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1.  Quality Control and Reproducibility in M-mode, Two-dimensional, and Speckle Tracking Echocardiography Acquisition and Analysis: The CARDIA Study, Year-25 Examination Experience 
Echocardiography (Mount Kisco, N.Y.)  2014;32(8):1233-1240.
Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultra-sound, particularly in novel techniques such as Speckle Tracking (STE). We evaluate the echocardiography assessment performance in the CARDIA study Y25 examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and Reading Center (RC) accuracy.
The CARDIA Y25 examination had 3,475 echocardiograms performed in 4 US Field Centers and analyzed in a Reading Center, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (2- and 4-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intra-class correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots.
For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and 4-chamber and 58% in 2-chamber. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with Echo RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains.
Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies.
PMCID: PMC4426079  PMID: 25382818
Echocardiography; reproducibility; speckle tracking echocardiography; quality control
2.  Screening for Cardiac Magnetic Resonance Scar Features by 12-lead ECG, in Patients with Preserved Ejection Fraction 
Increased QRS score and wide spatial QRS-T angle are independent predictors of cardiovascular mortality in the general population. Our main objective was to assess whether a QRS score ≥5 and/or QRS-T angle ≥105° enable screening of patients for myocardial scar features.
77 patients age ≤70 years with QRS score ≥5 AND/OR spatial QRS-T angle ≥105° as well as left ventricular ejection fraction (LVEF) >35% were enrolled in the study. All participants underwent complete clinical examination, signal averaged ECG (SAECG), 30-minute ambulatory ECG recording for T wave alternans (TWA), and late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Relationship between QRS score, QRS-T angle with scar presence and pattern, as well as gray zone, core, and total scar size by LGE-CMR were assessed.
Myocardial scar was present in 41 (53%) patients, of whom 19 (46%) exhibited a typical ischemic pattern. QRS score but not QRS-T angle was related to total scar size and gray zone size (R2=0.12, P=0.002; R2=0.17; P ≤0.0001 respectively). Patients with QRS scores ≥6 had significantly greater myocardial scar and gray zone size, increased QRS duration and QRS-T angle, a higher prevalence of late potentials (LP) presence, increased LV end-diastolic volume and decreased LVEF. There was a significant independent and positive association between TWA value and total scar (P=0.001) and gray zone size (P=0.01).
Patients with preserved LVEF and myocardial scar by CMR also have electrocardiographic features that could be involved in ventricular arrhythmogenesis.
PMCID: PMC4684490  PMID: 26806840
magnetic resonance imaging; death, sudden; screening; myocardial scar; T-wave alternans
3.  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
4.  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
5.  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
6.  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
7.  Association of CMR-Measured LA Function With Heart Failure Development 
JACC. Cardiovascular imaging  2014;7(6):570-579.
The goal of this study was to assess the association between left atrial (LA) volume and function measured with feature-tracking cardiac magnetic resonance (CMR) and development of heart failure (HF) in asymptomatic individuals.
Whether alterations of LA structure and function precede or follow HF development remains incompletely understood. We hypothesized that significant alterations of LA deformation and architecture precede the development of HF in the general population.
In a case-control study nested in MESA (Multi-Ethnic Study of Atherosclerosis), baseline LA volume and function assessed using CMR feature-tracking were compared between 112 participants with incident HF (mean age 68.4 ± 8.2 years; 66% men) and 224 age- and sex-matched controls (mean age 67.7 ± 8.9 years; 66% men). Participants were followed up for 8 years. All individuals were in normal sinus rhythm at the time of imaging, without any significant valvular abnormalities and free of clinical cardiovascular diseases.
Individuals with incident HF had greater maximal and minimal LA volume indexes (LAVImin) than control subjects (40 ± 13 mm3/m2 vs. 33 ± 10 mm3/m2 [p <0.001] for maximal LA index and 25 ± 11 mm3/m2 vs. 17 ± 7 mm3/m2 [p <0.001] for LAVImin). The HF case subjects also had smaller global peak longitudinal atrial strain (PLAS) (25 ± 11% vs. 38 ± 16%; p <0.001) and lower LA emptying fraction (40 ± 11% vs. 48 ± 9%; p <0.001) at baseline. After adjustment for traditional cardiovascular risk factors, left ventricular mass, and N-terminal pro–B-type natriuretic peptide, global PLAS (odds ratio: 0.36 per SD [95% confidence interval: 0.22 to 0.60]) and LAVImin (odds ratio: 1.65 per SD [95% confidence interval: 1.04 to 2.63]) were independently associated with incident HF.
Deteriorations in LA structure and function preceded development of HF. Lower global PLAS and higher LAVImin, measured using CMR feature-tracking, were independent markers of incident HF in a multiethnic population of asymptomatic individuals.
PMCID: PMC4129378  PMID: 24813967
feature-tracking MRI; heart failure; left atrial function; left atrial strain
8.  Race–Ethnic and Sex Differences in Left Ventricular Structure and Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography
Hypertension  2015;66(1):23-29.
Aortic size increases with age, but factors related to such dilatation in healthy young adult population have not been studied. We aim to evaluate changes in aortic dimensions and its principal correlates among young adults over a 20-year time period. Reference values for aortic dimensions in young adults by echocardiography are also provided.
Healthy CARDIA study participants aged 23–35 years in 1990–91 (n=3051) were included after excluding 18 individuals with significant valvular dysfunction. Aortic root diameter by M-mode echocardiography at Year-5 (43.7% men; age 30.2±3.6y) and Year-25 CARDIA exams were obtained. Univariable and multivariable analyses were performed to assess associations of aortic root diameter with clinical data at Years-5 and -25. Aortic root diameter from Year-5 was used to establish reference values of aortic root diameter in healthy young adults.
Aortic root diameter at Year-25 was greater in men (33.3±3.7 vs 28.7±3.4mm, p<0.001) and in whites (30.9±4.3 vs 30.5±4.1, p=0.006). On multivariable analysis, aortic root diameter at Year-25 was positively correlated with male gender, white ethnicity, age, height, weight, 20-year gain in weight, active smoking at baseline and 20-year increase in diastolic, systolic and mean arterial pressure. A figure showing the estimated 95th percentile of aortic root diameter by age and body surface area stratified by race and gender is provided.
This study demonstrates that smoking, blood pressure, and increase in body weight are the main modifiable correlates of aortic root dilation during young adulthood. Our study also provides reference values for aortic root diameter in young adults.
PMCID: PMC4465858  PMID: 25941347
Ascending Aorta; Aortic Diseases; Aortic Aneurysm; Echocardiography; Epidemiology
10.  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
12.  Alcohol Consumption and Myocardial Remodeling in Elderly Women and Men 
Circulation. Cardiovascular imaging  2015;8(6):10.1161/CIRCIMAGING.115.003523 e003523.
PMCID: PMC4453877  PMID: 26015268
echocardiography; cardiac remodeling; cardiomyopathy
13.  Extending the Study of the 6,8 Rearrangement in Flavylium Compounds to Higher pH Values: Interconversion between 6‐Bromo and 8‐Bromo‐apigeninidin 
ChemistryOpen  2016;5(3):236-246.
The rearrangement between isomers 6‐ and 8‐bromo‐apigeninidin (6 and 8) was studied by pH jumps using stopped flow, UV/Vis, NMR, and HPLC analysis. The system constitutes a pH‐dependent network of chemical reactions involving up to 18 different species. The dynamic network is equivalent to a single diprotic acid exhibiting two pK as, 2.55 and 5.4. Similar to other flavylium derivatives, the mole fraction of the species hemiketal and cis‐chalcone in both multistate isomers are negligible at the equilibrium. At pH 1, the pure isomers are slowly converted in a mixture containing about 50 % of isomers 6 and 8, while at pH 4, the system evolves to mixture of 10 % trans‐chalcone and 90 % of quinoidal bases. A series of pH jumps from pure isomer 6 at pH 1 to pH 6 and back to pH 1 leads to the same initial absorption spectra of the pure isomer 6. The same occurs for pure isomer 8, showing the lack of communication between the cis‐chalcones, at least in the time scale of few minutes. A pH jump from the equilibrated mixture of the isomers at pH 1.0 to 5.8 permits to follow a very slow isomerization.
PMCID: PMC5126205  PMID: 27933227
6,8 flavylium rearrangement; 6-bromo-apigeninidin; 8-bromo-apigeninidin; anthocyanins; UV/Vis
14.  Regional Left Ventricular Myocardial Dysfunction as a Predictor of Incident Cardiovascular Events 
We sought to examine the prognostic value of subclinical left ventricular (LV) regional myocardial dysfunction (RMD) measured by magnetic resonance imaging (MRI) among asymptomatic individuals.
LV RMD, defined as segmental impairment in systolic wall thickening, predicts adverse events in patients with established cardiovascular disease. MRI is highly accurate for detecting subtle RMD, of which the prognostic significance in a large multiethnic asymptomatic population is not known.
We used MRI to evaluate baseline regional LV myocardial function and prospectively followed a multiethnic (African American, Caucasian, Chinese, and Hispanic) population-based sample of 4,510 men and women without cardiovascular disease for a mean of 4.6 years. Regional myocardial dysfunction was defined as the presence of impaired systolic wall thickening (<10th percentile of segment-specific population distribution) in ≥2 contiguous LV segments within any given coronary artery territory.
Baseline prevalence of RMD was 25.6%. Heart failure developed in 34 (1.0%) and 30 (2.6%) participants without and with RMD, respectively (p < 0.001). After adjustment for demographics and traditional risk factors, RMD remained independently associated with incident heart failure (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.56 to 4.39; p < 0.001). The relationship persisted after further adjustment for biomarkers of reported association with cardiovascular disease and indexes of global LV systolic dysfunction and hypertrophy (HR: 1.80; 95% CI: 1.02 to 3.20; p = 0.044). Similarly, RMD independently conferred an increased risk for hard coronary events (myocardial infarction or death from coronary heart disease; HR: 1.75; 95% CI: 1.06 to 2.89; p = 0.029), the composite of hard coronary events and stroke (HR: 1.72; 95% CI: 1.16 to 2.56; p = 0.005), and all atherosclerotic cardiovascular events (HR: 1.50; 95% CI: 1.09 to 2.07; p = 0.012).
Among an asymptomatic multiethnic American cohort, RMD is an independent predictor beyond traditional risk factors and global LV assessment for incident heart failure and atherosclerotic cardiovascular events. The clinical utility of early recognition of this subclinical phenotype deserves further investigation.
PMCID: PMC4124734  PMID: 21511109
epidemiology; heart failure; magnetic resonance imaging; myocardial dysfunction; prognosis
15.  Prognostic Implications of Left Ventricular Dyssynchrony for Major Adverse Cardiovascular Events in Asymptomatic Women and Men: The Multi‐Ethnic Study of Atherosclerosis 
Left ventricular (LV) dyssynchrony is related to adverse outcomes in systolic heart failure, but its prognostic importance in asymptomatic population is not known. Our objective was to assess the prognostic implications of LV mechanical dyssynchrony in a large multiethnic population before the occurrence of global LV dysfunction.
Methods and Results
A total of 1392 participants in the Multi‐Ethnic Study of Atherosclerosis (MESA; mean age: 64.7 years; 46% were women) with cardiac magnetic resonance imaging at baseline were followed for a median duration of 8.3 years. Harmonic phase imaging analysis was used to derive systolic circumferential strain. Greater standard deviation of time to peak systolic strain (SD‐TPS) indicates greater dyssynchrony. With SD‐TPS as a continuous variable, Cox proportional hazards analysis was used to assess hazards ratio after adjusting for demographics, cardiovascular risk factors, LV mass‐to‐volume ratio, and ejection fraction. Using the 75th percentile of SD‐TPS as a cutoff, Kaplan–Meier analysis was performed between 2 categorical groups for each gender. Higher values of dyssynchrony in women predicted major adverse cardiovascular events, defined as myocardial infarction, heart failure, stroke, and death (hazard ratio: 1.01 per 1‐ms increment in SD‐TPS, P=0.015), hard coronary events (hazard ratio: 1.05 per 1‐ms increment in SD‐TPS, P=0.026), and cerebrovascular events (hazard ratio: 1.03 per 1‐ms increment in SD‐TPS, P=0.013). In contrast, dyssynchrony in men was not predictive of events. Kaplan–Meier analyses in women revealed increased event occurrence in the higher dyssynchrony group, but this was not the case in men.
In an asymptomatic cohort, greater LV dyssynchrony determined by cardiac magnetic resonance imaging predicts adverse cardiovascular outcome in women but not in men.
Clinical Trial Registration
URL: Unique identifier: NCT00005487.
PMCID: PMC4310386  PMID: 25092789
cardiac magnetic resonance imaging; cardiovascular events; left ventricular dyssynchrony; prognosis
16.  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
18.  Combining Coronary Angiography and Myocardial Perfusion by Computed Tomography in the Identification of Flow-Limiting Stenosis – The CORE320 study 
The combination of coronary computed tomography angiography (CTA) and myocardial CT perfusion (CTP) is gaining increasing acceptance, but a standardized approach to be implemented in the clinical setting is necessary.
To investigate the accuracy of a combined coronary CTA and myocardial CTP comprehensive protocol compared to coronary CTA alone, using a combination of invasive coronary angiography (ICA) and Single-Photon Emission Computed Tomography (SPECT) as reference.
Three-hundred eighty-one patients included in CORE320 trial were analyzed in this study. Flow-limiting stenosis was defined as the presence of ≥50% stenosis by ICA with a related perfusion deficit by SPECT. The combined CTA+CTP definition of disease was the presence of a ≥50% stenosis with a related perfusion deficit. All data sets were analyzed by two experienced readers, aligning anatomical findings by CTA with perfusion deficits by CTP.
Mean patient age was 62±6 years (66% male), 27% with prior history of myocardial infarction. In a per-patient analysis, sensitivity for CTA alone was 93% specificity was 54%, positive predictive value (PPV) was 55%; negative predictive value (NPV) 93% and overall accuracy was 69%. After combining CTA and CTP, sensitivity was 78%, specificity 73%, NPV 64%; PPV 0.85% and overall accuracy was 75%. In a per-vessel analysis, overall accuracy of CTA alone was 73%as compared to 79% for the combination of CTA and CTP (p<0.0001 for difference).
Combining coronary CTA and myocardial CTP findings through a comprehensive protocol is feasible. While sensitivity is lower, specificity and overall accuracy are higher than assessment by coronary CTA when compared against a reference standard of stenosis with an associated perfusion deficit.
PMCID: PMC4575835  PMID: 25977111
Coronary Computed Tomography Angiography; Myocardial Computed Tomography Perfusion; Myocardial Perfusion Imaging; Multislice Computed Tomography; Hybrid Imaging
19.  Evaluation of Age-Related Interstitial Myocardial Fibrosis With Cardiac Magnetic Resonance Contrast-Enhanced T1 Mapping in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of the American College of Cardiology  2013;62(14):10.1016/j.jacc.2013.05.078.
This study sought to determine the relationship of cardiovascular magnetic resonance (CMR) measures of tissue composition to age in the Multi-Ethnic Study of Atherosclerosis (MESA).
Animal and human studies have demonstrated increased collagen deposition in senescent hearts. New CMR indices of tissue composition by using T1 mapping are sensitive to the presence of myocardial fibrosis.
A total of 1,231 study participants (51% women; age range 54 to 93 years) of the MESA cohort were evaluated with T1 mapping by using 1.5-T CMR scanners. None of the participants had focal scar on delayed enhancement CMR. Single-slice T1 mapping was performed at the midventricular level before and at 12- and 25-min delay after administration of gadolinium contrast by using a modified Look-Locker inversion recovery sequence. The partition coefficient was determined by the slope of the linear relationship of (1/T1myo vs. 1/T1blood). The extracellular volume fraction (ECV) was derived accounting for the hematocrit level. Multivariable regression analyses were performed, adjusting for traditional risk factors and left ventricular structure.
Women had significantly greater partition coefficient, ECV, and precontrast T1 than men, as well as lower post-contrast T1 values (all p < 0.05). In general, linear regression analyses demonstrated that greater partition coefficient, pre-contrast T1 values, and ECV were associated with older age in men (multivariate regression coefficients = 0.01; 5.9 ms; and 1.04% per 10 years’ change; all p < 0.05). ECV was also significantly associated with age in women after multivariable adjustments.
CMR parameters that have been associated with myocardial fibrosis were related to older age in the MESA study. Women had higher ECV than men but less ECV change over time.
PMCID: PMC3807823  PMID: 23871886
aging; magnetic resonance imaging; myocardial fibrosis; T1 mapping
20.  Differences in the Incidence of Congestive Heart Failure by Ethnicity 
Archives of internal medicine  2008;168(19):2138-2145.
The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis.
During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06).
The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.
PMCID: PMC3038918  PMID: 18955644
22.  Progression of diffuse myocardial fibrosis assessed by cardiac magnetic resonance T1 mapping 
To evaluate long-term changes in diffuse myocardial fibrosis using cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and T1 mapping. Patients with chronic stable cardiomyopathy and stable clinical status (n = 52) underwent repeat CMR at a 6 month or greater follow up interval and had LGE and left ventricular (LV) T1 mapping CMR. Diffuse myocardial fibrosis (excluding areas of focal myocardial scar) was assessed by post gadolinium myocardial T1 times. Mean baseline age of 52 patients (66 % male) was 35 ± 19 years with a mean interval between CMR examinations of 2.0 ± 0.8 years. CMR parameters, including LV mass and ejection fraction, showed no change at follow-up CMR (p > 0.05). LVT1 times (excluding focal scar) decreased over the study interval (from 468 ± 106 to 434 ± 82 ms, p = 0.049). 38 Patients had no visual LGE−, while 14 were LGE+. For LGE− patients, greater change in LV mass and end systolic volume index were associated with change in T1 time (β = −2.03 ms/g/m2, p = 0.035 and β = 2.1 ms/mL/m2, p = 0.029, respectively). For LGE+ patients, scar size was stable between CMR1 and CMR2 (10.7 ± 13.8 and 11.5 ± 13.9 g, respectively, p = 0.32). These results suggest that diffuse myocardial fibrosis, as assessed by T1 mapping, progresses over time in patients with chronic stable cardiomyopathy.
PMCID: PMC4169726  PMID: 24903343
Cardiac magnetic resonance imaging; Diffuse myocardial fibrosis; Late gadolinium enhancement; T1 mapping; Non-ischemic and ischemic cardiomyopathy
23.  Multi-Ethnic Study of Atherosclerosis: Association between Left Atrial Function Using Tissue Tracking from Cine MR Imaging and Myocardial Fibrosis 
Radiology  2014;273(3):703-713.
Reduced regional and global functions of the left atrium are related to both regional replacement and diffuse myocardial fibrosis processes.
To investigate the association between left atrial (LAleft atrium) function and left ventricular myocardial fibrosis using cardiac magnetic resonance (MR) imaging in a multi-ethnic population.
Materials and Methods
For this HIPAA-compliant study, the institutional review board at each participating center approved the study protocol, and all participants provided informed consent. Of 2839 participants who had undergone cardiac MR in 2010–2012, 143 participants with myocardial scar determined with late gadolinium enhancement and 286 age-, sex-, and ethnicity-matched control participants were identified. LAleft atrium volume, strain, and strain rate were analyzed by using multimodality tissue tracking from cine MR imaging. T1 mapping was applied to assess diffuse myocardial fibrosis. The association between LAleft atrium parameters and myocardial fibrosis was evaluated with the Student t test and multivariable regression analysis.
The scar group had significantly higher minimum LAleft atrium volume than the control group (mean, 22.0 ± 10.5 [standard deviation] vs 19.0 ± 7.8, P = .002) and lower LAleft atrium ejection fraction (45.9 ± 10.7 vs 51.3 ± 8.7, P < .001), maximal LAleft atrium strain (Smaxmaximum LA strain) (25.4 ± 10.7 vs 30.6 ± 10.6, P < .001) and maximum LAleft atrium strain rate (SRmaxmaximum LA strain rate) (1.08 ± 0.45 vs 1.29 ± 0.51, P < .001), and lower absolute LAleft atrium strain rate at early diastolic peak (SRELA strain rate at early diastolic peak) (−0.77 ± 0.42 vs −1.01 ± 0.48, P < .001) and LAleft atrium strain rate at atrial contraction peak (SRALA strain rate at atrial contraction peak) (−1.50 ± 0.62 vs −1.78 ± 0.69, P < .001) than the control group. T1 time 12 minutes after contrast material injection was significantly associated with Smaxmaximum LA strain (β coefficient = 0.043, P = .013), SRmaxmaximum LA strain rate (β coefficient = 0.0025, P = .001), SRELA strain rate at early diastolic peak (β coefficient = −0.0016, P = .027), and SRALA strain rate at atrial contraction peakLA strain rate at atrial contraction peak (β coefficient −0.0028, P = .01) in the regression model. T1 time 25 minutes after contrast material injection was significantly associated with SRmaxmaximum LA strain rate (β coefficient = 0.0019, P = .016) and SRALA strain rate at atrial contraction peak (β coefficient = −0.0022, P = .034).
Reduced LAleft atrium regional and global function are related to both replacement and diffuse myocardial fibrosis processes.
Clinical trial registration no. NCT00005487
© RSNA, 2014
Online supplemental material is available for this article.
PMCID: PMC4314120  PMID: 25019562
24.  Association of Obesity in Early Adulthood and Middle Age with Incipient Left Ventricular Dysfunction and Structural Remodeling: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
JACC. Heart failure  2014;2(5):500-508.
We investigated the relationship of body mass index (BMI) and its 25-year change to left ventricular (LV) structure and function.
Longstanding obesity may be associated with clinical cardiac dysfunction and heart failure. Whether obesity relates to cardiac dysfunction during young adulthood and middle age has not been investigated.
The Coronary Artery Risk Development in Young Adults (CARDIA) enrolled white and black adults aged 18-30 years in 1985-86 (Year-0). At the Year-25, cardiac function was assessed by conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography (STE). Twenty-five year change in BMI (classified as Low:<27 Kg/m2 and High:≥27 Kg/m2) was categorized into four groups (Low-Low, High-Low, Low-High, and High-High). Multiple linear regression was used to quantify the association between categorical changes in BMI (Low-Low as reference) with LV structural and functional parameters obtained in middle age, adjusting for baseline and 25-year change in risk factors.
The mean BMI was 24.4 kg/m2 in 3,265 participants included at Year-0. Change in BMI adjusted for risk factors was directly associated with incipient myocardial systolic dysfunction assessed by STE (High-High:β-coefficient=0.67; Low-High:β-coefficient=0.35 for longitudinal peak-systolic strain) and diastolic dysfunction assessed by TDI (High-High:β-coefficient=-074; Low-High:β-coefficient=-0.45 for e′) and STE (High-High:β-coefficient= -0.06 for circumferential early-diastolic strain rate). Greater BMI was also significantly associated with increased LV mass/height (High-High:β-coefficient=26.11; Low-High:β-coefficient=11.87).
Longstanding obesity from young adulthood to middle age is associated with impaired LV systolic and diastolic function assessed by conventional echocardiography, TDI, and STE in a large bi-racial cohort of adults aged 43-55 years.
PMCID: PMC4194150  PMID: 25194290
echocardiography; speckle tracking echocardiography; tissue Doppler imaging; obesity; risk factors; left ventricular function; left ventricular remodeling
25.  Adipokines and the Right Ventricle: The MESA-RV Study 
PLoS ONE  2015;10(9):e0136818.
Obesity is associated with changes in both right (RV) and left (LV) ventricular morphology, but the biological basis of this finding is not well established. We examined whether adipokine levels were associated with RV morphology and function in a population-based multiethnic sample free of clinical cardiovascular disease.
We examined relationships of leptin, resistin, TNF-α, and adiponectin with RV morphology and function (from cardiac MRI) in participants (n = 1,267) free of clinical cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of each adipokine with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF).
Higher leptin levels were associated with significantly lower levels of RV mass, RVEDV, RVESV and stroke volume, but not RVEF, after adjustment for age, gender, race, height and weight. These associations were somewhat attenuated but still significant after adjustment for traditional risk factors and covariates, and were completely attenuated when correcting for the respective LV measures. There were no significant interactions of age, gender, or race/ethnicity on the relationship between the four adipokines and RV structure or function.
Leptin levels are associated with favorable RV morphology in a multi-ethnic population free of cardiovascular disease, however these associations may be explained by a yet to be understood bi-ventricular process as this association was no longer present after adjustment for LV values. These findings complement the associations previously shown between adipokines and LV structure and function in both healthy and diseased patients. The mechanisms linking adipokines to healthy cardiovascular function require further investigation.
PMCID: PMC4562601  PMID: 26348768

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