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Ciccarone Center Research

All Ciccarone Research Articles

Schnitzler’s syndrome associated with pancreatitis: a disease of IL-1 dysregulation.
By: Larocca CA, McEvoy JW, Ellis CL, Junkins-Hopkins J, Kolb T, Baer AN, Garibaldi BT.
Schnitzler's syndrome (SS) is a rare inflammatory disease of unknown origin characterized by chronic urticaria and monoclonal gammopathy (usually IgM) associated with at least two of the following components: fever, arthralgia or arthritis, bone pain, hepato- and/or splenomegaly, lymphadenopathy, elevated erythrocyte sedimentation rate, leukocytosis, and/or abnormal findings on bone morphological investigations. To date, about 100 cases have been described with only 4 being reported in the USA. The mean time to diagnosis from the onset of disease is 5.4 years, given the varied symptoms with which patients may present. The pathogenesis of SS remains unknown but likely involves dysregulation of the IL-1 pathway. We describe here a 48-year-old woman with a monoclonal IgM gammopathy and a 3-year history of chronic pruritic urticarial dermatosis, unexplained fevers, chronic polyarthritis, lymphadenopathy, leukocytosis, hepatomegaly, and weight loss. She also had a history of chronic pancreatitis as well as a family history of recurrent pancreatitis. The diagnosis of Schnitzler's syndrome was made, and she was successfully treated with the IL-1 receptor antagonist, anakinra.
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Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT.
By: Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, Hill NS, Barr RG, Rosenzweig EB, Post W, Tracy RP, Palevsky HI, Hassoun PM, Girgis RE; ASA-STAT Study Group.
Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We performed a randomized, double-blind, placebo-controlled 2×2 factorial clinical trial to determine the safety and efficacy of aspirin and simvastatin in patients with PAH. Neither aspirin nor simvastatin had a significant effect on the 6-minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications.
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The relationship between resting heart rate and incidence and progression of coronary artery calcification: The multi-ethnic study of atherosclerosis (MESA).
By: Rubin J, Blaha MJ, Budoff MJ, Rivera JJ, Shaw LJ, Blankstein R, Mallah MA, Carr JJ, Jones DL, Blumenthal RS, Nasir K.
Elevated resting heart rate has been independently associated with cardiovascular and all-cause mortality. The pathophysiological mechanisms by which this increased risk occurs are unclear. We hypothesized that elevated resting heart rate would be associated with increased development of atherosclerosis, as assessed by the incidence and progression of CAC. We concluded that elevated resting heart rate, a well-described predictor of cardiovascular mortality with unclear mechanism, is associated with increased incidence and progression of coronary atherosclerosis among individuals free of CVD at baseline.
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Association between obesity, high-sensitivity C-reactive protein greater than or equal to 2 mg/L, and subclinical atherosclerosis: implications of JUPITER from the Multi-Ethnic Study of Atherosclerosis.
By: Blaha MJ, Rivera JJ, Budoff MJ, Blankstein R, Agatston A, O’Leary DH, Cushman M, Lakoski S, Criqui MH, Szklo M, Blumenthal RS, Nasir K.

Levels of hsCRP are closely associated with abdominal obesity, metabolic syndrome, and atherosclerotic cardiovascular disease. The JUPITER trial has encouraged using hsCRP greater than or equal to 2 mg/L to guide statin therapy; however, the association of hsCRP and atherosclerosis, independent of obesity, remains unknown. We concluded that high hsCRP, as defined by JUPITER, was not associated with CAC and was mildly associated with carotid intima-media thickness (cIMT) in the absence of obesity. In contrast, obesity was associated with both measures of subclinical atherosclerosis independently of hsCRP status.

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Activated TLR signaling in atherosclerosis among women with lower Framingham risk score: the multi-ethnic study of atherosclerosis.
By: Huang CC, Liu K, Pope RM, Du P, Lin S, Rajamannan NM, Huang QQ, Jafari N, Burke GL, Post W, Watson KE, Johnson C, Daviglus ML, Lloyd-Jones DM.
Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis, the leading cause of CVD. However, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis. Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.
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Serum 25-hydroxyvitamin D, calcium, phosphorus, and electrocardiographic QT interval duration: findings from NHANES III and ARIC.
By: Zhang Y, Post WS, Dalal D, Bansal S, Blasco-Colmenares E, Jan De Beur S, Alonso A, Soliman EZ, Whitsel EA, Brugada R, Tomaselli GF, Guallar E.
Disturbances in 25-hydroxyvitamin D, calcium, and phosphorus concentrations have been associated with increased risks of total and cardiovascular mortality. It is possible that changes in electrocardiographic QT interval duration may mediate these effects, but the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration has not been evaluated in general population samples. The objective of the study was to evaluate the association of 25-hydroxyvitamin D, phosphorus, and calcium concentrations with QT interval duration in two large samples of the U.S. population. QT interval duration was inversely associated with the serum total and ionized calcium and positively associated with serum phosphorus.
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Polymorphisms of the beta adrenergic receptor predict left ventricular remodeling following acute myocardial infarction.
By: McLean RC, Hirsch GA, Becker LC, Kasch-Semenza L, Gerstenblith G, Schulman SP.
Prior studies demonstrate an association between specific beta-adrenergic receptor (?-AR) polymorphisms and clinical outcomes in patients with chronic heart failure and following acute coronary syndromes. The underlying mechanism may be due to differences in left ventricular remodeling. This study was undertaken to explore the relationship between LV remodeling after myocardial infarction and polymorphisms in the cardiac ?1-AR and ?2-AR genes. We found that polymorphisms of the ?1-AR and ?2-AR genes are associated with differential LV remodeling in patients treated with a ?1 receptor antagonist following ST-segment elevation myocardial infarction.
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Advanced chronic obstructive pulmonary disease is associated with high levels of high-density lipoprotein cholesterol.
By: Reed RM, Iacono A, DeFilippis AP, Eberlein M, Girgis RE, Jones SP.
Chronic obstructive pulmonary disease (COPD) is an inflammatory systemic disease associated with numerous extrapulmonary manifestations. Amongst these is an increased risk for cardiovascular disease. The mechanisms for this association remain unclear. We sought to examine lipid trends in a well-characterized cohort of patients with severe COPD.
Severe COPD is associated with increased levels of HDL-C, which is partially attributable to oral steroid use. HDL-C in this population is not associated with reduced risk of angiographically proven coronary artery disease.
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Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals.
By: Arking DE, Junttila MJ, Goyette P, Huertas-Vazquez A, Eijgelsheim M, Blom MT, Newton-Cheh C, Reinier K, Teodorescu C, Uy-Evanado A, Carter-Monroe N, Kaikkonen KS, Kortelainen ML, Boucher G, Lagacé C, Moes A, Zhao X, Kolodgie F, Rivadeneira F, Hofman A, Witteman JC, Uitterlinden AG, Marsman RF, Pazoki R, Bardai A, Koster RW, Dehghan A, Hwang SJ, Bhatnagar P, Post W, Hilton G, Prineas RJ, Li M, Köttgen A, Ehret G, Boerwinkle E, Coresh J, Kao WH, Psaty BM, Tomaselli GF, Sotoodehnia N, Siscovick DS, Burke GL, Marbán E, Spooner PM, Cupples LA, Jui J, Gunson K, Kesäniemi YA, Wilde AA, Tardif JC, O’Donnell CJ, Bezzina CR, Virmani R, Stricker BH, Tan HL, Albert CM, Chakravarti A, Rioux JD, Huikuri HV, Chugh SS.
Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping. Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD.
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Contemporary interpretation of lipid guidelines in modern medicine.
By: Blaha MJ, Blumenthal RS.
This chapter provides an in-depth look at the evidence base for our current national and international guidelines on cholesterol management through lifestyle and pharmacologic therapy.
Lupus Atherosclerosis Prevention Study (LAPS).
By: Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS.
CVD is one of the major causes of death in SLE. A study (200 patients with SLE without clinical CVD randomized to receive atorvastatin 40 mg daily or an identical placebo) was undertaken to investigate whether treatment with statins would reduce subclinical measures of atherosclerosis over a 2-year period. However, this study provided no evidence that atorvastatin reduces subclinical measures of atherosclerosis or disease activity over 2 years in patients with SLE. In fact, it does not reduce biochemical measures of inflammation. The anti-inflammatory effects of statins observed in the general population were not replicated in this SLE clinical trial.
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Letter regarding “Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both.
By: McEvoy JW.
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Abnormalities in arterial-ventricular coupling in older healthy persons are attenuated by sodium nitroprusside.
By: Chantler PD, Nussbacher A, Gerstenblith G, Schulman SP, Becker LC, Ferrucci L, Fleg JL, Lakatta EG, Najjar SS.
The coupling between arterial elastance (E(A); net afterload) and left ventricular elastance (E(LV); pump performance), known as E(A)/E(LV), is a key determinant of cardiovascular performance and shifts during exercise due to a greater increase in E(LV) versus E(A). This normal exercise-induced reduction in E(A)/E(LV) decreases with advancing age. In conclusion, some age-associated deficiencies in E(A)/E(LV), E(A), and E(LV), in older subjects can be acutely abolished by single-nucleotide polymorphisms (SNPs) infusion. This is relevant to common conditions in older subjects associated with a significant impairment of exercise performance such as frailty or heart failure with preserved ejection fraction.
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Localized calcific constrictive pericarditis masquerading as a basal aneurysm.
By: Blaha MJ, Panjrath G, Chacko M, Schulman SP.
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Usefulness of baseline obesity to predict development of a high ankle brachial index (from the Multi-Ethnic Study of Atherosclerosis).
By: Tison GH, Ndumele CE, Gerstenblith G, Allison MA, Polak JF, Szklo M.
An abnormally high ABI is associated with increased all-cause and cardiovascular mortality. The relation of obesity to incident high ABI has not been characterized. The aim of this study was to investigate the hypothesis that increased obesity — quantified by body weight, body mass index, waist circumference, and waist-to-hip-ratio — is positively associated with a high ABI (?1.3) and with mean ABI increases over a 4-year follow-up. Independent, positive, and graded associations of increasing obesity with prevalent and incident high ABI and with mean increases in ABI values over time were found. Weight and body mass index seemed to be at least as strongly, if not more strongly, associated with a high ABI than were measures of abdominal obesity.
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Relation of mitral annular calcium and coronary calcium (from the Multi-Ethnic Study of Atherosclerosis [MESA]).
By: Hamirani YS, Nasir K, Blumenthal RS, Takasu J, Shavelle D, Kronmal R, Budoff M.
Atherosclerosis is a complex diffuse disorder. The close correlation between CAC score on computed tomography and extent and severity of coronary atherosclerosis is well established. It has been suggested that mitral annular calcification (MAC) may be a manifestation of generalized atherosclerosis. We observed a strong association between MAC and increasing burden of CAC. This association weakened but persisted after adjustment for age, gender, and other traditional risk factors. These findings suggest that presence of MAC is an indicator of atherosclerotic burden rather than just a degenerative change of the mitral valve.
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Association between high-sensitivity C-reactive protein and coronary plaque subtypes assessed by 64-slice coronary computed tomography angiography in an asymptomatic population.
By: Rubin J, Chang HJ, Nasir K, Blumenthal RS, Blaha MJ, Choi EK, Chang SA, Yoon YE, Chun EJ, Choi SI, Agatston AS, Rivera JJ.
We evaluated 1,004 asymptomatic South Korean subjects (mean age, 49±9 years) who underwent coronary computed tomography angiography (CCTA) as part of a health screening evaluation. We examined the association between increasing CRP levels and plaque subtypes using multivariable linear and logistic regression analysis. We concluded that elevated levels of CRP are associated with an increased prevalence of mixed coronary atherosclerotic plaque (MCAP) as assessed by CCTA. Longitudinal studies will determine if the excess risk observed in persons with elevated CRP may be mediated, at least in part, by an increased burden of MCAP.
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Approach to smoking cessation in the patient with vascular disease.
By: Ratchford EV, Black JH 3rd.
In the patient with vascular disease, cigarette smoking is particularly perilous; the benefits of smoking cessation greatly exceed any risks associated with pharmacologic treatment. Multiple clinical trials have demonstrated the efficacy of pharmacologic therapy for smoking cessation. In parallel with aggressive counseling and pharmacotherapy for smoking cessation, cardiovascular risk reduction is critical.
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Association of left ventricular hypertrophy with incident hypertension: the multi-ethnic study of atherosclerosis.
By: Shimbo D, Muntner P, Mann D, Barr RG, Tang W, Post W, Lima J, Burke G, Bluemke D, Shea S.
Increased LV mass and changes in LV geometry may precede hypertension onset. The authors examined the associations of LV mass and geometry, assessed by cardiac magnetic resonance imaging, with hypertension incidence in 2,567 normotensive participants enrolled in 2000-2002 in MESA. Higher levels of LV concentric geometry, defined by higher LV mass to end-diastolic volume quartiles, were associated with higher risk of incident hypertension in a fully adjusted model. In a final model containing both quartiles of LV mass and LV mass/volume, along with all covariates including baseline blood pressure, higher LV mass quartiles were associated with incident hypertension, whereas higher LV mass/volume quartiles were not. In this multiethnic cohort, alterations in LV mass preceded hypertension onset among normotensive individuals.
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“Actually, it is more of a guideline than a rule.”
By: Blumenthal RS, Hasan RK.
This editorial discusses the challenges of designing a randomized controlled trial of coronary calcium scanning to improve risk prediction. It also emphasizes the theme of the iconic movie “Ghostbusters.”
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Statin therapy is associated with decreased pulmonary vascular pressures in severe COPD.
By: Reed RM, Iacono A, DeFilippis AP, Jones SR, Eberlein M, Lechtzin N, Girgis RE.
Pulmonary hypertension (PH) in COPD carries a poor prognosis. Statin therapy has been associated with numerous beneficial clinical effects in COPD, including a possible improvement in PH. We examined the association between statin use and pulmonary hemodynamics in a well-characterized cohort of patients undergoing evaluation for lung transplantation.
In patients with severe COPD, statin use is associated with significantly lower pulmonary artery wedge pressure (PAWP) and mean pulmonary arterial pressure (mPAP). These finding should be evaluated prospectively.
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Society for Atherosclerosis Imaging and Prevention Tomographic Imaging and Prevention Councils. Guideline for minimizing radiation exposure during acquisition of coronary artery calcium scans with the use of multidetector computed tomography.
By: Voros S, Rivera JJ, Berman DS, Blankstein R, Budoff MJ, Desai MY, Hecht HS, Nasir K, Santos RD, Taylor AJ, Weissman G.

Coronary artery calcium (CAC) scanning is an important tool for risk stratification in intermediate-risk, asymptomatic subjects without previous coronary disease. However, the clinical benefit of improved risk prediction needs to be balanced against the risk of the use of ionizing radiation. Although there is increasing emphasis on the need to obtain CAC scans at low-radiation exposure to the patient, very few practical documents exist to aid laboratories and health care professionals on how to obtain such low-radiation scans. The Tomographic Imaging Council of the Society for Atherosclerosis Imaging and Prevention, in collaboration with the Prevention Council and the Society of Cardiovascular Computed Tomography, created a task force and writing group to generate a practical document to address parameters that can be influenced by careful attention to image acquisition. Patient selection for CAC scanning should be based on national guidelines. It is recommended that laboratories performing CAC examinations monitor radiation exposure (dose-length-product [DLP]) and effective radiation dose (E) in all patients. DLP should be <200 mGy × cm; E should average 1.0-1.5 mSv and should be <3.0 mSv. On most scanner platforms, CAC imaging should be performed in an axial mode with prospective electrocardiographic triggering, using tube voltage of 120 kVp. Tube current should be carefully selected on the basis of patient size, potentially using chest lateral width measured on the topogram. Scan length should be limited for the coverage of the heart only. When patients and imaging parameters are selected appropriately, CAC scanning can be performed with low levels of radiation exposure.

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Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the multi-ethnic study of atherosclerosis (MESA).
By: Wassel CL, Pankow JS, Rasmussen-Torvik LJ, Li N, Taylor KD, Guo X, Goodarzi MO, Palmas WR, Post WS.
Circulating adiponectin is associated with both clinical and subclinical CVD. Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal cIMT, presence of CAC, and CAC scores (in those with CAC) in 2,847 participants in MESA. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African Americans and Hispanics. Replication as well as assessment of other ADIPOQ SNPs is warranted.
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Thoracic aortic calcification and coronary heart disease events: the multi-ethnic study of atherosclerosis (MESA).
By: Budoff MJ, Nasir K, Katz R, Takasu J, Carr JJ, Wong ND, Allison M, Lima JA, Detrano R, Blumenthal RS, Kronmal R.
The presence and extent of CAC is an independent predictor of CHD morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established. This study used risk factor and computed tomography scan data from 6,807 participants in MESA. Using the same images for each participant, TAC and CAC were each computed using the Agatston method. Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
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Mortality in individuals without known coronary artery disease but with discordance between the Framingham risk score and coronary artery calcium.
By: Ahmadi N, Hajsadeghi F, Blumenthal RS, Budoff MJ, Stone GW, Ebrahimi R.
A risk-management approach based on the Framingham risk score (FRS), although useful in preventing future CAD events, is unable to identify a considerable portion of patients with CAD who need aggressive medical management. CAC, an anatomic marker of atherosclerosis, correlates well with presence and extent of CAD. This study investigated mortality risk associated with CAC score and FRS in subjects classified as “low risk” versus “high risk” based on FRS. In conclusion, the prognostic value of CAC to predict future mortality is far superior to the FRS. Addition of CAC score to FRS significantly improves the identification and prognostication of patients without known CAD.
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Factors associated with presence and extent of coronary calcium in those predicted to be at low risk according to Framingham risk score (from the Multi-Ethnic Study of Atherosclerosis).
By: Okwuosa TM, Greenland P, Lakoski SG, Ning H, Kang J, Blumenthal RS, Szklo M, Crouse JR 3rd, Lima JA, Liu K, Lloyd-Jones DM.
Even among asymptomatic persons at low risk (<10% risk of an MI over the next decade) according to the Framingham risk score, high CAC scores signify a greater predicted risk of CHD events. We determined the noninvasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3,046 individuals at a low 10-year predicted risk (Framingham risk score <10%) of CHD events. In low-risk persons, the traditional risk factors alone predicted advanced CAC with high discrimination and calibration. The biomarker combinations with and without cIMT were also significantly associated with advanced CAC; however, the improvement in the prediction and estimation of the clinical risk were modest compared to the traditional risk factors alone.
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he relationship between insulin resistance and incidence and progression of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis (MESA).
By: Blaha MJ, DeFilippis AP, Rivera JJ, Budoff MJ, Blankstein R, Agatston A, Szklo M, Lakoski SG, Bertoni AG, Kronmal RA, Blumenthal RS, Nasir K.
We sought to determine whether insulin resistance predicts the incidence and progression of CAC. We studied 5,464 MESA participants not on hypoglycemic therapy. Each had baseline HOMA-IR and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up. HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome.
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By: Differences in coronary plaque composition by noninvasive computed tomography angiography in individuals with and without obstructive coronary artery disease.
CCTA has emerged as a promising non-invasive tool to detect CAD, which provides additional information about atherosclerotic plaque composition. We assessed whether differences in plaque composition and plaque burden exist across patients with more advanced as well as <50% coronary stenosis. Plaque composition is different according to severity of CAD with a higher mixed plaque and lesser non-calcified plaque burden among those patients with ?50% stenotic CAD. These findings should stimulate further investigations to assess the prognostic value of coronary plaque subtypes according to their underlying composition.
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Understanding the utility of zero coronary calcium as a prognostic test: a Bayesian approach.
By: Blaha MJ, Blumenthal RS, Budoff MJ, Nasir K.
This article discusses the proper interpretation of a zero coronary calcium score, which depends on whether the patient is asymptomatic, has atypical chest discomfort, or clearly angina discomfort.
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Abdominal aortic calcium and multisite atherosclerosis: the Multiethnic Study of Atherosclerosis.
By: Wong ND, Lopez VA, Allison M, Detrano RC, Blumenthal RS, Folsom AR, Ouyang P, Criqui MH.

Abdominal aortic calcification (AAC) is a measure of subclinical CVD. Data are limited regarding its relation to other measures of atherosclerosis. Among 1,812 subjects within the population-based MESA, we examined the cross-sectional relation of AAC with CAC, ankle brachial index (ABI), and CIMT, as well as multiple measures of subclinical CVD. Our study found that AAC is associated with an increased likelihood of other vascular atherosclerosis and its additive prognostic value to these other measures is of further interest.

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Coffee, alcohol, smoking, physical activity and QT interval duration: results from the Third National Health and Nutrition Examination Survey.
By: Zhang Y, Post WS, Dalal D, Blasco-Colmenares E, Tomaselli GF, Guallar E.
Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. We studied 7,795 men and women from NHANES III. Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors, including coffee and tea intake, smoking, and physical activity.
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The relationship between inflammation, obesity and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA).
By: Lakoski SG, Cushman M, Siscovick DS, Blumenthal RS, Palmas W, Burke G, Herrington DM.
It has been suggested that inflammation is important in the etiology of hypertension and that this may be most relevant among obese persons. To study this, we examined the independent relationships between obesity, inflammation-related proteins (interleukin-6 (IL-6), CRP and fibrinogen) and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis. The relationship between inflammation-related proteins and hypertension risk was predominantly explained by other hypertension risk factors. Obesity, independent of inflammation, remained a potent risk factor for future hypertension.
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Statins for primary prevention of cardiovascular disease.
By: Deckers JW, Blumenthal RS.
This insightful editorial discusses the rationale for selective use of statin therapy in asymptomatic adults with multiple risk factors who have never had a prior CVD event.
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Differences in coronary plaque composition with aging measured by coronary computed tomography angiography.
By: Tota-Maharaj R, Blaha MJ, Rivera JJ, Henry TS, Choi EK, Chang SA, Yoon YE, Chun EJ, Choi SI, Blumenthal RS, Chang HJ, Nasir K.
Little is known about the independent impact of aging on coronary plaque morphology and composition in the era of CCTA. We studied 1,015 consecutive asymptomatic South Korean subjects (49±10years, 64% men) who underwent 64-slice CCTA during routine health evaluation. Coronary plaque characteristics were analyzed on a per-segment basis according to the modified AHA classification. In conclusion, CCTA is an effective method for measuring age-related differences in the burden of individual coronary plaque subtypes. Future research is needed to determine whether the increase in mixed and calcified plaques seen with aging produce an independent contribution to the age-related increase in cardiovascular risk.
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Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.
By: Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, Farlow DN, Folsom AR, Fornage M, Forrester T, Fox E, Haiman CA, Hartiala J, Harris TB, Hazen SL, Heckbert SR, Henderson BE, Hirschhorn JN, Keating BJ, Kritchevsky SB, Larkin E, Li M, Rudock ME, McKenzie CA, Meigs JB, Meng YA, Mosley TH, Newman AB, Newton-Cheh CH, Paltoo DN, Papanicolaou GJ, Patterson N, Post WS, Psaty BM, Qasim AN, Qu L, Rader DJ, Redline S, Reilly MP, Reiner AP, Rich SS, Rotter JI, Liu Y, Shrader P, Siscovick DS, Tang WH, Taylor HA, Tracy RP, Vasan RS, Waters KM, Wilks R, Wilson JG, Fabsitz RR, Gabriel SB, Kathiresan S, Boerwinkle E.
CHD is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study in 8,090 African Americans from five population-based cohorts. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.
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Atherosclerosis imaging in multiple vascular beds—Enough heterogeneity to improve risk prediction?
By: Tison GH, Blaha MJ, Nasir K.

This editorial review looks at the incremental predictive value of finding above average amounts of subclinical atherosclerosis in vascular territories other than the coronary circulation and its potential effect on cardiovascular risk prediction.

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Role of vascular computed tomography in evaluation and prevention of cardiovascular disease.
By: Nasir K, Blumenthal RS, Wong ND, Budoff MJ.
Traditional global risk assessment approaches for CHD tend to underestimate long-term CVD risk in middle-aged men and in postmenopausal women with multiple risk factors. Non-contrast enhanced CT detection of CAC improves the ability to predict CVD risk. This chapter provides a superb review of the strengths and limitations of cardiac CT and CTA to measure coronary calcification and to provide information about the location, severity, and characteristics of atherosclerotic plaque.
Adjunctive lipid lowering therapy in the era of surrogate endpoints.
By: Silverman MG, Blaha MJ, Blumenthal RS.
Statins have been shown to reduce cardiovascular events. However, despite widespread use of statin therapy, residual cardiovascular risk remains, and this has left clinicians searching for an effective adjunctive therapy to optimize lipid profiles and reduce risk further. Our article provides clinicians with a practical approach to making decisions regarding adjunctive therapy in the absence of clinical outcomes data. Three ongoing clinical outcomes trials evaluating niacin and ezetimibe in combination with a statin will provide more definitive evidence regarding the safety and efficacy of these agents as adjunctive therapy.
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Prospective gating with 320-MDCT angiography: effect of volume scan length on radiation dose.
By: Khan A, Nasir K, Khosa F, Saghir A. Sarwar S, Clouse ME.
Radiation dose optimization remains an important concern in cardiac CT, and for 320-MDCT angiography, substantial dose reduction can be achieved by reducing volume scan length so that it is in concert with the patient's heart length.
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Statins for secondary prevention: might less in fact be more?
By: Muñoz D, Blumenthal RS.
This commentary discusses the dangers of drug interactions between high dose simvastatin and certain medications and suggests that the dose of simvastatin should be lowered to no more than 40 mg and in the presence of certain other medications, either 10 or 20 mg.
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Statin therapy in the prevention and treatment of atrial fibrillation.
By: Lee YL, Blaha MJ, Jones SR.
Atrial fibrillation (AF) is the most common adult rhythm disorder, and it is associated with a substantial rate of morbidity and economic burden. There is an increasing body of literature in which the authors investigated the pleiotropic effects of statin therapy in relation to AF. Its utility in patients with paroxysmal AF may be limited to the prevention of incident AF, but it does not appear to inhibit the progression of paroxysmal AF to chronic AF. Further large scale, randomized, placebo-controlled studies are needed in perioperative use in noncardiac surgery and in patients undergoing ablation or cardioversion of AF.
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Comparison of the racial/ethnic prevalence of regular aspirin use for the primary prevention of coronary heart disease from the multi-ethnic study of atherosclerosis.
By: Sanchez DR, Diez Roux AV, Michos ED, Blumenthal RS, Schreiner PJ, Burke GL, Watson K.
The regular use of aspirin (?3 days/week) was examined in a cohort of 6,452 White, Black, Hispanic, and Chinese patients without cardiovascular disease in 2000 to 2002 and 5,181 patients from the same cohort in 2005 to 2007. Framingham risk scores were stratified into low (<6% risk of MI over next decade), increased (6% to 9.9%), and high (?10%) risk. In 2000 to 2002 prevalences of aspirin use were 18% and 27% for those at increased and high risk, respectively. In conclusion, regular aspirin use in adults at increased and high risk for CHD remains suboptimal. Important racial/ethnic disparities exist for unclear reasons.
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Lower extremity peripheral artery disease in the absence of traditional risk factors. The Multi-Ethnic Study of Atherosclerosis.
By: Aboyans V, McClelland RL, Allison MA, McDermott MM, Blumenthal RS, Macura K, Criqui MH.
Lower-extremity peripheral artery disease (LE-PAD) is strongly related to traditional risk factors (smoking, hypertension, dyslipidemia, diabetes). We hypothesized that the prevalence of LE-PAD in the absence of traditional CVD risk factors is not negligible, and that this condition would remain associated with subclinical atherosclerosis in other territories. In the absence of traditional CVD risk factors, LE-PAD is still fairly common and associated with coronary artery disease.
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Vitamin D in atherosclerosis, vascular disease, and endothelial function.
By: Brewer LC, Michos ED, Reis JP.
Vitamin D deficiency has been linked to an increased risk of hypertension, diabetes, congestive heart failure, peripheral arterial disease, MI, CVA, and related mortality, even after adjustment for traditional cardiovascular risk factors. Accumulating evidence from experimental, clinical, and epidemiological studies suggests that vitamin D may also be associated with several indices of vascular function, including the development and progression of atherosclerotic cardiovascular disease. These findings may provide at least a partial explanation for several recent epidemiologic studies implicating low vitamin D status in the pathogenesis of cardiovascular disease. However, large-scale, well-conducted, placebo controlled clinical trials testing the efficacy of vitamin D supplementation in delaying, slowing, or reversing the atherosclerotic disease process have not yet been conducted. Until the results of these studies are available, we believe it is premature to recommend vitamin D as a therapeutic option in atherosclerosis.
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Cardiovascular imaging for assessing cardiovascular risk in asymptomatic men versus women: the multi-ethnic study of atherosclerosis (MESA).
By: Jain A, McClelland RL, Polak JF, Shea S, Burke GL, Bild DE, Watson KE, Budoff MJ, Liu K, Post WS, Folsom AR, Lima JA, Bluemke DA.
CAC, carotid IMT, and LV mass and geometry offer the potential to characterize incident CVD risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD. The study sample consisted of 4,965 MESA participants (48% men; mean age, 62±10 years). There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
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Endothelial function and dysfunction.
By: Corretti MC, Panjrath GS, Jones SR.
Vascular endothelium is a vast dynamic paracrine system that regulates several key biologic and molecular functions serving to maintain vascular health and homeostasis. Ongoing research in the development and application of noninvasive imaging techniques to measure endothelial function and dysfunction continues to focus on therapeutic strategies and prognosis.
Cardiovascular aging: the next frontier in cardiovascular prevention.
By: Najaar SS, Lakatta EG, Gerstenblith G.
Age is the dominant risk for CVD, but it has traditionally been viewed as a nonmodifiable risk factor. This chapter examines physiologic aging and clinical interventions to slow this process. Future studies should examine whether such interventions can slow the process of accelerated cardiovascular aging and attenuate the impact of age as the dominant risk factor for CVD.
Clinical utility of rosuvastatin and other statins for cardiovascular risk reduction among the elderly.
By: Long SB, Blaha MJ, Blumenthal RS, Michos ED.

Age is one of the strongest predictors of CVD risk. Treatment with statins can significantly reduce CVD events and mortality in both primary and secondary prevention. Yet despite the high CVD risk among the elderly, there is underutilization of statins in this population (ie, the treatment-risk paradox). Few studies have investigated the use of statins in the elderly, particularly for primary prevention and, as a result, guidelines for treating the elderly are limited. JUPITER is the largest primary prevention statin trial and enrolled a substantial number of elderly adults. Among the 5,695 JUPITER participants greater than or equal to 70 years of age, the absolute CVD risk reduction associated with rosuvastatin was actually greater than for younger participants. The implications of this JUPITER subanalysis and the broader role of statins among older adults is the subject of this review.

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Variation in atherosclerotic plaque composition according to increasing coronary artery calcium scores on computed tomography angiography.
By: Nasir K, Rivera JJ, Yoon YE, Chang SA, Choi SI, Chun EJ, Budoff MJ, Blumenthal RS, Chang HJ.
This study examines the prognostic importance of noncalcified, partially calcified (mixed), and predominantly calcified plaques on CCTA and the effect of the absolute coronary calcium scores on the composition of the various plaques.
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Relationships of mitral annular calcification to cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA).
By: Kanjanauthai S, Nasir K, Katz R, Rivera JJ, Takasu J, Blumenthal RS, Eng J, Budoff MJ.
The relationship between MAC, a fibrous, degenerative calcification of the mitral valve, and CVD risk factors is not well defined. Thus, we performed a cross-sectional study to determine which CVD risk factors are independently associated with MAC. We concluded that age, female gender, diabetes, and increased BMI were significantly associated with MAC. Prevalence of MAC was strongly associated with female gender and increasing age in all ethnicities.
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