CLINICAL RESEARCH: ATHEROSCLEROSIS
Subclinical Atherosclerosis and Incipient Regional Myocardial Dysfunction in Asymptomatic Individuals
The Multi-Ethnic Study of Atherosclerosis (MESA)
Verônica R.S. Fernandes, MD, PhD*,
Joseph F. Polak, MD, MPH ,
Thor Edvardsen, MD, PhD*,
Benilton Carvalho, MSc ,
Antoinette Gomes, MD ,
David A. Bluemke, MD, PhD*,||,
Khurram Nasir, MD, MPH*,
Daniel H. O'Leary, MD and
João A.C. Lima, MD, FACC*,||,*
* Division of Cardiology, Johns Hopkins University, Baltimore, Maryland
Division of Radiology, Tufts-New England Medical Center Department of Radiology, Boston, Massachusetts
Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
Department of Radiological Sciences, UCLA Medical Center, Los Angeles, California
|| Department of Radiology, Johns Hopkins University, Baltimore, Maryland
Manuscript received June 16, 2005;
revised manuscript received August 24, 2005,
accepted December 12, 2005.
* Reprint requests and correspondence: Dr. João A. C. Lima, The Johns Hopkins Hospital, Blalock 524, 600 North Wolfe Street, Baltimore, Maryland 21287 (Email: jlima{at}jhmi.edu).
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Abstract
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OBJECTIVES: This study sought to determine whether increased carotid intima-media thickness (IMT) is related to reduced regional myocardial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA).
BACKGROUND: Carotid artery IMT is an established index of subclinical atherosclerosis, and tagged magnetic resonance imaging (MRI) can detect incipient alterations of segmental function that precede overt myocardial failure.
METHODS: The MESA study is a prospective observational study including four ethnic groups free from clinical cardiovascular disease. Peak midwall systolic circumferential strain (ECC) and regional strain rates were calculated by harmonic phase from tagged MRI data of 500 participants. Systolic ECC and diastolic strain rate were regressed on IMT of the common carotid artery defined by ultrasound, with adjustments for body mass index, blood pressure, cholesterol, diabetes, smoking, left ventricular hypertrophy, C-reactive protein, age, and gender.
RESULTS: The mean participant age was 66 ± 10 years (mean ± SD). Among the 58 participants, 4% were male and the interquartile (25th to 75th percentile) range for IMT was 0.25 mm. Multiple linear regression analyses showed that increased IMT was related to reduced systolic regional function (less shortening ECC) in all myocardial regions (p < 0.05), except in the inferior wall. The analyses also showed that greater IMT was associated with a lower diastolic strain rate (diastolic reduced function) in all regions (p < 0.01), except in the anterior wall.
CONCLUSIONS: Greater carotid IMT is associated with alterations of myocardial strain parameters reflecting reduced systolic and diastolic myocardial function. These observations indicate a relationship between subclinical atherosclerosis and incipient myocardial dysfunction in a population free of clinical heart disease.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | CHF = congestive heart failure | | ECC = circumferential shortening strain | | HARP = harmonic phase | | HDL = high-density lipoprotein | | IMT = intima-media thickness | | LV = left ventricular | | LVH = left ventricular hypertrophy | | MESA = Multi-Ethnic Study of Atherosclerosis | | MRI = magnetic resonance imaging | | SRE = early diastolic strain rate | | SRS = peak systolic strain rate |
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Atherosclerosis is the main etiologic determinant of heart failure in the industrialized world (1). Therefore, the early and accurate identification of asymptomatic individuals with subclinical atherosclerosis who are at risk of developing congestive heart failure (CHF) caused by coronary artery disease (CAD) is the main starting point for the implementation of effective primary prevention strategies. Moreover, because treatment of asymptomatic persons with impaired left ventricular (LV) systolic function has been shown to delay the onset of overt heart failure (2), the identification of individuals with regional myocardial dysfunction but no symptoms becomes paramount to prevent overt symptomatic failure.
Carotid artery intima-media thickness (IMT) is a well-established subclinical marker of atherosclerosis. It indicates early manifestation of atherosclerosis in the carotid arteries (3–5), but is also associated with future cardiovascular events (6–8), asymptomatic myocardial ischemia (9), coronary risk factors (10), and changes in risk factors induced by therapeutic interventions (11). Similarly, cardiac magnetic resonance imaging (MRI) with tissue tagging can provide detailed analysis of global and regional LV function with great accuracy and reproducibility (12). Indeed, tagged MRI of the heart is considered to be the gold standard method for the detailed assessment of myocardial mechanics noninvasively (13). These properties make MRI tagging ideal for measuring incipient alterations of regional myocardial function in large epidemiologic studies designed to investigate the development and progression of subclinical cardiovascular disease, such as the Multi-Ethnic Study of Atherosclerosis (MESA).
Thus, the present study examines the hypothesis that early regional LV dysfunction assessed as alterations of myocardial strains by tagged MRI correlate directly to subclinical atherosclerosis in individuals without heart failure or history of any other clinical cardiac disease. We investigated this hypothesis in asymptomatic participants of the MESA trial, adjusting for traditional and nontraditional risk factors for CAD.
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Methods
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Study population.
The MESA trial design and population characteristics have been described in detail elsewhere (14). Briefly, the MESA trial is a prospective population-based observational cohort study of men and women from four different ethnic groups (Caucasian, African-American, Hispanic, and Chinese), ages 45 to 85 years old, who were free of clinical cardiovascular disease at enrollment.
Five hundred consecutive MRI studies with exact time information performed in the six field centers (Wake Forest University, North Carolina; Columbia University, New York; Johns Hopkins University, Maryland; University of Minnesota, Minnesota; Northwestern University, Illinois; and University of California at Los Angeles, California) were included in the regional function analyses. The study population consisted of 209 women and 291 men, and all participants gave informed consent for the study protocol, which was approved by the institutional review boards of all MESA Field Centers and MRI and Ultrasound Reading Centers.
MRI protocol.
Images were obtained using 1.5-T MR scanners (Signa LX and CVI, GE Medical Systems, Wankesha, Wisconsin, and Siemens Medical Solutions Vision and Sonata, Erlangen, Germany) using electrocardiogram-triggered segmented k-space fast spoiled gradient-echo (SPGR or FLASH) pulse sequence during breath holds. Dedicated phase array coils were used for signal acquisition. After concluding the standard imaging protocol, three tagged short-axis slices were acquired at the LV base, midlevel, and apex. Parallel striped tags were prescribed in two orthogonal orientations (0° and 90°) using identical pulse sequence with additional spatial modulation of magnetization (SPAMM) (15). The parameters for tagged MRI images were: field of view 40 cm; slice thickness 8 to 10 mm; repetition time 3.5 to 7.2 ms; echo time 2.0 to 4.2 ms; flip angle 12°; matrix size 256 x 96 to 140; 4 to 9 phase-encoding views per segment; temporal resolution 20 to 41 ms; and tag spacing 7 mm.
MRI data analysis.
The LV mass, LV end diastolic volume, and ejection fraction (EF) were determined for each study using commercially available software (MASS, version 4.2, Medis, the Netherlands). Short-axis tagged slices were analyzed by the harmonic phase (HARP) method (Diagnosoft, Palo Alto, California) to assess strain (16) as well as strain rate. Strain and strain rate provide complementary information on segmental myocardial function (17,18). Regional systolic circumferential shortening strains (ECC) were determined in four LV segments (anterior, lateral, posterior, and septal) from the LV midwall layer and strain rate was derived by integrating strain measurements over time for each LV segment.
Peak systolic strain and strain rate (SR) were assessed as illustrated in Figure 1. Peak systolic strain rate (SRS) and early diastolic strain rate (SRE) were obtained from strain measures from each segment (Fig. 1). By convention, systolic strains and systolic strain rates are negative, and increased negativity denotes enhanced function. The SRE could be assessed in 85% of all studies and represented the main index of diastolic function used.
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Figure 1 Representative strain rate (upper) and circumferential shortening strain (lower) curves from one participant. This example is showing a typical strain rate pattern with a marked E-wave in early diastole and a less pronounced A-wave close to end diastole. ECC = shortening circumferential strain; ERE = E-wave from diastolic strain rate; SRA = A-wave from diastolic strain rate; SRS = peak systolic strain rate.
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Carotid imaging protocol and data analysis.
The carotid arteries were evaluated with high-resolution B-mode ultrasonography. One real time transverse (short-axis) scanning sequence and one longitudinal image of the common carotid artery were acquired. Measurements were made at a central reading center by readers blinded to all clinical information. The maximal IMT of the common carotid artery was defined as the mean of the maximal IMT of the near and far wall on both the left and right sides, and it was measured at 10 mm proximal to the common carotid bulb (Fig. 2). The values were expressed as mean ± standard error in millimeters. The real-time transverse (short-axis) scanning sequence consists of a sweep of the carotid artery from the base of the common, up through the bulb, into the internal carotid, and back down to the base of the common carotid artery.
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Figure 2 Representative cartoon of a carotid artery showing the location for measurement in an ultrasound examination. The circle shows the common carotid segment used to measured intima-media thickness in our study.
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Reproducibility of HARP.
To assess the interobserver and intraobserver agreement for myocardial MR-tagged image analysis using the HARP technique, three independent observers performed two separate quantitative strain analyses of myocardial cine MR tagging images blindly in 24 MESA trial participants. Interobserver and intraobserver variability for all peak strain values (n = 2,592) related to tag persistence. Intraclass correlation coefficients R for interobserver and intraobserver agreement for peak systolic midwall ECC were 0.81 and 0.84, respectively, showing excellent agreement (19).
Statistical analysis.
Data are presented as mean ± standard error. Multiple linear regression was used to determine the relationship of common carotid IMT with regional systolic (ECC) and diastolic function (SRE). We considered the first model to be the simple linear regression of ECC or strain rate on IMT. The variables adjusted for in the second model were age, gender, body mass index, blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes, and smoking. Furthermore, to determine whether LV hypertrophy and inflammation attenuates the association between subclinical atherosclerosis and regional LV function, we added end-diastolic LV mass and C- reactive protein (third model). Finally, to evaluate whether the associations remained significant after adjustment for therapies for CAD risk factors, we added data on medications to control hypertension, diabetes, and hypercholesterolemia (fourth model). Differences in systolic strain and peak diastolic strain rate for various IMT tertiles across different myocardial regions were compared using one-way analysis of variance. Pairwise comparisons were made using post-hoc Bonferroni correction. Two-sided probability values <0.05 were considered statistically significant.
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Results
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Demographic and hemodynamic data as well as the risk factor profile for the subset of 500 participants enrolled in this substudy are presented in Table 1. The study population was 58.2% male, 20.6% African American, 46.8% Hispanic, 1.4% Chinese American, and 31.2% Caucasian with mean age of 66 ± 10 years.
Carotid IMT and regional LV systolic function.
The mean common carotid IMT for the 500 study participants was 0.86 ± 0.2 mm (mean ± SD) and the interquartile (25th to 75th percentile) range for IMT was 0.25 mm. Carotid IMT >1 mm was found in 106 (21%) participants. The odds of presenting with IMT >1mm were 69% higher for men compared with women (OR = 1.69; 95% CI 1.07 to 2.66).
Figure 3 shows mean systolic strains according to IMT categories among all myocardial regions. Consonant with the observed direct linear relationships between IMT and regional function in different myocardial regions (Table 2), participants in the highest tertiles for carotid IMT (highest IMT) had decreased circumferential shortening strains (in absolute ECC values) in the lateral, inferior, and septal walls when compared with individuals in the lowest IMT tertile. Significant differences in lateral wall peak systolic strains were observed between the first and second (ECC = –21% vs. –19.7%; p < 0.05), as well as between the first and third IMT tertiles (ECC = –21% vs. –19%; p < 0.0001). Moreover, septal wall peak systolic strains were significantly lower in the MESA trial participants in the third IMT tertile (ECC = –14.4%) compared with individuals in the first (ECC = –16.7%) and second (ECC = –16.2%) tertiles (p < 0.0001 for both). Similar differences were also evident in the inferior wall with reduced function shown between the first and third IMT tertiles (ECC = –14.8% vs. –13.4%; p < 0.05).
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Figure 3 Direct linear relationships between increased intima-media thickness (IMT) and regional decreased function in the different myocardial regions; participants in the highest tertiles for carotid IMT (highest IMT) had decreased circumferential shortening strain in absolute values of circumferential shortening strain (ECC) in the lateral, inferior, and septal walls when compared with individuals in the lowest tertiles (less IMT).
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The results of multiple linear regression analyses that also incorporated adjustment for risk factors and therapies to control CAD risk factors are shown in Table 2. Regression coefficients for ECC represent percent ECC differences for 0.1 mm IMT increments. The analyses for model 1 (unadjusted), model 2 (adjusted for age, gender, body mass index, blood pressure, total cholesterol, HDL cholesterol, diabetes, and smoking), model 3 (including C-reactive protein and left ventricular hypertrophy [LVH]) and model 4 (model 3 plus data on antihypertensive, diabetes, and lipid-lowering therapies) showed that increased IMT was associated with reduced regional LV function (expressed as a lower absolute value of ECC) in the lateral and septal wall of the LV (p < 0.05). In the inferior wall, the association between ECC and increased IMT was statistically significant only in the unadjusted model (model 1). Conversely, in the anterior wall, a significant positive association between increased carotid IMT and circumferential shortening strain (ECC) was seen only after adjustment for variables included in models 2, 3, and 4 (p < 0.05).
Carotid IMT and regional LV diastolic function.
Significant negative correlations between subclinical atherosclerosis and diastolic regional myocardial function were also detected (Table 3). Figure 4 shows that peak early diastolic strain rate was significantly lower among individuals in the third (greatest) IMT tertile compared with those in the first IMT tertile (least IMT) in the anterior (SRE = 1.3 s–1 vs. 1.5 s–1; p < 0.05), inferior (SRE = 1.37 s–1 vs. 1.67 s–1; p < 0.05), and septal walls of the LV (SRE = 0.98 s–1 vs. 1.42 s–1; p < 0.001). Moreover, diastolic function was also lower for participants in the second IMT tertile as compared with those individuals with the worst degree of subclinical atherosclerosis (third IMT tertile) in the anterior (SRE = 1.53 s–1 vs. 1.3 s–1; p < 0.05) and septal (1.2 s–1 vs. 0.98 s–1; p < 0.05) LV walls. Similar trends were observed for the lateral wall, but those were not statistically significant (Fig. 4). Linear unadjusted relationships were stronger in the septal and inferior walls (p < 0.001) compared with the anterior and lateral wall segments. More importantly, results shown in Table 3 also indicate strong associations between lower diastolic function expressed as reduced diastolic strain rate (SRE) and increased common carotid IMT even after adjustment for risk factors and therapies to control risk factors in the lateral, inferior, and septal walls seen in all models (Table 3). The SRE in the anterior wall showed a significant negative association (lower function) with common carotid IMT (p < 0.05) only in the unadjusted model (model 1).
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Figure 4 Mean diastolic strain rates in the different myocardial regions were significantly lower among individuals within the third tertile compared with the first intima-media thickness (IMT) tertile in the anterior, inferior, and septal walls (p < 0.05), as well as within the second IMT tertile as compared with those individuals in the first IMT tertile in the anterior and septal walls (p < 0.05). SRE = early diastolic strain rate (E-wave).
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Aging and regional LV systolic and diastolic dysfunction.
Because carotid IMT is directly related to age, we performed additional statistical analyses to control for the influence of aging on regional systolic and diastolic dysfunction as a potential confounder to the atherosclerosis-regional dysfunction relationship. These analyses showed that although diastolic myocardial dysfunction is influenced by age (Table 4), the effect of IMT on diastolic myocardial performance persisted despite additional statistical control for aging in the entire data set. On the other hand, the effect of aging on systolic myocardial function was much less pronounced and only the septal and lateral myocardial regions showed significant inverse relationships with aging. By contrast, LV ejection fraction increased with age among MESA trial participants (Table 4). Although important and in part novel, age-mediated influences did not alter the fundamental relationships between IMT and regional myocardial systolic and diastolic dysfunction reported in this study.
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Discussion
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This study provides evidence of a direct relationship between subclinical atherosclerosis and reduced regional LV systolic and diastolic function in asymptomatic individuals without previous clinical cardiovascular disease. We found consistent associations between carotid IMT and decreased myocardial systolic and diastolic strains measured by MRI tissue tagging, which is considered to be the gold-standard technique for regional LV functional assessment. Because these atherosclerosis-related alterations in LV function occur much earlier than previously anticipated, the findings have important implications to preventive efforts designed to curb the current "heart failure epidemics" seen in the U.S. and Europe.
Carotid IMT and regional systolic myocardial function..
This study challenges the notion that atherosclerosis, the most common etiology of heart failure in the industrialized world, impairs cardiac function by causing discrete clinical episodes of myocardial infarction or ischemia. We found that increased carotid IMT is associated with reduced regional myocardial systolic function in specific myocardial territories (p < 0.05) after adjustment for traditional and newer CAD risk factors. Indeed, the associations between increased IMT and reduced regional LV function remained significant after taking into account age, gender, blood pressure, cholesterol and HDL levels, cigarette smoking, diabetes, C-reactive protein levels, and LV mass, as well as therapy to control diabetes, hypertension, and hypercholesterolemia.
The IMT is a reliable indicator of the presence and extent of atherosclerosis in the coronary arteries and a common surrogate end point in epidemiologic studies (20–22) and clinical trials (23,24). Because asymptomatic global LV dysfunction is considered to be a subclinical marker of heart failure because of its frequent progression to symptomatic CHF (25,26), the IMT-related alterations of regional LV function reported in this study could represent the earliest signs of myocardial functional impairment in the heart failure continuum.
In this regard, potential mechanisms of incipient regional LV dysfunction induced by atherosclerosis deserve discussion. The IMT as a marker of atherosclerosis reflects a greater incidence of large epicardial vessel CAD with possible consequent distal damage induced by coronary occlusion and/or embolization secondary to plaque rupture. In a previous study, using the same MESA subcohort we have shown that large-vessel atherosclerosis indexed as coronary calcification of a specific arterial bed is associated with regional dysfunction measured by MRI tissue tagging in the corresponding perfusion territory (27). On the other hand, it is also possible that in the presence of asymptomatic cardiac disease with early subclinical atherosclerosis, increased resistance in smaller microvessels (28) might reduce coronary flow reserve or cause repeated stunning from recurrent ischemia, consequently altering local myocardial contractility. Recent studies by Sonoda et al. (29) have shown an inverse relationship between common carotid IMT and myocardial flow reserve in patients with coronary heart disease assessed by positron emission tomography. That study showed that thickened common carotid IMT was a good indicator of reduced myocardial flow reserve, commonly linked to early-phase coronary atherosclerosis (29). The latter studies complement our own results as well as other recent findings from the MESA trial, indicating that the magnitude of coronary calcification is also associated with impaired regional LV function (27). Finally, the relationship between increased IMT and reduced regional function persisted despite control for LVH (30) and hypertension (31), both known to also relate to incipient regional dysfunction (30,31).
In summary, a novel paradigm relating subclinical atherosclerosis to incipient myocardial systolic dysfunction emerges from previous and recent studies using more powerful methodology to measure the initial manifestations of cardiovascular pathologic processes.
Carotid IMT and regional myocardial diastolic function..
Similarly, our results show IMT-related alterations of myocardial relaxation in the absence of symptomatic heart failure. We found that greater carotid IMT is associated with diastolic impaired performance in specific LV wall segments (p < 0.05) after adjustment for CAD risk factors and aging. These results are also consistent with findings reported by Parrinello et al. (32), who showed strong relationships between increased IMT and diastolic dysfunction independent of the presence of LVH in a cohort of 142 uncomplicated individuals with recently discovered hypertension. Moreover, we also showed that the IMT-myocardial dysfunction relationship remained statistically significant despite control for the known effect of aging on diastolic dysfunction (33). In this regard, we also showed that despite the positive relationship between LV ejection fraction and age, regional systolic myocardial function is inversely related to age in specific myocardial territories (septal and lateral walls) (Table 4). The latter findings are novel, and support the concept that age-associated myocyte senescence may eventually lead to systolic dysfunction and heart failure (34).
In the Cardiovascular Health Study, Gottdiener et al. (35) showed that symptomatic CHF is frequently accompanied by intact systolic function. In that study, atherosclerosis indexed by carotid IMT was predictive of incident overt systolic and diastolic heart failure (8). Although clearly recognized as a common syndrome in clinical practice and prospective cohort studies of elderly populations (36), subclinical predictors of CHF with preserved systolic function remain undefined.
A recent study by Baicu et al. (37) showed that diastolic dysfunction is believed to be the main mechanism of symptomatic heart failure in individuals with a normal ejection fraction. The study indicates that patients with diastolic heart failure had normal measurements of LV systolic performance, function, and contractility. Abnormal relaxation may be an early response to cardiac overload caused by hypertension (8) and/or the combination of ventricular-arterial stiffening in response to stress demands (38) or other disease processes that cause CHF with preserved systolic function in the presence (39) or absence (40) of LVH. However, the persistent significance of the relationship between increased carotid IMT and regional diastolic dysfunction documented in this study after adjustment for hypertension and LVH in addition to other CAD risk factors and aging argues in favor of yet additional mechanisms that could contribute to myocardial dysfunction in individuals with increased carotid IMT. In this study, by controlling for CAD risk factors, we show that established subclinical disease indexed as increased carotid IMT is related to the presence of incipient subclinical regional systolic and diastolic dysfunction not independently, but in addition to the effects of traditional risk factors. Finally, structural alterations of the carotid arterial wall as the IMT increases are associated with modifications of intracellular matrix with increased collagen deposition and arterial stiffness (41), leading to increased pressure wave propagation, increased pressure afterload, and LV diastolic dysfunction (8,42). These alterations in carotid IMT could in part reflect the early associations with systolic and diastolic myocardial dysfunction reported in this study.
Methodologic considerations.
Our results show alterations in myocardial contractility in the absence of overt heart failure. However, the prognostic significance of regional myocardial dysfunction in individuals with increased IMT, as seen in our study, is yet to be determined. Furthermore, in our study the selection and enrollment of the sample studied was not completely random; consequently, the prevalence of the various risk factors may not exactly reflect the overall MESA study population. More importantly, because of the cross-sectional nature of our study, we cannot imply causality by describing relationships between subclinical atherosclerosis and regional myocardial alterations. Therefore, further prospective studies should be performed and longitudinal inferences await confirmation from such future observations.
Because tags fade sometimes before the following electrocardiographic QRS, strain profiles and curves do not always return to baseline (zero) at end diastole (19). Indeed, several other factors, including the normal beat-to-beat variation in stroke volume, may contribute to the limitations of MRI tagging. For these reasons, because strain rate is a derivative strain over time, and directly dependent on strain profile, 15% of strain rate curves could not be assessed reliably. In this regard, strain rate measured by echocardiography has superior temporal resolution.
By contrast, several other methodologic considerations underscore the importance of this study to our understanding of incipient myocardial dysfunction as potential predictors of CHF. From the statistical analysis standpoint, qualitative homogeneity was observed among models 2, 3, and 4, reflecting a consistent pattern of associations for regional indices of both systolic and diastolic function. Moreover, this is the first study relating carotid IMT to direct measurements of circumferential strain from MRI tissue tagging in a large sample of asymptomatic individuals with no previous history of clinical cardiovascular disease. These results are particularly important given the established value of the carotid IMT technique as an index of atherosclerosis in cardiovascular research (43), and the unique accuracy and reproducibility of MR tissue tagging as the gold-standard method for objective measurements of regional myocardial function.
Conclusions.
Our study documents for the first time the strong association of increased carotid IMT with regional LV systolic and diastolic dysfunction in asymptomatic individuals without a history of clinical cardiovascular disease. It also shows the ability of MRI tagging to measure myocardial strain and strain rate in large populations, and also provides important insight into the complex pathophysiology of incipient myocardial failure in industrialized populations.
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Acknowledgments
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The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
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Footnotes
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This study was supported by a NHLBI grant (RO1-HL66075-01) and MESA study contracts (NO1-HC-9808, NO1-HC-95168, and NO1-HC-95169). Dr. Lima is also supported by the Reynolds Foundation, and Dr. Fernandes was a recipient of a research grant from CAPES, Ministry of Education, Brazil Government. Daniel S. Berman, MD, acted as Guest Editor for this manuscript.
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