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1.  Left Ventricular Global Function Index By Magnetic Resonance Imaging- A Novel Marker for Assessment of Cardiac Performance for the Prediction Of Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(4):770-778.
LV function is generally assessed independent of structural remodeling and vice versa. The purpose of this study was to evaluate a novel LV global function index (LVGFI) that integrates LV structure with global function and to assess its predictive value for cardiovascular (CV) events throughout adult life in a multi-ethnic population of men and women without history of cardiovascular diseases at baseline. A total of 5004 participants in the Multi-Ethnic Study of Atherosclerosis underwent a cardiac magnetic resonance (CMR) study and were followed up for a median of 7.2 years. The LVGFI by CMR was defined by the ratio of stroke volume divided by LV total volume defined as the sum of mean LV cavity and myocardial volumes. Cox proportional hazard models were constructed to predict the end points of heart failure (HF), hard CV events and a combined endpoint of all CV events after adjustment for established risk factors, calcium score and biomarkers. A total of 579 (11.6%) incident events were observed during the follow-up period. In adjusted models, the end points of HF, hard CV events and all events were all significantly associated with LVGFI (HF, hazard ratio [HR]= 0.64, p<0.0001; hard CV events, HR=0.79, p=0.007; all events, HR=0.79, p<0.0001). LVGFI had a significant independent predictive value in the multivariable models for all CV event categories. The LVGFI was a powerful predictor of incident heart failure, hard CV events and a composite endpoint including all events in this multiethnic cohort.
doi:10.1161/HYPERTENSIONAHA.111.198028
PMCID: PMC3691067  PMID: 23424238
left ventricle; ejection fraction; heart failure; LV mass; LV global function index
2.  Atlas-Based Quantification of Cardiac Remodeling Due to Myocardial Infarction 
PLoS ONE  2014;9(10):e110243.
Myocardial infarction leads to changes in the geometry (remodeling) of the left ventricle (LV) of the heart. The degree and type of remodeling provides important diagnostic information for the therapeutic management of ischemic heart disease. In this paper, we present a novel analysis framework for characterizing remodeling after myocardial infarction, using LV shape descriptors derived from atlas-based shape models. Cardiac magnetic resonance images from 300 patients with myocardial infarction and 1991 asymptomatic volunteers were obtained from the Cardiac Atlas Project. Finite element models were customized to the spatio-temporal shape and function of each case using guide-point modeling. Principal component analysis was applied to the shape models to derive modes of shape variation across all cases. A logistic regression analysis was performed to determine the modes of shape variation most associated with myocardial infarction. Goodness of fit results obtained from end-diastolic and end-systolic shapes were compared against the traditional clinical indices of remodeling: end-diastolic volume, end-systolic volume and LV mass. The combination of end-diastolic and end-systolic shape parameter analysis achieved the lowest deviance, Akaike information criterion and Bayesian information criterion, and the highest area under the receiver operating characteristic curve. Therefore, our framework quantitatively characterized remodeling features associated with myocardial infarction, better than current measures. These features enable quantification of the amount of remodeling, the progression of disease over time, and the effect of treatments designed to reverse remodeling effects.
doi:10.1371/journal.pone.0110243
PMCID: PMC4215861  PMID: 25360520
3.  Relationship of CRP, IL-6, and Fibrinogen with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
International journal of cardiology  2013;168(4):3818-3824.
Background/objectives
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) 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 CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Conclusion
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
doi:10.1016/j.ijcard.2013.06.028
PMCID: PMC3805818  PMID: 23932860
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
4.  High Sensitivity C-Reactive Protein as an Independent Predictor of Progressive Myocardial Functional Deterioration: The Multi-Ethnic Study of Atherosclerosis 
American heart journal  2012;164(2):251-258.
Background
Systemic inflammation has been linked to the development of heart failure in population studies including MESA (Multi-Ethnic Study of Atherosclerosis) but little evidence exists regarding potential mechanism of this relationship. In this study, we used longitudinal MRI follow-up analysis to examine whether C-reactive protein (CRP) levels relate to progressive myocardial functional deterioration as a potential mechanism of incident heart failure.
Methods
Regional myocardial functional data from MESA participants who had baseline CRP measurement and also underwent tagged cardiac MRI both at baseline and at five-year follow-up were analyzed. Left ventricular (LV) midwall and mid-slice peak circumferential strain (Ecc), of which a more negative value denotes stronger regional myocardial function, was measured. Ecc change was calculated as the difference between baseline and follow-up Ecc.
Results
During the follow-up period, participants (n=785) with elevated CRP experienced a decrease in strain, independent of age, gender and ethnicity (B=0.081; ΔEcc change per 1mg/L CRP change, 95% CI 0.036–0.126, p<0.001, Model 1), and additionally beyond systolic blood pressure, heart rate, diabetes, smoking status, body mass index, current medication and glomerular filtration rate (B=0.099, 0.052–0.145, p<0.001, Model 2). The relationship remained statistically significant after further adjustment for LV mass, coronary calcium score and interim clinical coronary events (B=0.098, 0.049–0.147, p<0.001, Model 3).
Conclusion
Higher CRP levels are related to progressive myocardial functional deterioration independent of subclinical atherosclerosis and clinical coronary events in asymptomatic individuals without previous history of heart disease.
doi:10.1016/j.ahj.2012.05.010
PMCID: PMC3417227  PMID: 22877812
inflammation; myocardial function; magnetic resonance imaging
5.  Longitudinal Determinants of Left Ventricular Mass and Geometry: The CARDIA Study 
Circulation. Cardiovascular imaging  2013;6(5):10.1161/CIRCIMAGING.112.000450.
Background
The purpose of this study was to identify determinants of 20 year change in left ventricular (LV) mass (LVM) and LV geometry in black and white young adults in the CARDIA Study.
Methods and Results
We studied 2426 black and white men and women (54.7% Caucasian) aged 43-55 years with cardiovascular (CV) risk factor data and echocardiograms from CARDIA year 5 and 25 examinations. In regression models, year 25 LVM or relative wall thickness was the dependent variable and with year 5 echo values, age, gender, race, body mass index (BMI), change in BMI, mean arterial blood pressure, change in mean blood pressure, heart rate (HR), change in HR, tobacco use, presence of diabetes, alcohol use, and physical activity score as independent variables. LVM and relative wall thickness increased while prevalence of normal geometry declined from 84.2% to 69.7%. Significant determinants of year 25 LVM/m2.7 were year 5 LVM, year 5 and change in BMI, year 5 and change in mean arterial pressure, year 5 and change in HR, baseline diabetes, and year 5 tobacco and/or alcohol use (overall r2 = 0.40). Significant determinants of year 25 relative LV wall thickness were year 5 value, black race, change in BMI, year 5 and change in mean arterial pressure, starting smoking, and year 5 diabetes. (overall r2 = 0.11).
Conclusions
Prevalence of abnormal LV hypertrophy and geometry increased from young adulthood to middle age. Both young adult CV risk traits and change in these traits predicted change in LV mass/geometry.
doi:10.1161/CIRCIMAGING.112.000450
PMCID: PMC3873157  PMID: 23922005
echocardiography; left ventricular mass; blood pressure; obesity; risk assessment
6.  N-terminal Pro-B-Type Natriuretic Peptide, Left Ventricular Mass, and Incident Heart Failure: Multi-Ethnic Study of Atherosclerosis 
Circulation. Heart failure  2012;5(6):727-734.
Background
Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.
Methods and Results
A total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54–2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3–10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).
Conclusions
Plasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
doi:10.1161/CIRCHEARTFAILURE.112.968701
PMCID: PMC4124746  PMID: 23032197
N-terminal pro-B-type natriuretic peptide; heart failure; left ventricular mass
7.  Incidental findings on cardiac computed tomography in incident hemodialysis patients: the predictors of arrhythmic and cardiovascular events in end-stage renal disease (PACE) study 
BMC Nephrology  2014;15:68.
Background
This is the first study that has examined non-cardiac incidental findings in research cardiac computed tomography (CT) of hemodialysis patients and their relationship with patient characteristics.
Methods
We performed a cross-sectional analysis in the Predictors of Arrhythmic and Cardiovascular Events in End-Stage Renal Disease (PACE) study, a prospective cohort study on incident hemodialysis patients. Non-cardiac structures in the cardiac CT scan were reviewed and evaluated. The type and frequencies of non-cardiac incidental CT findings were summarized. Univariate and multivariate logistic regression were performed to analyze the associations between gender, older age, obesity, history of cardiovascular disease (CVD), smoking status, history of chronic pulmonary disease and history of cancer with presence of any incidental CT findings and, separately, pulmonary nodules.
Results
Among the 260 participants, a total of 229 non-cardiac incidental findings were observed in 145 participants (55.8% of all participants). Of these findings, pulmonary nodules were the most common incidental finding (24.2% of all findings), and 41.3% of them requiring further follow-up imaging per radiology recommendation. Vascular and gastrointestinal findings occurred in 11.8% and 15.3% of participants, respectively. Participants 65 years or older had a higher odds of any incidental findings (Odds Ratio (OR) =2.55; 95% Confidence Intervals (CI) 1.30, 4.99) and pulmonary nodules (OR = 4.80; 95% CI 2.51, 9.18). Prior history of CVD was independently and significantly associated with any incidental findings (OR = 2.00; 95% CI 1.19, 3.40); but not with the presence of pulmonary nodules.
Conclusions
We demonstrate that the prevalence of incidental findings by cardiac CT scanning is extremely high among patients on hemodialysis. Further investigations to follow-up on the high occurrence of incidental findings during our research study and potentially clinical studies raises important practical, ethical and medico-legal issues that need to be carefully considered in research projects using imaging studies.
doi:10.1186/1471-2369-15-68
PMCID: PMC4019788  PMID: 24885570
Incidental findings; Cardiac; Computed tomography; Hemodialysis; Prevalence; Pulmonary nodule
8.  Association Between Cardiovascular Autonomic Neuropathy and Left Ventricular Dysfunction 
Objectives
The goal of these studies was to determine the association between cardiovascular autonomic neuropathy (CAN) and indices of left ventricle (LV) structure and function in patients with type 1 diabetes (T1DM) in the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study.
Background
The pathophysiology of LV dysfunction in T1DM remains unclear, especially when the LV ejection fraction (EF) is preserved. Whether CAN is associated with LV dysfunction is unclear.
Methods
Indices of LV structure and function were obtained by cardiac magnetic resonance imaging (CMRI). CAN was assessed by cardiovascular reflex testing (R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing). Analyses were performed in 966 DCCT/EDIC participants with valid CMRI and CAN data (mean age 51 years, 52% men, mean diabetes duration 29 years, and mean glycosylated hemoglobin 7.9%).
Results
Systolic function (EF, end-systolic and end-diastolic volumes, stroke volumes) was not different in 371 subjects with CAN compared with 595 subjects without CAN. In multiple-adjusted analyses, participants with either abnormal R-R variation or a composite of abnormal R-R variation, abnormal Valsalva ratio, and postural blood pressure changes had significantly higher LV mass, mass-to-volume-ratio, and cardiac output compared with those with normal tests (p < 0.0001 for all). After further adjustment for traditional cardiovascular risk factors, subjects with abnormal R-R variation had higher LV mass and cardiac output compared with those with a normal R-R variation (p < 0.05).
Conclusions
In this large cohort of patients with T1DM, CAN is associated with increased LV mass and concentric remodeling as assessed by CMRI independent of age, sex, and other factors. (Diabetes Control and Complications Trial [DCCT];NCT00360815) (Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893)
doi:10.1016/j.jacc.2012.10.028
PMCID: PMC3616477  PMID: 23265339
cardiovascular autonomic neuropathy; left ventricle hypertrophy; myocardial dysfunction; type 1 diabetes
9.  Association of early adult modifiable cardiovascular risk factors with left atrial size over a 20-year follow-up period: the CARDIA study 
BMJ Open  2014;4(1):e004001.
Objectives
We investigate how early adult and 20-year changes in modifiable cardiovascular risk factors (MRF) predict left atrial dimension (LAD) at age 43–55 years.
Methods
The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled black and white adults (1985–1986). We included 2903 participants with echocardiography and MRF assessment in follow-up years 5 and 25. At years 5 and 25, LAD was assessed by M-mode echocardiography, then indexed to body surface area (BSA) or height. Blood pressure (BP), body mass index (BMI), heart rate (HR), smoking, alcohol use, diabetes and physical activity were defined as MRF. Associations of MRF with LAD were assessed using multivariable regression adjusted for age, ethnicity, gender and year-5 left atrial (LA) size.
Results
The participants were 30±4 years; 55% white; 44% men. LAD and LAD/height were modest but significantly higher over the follow-up period, but LAD/BSA decreased slightly. Increased baseline and 20-year changes in BP were related to enlargement of LAD and indices. Higher baseline and changes in BMI were also related to higher LAD and LAD/height, but the opposite direction was found for LAD/BSA. Increase in baseline HR was related to lower LAD but not LAD indices, when only baseline covariates were included in the model. However, baseline and 20-year changes in HR were significantly associated to LA size.
Conclusions
In a biracial cohort of young adults, the most robust predictors for LA enlargement over a 20-year follow-up period were higher BP and BMI. However, an inverse direction was found for the relationship between BMI and LAD/BSA. HR showed an inverse relation to LA size.
doi:10.1136/bmjopen-2013-004001
PMCID: PMC3902509  PMID: 24384901
Cardiology; Epidemiology
10.  Age, Gender and Hypertension-Related Remodeling Influences Left Ventricular Torsion Assessed by Tagged Cardiac Magnetic Resonance in Asymptomatic Individuals: The Multi-Ethnic Study of Atherosclerosis 
Circulation  2012;126(21):2481-2490.
Background
The aim of the present study was to evaluate how torsion is influenced by left ventricular (LV) remodeling associated with age, gender and hypertension in a large community-based population.
Methods and Results
Myocardial shortening and torsion were assessed by tagged cardiac magnetic resonance (CMR) in 1478 participants without clinically apparent cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA). Torsion was defined as the difference between apical and basal rotation, divided by slice distance. In multivariable linear regression models, older age was associated with lower stroke volume (−3.6 ml/decade, p<0.001) and higher LV mass –to-volume ratio (0.03 g/ml/decade, p<0.001) along with lower circumferential shortening (−0.17%/decade, p<0.05). Torsion, however, was greater at older ages (0.14 °/decade, p<0.001) and in women (0.37°/cm vs. men, p<0.001). Hypertensive participants had higher LV mass and LV mass –to-volume ratio (15.5g and 0.07 g/ml, respectively, p<0.001 for both). Circumferential shortening was lower in hypertensive (−0.42%, p<0.01), whereas torsion was higher after adjustment for age and gender (0.17°/cm, p<0.05).
Conclusions
Older age is associated with lower LV volumes and greater relative wall thickness, and accompanied by lower circumferential myocardial shortening, whereas torsion is greater with older age. Hypertensive individuals have greater LV volumes and relative wall thickness and lower circumferential shortening. Torsion, however, is greater in hypertension independent of age and gender. Torsion may therefore represent a compensatory mechanism to maintain an adequate stroke volume and cardiac output in the face of progressively reduced LV volumes and myocardial shortening associated with hypertension and aging.
doi:10.1161/CIRCULATIONAHA.112.093146
PMCID: PMC3558706  PMID: 23147172
Torsion; Hypertension; Age; remodeling; Cardiac Magnetic Resonance
11.  Screening Entire Health System ECG Databases to Identify Patients at Increased Risk of Death 
Background
Current methods to identify patients at higher risk for sudden cardiac death, primarily left ventricular ejection fraction (LVEF) ≤35%, miss ∼80% of patients who die suddenly. We tested the hypothesis that patients with elevated QRS scores (index of myocardial scar) and wide QRS-T angles (index abnormal depolarization-repolarization relationship) have high 1-year all-cause mortality and could be further risk-stratified with clinical characteristics.
Methods and Results
We screened all 12-lead ECGs (∼50,000 patients) over 6 months at 2 large hospital systems and analyzed clinical characteristics and 1-year mortality. Patients with ECGs obtained in hospital areas with known high mortality rates were excluded. At one hospital, QRS score ≥5 and QRS-T angle ≥105° identified 8.0% of patients and was associated with an odds ratio (OR) of 2.79 [95% confidence interval 2.10-3.69] for 1-year mortality compared to patients below both ECG thresholds (13.9% vs. 5.5% death rate). LVEF was >35% in 82% of the former group of patients and addition of ECG measures to LVEF increased the discrimination of death risk (p<0.0001). At the second hospital, the OR was 2.42 [1.95-3.01] for 1-year mortality (8.8% vs. 3.8%). Adjustment for patient characteristics eliminated inter-hospital differences. Multivariable adjusted OR combining data from both hospitals was 1.53 [1.28-1.83]. Increasing heart rate and chronic renal impairment further predicted mortality.
Conclusions
Screening hospital ECG databases with QRS scoring and QRS-T angle analysis identifies patients with high 1-year all-cause mortality and predominantly preserved LVEF. This approach may represent a widely-available method to identify patients at increased risk of death.
doi:10.1161/CIRCEP.113.000411
PMCID: PMC3992472  PMID: 24122522
electrocardiography; screening; arrhythmia; fibrosis; death; myocardial scar
12.  Inter-study reproducibility of cardiovascular magnetic resonance tagging 
Background
The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization.
Methods
Twenty-five participants underwent CMR tagging twice over 12 ± 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated ±15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle α were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined.
Results
LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart.
Conclusions
Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location.
Trial registration
This trial is registered as NCT00005487 at National Heart, Lung and Blood institute.
doi:10.1186/1532-429X-15-37
PMCID: PMC3667053  PMID: 23663535
CMR tagging; HARP; Test-retest reproducibility; SPAMM; Circumferential strain; Radial strain; Principal strains; Torsion
13.  The Association of Systemic Microvascular Changes with Lung Function and Lung Density: A Cross-Sectional Study 
PLoS ONE  2012;7(12):e50224.
Smoking causes endothelial dysfunction and systemic microvascular disease with resultant end-organ damage in the kidneys, eyes and heart. Little is known about microvascular changes in smoking-related lung disease. We tested if microvascular changes in the retina, kidneys and heart were associated with obstructive spirometry and low lung density on computed tomography. The Multi-Ethnic Study of Atherosclerosis recruited participants age 45–84 years without clinical cardiovascular disease. Measures of microvascular function included retinal arteriolar and venular caliber, urine albumin-to-creatinine ratio and, in a subset, myocardial blood flow on magnetic resonance imaging. Spirometry was measured following ATS/ERS guidelines. Low attenuation areas (LAA) were measured on lung fields of cardiac computed tomograms. Regression models adjusted for pulmonary and cardiac risk factors, medications and body size. Among 3,397 participants, retinal venular caliber was inversely associated with forced expiratory volume in one second (FEV1) (P<0.001) and FEV1/forced vital capacity (FVC) ratio (P = 0.04). Albumin-to-creatinine ratio was inversely associated with FEV1 (P = 0.002) but not FEV1/FVC. Myocardial blood flow (n = 126) was associated with lower FEV1 (P = 0.02), lower FEV1/FVC (P = 0.001) and greater percentage LAA (P = 0.04). Associations were of greater magnitude among smokers. Low lung function was associated with microvascular changes in the retina, kidneys and heart, and low lung density was associated with impaired myocardial microvascular perfusion. These cross-sectional results suggest that microvascular damage with end-organ dysfunction in all circulations may pertain to the lung, that lung dysfunction may contribute to systemic microvascular disease, or that there may be a shared predisposition.
doi:10.1371/journal.pone.0050224
PMCID: PMC3527439  PMID: 23284634
14.  Age-Related Changes in Aortic Arch Geometry: Relationship with Proximal Aortic Function and Left Ventricular Mass and Remodeling 
Objectives
To define age-related geometric changes of the aortic arch and determine their relationship to central aortic stiffness and left ventricular remodeling.
Background
The proximal aorta has been shown to thicken, enlarge in diameter and lengthen with aging in humans. However, no systematic study has described age-related longitudinal and transversal remodeling of the aortic arch and their relationship with left ventricular mass and remodeling.
Methods
We studied 100 subjects (55 women, 45 men, average age: 46±16 years) free of overt cardiovascular disease using magnetic resonance imaging to determine aortic arch geometry (length, diameters, height, width and curvature), aortic arch function (local aortic distensibility and arch pulse wave velocity PWV) and left ventricular volumes and mass. Radial tonometry was used to calculate central blood pressure.
Results
Aortic diameters and arch length increased significantly with age. The ascending aorta increased most with age leading to aortic arch widening and decreased curvature. These geometric changes of the aortic arch were significantly related to decreased ascending aortic distensibility, increased aortic arch PWV (p<0.001) and to increased central blood pressures (p<0.001). Increased ascending aortic diameter, lengthening and decreased curvature of the aortic arch (unfolding) were all significantly associated with increased LV mass and concentric remodeling independently of age, gender, body size and central blood pressure (p<0.01).
Conclusions
Age-related unfolding of the aortic arch is related to increased proximal aortic stiffness in individuals without cardiovascular disease and associated with increased LV mass and mass-to-volume ratio independent of age, body size, central pressure and cardiovascular risk factors.
doi:10.1016/j.jacc.2011.06.012
PMCID: PMC3508703  PMID: 21903061
magnetic resonance imaging; aortic geometry; aging; elasticity; left ventricular remodeling
15.  Effects of Prior Intensive Versus Conventional Therapy and History of Glycemia on Cardiac Function in Type 1 Diabetes in the DCCT/EDIC 
Diabetes  2013;62(10):3561-3569.
Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis and the risk of cardiovascular disease (CVD) events in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared with conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years of additional follow-up in EDIC, left ventricular (LV) indices were measured by cardiac magnetic resonance (CMR) imaging in 1,017 of the 1,371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume (EDV), end systolic volume, stroke volume (SV), cardiac output (CO), LV mass, ejection fraction, LV mass/EDV, or aortic distensibility (AD). Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LV mass, LV mass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters.
doi:10.2337/db12-0546
PMCID: PMC3781466  PMID: 23520132
16.  The renin-angiotensin system and right ventricular structure and function: The MESA-Right Ventricle Study 
Pulmonary Circulation  2012;2(3):379-386.
The pulmonary vasculature is an important site of renin-angiotensin metabolism. While angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (collectively AIABs) have a role in left ventricular (LV) disease, the impact of AIABs on right ventricular (RV) function is unknown. AIAB use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were obtained via cardiac magnetic resonance imaging. The relationship between AIAB use and RV measures was assessed using multivariable linear regression, stratified by race/ethnicity, and adjusted for multiple covariates. AIAB use was associated with lower RV mass (-0.7 g, 95% confidence interval [CI] -1.3 to -0.1, P=0.03) in African Americans (N=1012) after adjustment for multiple covariates including LV mass. Among Caucasians (N=1591), AIAB use was associated with larger RV end-diastolic volume (3.7 mL, 95% CI 0.7-6.8, P=0.02) after adjustment for LV volume. No significant associations were seen between AIAB use and other RV measures or in Hispanic or Chinese American participants. AIAB use was associated with RV morphology in a race-specific and LV-independent manner, suggesting the renin-angiotensin system may play a unique role in RV structure and function. The use of AIABs in those with RV dysfunction warrants further study.
doi:10.4103/2045-8932.101657
PMCID: PMC3487307  PMID: 23130107
angiotensin-converting enzyme inhibitor; angiotensin II receptor blockers; right ventricle; epidemiology; renin-angiotensin system
17.  Smoking Status and Metabolic Syndrome in the Multi-Ethnic Study of Atherosclerosis. A cross-sectional study 
Tobacco Induced Diseases  2012;10(1):9.
Background
Current smoking is associated with type 2 diabetes mellitus and impaired glucose tolerance but its association with the metabolic syndrome (metS), particularly with sufficiently sampled African American representation, has not been clearly established.
Objective
To assess whether a) metS is associated with smoking; b) any increased risk of metS among smokers is independent of body mass index (BMI) compared with non-smokers; c) smoking status is differentially associated with the metS and its components across different ethnic groups.
Methods
Cross sectional analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) a community population-based sample free of cardiovascular disease.
Results
Current smokers (N = 769) had higher risk of metS (odds ratio [OR, 95% confidence interval]: 1.4, 1.1-1.7) versus never (reference, N = 2981) and former smokers (1.0, 0.8-1.1, N = 2163) and for metS components: high waist circumference (WC) (OR:1.9, 1.2-2.1), low high density lipoprotein cholesterol (HDL-C) (1.5, 1.3-1.8), elevated plasma triglycerides (TG) (OR:1.4, 1.2-1.7) as well as high C-reactive protein (CRP, an inflammatory marker) concentration (OR: 1.6,1.3-2.0) compared to never and former smokers after adjustment for BMI. A smoking status by ethnicity interaction occurred such that African American current and former smokers had greater likelihood of low HDL-C than White counterparts.
Conclusions
This study found that smoking is associated with the metS and despite the lower BMI of current smokers the prevalence of low HDL-C, elevated TG and CRP is higher among them than among non-smokers. African Americans generally have higher HDL-C than Whites but smoking wipes out this advantage.
Multi-Ethnic Study of Atherosclerosis (MESA) ClinicalTrials.gov Identifier: NCT00005487
doi:10.1186/1617-9625-10-9
PMCID: PMC3489525  PMID: 22716943
Metabolic syndrome; Smoking; Ethnic groups; Body mass index
18.  Cardiac magnetic resonance T1 mapping of left atrial myocardium 
BACKGROUND
Cardiac magnetic resonance (CMR) T1 mapping is an emerging tool for objective quantification of myocardial fibrosis.
OBJECTIVES
To (a) establish the feasibility of left atrial (LA) T1 measurements, (b) determine the range of LA T1 values in patients with atrial fibrillation (AF) vs healthy volunteers, and (c) validate T1 mapping vs LA intracardiac electrogram voltage amplitude measures.
METHODS
CMR imaging at 1.5 T was performed in 51 consecutive patients before AF ablation and in 16 healthy volunteers. T1 measurements were obtained from the posterior LA myocardium by using the modified Look-Locker inversion-recovery sequence. Given the established association of reduced electrogram amplitude with fibrosis, intracardiac point-by-point bipolar LA voltage measures were recorded for the validation of T1 measurements.
RESULTS
The median LA T1 relaxation time was shorter in patients with AF (387 [interquartile range 364–428] ms) compared to healthy volunteers (459 [interquartile range 418–532] ms; P < .001) and was shorter in patients with AF with prior ablation compared to patients without prior ablation (P = .035). In a generalized estimating equations model, adjusting for data clusters per participant, age, rhythm during CMR, prior ablation, AF type, hypertension, and diabetes, each 100-ms increase in T1 relaxation time was associated with 0.1 mV increase in intracardiac bipolar LA voltage (P = .025).
CONCLUSIONS
Measurement of the LA myocardium T1 relaxation time is feasible and strongly associated with invasive voltage measures. This methodology may improve the quantification of fibrotic changes in thin-walled myocardial tissues.
doi:10.1016/j.hrthm.2013.05.003
PMCID: PMC3757110  PMID: 23643513
Atrial fibrillation; Cardiac magnetic resonance; T1 mapping; Left atrial fibrosis; Late gadolinium enhancement
19.  Association of resting heart rate with carotid and aortic arterial stiffness: Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01605.
Resting heart rate is an easily measured, non-invasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6,484 participants (98% of participants) using B-mode ultrasound and aortic distensibility was measured in 3,512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and AV-nodal blocking agents. Mean resting heart rate of participants (mean age 62 years, 47% male) was 63 beats per minute (SD 9.6 beats per minute). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (p for trend <0.001 and 0.009 respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of AV-nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared to a central (aorta) artery.
doi:10.1161/HYPERTENSIONAHA.113.01605
PMCID: PMC3838105  PMID: 23836802
heart rate; cardiovascular disease; stiffness; ultrasound; cardiac magnetic resonance imaging
20.  Factors Associated with Presence and Extent of Coronary Calcium in Individuals Predicted to be at Low Risk Based on Framingham Risk Score (From The Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2011;107(6):879-885.
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
doi:10.1016/j.amjcard.2010.10.072
PMCID: PMC3182475  PMID: 21376929
coronary calcium; biomarkers; novel markers; low-risk; risk factors
21.  Diagnostic Performance of Combined Noninvasive Coronary Angiography and Myocardial Perfusion Imaging Using 320-MDCT: The CT Angiography and Perfusion Methods of the CORE320 Multicenter Multinational Diagnostic Study 
OBJECTIVE
Coronary MDCT angiography has been shown to be an accurate noninvasive tool for the diagnosis of obstructive coronary artery disease (CAD). Its sensitivity and negative predictive value for diagnosing percentage of stenosis are unsurpassed compared with those of other noninvasive testing methods. However, in its current form, it provides no information regarding the physiologic impact of CAD and is a poor predictor of myocardial ischemia. CORE320 is a multicenter multinational diagnostic study with the primary objective to evaluate the diagnostic accuracy of 320-MDCT for detecting coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected CAD compared with the reference standard of conventional coronary angiography and SPECT myocardial perfusion imaging.
CONCLUSION
We aim to describe the CT acquisition, reconstruction, and analysis methods of the CORE320 study.
doi:10.2214/AJR.10.5689
PMCID: PMC3302727  PMID: 21940569
coronary atherosclerosis; coronary CT angiography; myocardial CT perfusion imaging; myocardial ischemia; SPECT
22.  Sex Hormones Are Associated with Right Ventricular Structure and Function 
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
doi:10.1164/rccm.201007-1027OC
PMCID: PMC3081282  PMID: 20889903
sex; sex hormones; right ventricle
23.  Selective Serotonin Reuptake Inhibitor Use Is Associated with Right Ventricular Structure and Function: The MESA-Right Ventricle Study 
PLoS ONE  2012;7(2):e30480.
Purpose
Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114).
Methods
SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex.
Results
After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48–5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19–1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02–12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes.
Conclusions
SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study.
doi:10.1371/journal.pone.0030480
PMCID: PMC3281845  PMID: 22363441
24.  Prognostic value of myocardial circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis 
European Heart Journal  2013;34(30):2354-2361.
Aims
Left ventricular (LV) circumferential strain (Ecc) is a sensitive index of regional myocardial function. Currently, no studies have assessed its prognostic value in general population. We sought to investigate whether Ecc has a prognostic value for predicting incident heart failure (HF) and other major cardiovascular events in asymptomatic individuals without a history of previous cardiovascular diseases.
Methods and results
We, prospectively, assessed incident HF and atherosclerotic events during a 5.5 ± 1.3-year period in 1768 asymptomatic individuals aged 45–84 (mean age 65 years; 47% female) who underwent tagged magnetic resonance imaging for strain determination. During the follow-up period, 39 (2.2%) participants experienced incident HF and 108 (6.1%) participants had atherosclerotic cardiovascular events. Average of peak Ecc of 12-LV segments (Ecc-global) and mid-slice (Ecc-mid) was −17.0 ± 2.4 and −17.5 ± 2.7%, respectively. Participants with average absolute Ecc-mid lower than −16.9% had a higher cumulative hazard of incident HF (log-rank test, P = 0.001). In cox regression analysis, Ecc-mid predicted incident HF independent of age, diabetes status, hypertension, interim myocardial infarction, LV mass index, and LV ejection fraction (hazard ratio 1.15 per 1%, 95% CI: 1.01–1.31, P = 0.03). This relationship remained significant after adjustment for LV-end-systolic wall stress into covariates. In addition, by adding Ecc-mid to risk factors, LV ejection fraction, and the LV mass index, both the global χ2 value (76.6 vs. 82.4, P = 0.04) and category-less net-reclassification index (P = 0.01, SE = 0.18, z = 2.53) were augmented for predicting HF. Circumferential strain was also significantly related to the composite atherosclerotic cardiovascular events, but its relationship was attenuated after introducing the LV mass index.
Conclusion
Circumferential shortening provides robust, independent, and incremental predictive value for incident HF in asymptomatic subjects without any history of previous clinical cardiovascular disease.
Clinical Trial Registration
http://www.clinicaltrials.gov. Unique identifier: NCT00005487.
doi:10.1093/eurheartj/eht133
PMCID: PMC3736058  PMID: 23644181
Myocardial function; Heart failure; Cardiovascular events
25.  Myocardial Delayed Enhancement in Pulmonary Hypertension: Pulmonary Hemodynamics, Right Ventricular Function, and Remodeling 
OBJECTIVE
The purpose of this study was to assess predictors of MRI-identified septal delayed enhancement mass at the right ventricular (RV) insertion sites in relation to RV remodeling, altered regional mechanics, and pulmonary hemodynamics in patients with suspected pulmonary hypertension (PH).
SUBJECTS AND METHODS
Thirty-eight patients with suspected PH were evaluated with right heart catheterization and cardiac MRI. Ten age- and sex-matched healthy volunteers acted as controls for MRI comparison. Septal delayed enhancement mass was quantified at the RV insertions. Systolic septal eccentricity index, global RV function, and remodeling indexes were quantified with cine images. Peak systolic circumferential and longitudinal strain at the sites corresponding to delayed enhancement were measured with conventional tagging and fast strain-encoded MRI acquisition, respectively.
RESULTS
PH was diagnosed in 32 patients. Delayed enhancement was found in 31 of 32 patients with PH and in one of six patients in whom PH was suspected but proved absent (p = 0.001). No delayed enhancement was found in controls. Delayed enhancement mass correlated with pulmonary hemodynamics, reduced RV function, increased RV remodeling indexes, and reduced eccentricity index. Multiple linear regression analysis showed RV mass index was an independent predictor of total delayed enhancement mass (p = 0.017). Regional analysis showed delayed enhancement mass was associated with reduced longitudinal strain at the basal anterior septal insertion (r = 0.6, p < 0.01). Regression analysis showed that basal longitudinal strain remained an independent predictor of delayed enhancement mass at the basal anterior septal insertion (p = 0.02).
CONCLUSION
In PH, total delayed enhancement burden at the RV septal insertions is predicted by RV remodeling in response to increased afterload. Local fibrosis mass at the anterior septal insertion is associated with reduced regional longitudinal contractility at the base.
doi:10.2214/AJR.09.4114
PMCID: PMC3034131  PMID: 21178051
delayed enhancement; fast strain-encoded imaging; MRI; pulmonary hypertension; tagging

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