outcomes for racial and ethnic minority groups.

TRICARE Management Activity Healthcare Facility Evidence-Based Design Survey.

UNLABELLED: This report summarizes findings from the TRICARE Management Activity (TMA) Healthcare Facility Evidence-Based Design Survey. TMA conducted 382 telephone interviews with active duty (AD) personnel and 36 interviews with AD spouses to solicit their opinions regarding 10 proposed healthcare facility design features that could improve the comfort and convenience of a hospital stay. The survey was composed of 10 multiple-choice questions that were based on recent findings in evidence-based healthcare facility design features. RESULTS: The 4 most important features for all respondents include having space in the patient room for overnight visitors, privacy features, and individual control of lighting and temperature. CONCLUSION: Developing specific hospital design plans will likely require continuing to work with patients and their loved ones to develop well-defined requirements. Potential study techniques include interviewing in facilities, holding focus groups, and observing patient and family behavior in the facility.

The association between oseltamivir use and adverse neuropsychiatric outcomes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza.

UNLABELLED: Recent reports out of Japan have linked therapeutic use of the oral neuraminidase inhibitor oseltamivir with adverse neuropsychiatric outcomes in adolescents. OBJECTIVE: To assess if protective measures should be taken to mitigate potential adverse outcomes among United States Department of Defense (DoD) pediatric beneficiaries who are prescribed oseltamivir therapeutically. STUDY GROUP: DoD healthcare beneficiaries, ages 1 through 21 years, who received a diagnosis of influenza from 1 October 2006 through 30 September 2007. METHODS: A retrospective cohort study using electronic healthcare service and pharmacy fill. Cross tabulations and propensity-adjusted logistic regression analyses were performed to compare the frequency of adverse neuropsychiatric outcomes among those treated therapeutically with oseltamivir with those that were not. RESULTS: The prevalences of neuropsychiatric diagnoses following the influenza diagnosis overall and among the treated and untreated groups were 3.5%, 3.0%, and 3.8%, respectively (p < .05). A statistically significant protective effect was associated with oseltamivir treatment (prevalence odds ratio (POR) = 0.82 (95% CI, 0.69, 0.96)) in a propensity-adjusted regression model. The model significantly associated increasing patient age with the likelihood of an adverse neuropsychiatric outcome, but the associations with patient gender and parental rank, a proxy used for socioeconomic status, were not statistically Significant. CONCLUSIONS: Our retrospective study found no evidence that oseltamivir treatment for influenza increased the risk of adverse neuropsychiatric outcomes among the study population. An additional study focusing on prospective medical surveillance of influenza patients is warranted.

Decreasing body temperature predicts early rehospitalization in congestive heart failure.

BACKGROUND: In congestive heart failure (CHF), a low body temperature at hospital admission predicts in-hospital mortality. We hypothesized that a postdischarge reduction in body temperature predicts early CHF rehospitalization and death. METHODS: We reviewed the records of 198 patients discharged after CHF hospitalization. We categorized the patients as hypothermic or normothermic (cutoff point, 36.3 degrees C/97.4 degrees F) according to body temperature at discharge. We classified the 2 groups according to the direction of temperature change between discharge and the first follow-up visit: normothermic/non-decreasing temperature (N+), normothermic/decreasing temperature (N-), hypothermic/non-decreasing temperature (H+), and hypothermic/decreasing temperature (H-). RESULTS: Ninety-three patients (47%) had decreasing temperatures, and 105 patients (53%) had non-decreasing temperatures. Kaplan-Meier analysis revealed a significant intergroup difference in survival (P = .01) and rehospitalization time (P = .005). On logistic regression, a decreasing temperature was significantly associated with rehospitalization within 180 days (odds ratio, 4.01; 95% confidence interval, 1.63-10.02; P = .003). On Cox regression, the hazard ratios for death were 3.19 (P = .07), 6.49 (P = .004), and 5.17 (P = .07), for the N-, H+, and H- groups, respectively, versus the N+ group. For rehospitalization time, the hazard ratios were 7.02 (P = .01), 4.24 (P = .08), and 13.43 (P = .005) for the N-, H+, and H- groups, respectively, versus the N+ group. CONCLUSION: Decreasing body temperatures can predict readmission, decreased time to rehospitalization, and (in combination with hypothermia) decreased survival.

A comparison of select cardiovascular outcomes by antidiabetic prescription drug classes used to treat type 2 diabetes among Military Health System beneficiaries, fiscal year 2003-2006.

BACKGROUND: Recent research suggests that there is an increased risk of cardiovascular outcomes among individuals with type 2 diabetes taking rosiglitazone (Avandia). OBJECTIVE: To determine if there is an increased incidence of select cardiovascular events, specifically acute myocardial infarction (AMI) and congestive heart failure (CHF), among Military Health System beneficiaries with type 2 diabetes who filled a prescription for Avandia compared with those who filled prescriptions for other antidiabetic medications. DESIGN: Cross-sectional analysis of data from fiscal year 2003-2006. PARTICIPANTS: Military Health System beneficiaries who are enrolled in TRICARE Prime [Health Maintenance Organization (HMO)-like option] with a diagnosis of type 2 diabetes. RESULTS: Average annual incidence of AMI and CHF was lowest among individuals who filled a prescription for biguanides (metformin) and greatest among those who filled a prescription for insulin. The incidence of AMI was highest among beneficiaries with a triple combination of antidiabetic drugs including insulin. The incidence of CHF was highest among those who took a sulfonylurea and Actos during the observation period (fiscal year 2003-2006). LIMITATIONS: This study has several limitations including the cross-sectional design and inability to make statistical comparisons across drug categories. CONCLUSIONS: There does not appear to be an increased annual incidence of AMI or CHF among TRICARE Prime beneficiaries with a diagnosis of type 2 diabetes who have filled a prescription for Avandia compared with those who filled prescriptions for other antidiabetic medications.

Devices in heart failure: potential methods for device-based monitoring of congestive heart failure.

Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and therapeutic refractoriness, that have an impact on outcomes. The onset of such conditions is sometimes heralded by subtle pathophysiologic changes, and the timely identification of these changes may promote the use of preventive measures. Consequently, device-based methods could in the future have an important role in the timely identification of the subtle pathophysiologic changes associated with congestive heart failure.

Quantification of roughness of calcific deposits in computed tomography scans of human coronary arteries.

OBJECTIVES: The incidence of coronary artery disease has been shown to be greater in patients with calcific deposits than in those without. It has been suggested that the pattern of distribution of coronary calcific deposits within coronary arteries is of greater predictive value for acute coronary events than the overall quantity. Whether roughness of calcific deposits is a predictor of acute coronary events is not known. We derived and tested an algorithm, Voxel-Based Bosselation (VBB), for noninvasive quantification of roughness of calcific deposits in human coronary arteries imaged by computed tomography (CT). METHODS AND RESULTS: VBB was tested on 213 coronary calcific deposits from electron beam CT scans of 27 patients. This algorithm evaluates the 3-dimensional connectedness of surface voxels of each deposit: smooth masses have low VBB and rough masses high VBB. The algorithm was calibrated with artificially generated phantoms as well as background noise mimicking calcific deposits and surrounding heart tissue. The VBB algorithm is applicable to calcific deposits of all scales and gradations. The VBB values of the deposits in this study did not correlate with deposit size further supporting its validity as a measurement of roughness. The VBB index corresponded directly with visual reconstruction using Phong-shaded algorithms. CONCLUSIONS: The VBB index, derived here, is a noninvasive method of quantifying the roughness of calcific deposits in CT scan data which can now be used in future clinical studies to determine possible correlations with increased plaque vulnerability and major acute coronary events.

Three-dimensional isotropic wavelets for post-acquisitional extraction of latent images of atherosclerotic plaque components from micro-computed tomography of human coronary arteries.

RATIONALE AND OBJECTIVES: The capability of wavelet transforms to separate signals into frequency bands is the basis for its use in image compression and storage, data management and transmission, and, recently, extraction of latent images of tissue components from noisy medical images. Analysis of temporal variations of radiofrequency backscatter of intravascular ultrasound with one-dimensional wavelets can detect lipid-laden plaque in coronary arteries with a sensitivity and specificity of >80%. In this study we evaluate the capability of a novel, 3-dimensional isotropic wavelet analysis to perform high resolution, non-directionally biased, statistically reliable, non-invasive discrimination between components of human coronary atherosclerotic plaques in micro-CT. MATERIALS AND METHODS: Coronary artery segments (5-15 mm) were excised at necropsy from 18 individuals with advanced coronary atherosclerosis. Specimens were imaged using a GE Locus SP ex vivo micro-CT scanner and processed for histological correlation (833 sections). The isotropic wavelet constructs were applied to the entire volume of CT data of each arterial segment to distinguish tissue textures of varying scales and intensities. Voxels were classified and plaque characterization achieved by comparing the relative magnitudes of these wavelet constituents to that of several reference plaque tissue components. RESULTS: Processing of micro-CT images via these isotropic wavelet algorithms permitted 3-D, color-coded, high resolution, digital discrimination between lumen, calcific deposits, lipid-rich deposits, and fibromuscular tissue providing detail not possible with conventional thresholding based on Hounsfield intensity units. Using the isotropic wavelets (with histology as the gold standard), lipid-rich pools approaching the size of the filter for the isotropic wavelet algorithm (0.25 mm [250 microns] in length) were identified with 81% sensitivity and 86% specificity. Calcific deposits, fibromuscular tissue, and lumen equal to or larger than the wavelet filter size were detected without error (100% sensitivity and specificity). CONCLUSION: Isotropic wavelet analysis permits high resolution, multi-dimensional identification of coronary atherosclerotic plaque components in micro-CT with sensitivity and specificity similar to that achieved with data obtained invasively (from IVUS in vivo) using one-dimensional wavelets. Further studies are necessary to test the applicability of this technology to clinical, multi-detector scanners.

Self assembly of amphiphilic C60 fullerene derivatives into nanoscale supramolecular structures.

BACKGROUND: The amphiphilic fullerene monomer (AF-1) consists of a "buckyball" cage to which a Newkome-like dendrimer unit and five lipophilic C12 chains positioned octahedrally to the dendrimer unit are attached. In this study, we report a novel fullerene-based liposome termed 'buckysome' that is water soluble and forms stable spherical nanometer sized vesicles. Cryogenic electron microscopy (Cryo-EM), transmission electron microscopy (TEM), and dynamic light scattering (DLS) studies were used to characterize the different supra-molecular structures readily formed from the fullerene monomers under varying pH, aqueous solvents, and preparative conditions. RESULTS: Electron microscopy results indicate the formation of bilayer membranes with a width of ~6.5 nm, consistent with previously reported molecular dynamics simulations. Cryo-EM indicates the formation of large (400 nm diameter) multilamellar, liposome-like vesicles and unilamellar vesicles in the size range of 50-150 nm diameter. In addition, complex networks of cylindrical, tube-like aggregates with varying lengths and packing densities were observed. Under controlled experimental conditions, high concentrations of spherical vesicles could be formed. In vitro results suggest that these supra-molecular structures impose little to no toxicity. Cytotoxicity of 10-200 muM buckysomes were assessed in various cell lines. Ongoing studies are aimed at understanding cellular internalization of these nanoparticle aggregates. CONCLUSION: In this current study, we have designed a core platform based on a novel amphiphilic fullerene nanostructure, which readily assembles into supra-molecular structures. This delivery vector might provide promising features such as ease of preparation, long-term stability and controlled release.

Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes.

Systemic infections can trigger heart attacks. We conducted an autopsy study to investigate the pathologic effect of systemic infections on coronary artery inflammation. We studied 14 atherosclerotic patients diagnosed with an acute systemic infection. Our control group (n=13) had atherosclerosis without infection. The groups were similar in luminal stenosis and age. Coronary artery sections were stained with H&E and markers for macrophages (CD68), T cells (CD3), and dendritic cells (S100). On pathologic examination, 5 infected patients had acute myocardial infarction with thrombosis. Macrophage density in plaques and in periadventitial fat was higher in the infected group (NS). The infected patients' adventitia had significantly more macrophages (1,577 +/- 1,872 vs 265 +/- 185 per mm(2); P=0.047). The macrophage density, similar in the control group's adventitia and plaque, was significantly greater in the infected group's adventitia than in the plaque. The adventitia and periadventitial fat of the infected group had more T cells than did samples from the control group (48.4 +/- 45.0 vs 14.1 +/- 6.3 per mm(2); P=0.002). The groups exhibited similar plaque T-cell density. The infected patients' plaques, but not the adventitia and periadventitial fat, had more dendritic cells than did the controls' (3.2 +/- 2.5 vs 0.3 +/- 0.5 per mm(2); P=0.022). To our knowledge, this is the 1st report to establish a connection between acute systemic infections and significant increases in inflammatory cells in the atherosclerotic coronary arteries of human beings. This offers a new therapeutic target for preventing heart attacks in high-risk patients.

Silent myocardial ischemia: Current perspectives and future directions.

Silent myocardial ischemia (SMI) is increasingly being recognized as part of the spectrum of ischemic heart disease. The spectrum of SMI ranges from asymptomatic coronary artery disease to critical illness necessitating intensive care. Although many diagnostic tools have been used to identify low- and high-risk subgroups, their use is limited by modest sensitivities and specificities. The present review identifies current concepts in the management of SMI in various clinical settings, as well as emerging technologies that may simplify the diagnosis and treatment of this condition.

Comparison of 60-day mortality in hospitalized heart failure patients with versus without hypothermia.

The use of aggressive treatments and the modification of current treatment in patients with heart failure (HF) relies heavily on the assessment of disease severity using prognostic markers. However, many such markers are unavailable in routine clinical practice, and others have little prognostic value. This study tested the hypothesis that low body temperature could predict short-term survival after discharge in patients hospitalized for HF. Data from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, which randomized 319 patients hospitalized for HF to receive placebo or tolvaptan, were retrospectively analyzed. Hypothermia was defined a priori as an oral body temperature <35.8 degrees C at randomization. Cox regression was used to analyze survival within a 60-day follow-up period. Hypothermia was observed in 32 patients (10%). Mortality rates at 60 days after discharge were 6.3% (20 of 319) overall, 9.4% (3 of 32) in hypothermic patients, and 5.9% (17 of 287) in nonhypothermic patients. Hypothermia was a strong multivariate predictor of mortality; hypothermic patients were 3.9 times more likely to die within 60 days than nonhypothermic patients (95% confidence interval 1.002 to 15.16, p = 0.0497) after adjustment for treatment group, age, and other confounders. Hypothermia was associated with such indicators of low cardiac output as an elevated blood urea nitrogen/creatinine ratio, narrow pulse pressure, and a reduced ejection fraction. In conclusion, hypothermia appears to be a strong predictor of mortality in patients with HF.

Usefulness of multidetector computed tomography for noninvasive evaluation of coronary arteries in asymptomatic patients.

This editorial addresses the capabilities, limitations, and potential of multidetector computed tomography (MDCT) for the noninvasive evaluation of coronary arteries in asymptomatic patients. The quantification of coronary calcium with MDCT correlates highly with that obtained by electron-beam computed tomography, but to date, neither has the capability of assessing the distribution of various morphologic patterns of calcium and their relation to other "soft" plaque components. Although MDCT can assess the thickness of the atherosclerotic wall and can readily identify calcific deposits, further plaque characterization (e.g., lipid pools and fibrous tissue), a prerequisite for the identification of most vulnerable lesions, is not yet a workable reality, even with the 64-slice machines in their current configuration. The noninvasive identification by MDCT of plaque components subtending vulnerable lesions will require additional improvement in the primary instrumentation, the use of hybrid constructs (e.g., with positron emission tomography and magnetic resonance imaging), the development of novel methods of post-acquisitional analysis to extract latent images of plaque components (e.g., signal analysis based on 3-dimensional wavelets), or the adaptation of molecular imaging techniques at the cell and gene levels to computed tomography. Such unique approaches may soon contribute a long list of additional parameters that could be evaluated on a noninvasive basis as predictors of acute coronary syndromes and overall patient vulnerability.

Superparamagnetic iron oxide-based method for quantifying recruitment of monocytes to mouse atherosclerotic lesions in vivo: enhancement by tissue necrosis factor-alpha, interleukin-1beta, and interferon-gamma.

BACKGROUND: It has been found recently that the MRI contrast agent superparamagnetic iron oxide (SPIO) localizes to aortic atherosclerotic plaques. We therefore asked whether SPIO might be used to monitor monocyte recruitment into aortic atherosclerotic plaques. METHODS AND RESULTS: Eleven female apo E knockout (K/O) mice, each 11 months old, were divided into 2 groups. Six mice received tissue necrosis factor-alpha (0.2 microg IP once), interleukin-1beta (0.2 micro g IP once), and interferon-gamma (100 U/g per day IP for 5 days); 5 received 0.5 mL saline containing 1% BSA and served as sham-treated atherosclerotic controls. Two wild-type C57BL/6 mice served as sham-treated nonatherosclerotic controls. Three hours after initial cytokine or sham treatment, all mice received SPIO by intravenous injection (1 mmol/kg iron). Six days later, all mice were euthanized, the hearts and aortas were perfused under physiological pressure, and the entire aortas were studied histologically. Atherosclerotic plaques in cytokine-treated mice contained more iron-positive macrophages per cross section than did those in sham-treated apo E K/O control mice (42+/-11.8 versus 11.6+/-5.9) (P<0.0001). Iron-laden macrophages were present either in subendothelial plaque surfaces or in thin layers overlying the internal elastic lamina, often at the edges of atherosclerotic plaques. No iron deposition was seen in aortas of the wild-type nonatherosclerotic control mice. Immunocytochemistry showed mostly macrophages and few T lymphocytes in atherosclerotic plaques of cytokine-treated mice. CONCLUSIONS: SPIO allows detection of iron-laden macrophages in the aortic subendothelium of apo E-deficient mice under basal conditions and monitoring of monocyte recruitment after cytokine injection.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.