Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2011 Sep 1.
Published in final edited form as: Am Heart J. 2010 Sep;160(3):479–486. doi: 10.1016/j.ahj.2010.06.001

Fibrinogen and Left Ventricular Myocardial Systolic Function: The Multi-Ethnic Study of Atherosclerosis

Raymond T Yan a, Veronica Fernandes b, Andrew T Yan c, Mary Cushman d, Alban Redheuil a, Russell Tracy d, Jens Vogel-Claussen e, Hossein Bahrami f, Khurram Nasir g, David A Bluemke h, Joao AC Lima a
PMCID: PMC2937158  NIHMSID: NIHMS230496  PMID: 20826256

Abstract

Background

Increasing evidence suggests that elevated plasma fibrinogen is associated with incident heart failure. However, the underlying pathophysiological mechanisms have not been well elucidated.

Methods

We examined the relationship between plasma fibrinogen level and peak systolic mid-wall circumferential strain(Ecc) at the base, mid-cavity and apex of the left ventricle measured by magnetic resonance imaging myocardial tagging in 1,096 participants without clinical cardiovascular disease enrolled in the Multi-Ethnic Study of Atherosclerosis(MESA).

Results

After adjustment for demographics, established risk factors and body-mass-index, elevated fibrinogen was independently associated with reductions in absolute Ecc indicative of impaired systolic function in all regions(all P=0.015). The relationships were consistently significant upon further adjustment for measures of atherosclerosis(all P≤0.024), and were modestly attenuated with regional heterogeneity after additional adjustment for other inflammatory biomarker and N-terminal pro-brain-natriuretic peptide. In this fully-adjusted model, every one-standard deviation(74mg/dL) increment in plasma fibrinogen was independently associated with a reduction in left ventricular absolute Ecc of 0.29%(95%CI=0.03%–0.59%, P=0.048) at the base, 0.22%(95%CI=0.006%–0.43%, P=0.044) at mid-cavity, 0.20%(95%CI=−0.035%–0.43%, P=0.097) at the apex, and 0.24%(95%CI=0.05–0.43, P=0.015) overall.

Conclusions

Among asymptomatic individuals without clinical cardiovascular disease, elevated fibrinogen is independently associated with impaired myocardial systolic function. These findings support roles of inflammation, procoagulation and hyperviscosity underlying hyperfibrinogenemia in the pathogenesis of incipient myocardial dysfunction.

Keywords: epidemiology, heart failure, myocardial function, fibrinogen, hyperviscosity, hypercoagulability, magnetic resonance imaging

Fibrinogen is the major circulating coagulation protein by mass and an important determinant of thrombogenicity and blood viscosity.1,2 As a non-specific acute phase reactant, fibrinogen is also a downstream component of the inflammatory cascade increasingly implicated in the pathogenesis of atherosclerosis, myocardial injury and heart failure.3,4 Many epidemiological studies and several meta-analyses have reported that elevated plasma fibrinogen level is associated with coronary artery disease, stroke and other adverse cardiovascular events.5–10 More recently, elevated fibrinogen has also been demonstrated to be associated with incident heart failure.11,12 However, the underlying pathophysiological mechanisms have not been well elucidated.

Cardiac magnetic resonance imaging(MRI) is considered the reference standard for assessment of left ventricular(LV) structure and function.13 In particular, magnetic resonance myocardial tagging can accurately measure subtle alterations in regional myocardial function, which may afford unique pathophysiological insights.13,14 Accordingly, this study tested the hypothesis that increased plasma fibrinogen, a multifunctional glycoprotein of intrinsic prothrombotic, inflammatory and rheological properties, is associated with subclinical impairment in regional systolic myocardial function as measured by MRI tagging, among a multi-ethnic asymptomatic population without known cardiovascular disease. Detailed characterization of such an association, in consideration with biomarkers related to different pathogenetic pathways, may provide novel insights into the complex mechanisms underlying incipient myocardial dysfunction and the increased risk of heart failure observed with hyperfibrinogenemia.

Methods

Study design and population

The Multi-Ethnic Study of Atherosclerosis(MESA) is a multicenter, prospective cohort study designed to examine the prevalence, correlates and progression of subclinical cardiovascular disease. Details of its rationale and methodology have been previously published.15 Briefly, the MESA cohort comprised of 6814 men and women of four self-reported ethnicities(African-American, Caucasian, Chinese and Hispanic) between 45–85 years of age without known cardiovascular disease at study entry. The cohort represents a population-based sample recruited from six communities(Baltimore County, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; Northern Manhattan and the Bronx, New York; and St. Paul, Minnesota) between 2000–2002. At baseline, all participants underwent detailed evaluation consisting of clinical questionnaires, physical examination and laboratory tests, which included serum creatinine and lipoprotein profile. In addition, novel biomarkers of reported associations with cardiovascular diseases including homocysteine, C-reactive protein(CRP), N-terminal pro-brain-natriuretic peptide(NT-proBNP) and fibrinogen were collected and analyzed centrally at a core laboratory(University of Vermont, Burlington).

Baseline clinical parameters, biomarkers and subclinical atherosclerosis imaging

At the baseline MESA enrollment examination, designated research personnel collected pre-specified clinical information on risk factors including smoking status(never/former/current) and amount(pack-years), hypertension, diabetes and medication use. Hypertension was defined by the recommendations of the seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Diabetes was diagnosed as per the American Diabetes Association criteria or the use of anti-hyperglycemic therapy.16 Physical examination, including measurements of blood pressure and anthropometric indices, was conducted in accordance with standardized protocol.

Baseline serum fibrinogen was quantitatively measured by immunoprecipitation of fibrinogen antigen using the BNII nephelometer(N-Antiserum to Human Fibrinogen; Dade Behring Inc., Deerfield, IL). Its intra- and inter-assay coefficients of variation were 2.7% and 2.6%, respectively. CRP was quantified by a high-sensitivity assay(N-High-Sensitivity CRP; Dade Behring, Deerfield, IL; inter-assay coefficient of variation:2.1–5.7%).

To evaluate the anatomic extent of subclinical atherosclerosis, the maximal intimal-medial thickness(IMT) of the common carotid arteries(mean of maximal IMT across the near and far walls of the left and right common carotid arteries 10mm proximal to the bulb) was measured by high-resolution B-mode ultrasonography.17,18 Coronary artery calcification as defined by the Agatston score was also determined on computed tomography of the chest, obtained using either an electron-beam or multi-detector scanner with a prospective ECG-triggered acquisition protocol.19 Details on methodology, standardization and reproducibility of baseline measurements of these validated biomarkers of subclinical atherosclerosis have been previously published.17–19

Magnetic resonance imaging of the left ventricle and myocardial tagging

In a MESA ancillary study, a subgroup of 1,178 participants from all six field centers additionally underwent myocardial tagging as part of their baseline(September/2001 to September/2002) MRI examination.20 All studies were performed using commercially available 1.5T whole-body MR scanners: Signa-LX/CVi (GE Medical Systems, Waukesha, WI) or Symphony/Sonata(Siemens Medical Systems, Erlangen, Germany). After acquisition of standard scout, two- and four- chambers and short-axis untagged cine images, tagged images were acquired using segmented k-space, electrocardiogram-triggered fast spoiled gradient echo pulse sequence(SPGR/FLASH) with short echo time and without gradient motion refocusing during 12–18 seconds of breath-hold at resting lung volume. Three tagged short-axis slices between the mitral valve plane and the apex of the LV, namely, the basal, mid-ventricular and apical slices, were imaged with parallel striped tags prescribed separately in two orthogonal orientations (0° and 90°) using spatial modulation of magnetization. Parameters for tagged images: field-of-view:40cm; slice thickness:8–10mm; tag spacing:7mm; matrix size:256x(96–140) with 4–9 phase encoding views/segment; repetition-time:3.5–7.2ms; echo-time:2.0–4.2ms; flip-angle:12°; a resulting yield of 9–27 phases/cardiac cycle and temporal resolution of 36±12ms.20

Image analysis and myocardial strain determination by harmonic phase imaging (HARP)

LV structural parameters(end-diastolic and end-systolic volumes, end-diastolic mass) and ejection fraction(measure of global systolic function) were determined from the short-axis cine images using standard commercially available software(MASS 4.2, MEDIS, Leiden, The Netherlands). Details on image analysis, data quality control, calculations and reproducibility of these measurements have been detailed elsewhere.20,21

The three short-axis tagged images were analyzed by harmonic phase imaging (HARPv2.0, DiagnoSoft Inc, Palo Alto, CA) -- a validated technique for determination of regional myocardial strain.22,23 To evaluate LV regional myocardial function, the mid-wall peak systolic circumferential strain(Ecc) at the base, mid-ventricle and apex(average of the septal, anterior, lateral and posterior segments within the respective tagged short-axis slice) of the LV were determined. Global-Ecc was computed as the average of basal, mid-ventricular and apical Ecc. All strain analyses were performed centrally at the MRI core laboratory(Johns Hopkins University). Intra-observer and inter-observer agreement for regional Ecc determined by this technique(intra-class correlation coefficients of 0.84 and 0.81, respectively) was previously reported.24 By convention, Ecc is negative as it designates systolic circumferential shortening. As such, a more negative value denotes greater systolic function.

Statistical analysis

Continuous variables with normal distributions are presented as mean±standard deviation (SD)(or median and inter-quartile range if otherwise), and categorical variables as frequencies and percentages. Logarithmic transformation was applied to variables with skewed distributions before entry into multivariable regression models. The associations of fibrinogen with clinical and other laboratory parameters, measures of subclinical atherosclerosis as well as regional LV functional parameters were examined by Kendall tau-b or chi-square for trend tests as appropriate across the study cohort stratified by fibrinogen tertiles.

Multivariable linear regression models were constructed in a hierarchical manner to examine the independent association between fibrinogen and (a) LV structural parameters(volumes and mass), (b) global LV systolic function(ejection fraction), and (c) each of the regional functional parameters(basal, mid-ventricular and apical Ecc) and global-Ecc. In the basic model(models-I), adjustment was made for demographics including age, gender and ethnicity. Heterogeneity across gender, ethnicity and sites was tested by introducing corresponding interaction terms with fibrinogen into the basic models. As no significant interaction was observed for all LV parameters(all P>0.15), the entire study cohort was analyzed without stratification. In model-II, additional adjustment was made for established risk factors including hypertension, diabetes, cigarette smoking, systolic blood pressure, low-density lipoprotein, total cholesterol, body-mass-index, and treatment with lipid-modifying, anti-hypertensive and anti-hyperglycemic therapies. Selection of these covariates was guided by knowledge of their association with fibrinogen and myocardial function as observed in this and prior studies.25 To further elucidate the pathogenetic link between fibrinogen and myocardial dysfunction, additional models were constructed with stepwise inclusion of plausible pathogenetic biomarkers. As atherosclerosis is implicated to mediate in part the effects of fibrinogen,26,27 carotid IMT and coronary artery calcification(Agatston score) were further introduced as additional covariates in model-III. Finally, biomarkers of known association with myocardial dysfunction including serum creatinine, homocysteine and CRP, as well as NT-proBNP as a surrogate biomarker of ventricular wall stress, were added stepwise into a set of more fully adjusted models(model IV-a to IV-d).21,28,29 To examine the extent of potential confounding or effect mediation by inflammation, the respective independent associations of myocardial function with fibrinogen and CRP, with and without reciprocal adjustment for each other, were determined.

Statistical analyses were performed using SPSS 15.0(SPSS Inc, Chicago, IL). Statistical significance was inferred at 2-sided p-value<0.05.

This study was supported by the National Heart, Lung, and Blood Institute grant. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Results

Among the 1,178 MESA tagging ancillary study cohort, 1096(93%) had analyzable tagging data with fibrinogen measurement and constituted the present study population.

The mean and standard deviation of plasma fibrinogen level in the study population was 346±74 mg/dL. Table-1 shows the baseline characteristics of this cohort stratified by fibrinogen tertiles. Participants with higher fibrinogen levels were older, more likely to be female and having hypertension(all P<0.001 for trend). In addition, they had higher body-mass-index and waist circumference, blood pressure, low-density lipoprotein and total cholesterol, greater anatomic extent of subclinical atherosclerosis with higher carotid IMT and Agatston score, as well as more elevated levels of homocysteine, CRP and NT-proBNP (all P<0.05 for trend).

Table 1.

Baseline characteristics of study population according to plasma fibrinogen tertiles

Plasma fibrinogen levels
 P for trend
First Tertile Second Tertile Third Tertile
Age, years 64±10 66±10 67±9 <0.001
Male,% 67.3 53.6 40.9 <0.001
Ethnicity,% <0.001
African American 25.7 25.8 32.3
Asian 11.1 8.2 8.3
Caucasian 38.1 33.5 27.1
Hispanic 25.1 32.5 32.3
Smoking status,% 0.62
Never 50.8 50.7 49.9
Former 39.4 35.2 38.2
Current 9.8 14.1 11.9
Smoking, pack-year 10±21 10±18 13±22 0.46
Diabetes mellitus,% 12.7 15.7 14.9 0.18
Hypertension,% 41.9 45.1 58.6 <0.001
Anti-hypertensive medication, % 38.4 36.0 48.9 0.004
Lipid-modifying medication, % 15.1 19.0 25.1 <0.001
Body mass index, kg/m2 26.7±4.4 27.9±4.4 28.8±4.9 <0.001
Waist circumference, cm 94±13 98±14 103±15 <0.001
Systolic blood pressure, mmHg 126±20 128±21 131±21 0.001
Diastolic blood pressure, mmHg 73±10 71±10 72±11 0.034
Fasting glucose, mg/dL 98±27 101±26 100±27 0.10
Total cholesterol, mg/dL 189±33 196±34 197±37 0.008
LDL-cholesterol, mg/dL 113±29 119±30 121±31 0.003
HDL-cholesterol, mg/dL 51±15 51±16 51±13 0.67
Triglycerides, mg/dL 128±70 133±76 128±70 0.72
Total cholesterol: HDL ratio 3.97±1.15 4.15±1.29 4.11±1.21 0.29
Serum creatinine, mg/dL 1.0±02 1.0±0.2 1.0±0.5 0.50
C-reactive protein (CRP), mg/ L* 0.90(0.50,1.90) 1.86(0.93,3.56) 3.44(1.81,6.65) <0.001
Homocysteine(umol/L)* 9.0(7.7,10.6) 9.1(7.6,11.0) 10.3(7.8,11.6) 0.030
N-terminal pro-brain-natriuretic-peptide(ρg/ml)* 54(21,108) 68(28,139) 70(34,142) 0.001
Carotid intimal-medial thickness, mm* 0.82(0.71,0.93) 0.85(0.75,0.98) 0.87(0.77,1.01) <0.001
Agatston coronary artery calcium score* 4(0,125) 11(0,154) 21(0,197) 0.007
Open in a new tab

Fibrinogen(mg/dL) tertiles: first, 155–312; second, 313–370; third, 371–945.

Continuous variables are presented as mean ± standard deviation unless otherwise stated.

*

Variables with skewed distributions and presented as median(inter-quartile range).

The regional and global systolic circumferential strain measurements across fibrinogen tertiles are depicted in Table-2. Higher plasma fibrinogen level was associated with reduced regional myocardial systolic function(less negative Ecc) consistently at the base, mid-ventricle and apex of the LV. Fibrinogen was also correlated positively with global Ecc, representing an inverse relationship between fibrinogen and overall LV systolic circumferential strain.

Table 2.

Regional and global peak systolic circumferential strain by plasma fibrinogen tertiles

Plasma fibrinogen
 P-value for trend
First Tertile Second Tertile Third Tertile
Basal Ecc −15.37±0.18 −14.99±0.18 −14.48±0.19 0.001
Mid-ventricular Ecc −17.40±0.14 −17.11±0.14 −16.90±0.15 0.011
Apical Ecc −18.02±0.15 −17.68±0.16 −17.54±0.15 0.037
Global Ecc −16.97±0.12 −16.58±0.13 −16.33±0.13 0.001
Open in a new tab

Fibrinogen(mg/dL) tertiles: first, 155–312; second, 313–370; third, 371–945.

Ecc=peak systolic circumferential strain. As Ecc designates systolic circumferential shortening and is negative by convention, less negative values indicate worse systolic function.

Data presented as mean±standard error of mean.

The results of hierarchical multivariable linear regression analyses demonstrating independent associations between fibrinogen and regional myocardial function are summarized in Table-3. For all the LV parameters examined, their relationships with fibrinogen were not heterogeneous across gender, ethnicities or sites (p-value for interaction all >0.15). After adjustment for demographic characteristics (model-I), higher plasma fibrinogen was independently associated with reduced regional Ecc consistently at the base, mid-ventricle and apex of the LV, as well as an overall reduction in LV global-Ecc. Introducing traditional cardiovascular risk factors and use of risk-factor modifying medications into the models(models-II) did not alter the magnitude or significance of the association between fibrinogen and each of these measures of myocardial function. In addition, all these associations remained significant upon further adjustment for subclinical atherosclerosis(models-III). Uniformly across these hierarchical models(models I, II and III), the magnitude of reduction in regional myocardial function independently associated with any given increment in plasma fibrinogen was largest at the base and smallest in the mid-ventricle(Table-3).

Table 3.

Independent association between plasma fibrinogen level and regional and global left ventricular systolic circumferential strain

Basal-Ecc Mid-ventricular-Ecc Apical-Ecc Global-Ecc
Regression coefficient for fibrinogen (95%CI)* P-value Regression coefficient for fibrinogen (95%CI)* P-value Regression coefficient for fibrinogen (95%CI)* P-value Regression coefficient for fibrinogen (95%CI)* P-value
Model I 0.33(0.11–0.55) 0.003 0.25(0.09–0.42) 0.002 0.26(0.08–0.44) 0.004 0.29(0.14–0.44) <0.001
Model II 0.33(0.10–0.56) 0.005 0.21(0.04–0.38) 0.015 0.26(0.08–0.45) 0.005 0.27(0.11–0.42) 0.001
Model III 0.33(0.10–0.56) 0.005 0.20(0.03–0.37) 0.022 0.27(0.08–0.45) 0.005 0.26(0.11–0.42) 0.001
Model IV-a 0.34(0.11–0.57) 0.004 0.20(0.03–0.38) 0.020 0.27(0.08–0.46) 0.005 0.27(0.11–0.43) 0.001
Model IV-b 0.33(0.10–0.56) 0.005 0.20(0.03–0.37) 0.024 0.25(0.06–0.44) 0.009 0.26(0.10–0.42) 0.001
Model IV-c 0.31(0.04–0.57) 0.022 0.21(0.01–0.40) 0.038 0.18(−0.030−0.40) 0.092 0.22(0.05–0.40) 0.014
Model IV-d 0.29(0.03–0.59) 0.048 0.22(0.006–0.43) 0.044 0.20(−0.035–0.43) 0.097 0.24(0.05–0.43) 0.015
Open in a new tab

Ecc=peak systolic circumferential strain; 95%CI=95% confidence interval.

Models-I: adjustment for demographics -- age, gender, ethnicity.

Models-II: adjustment for demographics plus cardiovascular risk factors–hypertension, systolic blood pressure, anti-hypertensive medications, diabetes and use of anti-hyperglycemic therapy, smoking(pack-year), levels of low-density lipoprotein and total cholesterol, use of lipid-modifying medications, and body-mass-index(weight in kilogram divided by the square of height in meter).

Models-III: adjustment for demographics, cardiovascular risk factors plus measures of subclinical atherosclerosis–carotid intimal-medial thickness(IMT) and coronary artery calcification(Agatston score).

Models-IV a-d: adjustment for demographics, cardiovascular risk factors, measures of subclinical atherosclerosis plus biomarkers of reported association with myocardial dysfunction and/or incident cardiovascular events among asymptomatic populations – (a) serum creatinine, (b) serum creatinine and homocysteine, (c) serum creatinine, homocysteine and C-reactive protein, (d) serum creatinine, homocysteine, C-reactive protein and N-terminal-pro-brain-natriuretic peptide.

*

Regression coefficients represent the absolute change in Ecc (positive values denote reduction in systolic function) per one-standard deviation increment in plasma fibrinogen level(74mg/dL). As Ecc designates systolic circumferential shortening and is negative by convention, positive regression coefficients indicate worse systolic function with higher fibrinogen.

In this study cohort, fibrinogen is positively correlated with CRP(Kendall τ-b correlation coefficient=0.34, p<0.001). The set of more fully adjusted models with additional stepwise inclusion of biomarkers are summarized in Table-3(models IV-a to IV-d). Of note, the independent association between each myocardial functional parameter and fibrinogen was not modified by renal function and additionally homocysteine(models IV-a and IV-b, respectively). Upon adjustment for these biomarkers and all previously included covariates, higher CRP was independently associated with reduced global-LV Ecc(regression coefficient=0.38 per 1-unit log[CRP],95%CI=0.04–0.72, p=0.028), but not after additional adjustment for fibrinogen (regression coefficient=0.16 per 1-unit log[CRP],95%CI=−0.22–0.55, p=0.40). In contrast, beyond the same covariates including CRP(models IV-c), elevated fibrinogen remained independently associated with reductions in global and all regional Ecc, although all the associations were attenuated and by the largest degree at the apex, after adjustment for the inflammatory marker CRP. The association was consistent and remained unchanged upon further adjustment for NT-proBNP in the fully-adjusted model (model-IVd, Table-3).

To confirm the robustness of our findings, similar results were obtained in a series of sensitivity analyses using alternative anthropometric indices, substitution of creatinine for estimated glomerular filtration rate, and additional adjustment for LV mass or LV mass index, albuminuria as a marker of subclinical vascular disease. Furthermore, alcohol consumption, physical activity and educational status as known correlates of plasma fibrinogen level25 were not found to affect our findings(data not shown).

In contradistinction to regional myocardial systolic function measured by MR tagging, fibrinogen was not significantly associated with regional diastolic function(early and late diastolic circumferential strain), as well as global LV structural(end-diastolic and end-systolic volumes, LV end-diastolic mass) and functional(ejection fraction) parameters in any of the hierarchical(Models I–IV) models(data not shown).

Discussion

In this study of a multi-ethnic asymptomatic population without clinical cardiovascular disease, our principal finding is that higher plasma fibrinogen level was associated with lower regional myocardial systolic circumferential strain, consistently in all anatomical regions of the left ventricle, and independent of demographic characteristics and established cardiovascular risk factors. Importantly, the associations remained significant upon controlling further for surrogates of subclinical atherosclerosis, and were only modestly attenuated after additional adjustment for other inflammatory biomarker and NT-proBNP. These observations suggest additional fibrinogen-related pathophysiological mechanisms, beyond atherosclerosis, inflammation and ventricular filling hemodynamics, may contribute to myocardial dysfunction.

Fibrinogen has been evaluated in epidemiological studies for its cross-sectional relationships with risk factors and prospective associations with cardiovascular outcomes, which appear consistent and generalizable.5–7,9,10,25 In a meta-analysis of 18 prospective studies encompassing 4,018 cases of coronary heart disease, the relative risk for plasma fibrinogen level in the top versus lowest tertile was 1.8(95%CI=1.6–2.0).10 A more recent meta-analysis by the Fibrinogen Studies Collaboration suggested that elevated fibrinogen was associated with significant age- and gender-adjusted increased risk for incident coronary artery disease and stroke, albeit the associations were attenuated on further adjustment for established cardiovascular risk factors and CRP.9 Similar associations have also been extended to incident peripheral arterial diseases.30 In accordance with these clinical observations, fibrinogen is significantly correlated with the anatomic extent of atherosclerotic diseases, suggesting that fibrinogen may in part mediate the downstream effects of risk factors on atherosclerosis and ultimately atherothrombotic events.5,7,26,31

While the association of fibrinogen with subclinical and overt atherosclerotic disease has been well described, very little is known specifically for heart failure until recently, and no information yet exists for its preclinical manifestation.11,12 In the Swedish Malmő Preventive population-based study of 6071 middle-aged men without clinical cardiovascular disease, higher baseline fibrinogen was found independently predictive of heart failure without interim myocardial infarction.11 In the larger and more diverse MESA cohort, increased baseline fibrinogen conferred an increased risk for incident heart failure(adjusted hazards ratio=1.25, 95%CI=1.02–1.53 per 1-SD[74mg/dL] increment in fibrinogen) over a median of 4.0-years.12 Yet, elucidation of the pathophysiologic significance of fibrinogen in the development and progression of heart failure has not been undertaken in these seminal investigations. This present study corroborates these recent clinical observations by demonstrating significant continuous cross-sectional relationships between elevated fibrinogen and reduced regional myocardial systolic function, an increasingly recognized early subclinical manifestation of heart failure.32

Plausible pathophysiological mechanisms

Fibrinogen plays a vital role in various interrelated pathophysiological processes with inflammation and atherogenesis being most commonly invoked to explain its link with overt cardiovascular disease. Fibrinogen is a prominent acute-phase reactant, a ligand and up-regulator for intercellular adhesion molecules which enhance monocyte and leukocyte adhesions to endothelial cells.33 On binding to leukocyte integrin receptor, fibrinogen facilitates chemotaxis vital to the inflammatory response.34 Fibrinogen also stimulates mononuclear cells expression of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, which induce nitric oxide-mediated negative inotropic effects and cardiac myocyte apoptosis in experimental animal models.4,35,36 Upon binding to endothelial cells, fibrinogen also causes release of vasoactive mediators and modulates endothelial cell permeability and migration, in addition to promoting smooth muscle cell proliferation, foam cell and atherosclerotic plaque formation.37 The complex interplay of these and other processes by which fibrinogen can initiate and contribute to atherogenesis and inflammation as two intricately related pathogenetic mechanisms has been well described.1,3,38

Indeed, both subclinical atherosclerosis and inflammation have been shown to be related to incipient myocardial dysfunction and incident heart failure.4,29,39–42 Nevertheless, the precise pathophysiologic mechanisms by which fibrinogen may affect cardiac function remain incompletely defined. Fibrinogen is known to augment platelet reactivity, aggregation and degranulation in response to adenosine diphosphate, thereby promoting platelet-rich microthrombi formation.43 Furthermore, elevated plasma fibrinogen promotes the generation of more extensive and less deformable thrombi, while impairing fibrinolysis by interference with plasminogen-receptor binding.44 The results of platelet hyper-reactivity, hypercoagulability from enhanced thrombogenicity and impaired fibrinolysis, alone and synergistically in combination, predispose to microvascular thrombosis.38 As a high-molecular weight glycoprotein accounting for more than 50% of plasma and whole blood viscosity, increases in plasma and whole blood viscosity with elevated circulating fibrinogen may also lead to more endothelial shear-stress damage, impaired erythrocyte deformability and reduced microcirculatory blood flow, predisposing to microvascular hypoperfusion, myocardial stunning and recurrent occult ischemia-reperfusion injury.45

The persistent independent inverse relationship between fibrinogen and regional myocardial function beyond adjustment for biomarkers of subclinical atherosclerosis, inflammation and ventricular wall stress suggests that these postulated pathogenetic mechanisms, cross-talking at the level of fibrinogen and conceivably in part independent mechanistically of atherosclerosis and inflammation, may contribute to subclinical impairment of myocardial function independent of altered ventricular filling dynamics. The modest attenuation after adjustment for CRP underscores potential confounding, or possible mediation, of some effects of fibrinogen on myocardial function via inflammation.

Methodological considerations

To our best knowledge, the present study is the first to investigate the relationship between hemostatic biomarker and myocardial function in a large asymptomatic population. Although as previously described individuals with elevated fibrinogen levels had more adverse risk factor profile,25 adjustments for these potential confounders had a negligible impact on the association, lending credence to the notion that fibrinogen may exert downstream detrimental effects on myocardial function. In addition to complementing existing evidence for the pathogenic link between inflammation and the heart failure syndrome continuum,4,42 our results more importantly raise the novel hypothesis that other haemorrheological alterations related to fibrinogen, notably hypercoagulability and hyperviscosity, may play a role in the pathogenesis of subclinical myocardial systolic dysfunction.

Our finding that the association between fibrinogen and regional myocardial function was differentially weakened upon adjustment for the inflammatory marker CRP is noteworthy. While it was previously reported that the relationship between CRP and myocardial strain was weaker in the region of the left circumflex artery relative to that of the other coronary territories, this regional heterogeneity was unchanged after adjusting for coronary calcium score in the corresponding regions, suggesting that such regional differences is not attributable to underlying atherosclerotic burden.29 A possible explanation is that the weaker and greater attenuation of fibrinogen-myocardial function association by CRP at the apex may represent regional differences in relative myocardial susceptibility to inflammatory injury, as compared to hypercoagulability or hyperviscosity-related hypoperfusion, and shear-stress insults. The precise pathophysiologic mechanisms for this regional heterogeneity should be explored in future studies. Finally, our study also underscores discrepancies between intrinsic myocardial function measured by MR tagging and conventional index of global LV function such as ejection fraction — the latter may be insensitive to the earliest deterioration in intrinsic myocardial function and thus inferior for the purpose of probing subclinical disease pathophysiology.

Several study limitations should be noted. Because of non-random and thus possible selective enrollment in this tagging ancillary study, our study cohort was not a true population-based sample. Our cross-sectional analyses precluded inferences on temporality and causality of our observations. Although MRI tagging has inferior temporal resolution compared to echocardiography and other technical limitations, it is widely accepted as a valid and useful tool to assess myocardial mechanical function.22,24 Moreover, the natural history and long-term prognostic significance of regional LV systolic dysfunction associated with increased fibrinogen remain to be determined. In these regards, serial MRI and longitudinal clinical follow-up underway will shed light on these important issues. Nonetheless, the present study affords unique and novel pathophysiologic insights. The strengths of this study include the relatively large sample of diverse individuals from four ethnic groups, availability of comprehensive and standardized clinical data as well as biomarkers, use of reproducible and sensitive techniques for accurate measurements of plasma fibrinogen and myocardial function in blinded core laboratories with extensive experience.22,24

In conclusion, among a diverse asymptomatic population without clinical cardiovascular disease, there exists a significant independent inverse relationship between elevated plasma fibrinogen and impaired LV myocardial systolic function, which is only attenuated by further adjustment for other inflammatory biomarker. These findings underscore the notion of a complex interplay between inflammation, procoagulation and hyperviscosity underlying hyperfibrinogenemia in the pathogenesis of myocardial dysfunction. Future studies should examine causality which may have important implications on novel targets for early prevention of myocardial systolic dysfunction and heart failure.

Acknowledgments

We thank all the investigators, staff, and 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.

Funding/Support

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. Raymond Yan was supported by fellowship awards from the Canadian Institutes of Health Research and the Royal College of Physicians and Surgeons of Canada.

Footnotes

Disclosure: None.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

(Multi-Ethnic Study of Atherosclerosis:http://clinicaltrials.gov/ct/show/NCT00005487)

References

  • 1.Tracy RP. Thrombin, inflammation, and cardiovascular disease: an epidemiologic perspective. Chest. 2003;124:49S–57S. doi: 10.1378/chest.124.3_suppl.49s. [DOI] [PubMed] [Google Scholar]
  • 2.Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost. 2003;89:601–9. [PubMed] [Google Scholar]
  • 3.Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999;340:115–26. doi: 10.1056/NEJM199901143400207. [DOI] [PubMed] [Google Scholar]
  • 4.Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002;91:988–98. doi: 10.1161/01.res.0000043825.01705.1b. [DOI] [PubMed] [Google Scholar]
  • 5.Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–5. doi: 10.1056/NEJM198408233110804. [DOI] [PubMed] [Google Scholar]
  • 6.Stec JJ, Silbershatz H, Tofler GH, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring Population. Circulation. 2000;102:1634–8. doi: 10.1161/01.cir.102.14.1634. [DOI] [PubMed] [Google Scholar]
  • 7.Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. Jama. 1987;258:1183–6. [PubMed] [Google Scholar]
  • 8.Folsom AR, Wu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities(ARIC) Study. Circulation. 1997;96:1102–8. doi: 10.1161/01.cir.96.4.1102. [DOI] [PubMed] [Google Scholar]
  • 9.Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005;294:1799–809. doi: 10.1001/jama.294.14.1799. [DOI] [PubMed] [Google Scholar]
  • 10.Danesh J, Collins R, Appleby P, et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477–82. doi: 10.1001/jama.279.18.1477. [DOI] [PubMed] [Google Scholar]
  • 11.Engstrom G, Hedblad B, Tyden P, et al. Inflammation-sensitive plasma proteins are associated with increased incidence of heart failure: a population-based cohort study. Atherosclerosis. 2009;202:617–22. doi: 10.1016/j.atherosclerosis.2008.05.038. [DOI] [PubMed] [Google Scholar]
  • 12.Bahrami H, Bluemke DA, Kronmal R, et al. Novel metabolic risk factors for incident heart failure and their relationship with obesity: MESA(Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008;51:1775–83. doi: 10.1016/j.jacc.2007.12.048. [DOI] [PubMed] [Google Scholar]
  • 13.Lima JA, Desai MY. Cardiovascular magnetic resonance imaging: current and emerging applications. J Am Coll Cardiol. 2004;44:1164–71. doi: 10.1016/j.jacc.2004.06.033. [DOI] [PubMed] [Google Scholar]
  • 14.Zerhouni EA, Parish DM, Rogers WJ, et al. Human heart: tagging with MR imaging--a method for noninvasive assessment of myocardial motion. Radiology. 1988;169:59–63. doi: 10.1148/radiology.169.1.3420283. [DOI] [PubMed] [Google Scholar]
  • 15.Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002;156:871–81. doi: 10.1093/aje/kwf113. [DOI] [PubMed] [Google Scholar]
  • 16.Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27(Suppl-1):S5–S10. doi: 10.2337/diacare.27.2007.s5. [DOI] [PubMed] [Google Scholar]
  • 17.O’Leary DH, Polak JF, Wolfson SK, Jr, et al. Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group. Stroke. 1991;22:1155–63. doi: 10.1161/01.str.22.9.1155. [DOI] [PubMed] [Google Scholar]
  • 18.Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis(MESA) Arch Intern Med. 2008;168:1333–9. doi: 10.1001/archinte.168.12.1333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Detrano RC, Anderson M, Nelson J, et al. Coronary calcium measurements: effect of CT scanner type and calcium measure on rescan reproducibility--MESA study. Radiology. 2005;236:477–84. doi: 10.1148/radiol.2362040513. [DOI] [PubMed] [Google Scholar]
  • 20.Natori S, Lai S, Finn JP, et al. Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity. AJR Am J Roentgenol. 2006;186:S357–65. doi: 10.2214/AJR.04.1868. [DOI] [PubMed] [Google Scholar]
  • 21.Nasir K, Tsai M, Rosen BD, et al. Elevated homocysteine is associated with reduced regional left ventricular function: the Multi-Ethnic Study of Atherosclerosis. Circulation. 2007;115:180–7. doi: 10.1161/CIRCULATIONAHA.106.633750. [DOI] [PubMed] [Google Scholar]
  • 22.Garot J, Bluemke DA, Osman NF, et al. Fast determination of regional myocardial strain fields from tagged cardiac images using harmonic phase MRI. Circulation. 2000;101:981–8. doi: 10.1161/01.cir.101.9.981. [DOI] [PubMed] [Google Scholar]
  • 23.Osman NF, Prince JL. Visualizing myocardial function using HARP MRI. Phys Med Biol. 2000;45:1665–82. doi: 10.1088/0031-9155/45/6/318. [DOI] [PubMed] [Google Scholar]
  • 24.Castillo E, Osman NF, Rosen BD, et al. Quantitative assessment of regional myocardial function with MR-tagging in a multi-center study: interobserver and intraobserver agreement of fast strain analysis with Harmonic Phase(HARP) MRI. J Cardiovasc Magn Reson. 2005;7:783–91. doi: 10.1080/10976640500295417. [DOI] [PubMed] [Google Scholar]
  • 25.Kaptoge S, White IR, Thompson SG, et al. Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration. Am J Epidemiol. 2007;166:867–79. doi: 10.1093/aje/kwm191. [DOI] [PubMed] [Google Scholar]
  • 26.Levenson J, Giral P, Megnien JL, et al. Fibrinogen and its relations to subclinical extracoronary and coronary atherosclerosis in hypercholesterolemic men. Arterioscler Thromb Vasc Biol. 1997;17:45–50. doi: 10.1161/01.atv.17.1.45. [DOI] [PubMed] [Google Scholar]
  • 27.Mauriello A, Sangiorgi G, Palmieri G, et al. Hyperfibrinogenemia is associated with specific histocytological composition and complications of atherosclerotic carotid plaques in patients affected by transient ischemic attacks. Circulation. 2000;101:744–50. doi: 10.1161/01.cir.101.7.744. [DOI] [PubMed] [Google Scholar]
  • 28.Nasir K, Rosen BD, Kramer HJ, et al. Regional left ventricular function in individuals with mild to moderate renal insufficiency: Multi-Ethnic Study of Atherosclerosis. Am Heart J. 2007;153:545–51. doi: 10.1016/j.ahj.2006.12.025. [DOI] [PubMed] [Google Scholar]
  • 29.Rosen BD, Cushman M, Nasir K, et al. Relationship between C-reactive protein levels and regional left ventricular function in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis. J Am Coll Cardiol. 2007;49:594–600. doi: 10.1016/j.jacc.2006.09.040. [DOI] [PubMed] [Google Scholar]
  • 30.Paraskevas KI, Baker DM, Vrentzos GE, et al. The role of fibrinogen and fibrinolysis in peripheral arterial disease. Thromb Res. 2008;122:1–12. doi: 10.1016/j.thromres.2007.06.003. [DOI] [PubMed] [Google Scholar]
  • 31.Lee AJ, Mowbray PI, Lowe GD, et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation. 1998;97:1467–73. doi: 10.1161/01.cir.97.15.1467. [DOI] [PubMed] [Google Scholar]
  • 32.Cicala S, de Simone G, Roman MJ, et al. Prevalence and prognostic significance of wall-motion abnormalities in adults without clinically recognized cardiovascular disease: the Strong Heart Study. Circulation. 2007;116:143–50. doi: 10.1161/CIRCULATIONAHA.106.652149. [DOI] [PubMed] [Google Scholar]
  • 33.van de Stolpe A, Jacobs N, Hage WJ, et al. Fibrinogen binding to ICAM-1 on EA. hy 926 endothelial cells is dependent on an intact cytoskeleton. Thromb Haemost. 1996;75:182–9. [PubMed] [Google Scholar]
  • 34.Forsyth CB, Solovjov DA, Ugarova TP, et al. Integrin alpha(M)beta(2)-mediated cell migration to fibrinogen and its recognition peptides. J Exp Med. 2001;193:1123–33. doi: 10.1084/jem.193.10.1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science. 1992;257:387–9. doi: 10.1126/science.1631560. [DOI] [PubMed] [Google Scholar]
  • 36.Szaba FM, Smiley ST. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood. 2002;99:1053–9. doi: 10.1182/blood.v99.3.1053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Hicks RC, Golledge J, Mir-Hasseine R, et al. Vasoactive effects of fibrinogen on saphenous vein. Nature. 1996;379:818–20. doi: 10.1038/379818a0. [DOI] [PubMed] [Google Scholar]
  • 38.Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109:2698–704. doi: 10.1161/01.CIR.0000131660.51520.9A. [DOI] [PubMed] [Google Scholar]
  • 39.Fernandes VR, Polak JF, Edvardsen T, et al. Subclinical atherosclerosis and incipient regional myocardial dysfunction in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis(MESA) J Am Coll Cardiol. 2006;47:2420–8. doi: 10.1016/j.jacc.2005.12.075. [DOI] [PubMed] [Google Scholar]
  • 40.O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340:14–22. doi: 10.1056/NEJM199901073400103. [DOI] [PubMed] [Google Scholar]
  • 41.Edvardsen T, Detrano R, Rosen BD, et al. Coronary artery atherosclerosis is related to reduced regional left ventricular function in individuals without history of clinical cardiovascular disease: Multiethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:206–11. doi: 10.1161/01.ATV.0000194077.23234.ae. [DOI] [PubMed] [Google Scholar]
  • 42.El-Menyar AA. Cytokines and myocardial dysfunction: state of the art. J Card Fail. 2008;14:61–74. doi: 10.1016/j.cardfail.2007.09.006. [DOI] [PubMed] [Google Scholar]
  • 43.Schneider DJ, Taatjes DJ, Howard DB, et al. Increased reactivity of platelets induced by fibrinogen independent of its binding to the IIb-IIIa surface glycoprotein: a potential contributor to cardiovascular risk. J Am Coll Cardiol. 1999;33:261–6. doi: 10.1016/s0735-1097(98)00515-4. [DOI] [PubMed] [Google Scholar]
  • 44.Koenig W, Ernst E. The possible role of hemorheology in atherothrombogenesis. Atherosclerosis. 1992;94:93–107. doi: 10.1016/0021-9150(92)90234-8. [DOI] [PubMed] [Google Scholar]
  • 45.Lowe GD. Blood rheology, haemostasis and vascular disease. Edinburgh: Churchill Livingstone; 1994. pp. 1169–1188. [Google Scholar]

RESOURCES