Reduction in Serum LDL Cholesterol Using a Nutrient Compendium in Hyperlipidemic Adults Unable or Unwilling to Use Statin Therapy: A Double-Blind Randomized Crossover Clinical Trial.

BACKGROUND: Many hyperlipidemic patients prescribed ß-hydroxy-ß-methylglutaryl coenzyme A reductase inhibitors (statins) are unable or unwilling to take them. A hedonically acceptable snack-based solution formulated from cholesterol-lowering food ingredients could represent a therapeutic alternative but has not been tested in this population. OBJECTIVES: To evaluate the effect of snacks containing a compendium of functional bioactives on fasting LDL cholesterol in statin candidates unwilling to use or intolerant to ≥1 statin drug. Secondary outcomes included changes in circulating total cholesterol (TC), triglycerides, HDL cholesterol, fasting glucose, insulin, and high-sensitivity C-reactive protein concentrations, as well as effects of single-nucleotide polymorphisms (SNPs) on outcome. METHODS: This multicenter, randomized, double-blind, free-living crossover study was composed of 2 regimented phases of 4 wk each, separated by a 4-wk washout. Eighteen men and 36 women, with a mean ± SD age of 49 ± 12 y and mean ± SD LDL cholesterol of 131 ± 32.1 mg/dL,  were instructed to ingest a variety of ready-to-eat snacks twice daily as a substitute for something they were consuming already. Other behavior changes were actively discouraged. Treatment products provided ≥5 g fiber, 1000 mg ω-3 (n-3) fatty acids, 1000 mg phytosterols, and 1800 µmol antioxidants per serving. Control products were calorie-matched like-items drawn from the general grocery marketplace. Serum lipids were measured at baseline and the end of each phase and compared using the ANOVA model. Compliance to study foods was confirmed by serum 18:3n-3 concentration assessment. RESULTS: Comparing intervention phase endpoints, LDL cholesterol was reduced a mean ± SD of 8.80 ± 1.69% (P < 0.0001), and TC was reduced a mean ± SD of 5.08 ± 1.12% (P < 0.0001) by treatment foods compared with control foods, whereas effects on other analytes did not differ between treatments. SNPs were not significantly related to outcomes (P ≥ 0.230). Compliance with study foods was 95%. CONCLUSIONS: Consumption of hedonically acceptable snacks containing a compendium of cholesterol-lowering bioactive compounds can rapidly and meaningfully reduce LDL cholesterol in adult patients unable or unwilling to take statin drugs. This trial was registered at clinicaltrials.gov as NCT02341924.

Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.

PURPOSE OF REVIEW: The purpose of this review article is to summarize the preclinical and clinical evidence supporting the notion of clonal hematopoiesis of indeterminate potential (CHIP), highlight current knowledge gap, and provide future directions. RECENT FINDINGS: Epidemiological studies show that advanced age is a major risk factor for the development of cardiovascular disease (CVD) and cancer, the two leading causes of morbidity and mortality worldwide. While the negative effect of aging on CVD is a reflection of cumulative exposure to various established traditional CVD risk factors, genetic sequencing of whole blood-derived DNA recently revealed that clonal mutations in myeloid stem cells are associated with higher risks of cardiovascular events and hematopoietic malignancies. The clinical repercussions of this biological state, termed CHIP, are increasingly appreciated. Historically, CHIP has been associated with an increased risk of hematological malignancies. However, new research is showing that CHIP is also associated with an increased risk of several cardiac-related conditions, including atherosclerosis, myocardial infarction, aortic valve stenosis, and congestive heart failure. CHIP is increasingly being appreciated worldwide as a CVD risk factor, and further studies are needed to better understand the complex relationship between these two disorders.

Lack of Evidence Linking Calcium With or Without Vitamin D Supplementation to Cardiovascular Disease in Generally Healthy Adults: A Clinical Guideline From the National Osteoporosis Foundation and the American Society for Preventive Cardiology.

DESCRIPTION: Calcium is the dominant mineral present in bone and a shortfall nutrient in the American diet. Supplements have been recommended for persons who do not consume adequate calcium from their diet as a standard strategy for the prevention of osteoporosis and related fractures. Whether calcium with or without vitamin D supplementation is beneficial or detrimental to vascular health is not known. METHODS: The National Osteoporosis Foundation and American Society for Preventive Cardiology convened an expert panel to evaluate the effects of dietary and supplemental calcium on cardiovascular disease based on the existing peer-reviewed scientific literature. The panel considered the findings of the accompanying updated evidence report provided by an independent evidence review team at Tufts University. RECOMMENDATION: The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time. In light of the evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper level of intake (defined by the National Academy of Medicine as 2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint.

Cholesterol Management in the Era of PCSK9 Inhibitors.

PURPOSE OF REVIEW: Cholesterol management in the current era is discussed. Aggressive reduction of low density lipoprotein (LDL) cholesterol plays a key role in primary and secondary prevention of heart disease. Statins are the recommended first-line therapy in patients with hyperlipidemia; however, additional complementary approaches are frequently needed for patients who fail to reach their target LDL. RECENT FINDINGS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide dramatic lowering of LDL and promise outcome benefit. Despite great enthusiasm about their cardiovascular benefit, concerns have been raised regarding their cost and added value to the healthcare system. Although cost-effectiveness studies have yielded inconclusive results, analyses suggest that the current cost of PCSK9 inhibitors is disproportionately high and must be significantly reduced to add positive net benefit to healthcare system. PCSK9 inhibitors significantly lower LDL cholesterol. Further outcome data and cost-effectiveness analyses are needed to overcome the current barriers with PCSK9 inhibitors that patients, physicians, and payers face.

Validation of a Brief Dietary Questionnaire for Use in Clinical Practice: Mini-EAT (Eating Assessment Tool).

Background There is a scarcity of validated rapid dietary screening tools for patient use in the clinical setting to improve health and reduce cardiovascular risk. The Healthy Eating Index (HEI) 2015 measures compliance with the 2015 to 2020 Dietary Guidelines for Americans but requires completion of an extensive diet assessment to compute, which is time consuming and impractical. The authors hypothesize that a 19-item dietary survey assessing consumption of common food groups known to affect health will be correlated with the HEI-2015 assessed by a validated food frequency questionnaire and can be further reduced without affecting validity. Methods and Results A 19-item Eating Assessment Tool (EAT) of common food groups was created through literature review and expert consensus. A cross-sectional survey was then conducted in adult participants from a preventive cardiology clinic or cardiac rehabilitation and in healthy volunteers (n=661, mean age, 36 years; 76% women). Participants completed an online 156-item food frequency questionnaire, which was used to calculate the HEI score using standard methods. The association between each EAT question and HEI group was analyzed by Kruskal-Wallis test. Linear regression models were subsequently used to identify univariable and multivariable predictors for HEI score for further reduction in the number of items. The final 9-item model of Mini-EAT was validated by 5-fold cross validation. The 19-item EAT had a strong correlation with the HEI score (r=0.73) and was subsequently reduced to the 9 items independently predictive of the HEI score: fruits, vegetables, whole grains, refined grains, fish or seafood, legumes/nuts/seeds, low-fat dairy, high-fat dairy, and sweets consumption, without affecting the predictive ability of the tool (r=0.71). Conclusions Mini-EAT is a 9-item validated brief dietary screener that correlates well with a comprehensive food frequency questionnaire. Future studies to test the Mini-EAT's validity in diverse populations and for development of clinical decision support systems to capture changes over time are needed.

Retrospective validation of acute heart failure risk stratification in the emergency department.

BACKGROUND: Heart Failure (HF) is a primary diagnosis for hospital admission from the Emergency Department (ED), although not all patients require hospitalization. The Emergency Heart Failure Mortality Risk Grade (EHMRG) estimates 7-day mortality in patients with acute HF in ED settings, but further validation is needed in the United States (US). OBJECTIVES: To validate EHMRG scores by risk-stratifying patients with acute HF in a large tertiary healthcare center in the US and analyze outcome measures to determine if EHMRG risk scores safely identify low-risk groups that may be discharged or managed in ED observation units (EDOUs). METHODS: A retrospective cohort analysis of 304 patients with acute HF presenting to an ED at a large, tertiary healthcare center was completed. EHMRG scores were calculated to stratify patients according to published thresholds. Mortality and major adverse cardiac event (MACE) rates were analyzed. RESULTS: No deaths occurred in very low and low-risk EHMRG groups at 7 days post discharge. 30-day mortality was significantly less in the lower risk groups (3.1%) when compared to all other patients (11.1%). MACE rates at 30 days in the very low risk group (15%) were significantly less when compared to all other patients (31.3%). Hospitalizations occurred in 23.4% of patients in lower risk groups. CONCLUSIONS: ED risk stratification with EHMRG differentiates high-risk patients requiring hospitalization from lower risk patients who can be safely managed in alternative settings with good outcomes. Data supports improved pathways for patients with acute HF during a time of high hospital volumes.

TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque.

Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell-mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell-mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.

Outcomes in patients with chest pain evaluated in a chest pain unit: the chest pain evaluation in the emergency room study cohort.

BACKGROUND: Limited data exist on the long-term outcomes of patients who undergo evaluation in a chest pain unit (CPU). METHODS: Our study included patients with chest pain at intermediate risk for acute cardiovascular events enrolled in the CHEER study. The primary outcome included a composite of death, myocardial infarction, acute heart failure, stroke, and out-of-hospital cardiac arrest. The secondary outcome included a composite of cardiovascular death, myocardial infarction, acute heart failure, stroke, revascularization, and unstable angina. Data were obtained through a medical record review. We compared outcomes between groups randomized to the CPU versus admission, those admitted from the CPU versus dismissed home, and those who were admitted versus dismissed home after a cardiac stress test in the emergency department. RESULTS: The final analysis included 407 patients. Median surveillance length was 5.5 years. No differences in the primary outcome or secondary outcome existed between patients randomized to the CPU versus admitted to hospital (21.6% vs 20.2% and 29.9% vs 33.0%, respectively, P > .05 for all comparisons). Patients admitted from the CPU had higher rates of the secondary outcome (adjusted hazard ratio 2.26) than patients dismissed from the CPU. Patients admitted after a cardiac stress test in the CPU had higher rates of the secondary outcome (adjusted hazard ratio 2.42) than patients dismissed from the CPU. CONCLUSIONS: A CPU does not increase long-term adverse outcomes in patients with chest pain at intermediate risk for an acute event.

Two dimensional penile ultrasound vibro-elastography for measuring penile tissue viscoelasticity: A pilot patient study and its correlation with penile ultrasonography.

The purpose of this research is to demonstrate the feasibility of a 2 dimensional (2D) penile ultrasound vibro-elastography (PUVE) technique for measuring the shear wave speed map over an area of regional of interest (ROI) in the penis. In PUVE, a 0.1 s harmonic vibration at a low frequency is generated on the surface of the penis using a handheld vibrator. An ultrasound probe is used to measure the resulting shear wave propagation in the penis. The shear wave speed is analyzed in the ROI of corpus cavernosum from both sides of penis using a 2D wave speed analysis technique. The shear wave speed of the penis is measured at three excitation frequencies of 100 Hz, 150 Hz, and 200 Hz. The viscoelasticity of penis is analyzed based on the wave speed dispersion with frequency. A pilot study was performed in men with ED and/or PD. It is found that both elasticity and viscosity of corpus cavernosa positively correlate with the peak systolic velocity (PSV) from penile ultrasonography. Both elasticity and viscosity of corpus cavernosa negatively correlate with the cardiovascular (CV) risk for patients with ED and/or PD. These results suggest that PUVE may provide a noninvasive and painless technique for assessing patients with ED/PD and their future CV risk. We will further evaluate PUVE in a large cohort of patients with ED/PD.

Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Plasma Ceramide Levels.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide striking lowering of low-density lipoprotein cholesterol (LDL-C) when added to maximum tolerated therapy in patients with hypercholesterolemia. Ceramides, novel cardiac risk markers, have been associated with increased cardiovascular mortality, independent of traditional cardiovascular risk factors. The Ceramide Risk Score (CRS) predicts the likelihood of adverse cardiovascular events within 1 to 3 years in patients with coronary artery disease. The effect of PCSK9 inhibition on plasma ceramides is not well known. The study examines the effect of PCSK9 inhibitors on plasma ceramides and CRS in patients with clinical indication for this therapy. Retrospective chart review of consecutive patients with hypercholesterolemia on PCSK9 inhibitors was conducted (n = 24; Mayo Clinic 2015 to 2018). Plasma ceramides were measured before the initiation of PCSK9 inhibitors and 2 to 12 months after treatment. CRS was calculated before and after therapy based on individual plasma concentrations of 4 ceramides. Treatment with PCSK9 inhibitors was associated with significant reduction in mean CRS and individual ceramides levels (p <0.0001). CRS significantly improved with PCSK9 therapy. PCSK9 inhibitors significantly decreased LDL-C levels by 63% (p <0.0001). The absolute reduction in CRS did not correlate with the absolute reduction in LDL-C (r = 0.31; confidence interval -0.10 to 0.64), indicating that CRS may evaluate a different pathway for risk reduction beyond LDL-C lowering. In conclusion, treatment with PCSK9 inhibitors is associated with significant reduction in CRS and distinct ceramide levels.

Clinical evaluation and diagnostic yield following evaluation of abnormal pulse detected using Apple Watch.

OBJECTIVE: The study sought to characterize the evaluation of patients who present following detection of an abnormal pulse using Apple Watch. MATERIALS AND METHODS: We conducted a retrospective review of patients evaluated for abnormal pulse detected using Apple Watch over a 4-month period. RESULTS: Among 264 included patients, clinical documentation for 41 (15.5%) explicitly noted an abnormal pulse alert. Preexisting atrial fibrillation was noted in 58 (22.0%). Most commonly performed testing included 12-lead echocardiography (n = 158; 59.8%), Holter monitor (n = 77; 29.2%), and chest x-ray (n = 64; 24.2%). A clinically actionable cardiovascular diagnosis of interest was established in only 30 (11.4%) patients, including 6 of 41 (15%) patients who received an explicit alert. DISCUSSION: False positive screening results may lead to overutilization of healthcare resources. CONCLUSIONS: The Food and Drug Administration and Apple should consider the unintended consequences of widespread screening for asymptomatic ("silent") atrial fibrillation and use of the Apple Watch abnormal pulse detection functionality by populations in whom the device has not been adequately studied.

Ceramides improve atherosclerotic cardiovascular disease risk assessment beyond standard risk factors.

Ceramides are bioactive lipids that act as secondary messengers for both intra- and inter-cellular signaling. Elevated plasma concentrations of ceramides are associated with multiple risk factors of atherosclerotic cardiovascular diseases and comorbidities including obesity, insulin resistance and diabetes mellitus. Furthermore, atherosclerotic plaques have been shown to be highly enriched with ceramides. Increases in ceramide content may accelerate atherosclerosis development by promoting LDL infiltration to the endothelium and aggregation within the intima of artery walls. Thus, ceramides appear to play a key role in the development of cardiometabolic disease due to their central location in major metabolic pathways that intersect lipid and glucose metabolism. Recently published data have shown that ceramides are not only of scientific interest but may also have diagnostic value. Their independent prognostic value for future cardiovascular outcomes over and above LDL cholesterol and other traditional risk factors have consistently been shown in numerous clinical studies. Thus, ceramide testing with a mass spectrometer offers a simple, reproducible and cost-effective blood test for risk stratification in atherosclerotic cardiovascular diseases.

Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.

Characteristics and Outcomes of Patients Treated With Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (The Mayo Clinic Experience).

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors represent a novel addition to the lipid-lowering armamentarium. We attempted to characterize a real-world group of patients with a clinical indication for PCSK9 inhibitors and describe their clinical outcomes and adverse effect profile. A retrospective chart review was conducted, evaluating all patients referred to preventive cardiology at the Mayo Clinic (Minnesota) between September, 2015 and December, 2018 for management of severe dyslipidemia. A total of 222 patients were referred and a recommendation to start a PCSK9 inhibitor was given to 164 patients (73.9%). Of these, 28 patients (17.1%) declined the use of a PCSK9 inhibitor. A total of 136 previous authorizations were submitted. Of these applications, 96 (70.6%) were approved and 17 (12.5%) were rejected. The cohort's mean age was 64.1 years (range 39 to 91). High-intensity statins and ezetimibe were used in 50 (52.1%) and 80 (83.3%) of the treated patients. Mean pretreatment low-density lipoprotein cholesterol was 167.9 mg/dl. At a median follow-up of 19.0 months, the mean low-density lipoprotein reduction was 60.9% (range 0 to 90.3%). Higher low-density lipoprotein cholesterol percent reductions were seen in younger patients (p value 0.048), patients on high-intensity statins (p value 0.027), those with statin intolerance (p value 0.046), and individuals with a higher baseline triglycerides (p value 0.047). Two (2.1%) patients underwent coronary revascularization, and 1 (1.0%) patient was hospitalized for unstable angina. No cardiovascular deaths occurred. Adverse events were reported in 12 (12.5%) patients, and were all minor (injection site reactions, myalgias, and flu-like illness). In conclusion, our study shows an efficacy and safety profile that is concordant with previous investigations. The use of a standardized application form was associated with a high insurance approval rate.

Cardiorespiratory Fitness and Coronary Artery Calcification in a Primary Prevention Population.

OBJECTIVE: To elucidate whether cardiorespiratory fitness (CRF) is protective or contributory to coronary artery disease plaque burden. PATIENTS AND METHODS: Study participants were working middle-aged men from the Mayo Clinic Executive Health Program who underwent coronary artery calcium (CAC) assessment and exercise treadmill testing for risk stratification. Data from January 1, 1995, through December 31, 2008, were considered. The CAC assessment score was used for lifelong plaque burden analysis; functional aerobic capacity (FAC) from treadmill testing was analyzed as 4 ranked categories of CRF. Known risk factors for cardiovascular disease, including family history, were also considered. RESULTS: In 2946 male patients in this retrospective, cross-sectional, observational study, known cardiovascular risk factor profiles and risk calculations tended to uniformly improve with increasing CRF, defined by the FAC level. Only the above-average group, or the third of 4 levels, was found consistently lower than other levels of FAC for CAC scores. The above-average group also had statistical significance after controlling for age, body mass index, and family history of coronary artery disease in a U-shaped distribution rather than the expected linear dose-response relationship. Plaque burden was significantly increased in patients with the highest FAC level (P=.005) compared with the above-average group despite the observed maximal risk factor optimization in all known conventional cardiovascular risk factors. CONCLUSION: For men, maximal CRF is associated with increased atherosclerosis, established with CAC scores. By comparison, average-to-moderate CRF appears to be cardioprotective regardless of either age or the influence of other contributing, recognized cardiac risk factors.

Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study.

BACKGROUND: The long-term natural history of lone atrial fibrillation is unknown. Our objective was to determine the rate and predictors of progression from paroxysmal to permanent atrial fibrillation over 30 years and the long-term risk of heart failure, thromboembolism, and death compared with a control population. METHODS AND RESULTS: A previously characterized Olmsted County, Minnesota, population with first episode of documented atrial fibrillation between 1950 and 1980 and no concomitant heart disease or hypertension was followed up long term. Of this unique cohort, 76 patients with paroxysmal (n=34), persistent (n=37), or permanent (n=5) lone atrial fibrillation at initial diagnosis met inclusion criteria (mean age at diagnosis, 44.2+/-11.7 years; male, 78%). Mean duration of follow-up was 25.2+/-9.5 years. Of 71 patients with paroxysmal or persistent atrial fibrillation, 22 had progression to permanent atrial fibrillation. Overall survival of the 76 patients with lone atrial fibrillation was 92% and 68% at 15 and 30 years, respectively, similar to 86% and 57% survival for the age- and sex-matched Minnesota population. Observed survival free of heart failure was slightly worse than expected (P=0.051). Risk for stroke or transient ischemic attack was similar to the expected population risk during the initial 25 years of follow-up but increased thereafter (P=0.004), although CIs were wide. All patients who had a cerebrovascular event had developed > or = 1 risk factor for thromboembolism. CONCLUSIONS: Comorbidities significantly modulate progression and complications of atrial fibrillation. Age or development of hypertension increases thromboembolic risk.

Long-term mortality with multiple treadmill exercise test abnormalities: comparison between patients with and without cardiovascular disease.

BACKGROUND: Poor exercise capacity, abnormal heart rate responses, and electrocardiographic abnormalities during treadmill exercise testing independently predict mortality. The combined relationship of these 3 variables to determine the incremental increase in mortality was compared in groups with and without known cardiovascular disease (CVD). METHODS: Patients referred for treadmill exercise testing during 1986 to 1991 were included. Exercise capacity <74% (of age- and gender-predicted value), heart rate reserve of <68 beat/min, and horizontal or down-sloping ST depression of > or =1 mm were considered abnormal. Cox proportional hazards regression was used to determine all-cause mortality (average follow-up of 16 years) based on the number of exercise test abnormalities (0, 1, 2, or all 3). RESULTS: Among 10,897 patients, 20.9% (n = 2,277) had CVD. Poor exercise capacity and limited heart rate reserve were associated with increased risk of mortality (P < .0001) in both groups; however, abnormal exercise electrocardiogram was associated with an increased risk of mortality in the no-CVD group only (P < .0001). A graded increase in mortality was observed with increase in number of abnormal exercise test results in both groups. Patients without CVD having 2 or 3 abnormal exercise test results had a similar age-adjusted risk of long-term mortality as those with CVD but normal exercise test results, with a hazard ratio comparing these groups = 1.01 (95% CI 0.79-1.28). CONCLUSIONS: The combinatorial approach validates the prognostic significance of multiple exercise test variables. The presence of > or =2 exercise test abnormalities may constitute a "CVD risk equivalent" in patients without CVD.

Interleukin 12 induces T-cell recruitment into the atherosclerotic plaque.

CD4 T cells, through the release of cytokines as well as direct effector functions, have been implicated in promoting inflammation of the atherosclerotic plaque. Plaque-infiltrating CD4 T cells include a specialized subset of (CD4+)CD28- T cells that express a unique profile of regulatory receptors and are responsive to novel microenvironmental cues. Here we report that (CD4+)CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. (CD4+)CD28- IL-12R+ cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of (CD4+)CD28- T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of (CD4+)CD28- T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, (CD4+)CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions.