A Technology-Assisted Web Application for Consumer Access to a Nonprescription Statin Medication.

BACKGROUND: Although statins reduce adverse cardiovascular outcomes, less than one-half of eligible patients receive treatment. A nonprescription statin has the potential to improve access to statins. OBJECTIVES: This study sought to assess concordance between clinician and consumer assessment of eligibility for nonprescription statin treatment using a technology assisted self-selection Web application (Web App) and evaluate effect on low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This study was a prospective actual use 6-month study to evaluate use of a Web App to qualify participants without a medical background for a moderate-intensity statin based on current guidelines. Participants entered demographic information, cholesterol values, blood pressure, and concomitant medications into the Web App, resulting in 3 possible outcomes: "do not use," "ask a doctor," and "OK to use." RESULTS: The study included 1,196 participants, with a median age of 63 years (Q1-Q3: 57-68 years); 39.6% were women, 79.3% were White, 11.7% were Black, and 4.1% had limited literacy. Mean LDL-C was 139.6 ± 28.3 mg/dL and the median calculated 10-year risk of atherosclerotic cardiovascular disease was 10.1% (Q1-Q3: 7.3%-14.0%). Initial Web App self-selection resulted in an outcome concordant with clinician assessment in 90.7% (95% CI: 88.9%-92.3%) of participants, and 98.1% (95% CI: 97.1%-98.8%) had a concordant final use outcome during treatment. Mean percent change in LDL-C was -35.5% (95% CI: -36.6% to -34.3%). Serious adverse events occurred in 27 (2.3%) participants, none related to the study drug. CONCLUSIONS: In this actual use study, a technology-assisted Web App allowed >90% of consumers to correctly self-select for statin use and achieve clinically important LDL-C reductions. (Technology-Assisted Cholesterol Trial in Consumers [TACTiC]; NCT04964544).

Feasibility of Lipid Screening During First Trimester of Pregnancy to Identify Women at Risk of Severe Dyslipidemia.

Background Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease, especially when disease presents at a young age. Despite national screening guidelines to perform a lipid profile test in children and young adults, many reproductive-age women have not undergone lipid screening. Our objective was to assess the feasibility of lipid screening during the first trimester of pregnancy as a strategy to increase lipid screening rates among women receiving prenatal care. Methods and Results A nonfasting lipid panel was incorporated into routine prenatal care among obstetricians at a single academic clinic. Educational materials and a clinical referral pathway were developed for patients with abnormal results. Over 6 months, 445 patients had a first prenatal care visit. Of the 358 patients who completed laboratory testing, 236 (66%) patients completed lipid testing. Overall, 59 (25%) patients had abnormal results. One patient with previously undiagnosed suspected familial hypercholesterolemia was identified. Barriers to ordering lipid tests included the burden of reviewing additional laboratory results and uncertainty about patient counseling. Conclusions Implementation of nonfasting lipid screening as part of routine prenatal care during the first trimester is feasible and may play a crucial role in timely diagnosis and management of lipid disorders in women of reproductive age. Future work should focus on optimizing health system workflow to minimize burden on clinical staff and facilitate follow-up with appropriate specialists.

Post-Acute Coronary Syndrome Disparities in Guideline-Directed Lipid Therapy and Insufficient Achievement of Optimal Low-Density Lipoprotein.

Lipid-lowering therapies are an established cornerstone of secondary prevention. For patients with clinical atherosclerotic cardiovascular disease, guidelines provide a class I recommendation for high-intensity statins. Furthermore, patients with low-density lipoprotein cholesterol (LDL-c) levels >70 mg/100 ml are considered at a higher risk for recurrent cardiovascular events. Previous trends in guideline-directed lipid therapy (GDLT) for secondary prevention have noted insufficiencies. In this study, we aimed to explore GDLT-prescribing patterns and assess subsequent effects on outcomes through LDL-c reduction. We used a cross-sectional study across a large, multisite university hospital system. Electronic medical records were queried for all admitted patients diagnosed with acute coronary syndrome. Data were collected for age, gender, race, and prescribed lipid medication at discharge and 1 year after discharge. Chi-square analysis was performed to assess the statistical differences in prescription rates and achieved optimal LDL-c levels. A total of 3,386 patients were studied with 2/3 of the population identified as non-Hispanic White men. Men were prescribed GDLT at a statistically significant higher rate than women, and subsequently, men were found to achieve optimal LDL-c at a statistically significant higher rate. Interestingly, Black and Hispanic patients were prescribed GDLT at the highest rates; however, these patients achieved optimal LDL-c levels at the lowest rates (significance only met for Black patients). East Indian patients achieved optimal LDL-c levels at the lowest rate among all racial groups, despite having average GDLT prescription rates. White and Asian groups achieved optimal LDL-c levels at the highest rates, with average GDLT prescription rates. Among all patients, those who achieved LDL-c levels <70 mg/100 ml were prescribed GDLT at a statistically higher rate than those who did not achieve LDL- c levels <70 mg/100 ml. We found distinct disparities in both GDLT-prescribing rates and achievement of optimal LDL-c levels for patients presenting with clinical atherosclerotic cardiovascular disease. Our findings may help delineate patients who should be considered at a higher risk for recurrent major adverse cardiovascular events. We also found an interesting paradox between GDLT-prescribing patterns and achievement of optimal LDL-c levels among certain racial groups. However, among all patients who achieved LDL-c levels <70 mg/100 ml, the majority were prescribed GDLT, supporting the efficacy of statins. Prescribing GDLT does not reliably achieve optimal LDL-c levels across genders and racial groups for unclear reasons. Our study adds to the growing body of knowledge assessing the complexity in secondary cardiovascular prevention.

Comparative Effects of Low-Dose Rosuvastatin, Placebo, and Dietary Supplements on Lipids and Inflammatory Biomarkers.

BACKGROUND: Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins. OBJECTIVES: The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers. METHODS: This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance. RESULTS: A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was -35.2% (95% CI: -41.3% to -29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups. CONCLUSIONS: Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. (Supplements, Placebo, or Rosuvastatin Study [SPORT]; NCT04846231).

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

The Use of Subclinical Atherosclerosis Imaging to Guide Preventive Cardiology Management.

PURPOSE OF THE REVIEW: Clinical atherosclerotic cardiovascular disease (ASCVD) requires years to manifest, providing a window of opportunity for preventive cardiovascular management. Subclinical atherosclerosis imaging leverages this long latency period to estimate and improve future ASCVD risk. RECENT FINDINGS: Coronary artery calcium (CAC) scoring has the most robust data in the detection of subclinical atherosclerosis. CAC scan significantly enhances cardiovascular risk stratification in addition to traditional risk models. Coronary computed tomography angiography data show similar strengths in subclinical atherosclerosis detection in addition to plaque morphology characterization with inherent limitations. Carotid intima-media thickness and ankle-brachial index are other modalities whose predictive value becomes incremental when added to the aforementioned modalities. When added to traditional risk models, subclinical atherosclerosis imaging modalities personalize future ASCVD risk stratification and assist in the initiation and rate of intensification of preventive therapies. Emerging imaging techniques exist but further research is required for primetime clinical use.

Incremental prognostic value of visually estimated coronary artery calcium in patients undergoing positron emission tomography imaging.

OBJECTIVE: Visually estimated coronary artery calcium (VECAC) from chest CT or attenuation correction (AC)/CT obtained during positron emission tomography (PET)-myocardial perfusion imaging (MPI) is feasible. Our aim was to determine the prognostic value of VECAC beyond conventional risk factors and PET imaging parameters, including coronary flow reserve (CFR). METHODS: We analysed 608 patients without known coronary artery disease who underwent PET-MPI between 2012 and 2016 and had AC/CT and/or chest CT images. We used Cox regression to estimate the association of VECAC categories (≤10, 11-400, >400 Agatston units (AU)) with the primary outcome of all-cause death, acute coronary syndrome or stroke (mean follow-up 4.3±1.8 years). C-statistics assessed the relationship between PET parameters and VECAC with the primary outcome. RESULTS: Mean age was 58±11 years, 65% were women and 67% were black. VECAC ≤10, 11-400 and >400 AU was observed in 68%, 12% and 20% of subjects, respectively. Compared with VECAC ≤10, VECAC categories 11-400 (HR 2.25, 95% CI 1.24 to 4.08) and >400 AU (HR 3.05, 95% CI 1.87 to 4.98) were associated with the primary outcome after adjusting for traditional risk factors, MPI findings and CFR. Adding VECAC to a model that included PET-MPI, CFR and clinical risk factors improved the prognostic value for the primary outcomes (c-statistic 0.71 to 0.75 with VECAC, p=0.01). CONCLUSIONS: VECAC is a potent predictor of events beyond traditional risk factors and PET imaging markers, including CFR. These data further support the importance for routine VECAC implementation.

Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis.

For patients with lupus erythematosus (LE) or dermatomyositis (DM), there is an urgent need to address a heightened risk of clinical events, chiefly heart attacks and strokes, caused by atherosclerotic cardiovascular disease (ASCVD). Patients with LE or DM frequently exhibit high levels of conventional risk factors for ASCVD events, particularly dyslipoproteinemia and hypertension; an amplified burden of atherosclerotic plaques; and increased age- and sex-adjusted rates of ASCVD events compared with the general population. The rate of ASCVD events exceeds what would be expected from conventional risk factors, suggesting that disease-specific autoimmune processes exacerbate specific, known pathogenic steps in atherosclerosis. Importantly, despite their heightened risk, patients with LE or DM are often undertreated for known causative agents and exacerbators of ASCVD. Herein, we propose an approach to assess and manage the heightened risk of ASCVD events in patients with LE or DM. Our approach is modeled in large part on established approaches to patients with diabetes mellitus or stage 3 or 4 chronic kidney disease, which are well-studied conditions that also show heightened risk for ASCVD events and have been explicitly incorporated into standard clinical guidelines for ASCVD. Based on the available evidence, we conclude that patients with LE or DM require earlier and more aggressive screening and management of ASCVD. We suggest that physicians consider implementing multipliers of conventional risk calculators to trigger earlier initiation of lifestyle modifications and medical therapies in primary prevention of ASCVD events, employ vascular imaging to quantify the burden of subclinical plaques, and treat to lower lipid targets using statins and newer therapies, such as PCSK9 inhibitors, that decrease ASCVD events in nonautoimmune cohorts. More clinical vigilance is needed regarding surveillance, prevention, risk modification, and treatment of dyslipidemias, hypertension, and smoking in patients with LE or DM. All of these goals are achievable.

Effect of Passive Choice and Active Choice Interventions in the Electronic Health Record to Cardiologists on Statin Prescribing: A Cluster Randomized Clinical Trial.

Importance: Statin therapy is underused for many patients who could benefit. Objective: To evaluate the effect of passive choice and active choice interventions in the electronic health record (EHR) to promote guideline-directed statin therapy. Design, Setting, and Participants: Three-arm randomized clinical trial with a 6-month preintervention period and 6-month intervention. Randomization conducted at the cardiologist level at 16 cardiology practices in Pennsylvania and New Jersey. The study included 82 cardiologists and 11 693 patients. Data were analyzed between May 8, 2019, and January 9, 2020. Interventions: In passive choice, cardiologists had to manually access an alert embedded in the EHR to select options to initiate or increase statin therapy. In active choice, an interruptive EHR alert prompted the cardiologist to accept or decline guideline-directed statin therapy. Cardiologists in the control group were informed of the trial but received no other interventions. Main Outcomes and Measures: Primary outcome was statin therapy at optimal dose based on clinical guidelines. Secondary outcome was statin therapy at any dose. Results: The sample comprised 11 693 patients with a mean (SD) age of 63.8 (9.1) years; 58% were male (n = 6749 of 11 693), 66% were White (n = 7683 of 11 693), and 24% were Black (n = 2824 of 11 693). The mean (SD) 10-year atherosclerotic cardiovascular disease (ASCVD) risk score was 15.4 (10.0); 68% had an ASVCD clinical diagnosis. Baseline statin prescribing rates at the optimal dose were 40.3% in the control arm, 39.1% in the passive choice arm, and 41.2% in the active choice arm. In adjusted analyses, the change in statin prescribing rates at optimal dose over time was not significantly different from control for passive choice (adjusted difference in percentage points, 0.2; 95% CI, -2.9 to 2.8; P = .86) or active choice (adjusted difference in percentage points, 2.4; 95% CI, -0.6 to 5.0; P = .08). In adjusted analyses of the subset of patients with clinical ASCVD, the active choice intervention resulted in a significant increase in statin prescribing at optimal dose relative to control (adjusted difference in percentage points, 3.8; 95% CI, 1.0-6.4; P = .008). No other subset analyses were significant. There were no significant changes in statin prescribing at any dose for either intervention. Conclusions and Relevance: The passive choice and active choice interventions did not change statin prescribing. In the subgroup of patients with clinical ASCVD, the active choice intervention led to a small increase in statin prescribing at the optimal dose, which could inform the design or targeting of future interventions. Trial Registration: ClinicalTrials.gov Identifier: NCT03271931.

Progression of retinopathy and incidence of cardiovascular disease: findings from the Chronic Renal Insufficiency Cohort Study.

PURPOSE: Chronic kidney disease (CKD) patients often develop cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess the association between progression of retinopathy and concurrent incidence of CVD events in participants with CKD. DESIGN: We assessed 1051 out of 1936 participants in the Chronic Renal Insufficiency Cohort Study that were invited to have fundus photographs obtained at two timepoints separated by 3.5 years, on average. METHODS: Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter calibre were assessed at a retinal image reading centre by trained graders masked to study participants' information. Participants with a self-reported history of CVD were excluded. Incident CVD events were physician adjudicated using medical records and standardised criteria. Kidney function and proteinuria measurements along with CVD risk factors were obtained at study visits. RESULTS: Worsening of retinopathy by two or more steps in the EDTRS retinopathy grading scale was observed in 9.8% of participants, and was associated with increased risk of incidence of any CVD in analysis adjusting for other CVD and CKD risk factors (OR 2.56, 95% CI 1.25 to 5.22, p<0.01). After imputation of missing data, these values were OR=1.66 (0.87 to 3.16), p=0.12. CONCLUSION: Progression of retinopathy is associated with higher incidence of CVD events, and retinal-vascular pathology may be indicative of macrovascular disease even after adjustment for kidney diseases and CVD risk factors. Assessment of retinal morphology may provide important information when assessing CVD in patients with CKD.

The "Centrality of Sepsis": A Review on Incidence, Mortality, and Cost of Care.

Sepsis is a serious and fatal medical condition that has overburdened the US healthcare system. The purpose of this paper is to provide a review of published literature on severe sepsis with a distinct focus on incidence, mortality, cost of hospital care, and postdischarge care. A review of the nature of postsepsis syndrome and its impact on septic patients is also included. The literature review was conducted utilizing the PubMed database, identifying 34 studies for inclusion. From the evaluation of these studies, it was determined that the incidence of sepsis continues to be on the rise according to three decades of epidemiological data. Readmissions, mortality, and length of stay were all higher among septic patients when compared to patients treated for other conditions. The cost of treating sepsis is remarkably high and exceeds the cost of treating patients with congestive heart failure and acute myocardial infarction. The overall cost of sepsis is reflective of not only the cost of initial hospitalization but also the postdischarge care costs, including postsepsis syndrome and cognitive and functional disabilities that require a significant amount of healthcare resources long term. Sepsis and its impact on patients and the US healthcare system is a current quality-of-life and cost-burden issue that needs to be addressed with a greater focus on preventative strategies.

A Clinical Guide to Combination Lipid-Lowering Therapy.

PURPOSE OF REVIEW: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction. RECENT FINDINGS: Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies. A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.

Updated cholesterol guidelines and intensity of statin therapy.

BACKGROUND: In November 2013, the American College of Cardiology and the American Heart Association released new cholesterol guidelines. Implications of these new guidelines for statin prescription remain uncertain, particularly in individuals already on statin therapy. OBJECTIVE: Our objective was to examine the impact of the guidelines on the intensity of statin therapy at a large academic medical center. METHODS: We queried the electronic health record at the University of Pennsylvania Health System to evaluate current practice patterns at a large academic institution in patients already on statin therapy. RESULTS: Among 40,036 statin-treated patients, 47% of patients may warrant an intensification of statin therapy according to the updated national cholesterol guidelines. CONCLUSIONS: These findings highlight the magnitude of potential changes in statin prescription patterns favoring higher potency statin therapy, a sizable shift that parallels the predicted increase in statin initiation.

Carotid intima-media thickness measurement promises to improve cardiovascular risk evaluation in head and neck cancer patients.

BACKGROUND: Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk). HYPOTHESIS: Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients. METHODS: Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT. RESULTS: Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique. CONCLUSIONS: Carotid IMT identified a much greater percentage of radiation-treated HNC patients at high CV risk compared with standard CV-risk calculators. By more accurately identifying the patients at high risk, this may lead to more effective prevention, and therefore a reduction in CV events.

Advanced lipid testing: when, why, and in whom?

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality in developed countries. The management of blood cholesterol with the use of statin drugs in at-risk patients is a pillar of medical therapy for the primary and secondary prevention of cardiovascular disease. Although the standard lipid panel is adequate to accurately assess cardiovascular disease risk in most patients, there are some situations in which conventional cholesterol testing does not fully identify cardiovascular risk or reflect disease progression. A number of advanced lipid tests can assist the clinician when assessing a patient's cardiovascular disease risk, including measurement of low-density lipoprotein particle number.

Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations.

BACKGROUND: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain. METHODS: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score. Low-, high-, and very-high-risk values of CAC, CIMT, and hsCRP were defined as: 0, 100, 400 Agatston units; 25th percentile without plaque, 75th percentile without plaque, 75th percentile with plaque; and 1.0, 3.0, 7.0 mg/L. RESULTS: Incorporation of low-, high-, and very-high-risk CAC values using the MESA risk score resulted in greater changes in absolute risk from the Framingham risk score than the addition of either CIMT or hsCRP values using the ARIC or Reynolds risk scores. CONCLUSIONS: Although certain values of CAC, CIMT, and hsCRP have been similarly designated as low, high, or very-high risk, incorporation of these thresholds into validated risk equations yielded substantially different levels of absolute cardiovascular risk. Use of available risk equations may be advisable to calculate absolute risk rather than relying on risk-marker thresholds derived from relative risk estimates.

Agents that bind annexin A2 suppress ocular neovascularization.

TM601 is a synthetic polypeptide with sequence derived from the venom of the scorpion Leiurus quinquestriatus that has anti-neoplastic activity. It has recently been demonstrated to bind annexin A2 on cultured tumor and vascular endothelial cells and to suppress blood vessel growth on chick chorioallantoic membrane. In this study, we investigated the effects of TM601 in models of ocular neovascularization (NV). When administered by intraocular injection, intravenous injections, or periocular injections, TM601 significantly suppressed the development of choroidal NV at rupture sites in Bruch's membrane. Treatment of established choroidal NV with TM601 caused apoptosis of endothelial cells and regression of the NV. TM601 suppressed ischemia-induced and vascular endothelial growth factor-induced retinal NV and reduced excess vascular permeability induced by vascular endothelial growth factor. Immunostaining with an antibody directed against TM601 showed that after intraocular or periocular injection, TM601 selectively bound to choroidal or retinal NV and co-localized with annexin A2, which is undetectable in normal retinal and choroidal vessels, but is upregulated in endothelial cells participating in choroidal or retinal NV. Intraocular injection of plasminogen or tissue plasminogen activator, which like TM601 bind to annexin A2, also suppressed retinal NV. This study supports the hypothesis that annexin A2 is an important target for treatment of neovascular diseases and suggests that TM601, through its interaction with annexin A2, causes suppression and regression of ocular NV and reduces vascular leakage and thus may provide a new treatment for blinding diseases such as neovascular age-related macular degeneration and diabetic retinopathy.