Validation of Opportunistic Artificial Intelligence-Based Bone Mineral Density Measurements in Coronary Artery Calcium Scans.

BACKGROUND: Previously we reported a manual method of measuring thoracic vertebral bone mineral density (BMD) using quantitative CT in noncontrast cardiac CT scans used for coronary artery calcium (CAC) scoring. In this report, we present validation studies of an artificial intelligence-based automated BMD measurement (AutoBMD) that recently received FDA approval as an opportunistic add-on to CAC scans. METHODS: A deep learning model was trained to detect vertebral bodies. Subsequently, signal processing techniques were developed to detect intervertebral discs and the trabecular components of the vertebral body. The model was trained using 132 CAC scans comprising 7,649 slices. To validate AutoBMD, we used 5,785 cases of manual BMD measurements previously reported from CAC scans in the Multi-Ethnic Study of Atherosclerosis. RESULTS: Mean ± SD for AutoBMD and manual BMD were 166.1 ± 47.9 mg/cc and 163.1 ± 46 mg/cc, respectively (P = .006). Multi-Ethnic Study of Atherosclerosis cases were 47.5% male and 52.5% female, with age 62.2 ± 10.3. A strong correlation was found between AutoBMD and manual measurements (R = 0.85, P < .0001). Accuracy, sensitivity, specificity, positive predictive value and negative predictive value for AutoBMD-based detection of osteoporosis were 99.6%, 96.7%, 97.7%, 99.7% and 99.8%, respectively. AutoBMD averaged 15 seconds per report versus 5.5 min for manual measurements (P < .0001). CONCLUSIONS: AutoBMD is an FDA-approved, artificial intelligence-enabled opportunistic tool that reports BMD with Z-scores and T-scores and accurately detects osteoporosis and osteopenia in CAC scans, demonstrating results comparable to manual measurements. No extra cost of scanning and no extra radiation to patients, plus the high prevalence of asymptomatic osteoporosis, make AutoBMD a promising candidate to enhance patient care.

AI-enabled cardiac chambers volumetry in coronary artery calcium scans (AI-CACTM) predicts heart failure and outperforms NT-proBNP: The multi-ethnic study of Atherosclerosis.

INTRODUCTION: Coronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF). METHODS: We applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years. RESULTS: Over 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p â€‹< â€‹0.0001), and comparable to clinical risk factors (0.85, p â€‹= â€‹0.4141). Category-free Net Reclassification Index (NRI) [95% CI] adding AI-CAC LV significantly improved on clinical risk factors (0.32 [0.16,0.41]), NT-proBNP (0.46 [0.33,0.58]), and Agatston score (0.71 [0.57,0.81]) for HF prediction at 15 years (p â€‹< â€‹0.0001). CONCLUSION: AI-CAC volumetry significantly outperformed NT-proBNP and the Agatston CAC score, and significantly improved the AUC and category-free NRI of clinical risk factors for incident HF prediction.

AI-enabled left atrial volumetry in coronary artery calcium scans (AI-CACTM) predicts atrial fibrillation as early as one year, improves CHARGE-AF, and outperforms NT-proBNP: The multi-ethnic study of atherosclerosis.

BACKGROUND: Coronary artery calcium (CAC) scans contain actionable information beyond CAC scores that is not currently reported. METHODS: We have applied artificial intelligence-enabled automated cardiac chambers volumetry to CAC scans (AI-CACTM) to 5535 asymptomatic individuals (52.2% women, ages 45-84) that were previously obtained for CAC scoring in the baseline examination (2000-2002) of the Multi-Ethnic Study of Atherosclerosis (MESA). AI-CAC took on average 21 â€‹s per CAC scan. We used the 5-year outcomes data for incident atrial fibrillation (AF) and assessed discrimination using the time-dependent area under the curve (AUC) of AI-CAC LA volume with known predictors of AF, the CHARGE-AF Risk Score and NT-proBNP. The mean follow-up time to an AF event was 2.9 â€‹± â€‹1.4 years. RESULTS: At 1,2,3,4, and 5 years follow-up 36, 77, 123, 182, and 236 cases of AF were identified, respectively. The AUC for AI-CAC LA volume was significantly higher than CHARGE-AF for Years 1, 2, and 3 (0.83 vs. 0.74, 0.84 vs. 0.80, and 0.81 vs. 0.78, respectively, all p â€‹< â€‹0.05), but similar for Years 4 and 5, and significantly higher than NT-proBNP at Years 1-5 (all p â€‹< â€‹0.01), but not for combined CHARGE-AF and NT-proBNP at any year. AI-CAC LA significantly improved the continuous Net Reclassification Index for prediction of AF over years 1-5 when added to CHARGE-AF Risk Score (0.60, 0.28, 0.32, 0.19, 0.24), and NT-proBNP (0.68, 0.44, 0.42, 0.30, 0.37) (all p â€‹< â€‹0.01). CONCLUSION: AI-CAC LA volume enabled prediction of AF as early as one year and significantly improved on risk classification of CHARGE-AF Risk Score and NT-proBNP.

AI-enabled Left Atrial Volumetry in Cardiac CT Scans Improves CHARGE-AF and Outperforms NT-ProBNP for Prediction of Atrial Fibrillation in Asymptomatic Individuals: Multi-Ethnic Study of Atherosclerosis.

Background: Coronary artery calcium (CAC) scans contain actionable information beyond CAC scores that is not currently reported. Methods: We have applied artificial intelligence-enabled automated cardiac chambers volumetry to CAC scans (AI-CAC), taking on average 21 seconds per CAC scan, to 5535 asymptomatic individuals (52.2% women, ages 45-84) that were previously obtained for CAC scoring in the baseline examination (2000-2002) of the Multi-Ethnic Study of Atherosclerosis (MESA). We used the 5-year outcomes data for incident atrial fibrillation (AF) and compared the time-dependent AUC of AI-CAC LA volume with known predictors of AF, the CHARGE-AF Risk Score and NT-proBNP (BNP). The mean follow-up time to an AF event was 2.9±1.4 years. Results: At 1,2,3,4, and 5 years follow-up 36, 77, 123, 182, and 236 cases of AF were identified, respectively. The AUC for AI-CAC LA volume was significantly higher than CHARGE-AF or BNP at year 1 (0.836, 0.742, 0.742), year 2 (0.842, 0.807,0.772), and year 3 (0.811, 0.785, 0.745) (p<0.02), but similar for year 4 (0.785, 0.769, 0.725) and year 5 (0.781, 0.767, 0.734) respectively (p>0.05). AI-CAC LA volume significantly improved the continuous Net Reclassification Index for prediction of AF over years 1-5 when added to CAC score (0.74, 0.49, 0.53, 0.39, 0.44), CHARGE-AF Risk Score (0.60, 0.28, 0.32, 0.19, 0.24), and BNP (0.68, 0.44, 0.42, 0.30, 0.37) respectively (p<0.01). Conclusion: AI-CAC LA volume enabled prediction of AF as early as one year and significantly improved on risk classification of CHARGE-AF Risk Score and BNP.

AI-enabled Cardiac Chambers Volumetry and Calcified Plaque Characterization in Coronary Artery Calcium (CAC) Scans (AI-CAC) Significantly Improves on Agatston CAC Score for Predicting All Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

Background: Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) algorithms applied to CAC scans may provide significant improvement in prediction of all cardiovascular disease (CVD) events in addition to CHD, including heart failure, atrial fibrillation, stroke, resuscitated cardiac arrest, and all CVD-related deaths. Methods: We applied AI-enabled automated cardiac chambers volumetry and automated calcified plaque characterization to CAC scans (AI-CAC) of 5830 individuals (52.2% women, age 61.7±10.2 years) without known CVD that were previously obtained for CAC scoring at the baseline examination of the Multi-Ethnic Study of Atherosclerosis (MESA). We used 15-year outcomes data and assessed discrimination using the time-dependent area under the curve (AUC) for AI-CAC versus the Agatston Score. Results: During 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow up for AI-CAC vs Agatston Score was (0.784 vs 0.701), (0.771 vs. 0.709), (0.789 vs.0.712) and (0.816 vs. 0.729) (p<0.0001 for all), respectively. The category-free Net Reclassification Index of AI-CAC vs. Agatston Score at 1-, 5-, 10-, and 15-year follow up was 0.31, 0.24, 0.29 and 0.29 (p<.0001 for all), respectively. AI-CAC plaque characteristics including number, location, and density of plaque plus number of vessels significantly improved NRI for CAC 1-100 cohort vs. Agatston Score (0.342). Conclusion: In this multi-ethnic longitudinal population study, AI-CAC significantly and consistently improved the prediction of all CVD events over 15 years compared with the Agatston score.

Opportunistic AI-enabled automated bone mineral density measurements in lung cancer screening and coronary calcium scoring CT scans are equivalent.

Rationale and objectives: We previously reported a novel manual method for measuring bone mineral density (BMD) in coronary artery calcium (CAC) scans and validated our method against Dual X-Ray Absorptiometry (DEXA). Furthermore, we have developed and validated an artificial intelligence (AI) based automated BMD (AutoBMD) measurement as an opportunistic add-on to CAC scans that recently received FDA approval. In this report, we present evidence of equivalency between AutoBMD measurements in cardiac vs lung CT scans. Materials and methods: AI models were trained using 132 cases with 7649 (3 mm) slices for CAC, and 37 cases with 21918 (0.5 mm) slices for lung scans. To validate AutoBMD against manual measurements, we used 6776 cases of BMD measured manually on CAC scans in the Multi-Ethnic Study of Atherosclerosis (MESA). We then used 165 additional cases from Harbor UCLA Lundquist Institute to compare AutoBMD in patients who underwent both cardiac and lung scans on the same day. Results: Mean±SD for age was 69 ± 9.4 years with 52.4% male. AutoBMD in lung and cardiac scans, and manual BMD in cardiac scans were 153.7 ± 43.9, 155.1 ± 44.4, and 163.6 ± 45.3 g/cm3, respectively (p = 0.09). Bland-Altman agreement analysis between AutoBMD lung and cardiac scans resulted in 1.37 g/cm3 mean differences. Pearson correlation coefficient between lung and cardiac AutoBMD was R2 = 0.95 (p < 0.0001). Conclusion: Opportunistic BMD measurement using AutoBMD in CAC and lung cancer screening scans is promising and yields similar results. No extra radiation plus the high prevalence of asymptomatic osteoporosis makes AutoBMD an ideal screening tool for osteopenia and osteoporosis in CT scans done for other reasons.

High Frequency of Microvascular Dysfunction in US Outpatient Clinics: A Sign of High Residual Risk? Data from 7,105 Patients.

Previous studies have linked peripheral microvascular dysfunction measured by arterial tonometry to high residual risk in on-statin patients. Digital thermal monitoring (DTM) of microvascular function is a new and simplified technique based on fingertip temperature measurements that has been correlated with the burden of atherosclerosis and its risk factors. Here, we report analyses of DTM data from two large US registries: Registry-I (6,084 cases) and Registry-II (1,021 cases) across 49 US outpatient clinics. DTM tests were performed using a VENDYS device during a 5-minute arm-cuff reactive hyperemia. Fingertip temperature falls during cuff inflation and rebounds after deflation. Adjusted maximum temperature rebound was reported as vascular reactivity index (VRI). VRI distributions were similar in both registries, with mean ± SD of 1.58 ± 0.53 in Registry-I and 1.52 ± 0.43 in Registry-II. In the combined dataset, only 18% had optimal VRI (≥2.0) and 82% were either poor (<1.0) or intermediate (1.0-2.0). Women had slightly higher VRI than men (1.62 ± 0.56 vs. 1.54 ± 0.47, p < 0.001). VRI was inversely but mildly correlated with age (r = -0.19, p < 0.001). Suboptimal VRI was found in 72% of patients <50 years, 82% of 50-70 years, and 86% of ≥70 years. Blood pressure was not correlated with VRI. In this largest registry of peripheral microvascular function measurements, suboptimal scores were highly frequent among on-treatment patients, possibly suggesting a significant residual risk. Prospective studies are warranted to validate microvascular dysfunction as an indicator of residual risk.

Sensitivity of digital thermal monitoring parameters to reactive hyperemia.

Both structural and functional evaluations of the endothelium exist in order to diagnose cardiovascular disease (CVD) in its asymptomatic stages. Vascular reactivity, a functional evaluation of the endothelium in response to factors such as occlusion, cold, and stress, in addition to plasma markers, is the most widely accepted test and has been found to be a better predictor of the health of the endothelium than structural assessment tools such as coronary calcium scores or carotid intima-media thickness. Among the vascular reactivity assessment techniques available, digital thermal monitoring (DTM) is a noninvasive technique that measures the recovery of fingertip temperature after 2-5 min of brachial occlusion. On release of occlusion, the finger temperature responds to the amount of blood flow rate overshoot referred to as reactive hyperemia (RH), which has been shown to correlate with vascular health. Recent clinical trials have confirmed the potential importance of DTM as an early stage predictor of CVD. Numerical simulations of a finger were carried out to establish the relationship between DTM and RH. The model finger consisted of essential components including bone, tissue, major blood vessels (macrovasculature), skin, and microvasculature. The macrovasculature was represented by a pair of arteries and veins, while the microvasculature was represented by a porous medium. The time-dependent Navier-Stokes and energy equations were numerically solved to describe the temperature distribution in and around the finger. The blood flow waveform postocclusion, an input to the numerical model, was modeled as an instantaneous overshoot in flow rate (RH) followed by an exponential decay back to baseline flow rate. Simulation results were similar to clinically measured fingertip temperature profiles in terms of basic shape, temperature variations, and time delays at time scales associated with both heat conduction and blood perfusion. The DTM parameters currently in clinical use were evaluated and their sensitivity to RH was established. Among the parameters presented, temperature rebound (TR) was shown to have the best correlation with the level of RH with good sensitivity for the range of flow rates studied. It was shown that both TR and the equilibrium start temperature (representing the baseline flow rate) are necessary to identify the amount of RH and, thus, to establish criteria for predicting the state of specific patient's cardiovascular health.

The association of nadir CD4-T cell count and endothelial dysfunction in a healthy HIV cohort without major cardiovascular risk factors.

OBJECTIVES: HIV-infected population may have increased risk of cardiovascular disease. The prevalence of traditional cardiovascular disease risk factors such as hypertension, diabetes and dyslipidemia in HIV-infected individuals has made it difficult to assess the direct effects of HIV and immune factors on endothelial dysfunction and associated increased risk of atherosclerosis. The purpose of this study was to investigate indicators of endothelial dysfunction in an HIV cohort without hypertension and diabetes. METHODS: We studied 19 HIV-infected patients between the ages of 25-76 years old with effectively suppressed viral load and without diagnosis of hypertension or diabetes. Endothelial function was measured by digital thermal monitoring of vascular reactivity using the VENDYS technique. Endothelial function was reported as vascular reactivity index. Systolic blood pressure and diastolic blood pressure at the time of VENDYS test were measured and latest lipid panels were recorded. The association between vascular reactivity index and CD4-T cells count, different antiretroviral therapy types (non-nucleoside reverse transcriptase, nucleoside reverse transcriptase, protease inhibitors, integrase inhibitors), vitamins use, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol was investigated. RESULTS: Mean vascular reactivity index was 1.87 ± 0.53. Vascular reactivity index, marker of endothelial dysfunction, showed a significant correlation with lower nadir CD4 count (p = 0.003) as well as low-density lipoprotein cholesterol (p = 0.02). No additional significant correlation between vascular reactivity index and the rest of the investigated variables was found. CONCLUSION: Vascular reactivity index, a clinical predictor of endothelial dysfunction, is associated with lower nadir CD4-T cell and low-density lipoprotein cholesterol in HIV-infected men with no history of hypertension or diabetes and before clinical evidence of cardiovascular disease.

Vascular dysfunction measured by fingertip thermal monitoring is associated with the extent of myocardial perfusion defect.

BACKGROUND: Previous studies have shown that vascular dysfunction measured by digital thermal monitoring (DTM) during an arm-cuff reactive hyperemia procedure correlates with the severity of coronary artery disease measured by coronary artery calcium in asymptomatic patients. Current study investigates the correlation between DTM and abnormal myocardial perfusion imaging (MPI). METHODS: About 116 consecutive patients with chest discomfort, age 57 +/- 10 years, underwent MPI, DTM and Framingham Risk Score (FRS) assessment. Fingertip temperature rebound (TR), DTM index of vascular reactivity, was assessed after a 2-minute arm-cuff reactive hyperemia test. The extent of myocardial perfusion defect was measured by summed stress score (SSS). RESULTS: TR decreased from SSS < 4 (1.61 +/- 0.15) to 4 < or = SSS < or = 8 (0.5 +/- 0.22) to 9 < or = SSS < or = 13 (0.26 +/- 0.15) to SSS > 13 (-0.37 +/- 0.19) (P = .0001). After adjusting for cardiac risk factors, the odds ratio of the lowest versus two upper tertiles of TR was 3.93 for SSS > or = 4 and 9.65 for SSS > or = 8 compared to SSS < 4. TR correlated well with SSS (r = -0.88, P = .0001). Addition of TR to FRS increased the area under the ROC curve to predict abnormal MPI, SSS > or = 4, from 0.65 to 0.84 (P < .05). CONCLUSION: Vascular dysfunction measured by DTM is associated with the extent of myocardial perfusion defect independent of age, gender, and cardiac risk factors.

Radiation exposure and coronary artery calcium scans in the society for heart attack prevention and eradication cohort.

Coronary artery calcium (CAC) scoring is used in asymptomatic patients to improve their clinically predicted risk for future cardiovascular events. Current CT protocols seek to reduce radiation exposure without diminishing image quality. Reported radiation exposure remains widely variable (0.8-5 mSv) depending on the type of protocol. In this study, we report the radiation exposure of CAC scoring from the Society for Heart Attack Prevention and Eradication (SHAPE) early detection program cohort sites, which spanned multiple centers using 64-MDCT (multi-detector computed tomography) scanners. We reviewed radiation exposure in milliSieverts (mSv) for 82,214 participants from the SHAPE early detection program cohort who underwent CAC scoring. This occurred over a 2.5-year period (2012-2014) divided among 33 sites in 7 countries with four different types 64-MDCT scanners. The effective radiation dose was reported as mSv. Mean radiation dosing amongst all 82,214 participants was 1.03 mSv, a median dose of 0.94 mSv. The mean radiation dose ranged from 0.76 to 1.31 mSv across the 33 sites involved with the SHAPE program cohort. Subgroup analysis by age, gender or body mass index (BMI) less than 30 kg/m2 showed no variability. Radiation dose in patients with BMI > 30 kg/m2 were significantly greater than other subgroups (µ = 1.96 mSv, p < 0.001). The use of 64-MDCT scanners and protocols provide the effective radiation dose for CAC scoring, which is approximately 1 mSv. This is consistently lower than previously reported for CAC scanning, regardless of scanner type, age or gender. In contrast, a greater BMI influenced mean radiation doses.

Coronary artery calcium testing: A call for universal coverage.

Heart attacks kill more Americans than all cancers combined. Fatal heart attack victims have no symptoms until minutes before they die, hence early detection of high-risk asymptomatic individuals is needed. Even though heart attacks kill and cost more than cancers, as a nation we spend over 20 times more on screening for asymptomatic cancer than for asymptomatic atherosclerotic cardiovascular disease (ASCVD), the underlying cause of heart attacks. Currently, payers only cover screening for risk factors of ASCVD such as blood pressure and blood cholesterol. This approach tends to miss high-risk and over-treat low-risk individuals. Although treadmill stress testing with ECG is not indicated for ASCVD detection in asymptomatic individuals, it is done often, and frequently leads to misleading conclusions or unnecessary downstream diagnostic procedures. For example, former President Clinton had passed his treadmill stress tests for several years during his presidential annual checkup but had a heart attack shortly after his presidency. This common practice is a waste of our limited resources. Instead, a more accurate risk assessment using coronary artery calcium (CAC) testing is available; and has just been adopted by ACC/AHA guidelines, however payers do not cover it. CAC is measured non-invasively with a 5-minute CT-scan of the heart, and costs less than $200, whereas cancer screening with colonoscopy and mammography costs over $3000. There is an opportunity to save lives and dollars if CAC testing is covered for appropriately selected individuals. Texas has already passed HB1290 to mandate CAC coverage. Other states must step up and take actions.

Image-based gating of intravascular ultrasound pullback sequences.

Intravascularultrasound (IVUS) sequences recorded in vivo are subject to a wide array of motion artifacts as the majority of these studies are performed within the coronary arteries of a beating heart. To eliminate these artifacts, an electrocardiogram (ECG) signal is typically used to gate (collect) those frames recorded at the points in time associated with a particular fraction of the cardiac cycle. However, this technique may be suboptimal for a number of reasons, among which is the difficulty of determining the optimal fraction at which to gate. This value is generally nonobvious. To circumvent this problem, we introduce a frame-gating method for IVUS pullbacks that mimics ECG (i.e., in the sense that it selects only one frame per cardiac cycle), but will automatically choose the fraction of the cycle that renders the most stable gated frame set. Stability here is gauged by measuring interframe similarity. Our method operates exclusively on the imagery data and does not require ECG or any form of image segmentation or other high-level image analysis. To validate our algorithm, we compare its behavior versus true ECG gating.

Acute and Subacute Triggers of Cardiovascular Events.

Inability to predict short-term cardiovascular (CV) events and take immediate preemptive actions has long been the Achilles heel of cardiology. However, certain triggers of these events have come to light. Although these triggers are nonspecific and are part of normal life, studying their temporal relationship with the onset of CV events provides an opportunity to alert high-risk atherosclerotic patients who may be most vulnerable to such triggers, the "vulnerable patient". Herein, we review the literature and shed light on the epidemiology and underlying pathophysiology of different triggers. We describe that certain adrenergic triggers can precipitate a CV event within minutes or hours; whereas triggers that elicit an immune or inflammatory response such as infections may tip an asymptomatic "vulnerable patient" to become symptomatic days and weeks later. In conclusion, healthcare providers should counsel high-risk CV patients (e.g., in secondary prevention clinics or those with coronary artery Calcium >75th percentile) on the topic, advise them to avoid such triggers, take protective measures once exposed, and seek emergency care immediately after becoming symptomatic after such triggers. Furthermore, clinical trials targeting triggers (prevention or intervention) are needed.

Machine Learning Outperforms ACC / AHA CVD Risk Calculator in MESA.

Background Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease ( CVD ) in certain high-risk individuals, therefore missing opportunities for intensive therapy and preventing CVD events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning ( ML ) to tackle this problem. Methods and Results We developed a ML Risk Calculator based on Support Vector Machines ( SVM s) using a 13-year follow up data set from MESA (the Multi-Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD-free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort. ACC / AHA Risk Calculator, based on 7.5% 10-year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and AUC 0.71. In contrast, ML Risk Calculator recommended only 11.4% to take statin, and only 14.4% of "Hard CVD " events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and AUC 0.92. Similar results were found for prediction of "All CVD " events. Conclusions The ML Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the ML model in other cohorts and to explore its ability in short-term CVD risk prediction.

From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report.

Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because <10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.

New Indices of Endothelial Function Measured by Digital Thermal Monitoring of Vascular Reactivity: Data from 6084 Patients Registry.

Background. Endothelial function is viewed as a barometer of cardiovascular health and plays a central role in vascular reactivity. Several studies showed digital thermal monitoring (DTM) as a simple noninvasive method to measure vascular reactivity that is correlated with atherosclerosis risk factors and coronary artery disease. Objectives. To further evaluate the relations between patient characteristics and DTM indices in a large patient registry. Methods. DTM measures were correlated with age, sex, heart rate, and systolic and diastolic blood pressure in 6084 patients from 18 clinics. Results. DTM vascular reactivity index (VRI) was normally distributed and inversely correlated with age (r = -0.21, p < 0.0001). Thirteen percent of VRI tests were categorized as poor vascular reactivity (VRI < 1.0), 70 percent as intermediate (1.0 ≤ VRI < 2.0), and 17 percent as good (VRI ≥ 2.0). Poor VRI (<1.0) was noted in 6% of <50 y, 10% of 50-70 y, and 18% of ≥70 y. In multiple linear regression analyses, age, sex, and diastolic blood pressure were significant but weak predictors of VRI. Conclusions. As the largest database of finger-based vascular reactivity measurement, this report adds to prior findings that VRI is a meaningful physiological marker and reflects a high level of residual risk found in patients currently under care.

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.

Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice.

BACKGROUND: The role of infection in the development and complications of atherosclerosis has been the focus of much attention. We reported previously that influenza vaccination was associated with reduced risk of recurrent myocardial infarction. Here, we report the effect of influenza A virus on the apolipoprotein E-deficient (apoE(-/-)) mouse, an animal model of atherosclerosis. METHODS AND RESULTS: Twenty-four apoE(-/-) mice >24 months old were injected with 1 LD(50) (lethal dose 50) of influenza A virus. Ten wild-type C57BL/6 infected mice and 11 noninfected age-matched apoE(-/-) mice served as controls. Multiple aortic sections were studied histologically 3, 5, and 10 days later. The infected mice showed markedly increased intimal cellularity compared with the noninfected apoE(-/-) mice. No aortic abnormalities were seen in infected wild-type mice. Ten infected apoE(-/-) mice had a significant subendothelial infiltrate composed of a heterogeneous group of cells that stained positively for smooth muscle cell actin, F4/80 (macrophages), and CD3 (T lymphocytes). One case of subocclusive platelet and fibrin-rich thrombus was seen. CONCLUSIONS: This study shows that influenza infection promotes inflammation, smooth muscle cell proliferation, and fibrin deposition in atherosclerotic plaques.

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.