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J Am Coll Cardiol, 2007; 49:594-600, doi:10.1016/j.jacc.2006.09.040 (Published online 19 January 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CARDIAC IMAGING

Relationship Between C-Reactive Protein Levels and Regional Left Ventricular Function in Asymptomatic Individuals

The Multi-Ethnic Study of Atherosclerosis

Boaz D. Rosen, MD*, Mary Cushman, MD{dagger}, Khurram Nasir, MD, MPH*, David A. Bluemke, MD, PhD{ddagger}, Thor Edvardsen, MD, PhD*, Verônica Fernandes, MD, PhD*, Shenghan Lai, MD, PhD§, Russell P. Tracy, PhD{dagger} and João A.C. Lima, MD, FACC*,{ddagger},*

* Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland
{dagger} Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont
{ddagger} Radiology Department, Johns Hopkins Medical Institutions, Baltimore, Maryland
§ Department of Epidemiology, Bloomberg School of Public Health and Hygiene, Johns Hopkins University, Baltimore, Maryland

Manuscript received May 16, 2006; revised manuscript received September 8, 2006, accepted September 28, 2006.

* Reprint requests and correspondence: Dr. João A. C. Lima, Cardiology Division, Blalock 524, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287-0409. (Email: jlima{at}jhmi.edu).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Appendix
 References
 
OBJECTIVES: This study sought to investigate the relationship between C-reactive protein (CRP) and regional left ventricular (LV) function in asymptomatic individuals without a history of cardiovascular disease.

BACKGROUND: C-reactive protein is associated with an increased risk for developing cardiovascular disease. However, the relationship between CRP and subclinical LV dysfunction has not been evaluated in asymptomatic individuals.

METHODS: Regional myocardial function was analyzed as peak systolic circumferential shortening strain (Ecc) using the harmonic-phase method by tagged magnetic resonance imaging in 1,164 individuals without symptomatic cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis) trial (age 66.4 ± 9.6 years old). Regions were defined by coronary territories: left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). The relationship between log-CRP concentration and Ecc was studied by multivariable linear regression after adjustment for demographic characteristics, risk factors, and therapy (including hormone replacement therapy).

RESULTS: For each region, associations differed by gender with no association of CRP and regional LV function among women. In men, after adjustment, higher log-CRP was significantly associated with lower (absolute) Ecc in the LAD and RCA regions (regression coefficient 0.37 per unit higher log-CRP [95% confidence interval [CI] 0.08 to 0.65] and 0.31 [95% CI 0.02 to 0.59], respectively) and peak systolic Ecc overall (regression coefficient 0.32 [95% CI 0.05 to 0.58]). In the LCX region, the association was weaker (p = 0.06).

CONCLUSIONS: Among individuals without evident heart failure or other cardiovascular disorders, higher CRP was associated with lower systolic myocardial function in all regions in men but not in women. These findings support the role of inflammation and atherosclerosis in incipient myocardial dysfunction. (Multi-Ethnic Study of Atherosclerosis; http://clinicaltrials.gov/ct/show/NCT00005487 [ClinicalTrials.gov] ).

Abbreviations and Acronyms
  CAD = coronary artery disease
  CHF = congestive heart failure
  CI = confidence interval
  CRP = C-reactive protein
  Ecc = circumferential strain
  IQR = interquartile range
  LAD = left anterior descending artery
  LCX = left circumflex artery
  LV = left ventricular
  MESA = Multi-Ethnic Study of Atherosclerosis
  RCA = right coronary artery

Inflammation plays an important role in the development and progression of atherosclerosis and congestive heart failure (CHF) (1). The inflammatory process contributes to the formation of early atherosclerotic plaques in the form of lipid-laden macrophages and induces plaque weakening and rupture leading to acute coronary syndromes and sudden death (2,3). Furthermore, many circulating markers of inflammation, particularly C-reactive protein (CRP), are associated with increased morbidity and mortality in asymptomatic individuals and in patients with cardiovascular disease and CHF (4–9).

Coronary artery disease (CAD) is the major cause of left ventricular (LV) dysfunction and CHF (10). In this regard, traditional risk factors for CAD as well as CRP are predictors of CHF. Indeed, in the Health ABC (Health, Aging, and Body Composition) study, among all major cardiovascular events, CRP was most strongly associated with future CHF (11).

Because CAD is regional, it is intuitive to expect that the progressive LV dysfunctional process that underlies CHF would commence as a regional process that eventually results in global dysfunction and failure. In this regard, although most studies relating inflammatory markers to the development of CAD used clinical events as end points, none have yet examined the relationship between systemic markers of inflammation and regional LV dysfunction in asymptomatic individuals.

The goal of this study was to investigate the association between CRP and the presence and extent of regional LV dysfunction in asymptomatic participants of the MESA (Multi-Ethnic Study of Atherosclerosis) trial. Our hypothesis was that higher levels of CRP would be related to regional LV dysfunction involving 1 or more coronary territories independently of traditional risk factors.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 Appendix
 References
 
The MESA trial is a prospective study designed to evaluate mechanisms underlying the development and progression of subclinical cardiovascular disease in asymptomatic individuals (12). There were 6,814 men and women, 45 to 85 years of age, from 4 ethnicities (non-Hispanic white, African American, Hispanic, and Chinese) enrolled at 6 field centers (Winston Salem, North Carolina; New York, New York; Baltimore, Maryland; Minneapolis, Minnesota; Chicago, Illinois; and Los Angeles, California). At entry, all participants underwent extensive evaluation including clinical history, physical examination, and laboratory tests including fasting glucose, lipid panel, and CRP. The MESA protocol was approved by the institutional review boards in all participating centers. Informed consent was obtained from all study participants.

Tagged MRI studies.   In an ancillary study of MESA, 1,184 participants randomly selected underwent tagged magnetic resonance imaging (MRI) studies at enrollment (from September 2001 to September 2002) in 6 centers. Images were acquired by whole-body scanners (1.5 CVi, General Electric Medical Systems, Waukesha, Wisconsin, and Sonata/Symphony Siemens Medical Solutions, Erlangen, Germany) using electrocardiograph-triggered segmented k-space fast spoiled gradient-echo pulse sequence during breath holds. After completing the standard protocol, 3 tagged short-axis slices (base to apex) were obtained. Parallel striped tags were prescribed in 2 orthogonal orientations (0° and 90°) using electrocardiograph-triggered fast gradient echo sequence with spatial modulation of magnetization.

Parameters for tagged images were: field of view 40 cm; slice thickness 7 to 8 mm; repetition time 6 ms; echo time 3.0 ms; flip angle 10° to 12°; phase encoding views 128 with 6 phase encoding views per segment; temporal resolution 40 ms; tag spacing 7 mm.

The LV mass was determined for each participant using dedicated commercially available software (MASS, version 4.2, Medis, Leiden, the Netherlands) at end diastole.

Strain analysis.   Short-axis tagged slices were analyzed using HARP (harmonic phase). The HARP program (Diagnosoft, Palo Alto, California) enables a fast determination of myocardial strain (13–15). In the present study, peak systolic midwall circumferential strain (Ecc) was determined in 12 segments in 3 slices. By convention, systolic Ecc is normally negative because of circumferential shortening, and reduced (absolute) Ecc values reflect decreased regional function (for example, Ecc = –12% reflects lower regional function when compared with Ecc = –18%). Regional strains were analyzed according to coronary perfusion areas (left anterior descending artery [LAD], left circumflex artery [LCX], and right coronary artery [RCA] territories). Assignment to coronary territories was done according to published standards (16). Peak global systolic strain was defined as the peak midwall Ecc averaged across all midwall segments.

Risk factors and CRP concentrations.   Hypertension was defined as diastolic blood pressure ≥90 mm Hg, systolic blood pressure ≥140 mm Hg, or receiving treatment for hypertension. High-normal diastolic blood pressure was defined as <90 and ≥85 mm Hg. Dyslipidemia was defined as total cholesterol ≥240 mg/dl, low-density lipoprotein cholesterol ≥160 mg/dl, triglycerides ≥150 mg/dl, high-density lipoprotein cholesterol <45 mg/dl, or receiving treatment for hyperlipidemia. Diabetic individuals were defined as either having fasting plasma glucose ≥126 mg/dl or receiving treatment for diabetes. Impaired fasting glucose was defined as glucose ≥100 and <126 mg/dl. Smoking status was defined as current smoking, former smoking, or never smoked.

C-reactive protein was measured using the BNII nephelometer (N High-Sensitivity CRP; Dade Behring, Deerfield, Illinois). Analytical intra-assay coefficients of variation (CVs) range from 2.3% to 4.4%, and interassay CVs range from 2.1% to 5.7%.

Statistical analysis.   The distribution of CRP was skewed; therefore, log-transformation was performed. Data for CRP are presented as median and interquartile range (IQR). All analyses were done using STATA-8 software (Stata Corp., College Station, Texas). The CRP levels in different subgroups were compared using the Mann-Whitney U and Kruskal-Wallis tests.

Linear regression was used to study the relationship between log-CRP and regional Ecc. To test whether the relationship between regional LV function and CRP differed by gender, age, ethnicity, or central obesity indexed by waist circumference, interaction terms between CRP and these factors were included in the initial multivariable regression models. Only the gender x log-CRP interaction was significant in most of the regions (p values for interactions were 0.1, 0.07, 0.03, and 0.04 for Ecc in the LAD, LCX, RCA, and peak global Ecc, respectively). Therefore, men and women were analyzed separately.

Multivariable linear regression was used to study the independence of the association of log-CRP with regional Ecc. Variables included as potential confounders were age, ethnicity, waist circumference, hypertension, total cholesterol, treatment for hypertension or high cholesterol, diabetes mellitus, and smoking status. In women, hormone replacement therapy use was also included (current use vs. former and never use). Regression was performed in 3 steps. Model I (demographic parameters) included age, ethnicity, and waist circumference. Model II (risk factors): history of hypertension, antihypertensive medication, cholesterol, antihyperlipidemic medication, smoking status, and history of diabetes mellitus in addition to the variables included in Model I. In women, adjustment for hormone replacement therapy status (current users vs. nonusers) was added. Model III included demographic parameters (I), risk factors (II), and LV mass or coronary artery calcium scores in the corresponding arteries (e.g., coronary artery calcium scores in the LAD for Ecc LAD). Statistical significance was defined as p < 0.05.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 Appendix
 References
 
Risk factor profiles of the study participants are shown in Table 1. A total of 1,184 individuals underwent tagged MRI, of whom there were 1,164 (98.3%) participants with available CRP data. Their mean age was 66.4 ± 10 years. Compared with the overall MESA trial cohort (total 6,814 participants), the studied subgroup included a higher percentage of men (54% vs. 47%, p < 0.001), a greater number of Caucasians, and a smaller number of Hispanic individuals (p < 0.001 for both ethnic groups). However, the distributions of risk factors and CRP concentrations did not differ from the overall MESA trial cohort. Men had a higher diastolic blood pressure and LV mass compared with women, and were more likely to be current or former smokers. Women had a higher body mass index and higher cholesterol levels (total, low-density lipoprotein, and high-density lipoprotein cholesterol) than men.


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  		Table 1. Risk Factor Profile of the Study Participants
 
CRP and participant characteristics.   Median CRP concentrations in men were 1.3 mg/l (IQR 0.7 to 3.0 mg/l), and in women 2.6 mg/l (IQR 1.2 to 5.7 mg/l, p < 0.001). Among women but not men, CRP was significantly lower among those receiving lipid-lowering therapy compared with nonusers (2.1 mg/l [IQR 0.6 to 3.0 mg/l] vs. 2.7 mg/l [IQR 1.3 to 5.9 mg/l], p = 0.02). A total of 27% of the women included in the cohort were current users of hormone replacement therapy. Women who were currently using hormone replacement therapy had significantly higher CRP levels compared with former or never-treated women (3.5 mg/l [IQR 1.8 to 6.7 mg/l] vs. 2.3 mg/l [IQR 1.1 to 4.9 mg/l], p = 0.0004). In both genders, current cigarette smokers had higher CRP levels than former smokers or persons who had never smoked (p = 0.001).

Finally, there was a positive relationship between LV mass and log-CRP in women (regression coefficient 4.5 g LV mass per 1 unit higher log-CRP [mg/l], 95% confidence interval [CI] 2.4 to 6.5, p < 0.001) and in men (regression coefficient 5.0 g LV mass per 1 unit higher log-CRP [mg/l], 95% CI 2.0 to 8.0, p = 0.001). This relationship remained significant after multivariate adjustment for demographic characteristics and risk factors.

Relationships between log-CRP and regional LV function.   Because of a significant gender interaction, results are shown separately for men and women. The unadjusted associations of CRP and regional LV function for men and women are shown in Figure 1. In addition, these relationships are shown as regression coefficients in Table 2. A positive regression coefficient indicates an association between higher log-CRP and lower absolute Ecc values, i.e., reduced regional LV function. Higher log-CRP was associated with lower regional LV function in all regions in men but not in women (Fig. 1, Table 2).


Figure 1
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  		Figure 1 Peak Regional Systolic Ecc (%) by CRP Quartiles (mg/l) in Men and Women

(A) Mean + SE error bars of peak systolic circumferential strain (Ecc) in the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) regions are shown. Open bars, dotted bars, ruled bars, and solid bars indicate 1st, 2nd, 3rd, and 4th quartiles of C-reactive protein (CRP) levels, respectively. (B) Simple linear regression was used to determine the trend. The p values indicate significance levels. By convention, systolic Ecc is normally negative because of circumferential shortening. Therefore, lower (absolute) values of Ecc reflect decreased regional function.

 

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  		Table 2. Relationship Between Regional Ecc and Log-CRP in Men and Women
 
In men, after adjustment for age, ethnicity, and traditional risk factors, the relationship between log-CRP and lower regional LV function was attenuated slightly for different regions (Table 3, models I and II). Similar results were seen when waist circumference was substituted by body mass index in the regression model. However, after further adjustment for LV mass, the relationship between log-CRP and Ecc weakened and remained statistically significant only in the LAD territory (Table 3, model III). In contrast, the results were not markedly changed after adjusting for coronary calcium scores in the corresponding regions (data not shown).


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  		Table 3. Relationship Between Regional Ecc and Log-CRP in Men and in Women After Adjustment for Demographic Parameters; Demographic Parameters and Risk Factors; and Demographic Parameters, Risk Factors, and LV Mass
 
In women, in addition to the other covariates, hormone replacement therapy use was added to the regression model. However, no associations between log-CRP and regional Ecc values were observed (Table 3). Results remained unchanged after including LV mass in the regression model.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Appendix
 References
 
The main finding of this study is that higher CRP concentration is related to lower regional LV function determined by Ecc in men, but not in women without evident heart failure or CAD in the MESA trial. This association was only modestly attenuated with adjustment for demographic parameters and risk factors. Additional adjustment for LV mass measured by MRI weakened this relationship.

Inflammatory markers including CRP are associated with an increased risk for cardiovascular morbidity and mortality in asymptomatic men and women, and in patients with acute coronary syndromes (1,4–6,8,17,18). Furthermore, in the Health ABC study, among major cardiovascular events, CRP was most closely correlated with risk of future CHF (11). Our findings document the association between CRP and LV dysfunction among subjects without clinical heart failure or coronary disease. In contrast to our study, gender interactions were not observed in previous studies of clinical outcomes.

We hypothesize that the presence of subclinical atherosclerosis, endothelial dysfunction, and LV hypertrophy might underlie the association between CRP and regional LV dysfunction. These mechanisms are probably not mutually exclusive, and each may contribute substantially to the relationship between CRP and regional LV dysfunction.

Inflammation plays an important role in the development and progression of atherosclerosis. In the early stages of atherogenesis, local inflammatory stimuli including oxidized low-density lipoprotein lead to cytokine production (1,2,19). These cytokines in turn induce endothelial adhesion and migration of monocytes into the lesion area, producing early atherosclerotic lesions. The CRP seems to play a role in this process by facilitating the activation of inflammatory cells and enhancing cytokine production. Furthermore, the inflammatory process is associated with plaque weakening, rupture, and thrombus formation (1–4). Thus, it is logical to think that the relationship between CRP and regional LV dysfunction may be related to the association of CRP with these inflammatory processes known to promote local atherosclerosis. In this regard, it is important to mention that the relationship between CRP and regional LV function was not modulated by coronary calcium score.

This process may or not be associated with small regions of myocardial infarction or scar tissue, even in the absence of epicardial CAD, possibly because of local thrombosis or embolism. These areas can be detected using delayed contrast hyperenhancement (20,21). Indeed, scars indicative of unrecognized myocardial infarctions have been detected by delayed hyperenhancement in a considerable number (20%) of elderly individuals participating in a community-based study in Sweden (22). Unfortunately, this technique has not been used in the MESA trial, and this plausible explanation could not be studied.

Additionally, CRP may be related to incipient myocardial dysfunction through its well-established association with endothelial dysfunction. The CRP may directly alter endothelial function by reducing local production of nitric oxide, or indirectly by increasing levels of reactive oxygen species, thus reducing endothelial induced vasodilation (2,23–26).

A third possible mechanism pertains to the association between CRP and LV mass. We observed a significant association between CRP and LV mass. This relationship has been shown previously in patients with hypertension and renal failure (27,28). It has been previously shown that concentric LV hypertrophy is related to decreased myocardial function (29–32). In the current study, after adjustment for LV mass, the association of higher CRP concentrations and reduced myocardial strain (Ecc) was attenuated, suggesting that the relationship between CRP and regional LV function might be linked to the association between CRP and LV mass.

An unexpected finding of this study was the gender difference in the association of CRP and regional LV dysfunction. In men but not women, higher CRP was significantly associated with regional LV dysfunction. Substantial gender differences in the presence of risk factors, shown in Table 1, may partly explain this difference, but the gender difference remained after controlling for those variables. It is theoretically possible, but unlikely, that women with elevated CRP and reduced regional LV function developed symptoms earlier than men, and were therefore excluded from the MESA trial. A third and more plausible explanation is that gender-specific differences in the association between CRP and regional LV function are modulated through gender-related differences in LV mass. Previous studies have described gender-specific differences in LV remodeling and the development of LV dysfunction and CHF (33–38). The association between CRP levels and LV mass and the gender-specific differences in the CRP/regional dysfunction relationship fit this finding of gender differences in the cardiac remodeling process. In contrast, the Cardiovascular Health Study and the Health ABC investigators reported a significant association between higher CRP levels and the incidence of CHF in both genders (11,39). These discrepancies suggest that in older individuals, gender-related differences in the CRP LV dysfunction relationships might disappear as women catch up with men in the degree of atherosclerosis and inflammation. However, this possibility should be further explored.

Finally, the finding of regional differences in the association between CRP and Ecc is noteworthy. The relationship between CRP and regional function in the LAD and RCA seems to be stronger than in the LCX territory. This may be attributable to statistical power, because the variation in the LCX has been found to be slightly greater than in other regions, probably because of a decreased signal-to-noise ratio in the posterior wall. In addition, in a different study, we have shown a greater coronary artery calcium score and a higher extent of significant CAD in the LAD region compared with other regions (unpublished data). Further studies should be performed to clarify these findings.

Methodological considerations.   Our study includes 1,164 subjects, making this one of the largest MRI studies of quantitative regional myocardial function that we are aware of. The HARP software is a robust analytical tool that allows for efficient and reliable determinations of regional LV function by MRI tagging (13,15). Aside from its size, the MESA trial entails a heterogeneous population from different ethnicities.

On the other hand, the cross-sectional study design impairs the ability to establish the temporal nature of the association. Participants were selected to participate in the MESA trial through a population-based process designed to minimize biases typically associated with studies of volunteers. However, they may not represent a random sample of the population. In addition, excluding symptomatic patients could have affected the results of this study, as discussed earlier.

Temporal resolution is an important determinant of the quality of strain measurement. In the present study, the mean temporal resolution was 40 ms. This temporal resolution is lower than the resolution that can be achieved by echocardiography (i.e., 7 to 10 ms). However, MRI is not limited by acoustic windows and scanning angles and can provide a detailed strain map of the entire myocardium. In addition, a previous study has shown a high correlation between strain values measured by echocardiography and tagged MRI (40).

Finally, except for a small study that measured only for regional myocardial perfusion, contrast-enhanced MR images were not acquired routinely in the MESA trial. Therefore, we could not address the possibility that areas with reduced regional function may indeed reflect silent infracted regions manifesting as a delayed enhancement pattern.

In conclusion, we document an inverse relationship between CRP levels and regional LV function in men. This association was seen in all regions and did not change after adjusting for age, traditional risk factors, or medical treatment. In contrast, such a relationship was not evident in women. The association between CRP and LV function was attenuated by adjustment for LV mass. Further studies are warranted to elucidate the interrelationship between inflammation, LV mass, and gender in the development of LV dysfunction and heart failure.


   Appendix
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
References
 
For a list of multivariate regression models, please see the online version of this article.


   Acknowledgments
 
The authors thank the participants of the MESA trial and the entire community of MESA investigators and staff for their support and valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.


   Footnotes
 
This study was supported by the National Heart, Lung, and Blood Institute grant (RO1-HL66075-01) and the Multi-Ethnic Study of Atherosclerosis study contracts (NO1-HC-95162, NO1-HC-95168, and NO1-HC-95169). Dr. Lima is also supported by the Johns Hopkins Reynolds Center, and Dr. Rosen is supported by the Israeli Heart Society and the Organization of American Physician Fellowship for Medicine in Israel. Peter Libby, MD, acted as Guest Editor for this article.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 Appendix
 References
 

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H. Bahrami, D. A. Bluemke, R. Kronmal, A. G. Bertoni, D. M. Lloyd-Jones, E. Shahar, M. Szklo, and J. A.C. Lima
Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study.
J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1775 - 1783.
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