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1.  Fractal Analysis of Myocardial Trabeculations in 2547 Study Participants: Multi-Ethnic Study of Atherosclerosis 
Radiology  2015;277(3):707-715.
Left ventricular trabeculations are influenced by race and/or ethnicity, and more importantly by cardiac loading conditions and comorbidity.
To quantitatively determine the population variation and relationship of left ventricular (LV) trabeculation to LV function, structure, and clinical variables.
Materials and Methods
This HIPAA-compliant multicenter study was approved by institutional review boards of participating centers. All participants provided written informed consent. Participants from the Multi-Ethnic Study of Atherosclerosis with cardiac magnetic resonance (MR) data were evaluated to quantify LV trabeculation as a fractal dimension (FD). Entire cohort participants free of cardiac disease, hypertrophy, hypertension, and diabetes were stratified by body mass index (BMI) into three reference groups (BMI <25 kg/m2; BMI ≥25 kg/m2 to <30 kg/m2; and BMI ≥30 kg/m2) to explore maximal apical FD (FDMaxApical). Multivariable linear regression models determined the relationship between FD and other parameters.
Included were 2547 participants (mean age, 68.7 years ± 9.1 [standard deviation]; 1211 men). FDMaxApical are in arbitrary units. FDMaxApical reference ranges for BMI 30 kg/m2 or greater (n = 163), 25 kg/m2 or greater to less than 30 kg/m2 (n = 206), and less than 25 kg/m2 (n = 235) were 1.203 ± 0.06 (95% confidence interval: 1.194, 1.212), 1.194 ± 0.06 (95% confidence interval: 1.186, 1.202), and 1.169 ± 0.05 (95% confidence interval: 1.162, 1.176), respectively. In the entire cohort, adjusted for anthropometrics, trabeculation was higher in African American participants (standardized β [sβ] = 0.09; P ≤ .001) and Hispanic participants (sβ = 0.05; P = .013) compared with white participants and was also higher in African American participants compared with Chinese American participants (sβ = 0.08; P = .01), and this persisted after adjustment for hypertension and LV size. Hypertension (sβ = 0.07; P < .001), LV mass (sβ = 0.22; P < .001), and wall thickness (sβ = 0.27; P < .001) were positively associated with FDMaxApical even after adjustment. In the group with BMIs less than 25 kg/m2, Chinese American participants had less trabeculation than white participants (sβ = −0.15; P = .032).
Fractal analysis of cardiac MR imaging data measures endocardial complexity, which helps to differentiate normal from abnormal trabecular patterns in healthy versus diseased hearts. Trabeculation is influenced by race and/or ethnicity and, more importantly, by cardiac loading conditions and comorbidities. Clinicians who interpret cine MR imaging data should expect slightly less endocardial complexity in Chinese American patients and more in African American patients, Hispanic patients, hypertensive patients, and those with hypertrophy.
© RSNA, 2015
Online supplemental material is available for this article.
PMCID: PMC4666098  PMID: 26069924
2.  Abnormal Myocardial Function Is Related to Myocardial Steatosis and Diffuse Myocardial Fibrosis in HIV-Infected Adults 
The Journal of Infectious Diseases  2015;212(10):1544-1551.
Background. Impaired cardiac function persists in the era of effective human immunodeficiency virus (HIV) therapy, although the etiology is unclear. We used magnetic resonance imaging (MRI) to measure intramyocardial lipid levels and fibrosis as possible contributors to HIV-associated myocardial dysfunction.
Methods. A cross-sectional study of 95 HIV-infected and 30 matched-healthy adults, without known cardiovascular disease (CVD) was completed. Intramyocardial lipid levels, myocardial fibrosis, and cardiac function (measured on the basis of strain) were quantified by MRI.
Results. Systolic function was significantly decreased in HIV-infected subjects as compared to controls (mean radial strain [±SD], 21.7 ± 8.6% vs 30.5 ± 14.2%; P = .004). Intramyocardial lipid level and fibrosis index were both increased in HIV-infected subjects as compared to controls (P ≤ .04 for both) and correlated with the degree of myocardial dysfunction measured by strain parameters. Intramyocardial lipid levels correlated positively with antiretroviral therapy duration and visceral adiposity. Further, impaired myocardial function was strongly correlated with increased monocyte chemoattractant protein 1 levels (r = 0.396, P = .0002) and lipopolysaccharide binding protein levels (r = 0.25, P = .02).
Conclusions. HIV-infected adults have reduced myocardial function as compared to controls in the absence of known CVD. Decreased cardiac function was associated with abnormal myocardial tissue composition characterized by increased lipid levels and diffuse myocardial fibrosis. Metabolic alterations related to antiretroviral therapy and chronic inflammation may be important targets for optimizing long-term cardiovascular health in HIV-infected individuals.
PMCID: PMC4621251  PMID: 25964507
HIV; intramyocardial lipid; myocardial strain; magnetic resonance spectroscopy; antiretroviral therapy
3.  Prevalence of and factors associated with myocardial scar in a U.S. Cohort 
JAMA  2015;314(18):1945-1954.
Myocardial scarring leads to cardiac dysfunction and poor prognosis. The prevalence of and factors associated with unrecognized myocardial infarction and scar have not been previously defined using current methods in a multi-ethnic US population.
To determine prevalence of and factors associated with myocardial scar in middle and older aged individuals in the United States (U.S).
Design, Setting, and Participants
Multi-Ethnic Study of Atherosclerosis (MESA) is a population based cohort in the U.S. MESA participants were 45-84 years old and free of clinical cardiovascular disease (CVD) at baseline in 2000-2002. In the 10th year examination of MESA (2010-2012), 1840 participants underwent cardiac magnetic resonance imaging (CMR) with gadolinium to detect myocardial scar. CVD risk factors and coronary artery calcium scores were measured at baseline and year 10. Logistic regression models were used to estimate adjusted odds ratios for myocardial scar.
Cardiovascular risk factors, coronary artery calcium, left ventricle size and function, carotid intima media thickness
Main Outcome Measure
Myocardial scar detected by CMR.
Of 1840 participants (mean age 68±9 yrs, 52% male), 146 had myocardial scars (7.9%). Most myocardial scars (114/146, 78%) were undetected by electrocardiogram or by clinical adjudication. In adjusted models, age, male gender, body mass index, hypertension, and current smoking at baseline were associated with myocardial scar at year 10 [OR (95% CI): 1.6 (1.4, 1.9) per 8.9 years, p<0.001; 5.8 (3.6, 9.2) men vs. women, p<0.001; 1.3 (1.1, 1.6) per 4.8 kg/m2, p=0.005, 1.6 (1.1, 2.3) for hypertension present, p=0.009; 2.0 (1.2, 3.3) current vs. never smokers, p=0.006, respectively]. Age, gender and ethnicity adjusted CAC score at baseline was also associated with myocardial scar at year 10 [CAC categories of 1-99, 100-399 and ≥ 400 vs. CAC =0: OR (95% CI): 2.4 (1.5, 3.9), 3.0 (1.7, 5.1), 3.3 (1.7, 6.1), respectively, p≤0.001]. CAC score significantly added to the association of myocardial scar with age, gender, ethnicity and traditional CVD risk factors (c-statistic: 0.81 vs. 0.79, with vs. without CAC, respectively, p=0.012).
Conclusions and Relevance
The prevalence of myocardial scars in a US community based multiethnic cohort was 7.9%, of which 78% were unrecognized by electrocardiography or clinical evaluation. Further studies are needed to understand the clinical consequences of these undetected scars and the utility of their identification.
PMCID: PMC4774246  PMID: 26547466
4.  Progress in the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia by CMR Using Feature Tracking 
Circulation. Cardiovascular imaging  2015;8(11):10.1161/CIRCIMAGING.115.004167 e004167.
PMCID: PMC4635520  PMID: 26534933
5.  Cholesterol efflux capacity in humans with psoriasis is inversely related to non-calcified burden of coronary atherosclerosis 
European Heart Journal  2015;36(39):2662-2665.
Cholesterol efflux capacity (CEC) was recently shown to predict future cardiovascular (CV) events. Psoriasis both increases CV risk and impairs CEC. However, whether having poor CEC is associated with coronary plaque burden is currently unknown. We aimed to assess the cross-sectional relationship between coronary plaque burden assessed by quantitative coronary computed tomography angiography (CCTA) with CEC in a well-phenotyped psoriasis cohort.
Methods and results
Total burden and non-calcified burden (NCB) plaque indices were assessed in 101 consecutive psoriasis patients using quantitative software. Cholesterol efflux capacity was quantified using a cell-based ex vivo assay measuring the ability of apoB-depleted plasma to mobilize cholesterol from lipid-loaded macrophages. Cholesterol efflux capacity was inversely correlated with NCB (unadjusted β-coefficient −0.33; P < 0.001), and this relationship persisted after adjustment for CV risk factors (β −0.24; P < 0.001), HDL-C levels (β −0.22; P < 0.001), and apoA1 levels (β −0.19; P < 0.001). Finally, we observed a significant gender interaction (P < 0.001) whereby women with low CEC had higher NCB compared to men with low CEC.
We show that CEC is inversely associated with prevalent coronary plaque burden measured by quantitative CCTA. Low CEC may therefore be an important biomarker for subclinical coronary atherosclerosis in psoriasis.
PMCID: PMC4604260  PMID: 26188212
Cholesterol efflux capacity (CEC); HDL efflux; Non-calcified plaque burden; Coronary plaque burden; Quantitative coronary computed tomography angiography (CCTA); Psoriasis; Inflammatory atherogenesis; Lipids
6.  Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women 
Radiology  2015;277(1):73-80.
Total and noncalcified plaque indexes were associated with Framingham Risk Score and the 2013 American Heart Association risk score in asymptomatic individuals.
To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk.
Materials and Methods
This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320–detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes.
The mean age of the subjects was 65.5 years ± 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1–434). The total coronary plaque index was higher in men than in women (42.06 mm2 ± 9.22 vs 34.33 mm2 ± 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm2; P = .03) and in those with higher simvastatin doses (by 0.44 mm2/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (β = 0.80 mm2/10 mm Hg; P = .03), diabetes (β = 4.47 mm2; P = .03), and low-density lipoprotein (LDL) cholesterol level (β = 0.04 mm2/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score.
LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk.
© RSNA, 2015
Online supplemental material is available for this article.
PMCID: PMC4613877  PMID: 26035436
7.  Regional Strain Analysis with Multidetector CT in a Swine Cardiomyopathy Model: Relationship to Cardiac MR Tagging and Myocardial Fibrosis 
Radiology  2015;277(1):88-94.
Our results indicate that multidetector CT regional strain analysis has the potential to detect abnormalities in myocardial function in cardiomyopathy in a manner similar to cardiac MR strain analysis.
To investigate the use of cine multidetector computed tomography (CT) to detect changes in myocardial function in a swine cardiomyopathy model.
Materials and Methods
All animal protocols were in accordance with the Principles for the Utilization and Care of Vertebrate Animals Used in Testing Research and Training and approved by the University of Missouri Animal Care and Use Committee. Strain analysis of cine multidetector CT images of the left ventricle was optimized and analyzed with feature-tracking software. The standard of reference for strain was harmonic phase analysis of tagged cardiac magnetic resonance (MR) images at 3.0 T. An animal model of cardiomyopathy was imaged with both cardiac MR and 320-section multidetector CT at a temporal resolution of less than 50 msec. Three groups were evaluated: control group (n = 5), aortic-banded myocardial hypertrophy group (n = 5), and aortic-banded and cyclosporine A– treated cardiomyopathy group (n = 5). Histologic samples of the myocardium were obtained for comparison with strain results. Dunnett test was used for comparisons of the concentric remodeling group and eccentric remodeling group against the control group.
Collagen volume fraction ranged from 10.9% to 14.2%; lower collagen fraction values were seen in the control group than in the cardiomyopathy groups (P < .05). Ejection fraction and conventional metrics showed no significant differences between control and cardiomyopathy groups. Radial strain for both cardiac MR and multidetector CT was abnormal in both concentric (cardiac MR 25.1% ± 4.2; multidetector CT 28.4% ± 2.8) and eccentric (cardiac MR 23.2% ± 2.0; multidetector CT 24.4% ± 2.1) remodeling groups relative to control group (cardiac MR 18.9% ± 1.9, multidetector CT 22.0% ± 1.7, P < .05, all comparisons). Strain values for multidetector CT versus cardiac MR showed better agreement in the radial direction than in the circumferential direction (r = 0.55, P = .03 vs r = 0.40, P = .13, respectively).
Multidetector CT strain analysis has potential to identify regional wall-motion abnormalities in cardiomyopathy that is not otherwise detected using conventional metrics of myocardial function.
© RSNA, 2015
PMCID: PMC4613883  PMID: 25853636
8.  Rare Complication of non-Treated Abdominal Aortic Aneurysm: Extensive Thrombus in Right Cardiac Chambers 
Arquivos Brasileiros de Cardiologia  2016;107(4):378-380.
A 78-year-old patient presented with shortness of breath after falling down. Transthoracic echocardiogram showed an extensive thrombus in the right atrium (RA), extensive thrombosis of the inferior vena cava (IVC), and abdominal aortic aneurysm (AAA). A magnetic resonance confirmed the thrombosis of the RA extending to the IVC, which was apparently fused to the abdominal aortic aneurysm (compression? erosion?). This case illustrates a severe and rare complication of a non-treated AAA. There probably was IVC erosion by the aortic aneurysm, leading to blood stasis and extensive thrombosis of the IVC and right cardiac chambers.
PMCID: PMC5102485  PMID: 27849260
Aortic Aneurysm, Abdominal / complications; Thrombosis; Heart Atria; Echocardiography
9.  Comparison of Outcomes in Patients with Non-Obstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy 
The American journal of cardiology  2015;116(6):938-944.
Non-obstructive hypertrophic cardiomyopathy (HC) patients are considered low-risk, generally not requiring aggressive intervention. However, non- and labile-obstructive HC have been traditionally classified together and it is unknown if these 2 sub-groups have distinct risk profiles. We compared cardiovascular outcomes in 293 HC patients (96 non-obstructive, 114 labile-obstructive and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3±3.6 years. A sub-group (34 non-obstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography (PET). The mean number of sudden cardiac death risk factors was similar among groups (non-obstructive: 1.4 vs. labile-obstructive: 1.2 vs. obstructive: 1.4 risk factors, p=0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had LGE≥20% of myocardial mass [23(30%) vs. 19(18%) labile-obstructive and 8(11%) obstructive, p=0.01]. Fewer labile-obstructive patients had regional PET perfusion abnormalities [12(46%) vs. non-obstructive 30(81%) and obstructive 17(85%), p=0.003]. During follow-up, 60 events were recorded (36 VT/VF, including 30 defibrillator discharges, 12 heart failure worsening and 2 deaths). Non-obstructive patients were at higher risk of VT/VF at follow-up, when compared to labile-obstructive (HR 0.18, 95%CI 0.04–0.84, p=0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response and septum≥3cm (p=0.04). Appropriate defibrillator discharges were more frequent in non-obstructive [8(18%)] compared to labile-obstructive [0(0%), p=0.02] patients. In conclusion, non-obstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.
PMCID: PMC4554842  PMID: 26239580
hypertrophic cardiomyopathy; arrhythmia; defibrillation
10.  Liver Fat, Statin Use, and Incident Diabetes: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;242(1):211-217.
Background and Aims
To balance competing cardiovascular benefits and metabolic risks of statins, markers of type 2 diabetes (T2D) susceptibility are needed. We sought to define a competing risk/benefit of statin therapy on T2D and cardiovascular disease (CVD) events using liver attenuation and coronary artery calcification (CAC).
Methods and Results
3,153 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) without CVD, T2D/impaired fasting glucose, or baseline statin therapy had CT imaging for CAC and hepatic attenuation (hepatic steatosis). Cox models and rates of CVD and T2D were calculated to assess the role of liver attenuation in T2D and the relative risks/benefits of statins on CVD and T2D. 216 T2D cases were diagnosed at median 9.1 years follow-up. High liver fat and statin therapy were associated with diabetes (HR 2.06 [95%CI 1.52–2.79, P<0.0001] and 2.01 [95%CI 1.46–2.77, P<0.0001], respectively), after multivariable adjustment. With low liver fat and CAC=0, the number needed to treat (NNT) for statin to prevent one CVD event (NNT 218) was higher than the number needed to harm (NNH) with an incident case of T2D (NNH 68). Conversely, those with CAC >100 and low liver fat were more likely to benefit from statins for CVD reduction (NNT 29) relative to T2D risk (NNH 67). Among those with CAC >100 and fatty liver, incremental reduction in CVD with statins (NNT 40) was less than incremental risk increase for T2D (NNH 24).
Liver fat is associated with incident T2D and stratifies competing metabolic/CVD risks with statin therapy. Hepatic fat may inform T2D surveillance and lipid therapeutic strategies.
PMCID: PMC4546884  PMID: 26209814
11.  Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study 
Rationale: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease.
Objectives: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema.
Methods: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below −950 Hounsfield units (−950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output.
Measurements and Main Results: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema−950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers.
Conclusions: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.
PMCID: PMC4595687  PMID: 26067761
pulmonary microvascular blood flow (PMBF); gadolinium-enhanced MRI; chronic obstructive pulmonary disease (COPD); lung emphysema; small airway disease
12.  Particulate Matter Exposure and Cardiopulmonary Differences in the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2016;124(8):1166-1173.
Particulate matter (PM) exposure may directly affect the pulmonary vasculature. Although the pulmonary vasculature is not easily measurable, differential associations for right ventricular (RV) and left ventricular (LV) mass may provide an indirect assessment of pulmonary vascular damage.
We tested whether long-term exposure to PM < 2.5 μm (PM2.5) is associated with greater RV mass and RV mass/end-diastolic volume ratio relative to the LV.
The Multi-Ethnic Study of Atherosclerosis performed cardiac magnetic resonance (CMR) imaging among participants 45–84 years old without clinical cardiovascular disease in 2000–2002 in six U.S. cities. A fine-scale spatiotemporal model estimated ambient PM2.5 exposure in the year before CMR; individually weighted estimates accounted for indoor exposure to ambient PM2.5. Linear regression models were adjusted for demographics, anthropometrics, smoking status, cardiac risk factors, and LV parameters, with additional adjustment for city.
The 4,041 included participants had a mean age of 61.5 years, and 47% were never smokers. The mean ambient PM2.5 was 16.4 μg/m3 and individually weighted PM2.5 was 11.0 μg/m3. PM2.5 exposure was associated with greater RV mass [ambient: 0.11 g per 5 μg/m3 (95% CI: –0.05, 0.27); individually weighted: 0.20 g per 5 μg/m3 (95% CI: 0.04, 0.36)] and a greater RV mass/end-diastolic volume ratio conditional on LV parameters. City-adjusted results for RV mass were of greater magnitude and were statistically significant for both measures of PM2.5, whereas those for RV mass/end-diastolic volume ratio were attenuated.
Long-term PM2.5 exposures were associated with greater RV mass and RV mass/end-diastolic volume ratio conditional on the LV; however, additional adjustment for city attenuated the RV mass/end-diastolic volume findings. These findings suggest that PM2.5 exposure may be associated with subclinical cardiopulmonary differences in this general population sample.
Aaron CP, Chervona Y, Kawut SM, Diez Roux AV, Shen M, Bluemke DA, Van Hee VC, Kaufman JD, Barr RG. 2016. Particulate matter exposure and cardiopulmonary differences in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 124:1166–1173;
PMCID: PMC4977039  PMID: 26859533
13.  Visceral Adiposity and Left Ventricular Remodeling: the Multi-Ethnic Study of Atherosclerosis 
Background and Aims
Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat (VF) and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods and Results
We performed a post-hoc analysis on 1,151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to-volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm2/m) with height-indexed LV mass (per height2.7) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (ρ =0.36 and 0.12, P<0.0001, respectively), while only VF area was associated with LVMV (ρ =0.28, P<0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes.
Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted.
PMCID: PMC4468023  PMID: 26033394
Obesity; Cardiac magnetic resonance imaging; Visceral Adiposity; Remodeling
14.  Association of Sleep Apnea and Snoring With Incident Atrial Fibrillation in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2015;182(1):49-57.
The association between sleep apnea and atrial fibrillation (AF) has not been examined in a multiethnic adult population in prospective community-based studies. We prospectively (2000–2011) investigated the associations of physician-diagnosed sleep apnea (PDSA), which is considered more severe sleep apnea, and self-reported habitual snoring without PDSA (HS), a surrogate for mild sleep apnea, with incident AF in white, black, and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of clinical cardiovascular disease at baseline (2000–2002). Cox proportional hazards models were used to assess the associations, with adjustment for socioeconomic status, traditional vascular disease risk factors, race/ethnicity, body mass index, diabetes, chronic kidney disease, alcohol intake, and lipid-lowering therapy. Out of 4,395 respondents to a sleep questionnaire administered in MESA, 181 reported PDSA, 1,086 reported HS, and 3,128 reported neither HS nor PDSA (unaffected). Over an average 8.5-year follow-up period, 212 AF events were identified. As compared with unaffected participants, PDSA was associated with incident AF in the multivariable analysis, but HS was not (PDSA: hazard ratio = 1.76, 95% confidence interval: 1.03, 3.02; HS: hazard ratio = 1.02, 95% confidence interval: 0.72, 1.44). PDSA, a marker of more severe sleep apnea, was associated with higher risk of incident AF in this analysis of MESA data.
PMCID: PMC4479113  PMID: 25977516
atrial fibrillation; longitudinal studies; sleep apnea; snoring
15.  Noninvasive Imaging of Atherosclerotic Plaque Progression: Status of Coronary CT Angiography 
Circulation. Cardiovascular imaging  2015;8(7):10.1161/CIRCIMAGING.115.003316 e003316.
The process of coronary artery disease progression is infrequently visualized. Intravascular ultrasound has been used to gain important insights but is invasive and therefore limited to high risk patients. For low to moderate risk patients, noninvasive methods may be useful to quantitatively monitor plaque progression or regression, and to understand and personalize atherosclerosis therapy.
This review discusses the potential for coronary CT angiography (CCTA) to evaluate the extent and subtypes of coronary plaque. CT technology is evolving and image quality of the method approaches the level required for plaque progression monitoring. Methods to quantify plaque on CT angiography are reviewed as well as a discussion of their use in clinical trials. Limitations of CCTA compared to competing modalities include limited evaluation of plaque subcomponents and incomplete knowledge of the value of the method especially in patients with low to moderate cardiovascular risk.
PMCID: PMC4499869  PMID: 26156016
imaging; coronary disease; plaque; atherosclerosis
16.  Obesity Is Associated With Progression of Atherosclerosis During Statin Treatment 
This study aimed to determine the relationship of statin therapy and cardiovascular risk factors to changes in atherosclerosis in the carotid artery.
Methods and Results
Carotid magnetic resonance imaging was used to evaluate 106 hyperlipidemic participants at baseline and after 12 months of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor (statin) treatment. Multivariable logistic regression was used to determine factors associated with progression (change in carotid wall volume >0) or regression (change ≤0) of carotid atherosclerosis. Computed tomography coronary calcium scores were obtained at baseline for all participants. The median age was 65 years (interquartile range 60–69 years), and 63% of the participants were male. Body mass index >30, elevated C‐reactive protein, and hypertension were associated with increased carotid wall volume (obesity: odds ratio for progression 4.6, 95% CI 1.8–12.4, P<0.01; C‐reactive protein: odds ratio for progression 2.56, 95% CI 1.17–5.73, P=0.02; hypertension: odds ratio 2.4, 95% CI 1.1–5.3, P<0.05). Higher statin dose was associated with regression of carotid wall volume (P<0.05). In multivariable analysis, obesity remained associated with progression (P<0.01), whereas statin use remained associated with regression (P<0.05). Change in atheroma volume in obese participants was +4.8% versus −4.2% in nonobese participants (P<0.05) despite greater low‐density lipoprotein cholesterol reduction in obese participants.
In a population with hyperlipidemia, obese patients showed atheroma progression despite optimized statin therapy.
Clinical Trial Registration
URL: Unique identifier: NCT01212900.
PMCID: PMC5015399  PMID: 27413040
carotid artery; carotid magnetic resonance imaging; obesity; Atherosclerosis; Vascular Disease; Magnetic Resonance Imaging (MRI); Blood Pressure
17.  Pericardial Fat and Right Ventricular Morphology: The Multi-Ethnic Study of Atherosclerosis- Right Ventricle Study (MESA-RV) 
PLoS ONE  2016;11(6):e0157654.
Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Proposed mechanisms may be relevant in right heart failure, but relationships between pericardial fat and right ventricular (RV) morphology have not been explored.
The Multi-Ethnic Study of Atherosclerosis is a prospective cohort that enrolled participants without clinical cardiovascular disease. Pericardial fat was measured using computed tomography and RV parameters using cardiac MRI. Linear regression estimated associations of pericardial fat with RV mass, RV end diastolic volume (RV-EDV), RV end systolic volume (RV-ESV), RV stroke volume (RV-SV), and RV ejection fraction (RV-EF). Limited models adjusted for age, gender, race, height, and study site with and without weight. Fully adjusted models also accounted for socioeconomic parameters and health behaviors. Adjustment for left ventricular morphology, metabolic syndrome, and systemic inflammation was also performed.
The study sample included 3988 participants with complete assessment of RV morphology, pericardial fat and all covariates. Greater pericardial fat volume was associated with reduced RV mass (-0.3g per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-EDV (-3.7ml per 40 cm3 increase in pericardial fat, p<0.001), smaller RV-ESV (-1.0ml per 40cm3 increase in pericardial fat, p<0.001), and smaller RV-SV (-2.7mL per 40 cm3 increase in pericardial fat, p<0.001) in participants after adjustment for weight. Associations were unchanged when accounting for health behaviors, markers of systemic inflammation, and the metabolic syndrome.
Greater pericardial fat was associated with reduced RV mass, smaller RV-EDV, smaller RV-ESV, and smaller RV-SV in participants after adjustment for weight. Relationships between pericardial fat and RV morphology could be relevant to diseases of right heart failure.
PMCID: PMC4911142  PMID: 27311062
18.  Ability of Reduced Lung Function to Predict Development of Atrial Fibrillation in Persons 45–84 Years of Age (From the Multi-Ethnic Study of Atherosclerosis-Lung Study) 
The American journal of cardiology  2015;115(12):1700-1704.
Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease (COPD). Epidemiological studies have found inconsistent associations between lung function and AF, and none have studied pulmonary emphysema, which overlaps only partially with COPD in the general population. In this study, we assessed the relationship between lung function measured by spirometry, the percent of emphysema-like lung on computed tomography and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) study is a multicenter cohort study following 6814 subjects free of clinical cardiovascular disease including AF at baseline. Spirometry was performed in a subset of 3965 participants. Percent emphysema was defined on baseline CT scans as lung regions <950 hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percent emphysema with AF. 3811 participants with valid spirometry results were included in this study. The mean age was 64.5±9.8 years and 49.4% were men. AF developed in 149 individuals (3.8%) over a mean follow-up of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk of AF (HR 1.21 and 1.19 per 500ml respectively; p<0.001) after adjustment of demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multi-ethnic community-based sample of individuals free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk of AF.
PMCID: PMC4450133  PMID: 25900353
Atrial Fibrillation; Lung function; Emphysema
20.  The Association of Menopausal Age and NT-proBrain Natriuretic Peptide: The Multi-Ethnic Study of Atherosclerosis 
Menopause (New York, N.Y.)  2015;22(5):527-533.
Menopausal age could affect the risk of developing cardiovascular disease (CVD). The purpose of this study was to investigate the associations of early menopause (menopause occurring before 45 years of age) and menopausal age with NT-pro brain natriuretic peptide (NT-proBNP), a potential risk marker of CVD and heart failure (HF).
Our cross-sectional study included 2275 postmenopausal women, aged 45–85 years, without clinical CVD (2000–2002), from the Multi-Ethnic Study of Atherosclerosis. Participants were classified as having or not having early menopause. NT-proBNP was log-transformed. Multivariable linear regression was used for analysis.
There were 561 women with early menopause. The median NT-proBNP value was 79.0 (41.1–151.6) pg/ml for all participants with values of 83.4 (41.4–164.9) pg/ml and 78.0 (40.8–148.3) pg/ml for women with and without early menopause respectively. The mean (SD) age was 65 (10.1) and 65 (8.9) years for women with and without early menopause respectively. There were no significant interactions between menopausal age and ethnicity. In multivariable analysis, early menopause was associated with a 10.7% increase in NT-proBNP while each year increase in menopausal age was associated with a 0.7% decrease in NT-proBNP.
Early menopause is associated with greater NT-proBNP levels while each year increase in menopausal age is associated with lower NT-proBNP levels in postmenopausal women.
PMCID: PMC4387119  PMID: 25290536
Menopause; NT-proBNP; Sex hormones
21.  Evolution of aortic wall thickness and stiffness with atherosclerosis: Long-term follow up from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2015;65(5):1015-1019.
The study was performed to determine age, gender, and time-dependent changes in aortic wall thickness (AWT), and to evaluate cross-sectional associations between AWT and arterial stiffness in older adults. Three hundred seventy-one (371) longitudinal and 426 cross-sectional measurements of AWT from cardiovascular magnetic resonance (CMR) imaging studies conducted within the Multi-Ethnic Study of Atherosclerosis (MESA) were analyzed at two points in time: in 2000-2002 and then again from follow-up examinations in 2010-2012. Aortic wall thickness was determined from a double inversion recovery black-blood fast spin-echo sequence, and aortic stiffness was measured from a phase-contrast cine gradient echo sequence. The thickness of the mid-thoracic descending aortic wall was measured and correlated to distensibility of the ascending aorta (AAD) and aortic pulse wave velocity (PWV). The average rate of AWT change was 0.032mm per year. The increase in AWT was greater for those aged 45 to 54 years relative to individuals older than age 55 years (p-trend<0.001). Ascending aortic distensibility was lower (p<0.001) and PWV was higher (p=0.012) for hypertensive subjects. After adjustment for traditional risk factors, AAD was significantly related to AWT in participants without hypertension. Hypertension was associated with increased aortic stiffness independent of aortic wall thickness.
PMCID: PMC4410010  PMID: 25776078
MR imaging; aortic wall thickness; longitudinal changes; arterial stiffness; hypertension
22.  Multiparametric and Multimodality Functional Radiological Imaging for Breast Cancer Diagnosis and Early Treatment Response Assessment 
Breast cancer is the second leading cause of cancer death among US women, and the chance of a woman developing breast cancer sometime during her lifetime is one in eight. Early detection and diagnosis to allow appropriate locoregional and systemic treatment are key to improve the odds of surviving its diagnosis. Emerging data also suggest that different breast cancer subtypes (phenotypes) may respond differently to available adjuvant therapies. There is a growing understanding that not all patients benefit equally from systemic therapies, and therapeutic approaches are being increasingly personalized based on predictive biomarkers of clinical benefit. Optimal use of established and novel radiological imaging methods, such as magnetic resonance imaging and positron emission tomography, which have different biophysical mechanisms can simultaneously identify key functional parameters. These methods provide unique multiparametric radiological signatures of breast cancer, that will improve the accuracy of early diagnosis, help select appropriate therapies for early stage disease, and allow early assessment of therapeutic benefit.
PMCID: PMC4481707  PMID: 26063885
23.  Noninvasive Multimodality Imaging in ARVD/C 
JACC. Cardiovascular imaging  2015;8(5):597-611.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a familial cardiomyopathy resulting in progressive right ventricular (RV) dysfunction and malignant ventricular arrhythmias. Although ARVD/C is generally considered an inherited cardiomyopathy, the arrhythmogenic nature of the disease is striking. Affected individuals typically present in the second to fourth decade of life with arrhythmias originating from the right ventricle. Over the past decade, pathogenic ARVD/C-causing mutations have been identified in 5 genes encoding the cardiac desmosome. Disruption of the desmosomal connection system between cardiomyocytes may be represented structurally by ventricular enlargement, global or regional contraction abnormalities, RV aneurysms, or fibrofatty replacement. These abnormalities are typically observed in predilection areas, including the subtricuspid region, basal RV free wall, and left ventricular posterolateral wall. As such, structural and functional abnormalities on cardiac imaging constitute an important diagnostic criterion for the disease. This paper discusses the current status and role of echocardiography, cardiac magnetic resonance imaging, and computed tomography for suspected ARVD/C.
PMCID: PMC4755585  PMID: 25937197
arrhythmogenic right ventricular dysplasia/cardiomyopathy; cardiac magnetic resonance; computed tomography; echocardiography; imaging
24.  Oestradiol metabolism and androgen receptor genotypes are associated with right ventricular function 
The European respiratory journal  2015;47(2):553-563.
Sex hormones are linked to right ventricular (RV) function, but the relationship between genetic variation in these pathways and RV function is unknown.
We performed a cross-sectional study of 2761 genotyped adults without cardiovascular disease. The relationships between RV measures and single nucleotide polymorphisms (SNPs) in 10 candidate genes were assessed. Urinary oestradiol (E2) metabolites produced by cytochrome P4501B1 (CYP1B1) and serum testosterone were measured in women and men respectively. In African-American (AA) women, the CYP1B1 SNP rs162561 was associated with RV ejection fraction (RVEF), such that each copy of the A allele was associated with a 2.0% increase in RVEF. Haplotype analysis revealed associations with RVEF in AA (global p<7.2×10−6) and white (global p=0.05) women. In white subjects, higher E2 metabolite levels were associated with significantly higher RVEF. In men, androgen receptors SNPs (rs1337080; rs5918764) were significantly associated with all RV measures and modified the relationship between testosterone and RVEF.
Genetic variation in E2 metabolism and androgen signalling was associated with RV morphology in a sex-specific manner. The CYP1B1 SNP identified is in tight linkage disequilibrium with SNPs associated with pulmonary hypertension and oncogenesis, suggesting these pathways may underpin sexual dimorphism in RV failure.
PMCID: PMC4831135  PMID: 26647441
25.  Association of Subclinical Atherosclerosis Using Carotid Intima-Media Thickness, Carotid Plaque, and Coronary Calcium Score with Left Ventricular Dyssynchrony: The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2015;239(2):412-418.
The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort.
Methods and Results
Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n=2,062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n=2,039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7msec/mm change in IMT, p=0.020), ICA-IMT (19.2 msec/mm change in IMT, p<0.001), carotid plaque score (1.2 msec/unit change in score, p<0.001), and log transformed CAC+1 (0.66 msec/unit log-CAC+1, p=0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min.
In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block.
PMCID: PMC4361257  PMID: 25682041
Left Ventricular Dyssynchrony; Carotid IMT; Coronary Calcium Score; Atherosclerosis

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