Published online before print February 16, 2009, doi: 10.1161/CIRCULATIONAHA.108.821769
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(Circulation. 2009;119:1101-1107.)
© 2009 American Heart Association, Inc.
Epidemiology |
Relations of Matrix Remodeling Biomarkers to Blood Pressure Progression and Incidence of Hypertension in the Community
From the National Heart, Lung, and Blood Institute’s Framingham Heart Study (R.D., M.J.P., T.J.W., D.L., E.J.B., R.S.V.), Framingham, Mass; Division of Aging (R.D.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Medicine (R.D.), Alice Peck Day Memorial Hospital, Lebanon, NH; Department of Mathematics and Statistics (M.J.P., P.S., K.P.), Boston University, Boston, Mass; Division of Cardiology (T.J.W.), Massachusetts General Hospital, Boston, Mass; Center for Population Studies (D.L.), National Heart, Lung, and Blood Institute, Bethesda, Md; and the Myocardial Biology Unit (D.A.S., W.S.C.), Cardiology Section (W.S.C., E.J.B., R.S.V.), and Section of Preventive Medicine and Epidemiology (E.J.B., R.S.V.), Boston University School of Medicine, Boston, Mass.
Correspondence to Ramachandran S. Vasan, MD, Framingham Heart Study, 73 Mount Wayte Ave, Suite 2, Framingham, MA 01702-5803. E-mail vasan{at}bu.edu
Received July 27, 2008; accepted December 15, 2008.
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Abstract |
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Background— Biomarkers of extracellular matrix remodeling are associated with prevalent hypertension in cross-sectional studies, but their relations to longitudinal changes in blood pressure (BP) and hypertension incidence are unknown.
Methods and Results— We evaluated 595 nonhypertensive Framingham Offspring Study participants (mean age 55 years; 360 women) without prior heart failure or myocardial infarction who underwent routine measurements of plasma tissue inhibitor of metalloproteinase-1 (TIMP-1), metalloproteinase-9 (MMP-9), and procollagen III N-terminal peptide. We related plasma TIMP-1, procollagen III N-terminal peptide, and MMP-9 to the incidence of hypertension and progression of BP by 
1 category (defined on the basis of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). On follow-up (4 years), 81 participants (51 women) developed hypertension, and 198 (114 women) progressed to a higher BP category. In multivariable models, a 1-SD increment of log-TIMP-1 was associated with a 50% higher incidence of hypertension (95% CI 1.08 to 2.08) and a 21% (95% CI 1.00 to 1.47) higher risk of BP progression. Individuals in the top TIMP-1 tertile had a 2.15-fold increased risk of hypertension (95% CI 0.99 to 4.68) and 1.68-fold (95% CI 1.05 to 2.70) increased risk of BP progression relative to the lowest tertile. Individuals with detectable MMP-9 had a 1.97-fold higher risk of BP progression (95% CI 1.06 to 3.64) than those with undetectable levels. Plasma procollagen III N-terminal peptide was not associated with hypertension incidence or BP progression.
Conclusions— In the present community-based sample, higher TIMP-1 and MMP-9 concentrations were associated with BP progression on follow-up. Additional studies are warranted to confirm our findings.
Key Words: hypertension • collagen • epidemiology • metalloproteinases • risk factors
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Introduction |
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The pathophysiological mechanisms underlying vascular remodeling include the processes that regulate the turnover of extracellular matrix collagen.1 In recent years, scientists have studied many biomarkers of matrix remodeling that closely reflect the ongoing process of continuous matrix breakdown and synthesis. Three such families of biomarkers that are associated with regulation of the extracellular collagen matrix are matrix metalloproteinases (MMPs), which are associated with degradation of collagen; tissue inhibitors of metalloproteinases (TIMPs), which inhibit the activity of metalloproteinases; and procollagen peptides, which reflect the actual turnover of extracellular collagen.2–4 Of the numerous biomarkers that belong to these 3 families of matrix biomarkers, MMP-9, TIMP-1 proteins, and plasma procollagen III N-terminal peptide (PIIINP) have been studied extensively in experimental investigations and have been widely implicated in the complex process of vascular remodeling.1–4
Clinical Perspective p 1107
In clinical studies, high circulating concentrations of TIMP-1 have been associated with the presence of left ventricular (LV) hypertrophy,5 prevalent hypertension,6–10 congestive heart failure,11 and increased cardiac mortality.12 Compared with studies that have evaluated circulating TIMP-1, cross-sectional investigations relating plasma MMP-9 and PIIINP to hypertension have yielded conflicting results. Some studies reported higher plasma concentrations of MMP-96,13,14 and higher plasma PIIINP15 in hypertensive individuals than in their nonhypertensive counterparts, whereas others have noted lower MMP-9 concentrations16,17 or observed no association of PIIINP10 with hypertension status. Of note, a polymorphism in the MMP9 gene has been associated with systolic hypertension and with arterial stiffness in 1 study,18 but the findings have yet to be replicated. One challenge inherent in the aforementioned cross-sectional studies is that it is impossible to determine whether the altered circulating concentrations of extracellular matrix markers are a consequence of hypertension (and associated vascular remodeling), or if they predate and participate in the pathophysiological vascular changes that contribute to the development of high blood pressure (BP); only prospective studies can clarify this issue. Accordingly, we examined prospectively the relations of plasma concentrations of 3 biomarkers of extracellular matrix remodeling (TIMP-1, MMP-9, and PIIINP) to the incidence of hypertension and to longitudinal tracking of BP in a community-based sample.
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Methods |
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The Framingham Heart Study began in 1948 with the recruitment of 5209 white individuals of European descent who were residents of Framingham, Mass (referred to as the original cohort).19 In 1971, the offspring of the original cohort and their spouses (n=5124) were enrolled in the Framingham Offspring Study.20 Participants who attended the sixth examination cycle of the Framingham Offspring Study (n=3532) were eligible for the present investigation. At that examination, all attendees underwent routine physical examination, laboratory assessment of cardiovascular disease risk factors, and transthoracic echocardiography. The Framingham Heart Study protocol was approved by the Boston University Medical Center Institutional Review Board, and all participants signed written informed consent.
At the sixth examination cycle, plasma concentrations of TIMP-1, MMP-9, and PIIINP were measured in a subsample chosen to maximize scientific yield and to permit the judicious use of precious and scarce nonrenewable serological resources (given the relative novelty of these biomarkers from the perspective of an epidemiological cohort). Previously, investigators have reported associations of extracellular matrix biomarkers with hypertension and related traits (LV remodeling, hypertrophy, and heart failure)7,10,11,15 in high-risk samples. Therefore, first we examined the sex-specific distributions of echocardiographic LV internal dimensions (LVID) and LV wall thickness (LVWT) of attendees. Next, we sampled participants with both LVID and LVWT measurements below the sex-specific 50th percentile (the referent LV group; n=605) and individuals with either the LVID or LVWT at or above the sex-specific 90th percentile (referred to as the remodeled LV group; n=439), as detailed elsewhere.21,22 We measured plasma concentrations of the matrix biomarkers in the referent and remodeled LV groups, and participants with available biomarkers were eligible for the present investigation (n=1026 for TIMP-1, 943 for PIIINP, and 700 for MMP-9). A smaller proportion of individuals had MMP-9 measurements, because plasma concentrations were not detectable in a majority of persons, as detailed elsewhere.5 We excluded participants for the following reasons: prevalent hypertension,23 including the use of antihypertensive medications (n=365); prevalent heart failure (n=3) or myocardial infarction (n=17); serum creatinine >2.0 mg/dL (n=6) or missing covariates (n=4); and nonattendance at the follow-up examination (n=36). Thus, after exclusions, we had 595 nonhypertensive participants (360 women) in our final sample, all of whom had available plasma concentrations of TIMP-1; of these, 545 individuals had available plasma PIIINP concentrations, and 351 had available plasma MMP-9 measurements.
Measurement of Risk Factors and BP
At the sixth Framingham Heart Study examination, attendees underwent physical examination, including anthropometry and BP measurements. Body mass index was calculated by dividing weight in kilograms by height in meters squared. BP readings were obtained with a mercury column sphygmomanometer and a cuff of the appropriate size. The examination BP was the average of 2 physician-obtained measurements made on the left arm of participants after they had rested for 5 minutes in a sitting position. The BP of participants was grouped on the basis of the categories defined by the sixth report of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure24: Systolic BP <120 mm Hg and diastolic BP <80 mm Hg; systolic BP 120 to 129 mm Hg or diastolic BP 80 to 84 mm Hg; or systolic BP 130 to 139 mm Hg or diastolic BP 85 to 89 mm Hg.
Measurement of Biomarkers
Blood samples were obtained from attendees after an overnight fast (typically between 7:30 AM and 9 AM in the morning) and centrifuged, and the plasma was frozen at –80°C until the assay was run. All 3 matrix biomarkers were measured in duplicate with 2-site sandwich ELISA assays for TIMP-1 and MMP-9 and a radioimmunoassay for PIIINP (Amersham Pharmacia Biotech, Sunnyvale, Calif). Plasma total TIMP-1 assays measured free TIMP-1 and complexes of TIMP-1 with MMPs, whereas the total MMP-9 assay measured MMP-9, ProMMP-9/TIMP-1, and MMP-9 complexed with various TIMPs. Intra-assay coefficients of variation were <5% for TIMP-1, <18% for MMP-9, and 6% for PIIINP.
Echocardiographic Measurements
As noted above, all attendees at the sixth examination cycle underwent routine transthoracic M-mode 2D and Doppler color flow echocardiography with a Sonos 1000 Hewlett-Packard machine. The internal dimensions of the left ventricle (LVID), the thicknesses of the posterior wall and interventricular septum at end diastole, and left atrial size at end systole were obtained by averaging digital M-mode measurements in 3 cardiac cycles with a leading-edge technique and according to the American Society of Echocardiography guidelines.25 LVWT was derived by adding the diastolic thicknesses of the interventricular septum and the posterior wall. LV mass was calculated by the following formula26: 0.8 [1.04 (LVID+LVWT)3– (LVIDD)3]+0.6. The reproducibility of echocardiographic measurements was good, as has been reported previously.27
BP Outcomes on Follow-Up
At follow-up, approximately 3 years after the sixth examination, participants attended the seventh examination cycle, at which time they underwent a routine examination that included measurement of their BP. Three BP outcomes on follow-up were evaluated: (1) Progression in BP by 1 or more categories (as defined by the sixth report of Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure)24; (2) development of hypertension, defined as a systolic BP 140 mm Hg or a diastolic BP 90 mm Hg, or use of antihypertensive medications23; and (3) continuous changes in systolic and diastolic BP.
Statistical Analyses
The baseline characteristics of the participants were assessed by sex and according to tertiles of plasma TIMP-1 and PIIINP concentrations. Our primary outcome of interest was new onset of hypertension and progression of BP category at the follow-up examination (seventh examination cycle). First, we estimated the unadjusted and the age- and sex-adjusted proportions of individuals who developed hypertension and BP progression on follow-up for the overall sample according to tertiles of TIMP-1 and PIIINP, as well as detectability of MMP-9. Second, multivariable logistic regression models were constructed to analyze the association of plasma TIMP-1, PIIINP, and MMP-9 concentrations with the incidence of hypertension and BP progression. Plasma TIMP-1 and PIIINP levels were assessed both as categorical variables (tertiles, with the lowest tertile serving as the referent) and as continuous variables (natural-logarithmically transformed to normalize the skewed distributions), whereas plasma MMP-9 concentration was modeled as a binary variable (detectable versus undetectable levels). Two sets of models were constructed, model I with adjustment for age, sex, and LV sampling group (referent group versus LV remodeled group) and model II with adjustment for age, sex, baseline systolic and diastolic BP, body mass index, percentage weight change on follow-up, smoking, diabetes mellitus, and LV sampling group (as defined above).
In models that incorporated tertiles of TIMP-1 and PIIINP, we compared the incidences of hypertension and BP progression in the second and top tertiles with those in the first tertile, which served as the referent. We also tested for a trend of rising incidence of hypertension and BP progression across tertiles of these markers.
We performed additional analyses examining the relations of matrix biomarkers to longitudinal changes in systolic and diastolic BP, analyzed as continuous variables; censored normal regression28 was used to account for treatment for high BP at the follow-up examination. These models were adjusted for the covariates noted above (model II).
Secondary Analyses
We repeated all analyses with adjustment for LV mass (a composite variable derived from LVID and LVWT, the 2 variables used to define the sampling scheme) in addition to LV group to reduce the possibility of any residual confounding due to the sampling scheme, because higher LV mass has been associated with incident hypertension.29 To further clarify differences based on sampling group and to analyze whether the relations of matrix biomarkers to the incidence of hypertension and to progression to a higher BP category are influenced by the presence of LV remodeling, we repeated all analyses but restricted the sample to the referent group, ie, those with <50th sex-specific percentile of LVID and LVWT.
All analyses were performed with the PROC LOGISTIC procedure in SAS (SAS Institute, Inc, Cary, NC) and the CNREG routine in Stata (StataCorp LP, College Station, Tex).30 A 2-sided probability value of 0.05 was considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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The baseline characteristics of participants are displayed in Table 1. Concentrations of extracellular matrix biomarkers were similar in men and women. The clinical characteristics of the study sample according to tertiles of TIMP-1 and PIIINP levels are displayed in Table I in the supplemental Appendix. Individuals in the highest tertile of TIMP-1 and PIIINP were older, were more likely to be men, and had higher mean body mass index and systolic BP and a higher prevalence of diabetes. Sample sizes for individuals with availability of each of the 3 matrix biomarkers varied, but an assessment of the clinical characteristics for the samples did not reveal any major differences (Table II, supplemental Appendix). Additionally, there were no significant differences in clinical characteristics of participants with measured biomarkers compared with the rest of the attendees at the same examination cycle, as reported previously.21
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On follow-up (mean 4 years), 81 participants (51 women) developed hypertension, and 198 (114 women) progressed to a higher BP category. We observed modest longitudinal changes in systolic BP (mean 1.85 mm Hg, SD 11.90) and diastolic BP (mean 0.15 mm Hg, SD 7.63), disregarding the effect of treatment on follow-up. The proportion of individuals who developed hypertension and the proportion who progressed to a higher BP category rose (Table 2) with increasing tertiles of plasma TIMP-1 and PIIINP concentrations, as well as with detectable MMP-9 concentrations (compared with those with undetectable MMP-9).
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Association of Plasma TIMP-1 Concentrations With BP Progression and Hypertension
We observed a 31% to 50% higher incidence of hypertension and a 21% increased risk of progression to a higher BP category with an increase of 1 SD of log-TIMP-1 (0.15 ng/mL; Table 3). These results remained unchanged after the exclusion of participants with atrial fibrillation (n=5). Individuals in the top tertile of TIMP-1 had a >2-fold higher incidence of hypertension and a 68% to 74% higher likelihood of progression to a higher BP category (Table 3). We also observed a statistically significant trend of higher incidence of hypertension and progression to higher BP category with increasing TIMP-1 tertiles. These results remained unchanged in analyses that adjusted for LV mass (data not shown). In censored normal regression analyses to evaluate change in BP as a continuous variable, plasma TIMP-1 concentration was positively associated with systolic and diastolic BP change, but the results did not reach statistical significance (P=0.082 and 0.317, respectively).
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Association of Plasma MMP-9 Concentrations With Progression of BP and Hypertension
In the study sample, a majority of individuals did not have a detectable concentration of MMP-9 (n=293). Individuals with detectable levels of MMP-9 (n=60) had a 2-fold increased risk of progression to a higher BP category compared with those with undetectable MMP-9 (Table 3). These results remained unchanged in analyses that adjusted for LV mass (data not shown). Individuals with detectable MMP-9 did not have a statistically significant higher risk of developing hypertension in these analyses, although the point estimate of the ORs exceeded 1 (Table 3). Plasma MMP-9 was associated with changes in systolic and diastolic BP analyzed as continuous variables (P=0.024 and 0.076, respectively).
Association of PIIINP Levels With Progression of BP and Hypertension
Plasma PIIINP levels were related neither to incident hypertension nor to progression of BP category in any of the models evaluated (Table 3). Analyses of change in systolic and diastolic BP as continuous variables confirmed these findings (P=0.847 and 0.584, respectively).
Because there was no association of plasma PIIINP with BP outcomes, we calculated our statistical power to detect associations. We estimated that we had 80% power (at 
=0.05) to detect an association of a magnitude of a hazard ratio of 1.83 and 1.31 for incident hypertension and progression of BP category, respectively, per 1-SD increment in log-PIIINP (SD=0.62 ng/mL).
Secondary Analyses
In the referent LV subsample (n=433), 130 participants progressed to a higher BP category, and 45 developed hypertension on follow-up. In this sample, a 1-SD increase in log TIMP-1 concentrations was associated with a 28% to 31% higher risk of progression of BP category (Table 4). Participants in the uppermost tertile of TIMP-1 had approximately twice the risk of advancing to a higher BP category as those in the first tertile (P for trend <0.02 in both models; Table 4). These relations remained unchanged after additional adjustment for LV mass (data not shown). However, TIMP-1 was not associated with hypertension in this sample, although the point estimate of the ORs exceeded 1 (Table 4). The positive association of detectable MMP-9 concentrations with progression of BP category was attenuated slightly (Table 4). Detectable MMP-9 was not related to incident hypertension and plasma PIIINP levels were not associated with incident hypertension or with progression of BP in this subgroup of individuals (Table 4).
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Discussion |
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Principal Findings
Our principal findings are 2-fold. First, higher plasma TIMP-1 was associated with greater risk of progression of BP and incidence of hypertension. Analyses of plasma MMP-9 were hampered by low rates of detectability. Nonetheless, detectable plasma MMP-9 was associated with higher likelihood of BP progression. The associations of TIMP-1 and detectable MMP-9 with BP progression were maintained in analyses restricted to a healthier subsample (referent group) and on adjustment for LV mass. Analyses of BP change as a continuous variable corroborated these findings. Second, plasma PIIINP was not associated with either BP outcome in multivariable analyses, even though unadjusted analyses demonstrated a trend for increases in rates of BP progression and hypertension incidence; these findings likely suggest confounding of the relations of PIIINP and BP outcomes by covariates such as body mass index that are related both to the biomarker and to BP.22 The present results may also reflect limited statistical power to detect modest associations of this biomarker with BP tracking.
Mechanisms Underlying the Observed Association of Matrix Biomarkers and BP Outcomes
Experimental and clinical studies have suggested that an increase in vascular collagen volume density occurs in essential hypertension.31,32 Plasma TIMP-1 blocks the activation of several MMPs and prevents their catalytic activity.33 Hence, higher plasma TIMP-1 levels likely reflect lesser activity of MMPs and greater accrual of collagen matrix, including within the vascular wall.4,34 Prior clinical data suggest associations of higher TIMP-1 concentrations with prevalent hypertension.6–10 Researchers have also observed decreases in plasma TIMP-1 concentrations in patients with hypertension after treatment with antihypertensive drugs.7 Our prospective observations are consistent with these prior findings.
In contrast, results of investigations relating plasma MMP-9 levels to prevalent hypertension have been inconsistent.6,13,14,16,17 Human vascular endothelium contains several types of collagen. Plasma MMP-9 is a type of gelatinase B that digests gelatin and type IV and V collagen, which are found in subendothelial basement membrane. Hence, it has been proposed that diminished activity of MMP-9 is associated with accumulation of extracellular matrix in the resistance arteries, thereby contributing to hypertension. However, in the present study, we observed a positive association of detectable MMP-9 and BP progression, which would appear to be the opposite of what would be expected (based on its biological actions) and warrants explanation. One possibility is that we measured total MMP-9, which includes MMP-9 complexed with TIMPs, so it is conceivable that the association of total MMP-9 may reflect the effects of TIMPs. Such an explanation is rendered less likely because the proportion of individuals with detectable MMP-9 decreased across tertiles of TIMP-1 (supplemental Appendix). A more likely possibility is that MMP-9 may reflect the increased matrix breakdown and vascular inflammation that are characteristic of the early stages of vascular remodeling in experimental models of hypertension.35,36 As hypertension progresses, increased matrix turnover transitions to greater fibrosis, as reflected by increases in TIMP-1 levels.11,37 Consistent with this proposed temporal course of MMP/TIMP activation in early hypertension is the observation that levels of both TIMP-1 and MMP-9 are higher in patients with hypertension in some reports,6,9,13 which possibly indicates a case mix of individuals at different points along the spectrum of hypertension, vascular remodeling, and LV hypertrophy.
Strengths and Limitations of the Study
The moderate-sized community-based sample, adjustment for multiple covariates, and comprehensive analyses of multiple BP outcomes are strengths of the present investigation; however, several limitations must be emphasized. We did not measure matrix markers in individuals whose LVID and LVWT were in an intermediate range (50th to 90th percentiles). We also did not adjust for left atrial size or LV diastolic function in the analyses; however, we adjusted for LV group and LV mass (which indirectly accounts for LVID) in all analyses. Also, we did not measure the circulating concentrations of other biomarkers such as MMP-1 or MMP-2 or other types of TIMP levels (eg, TIMP-2, TIMP-4) to examine their associations with BP tracking and hypertension incidence. In addition, although we did not find any association of PIIINP with BP outcomes, it is possible that other biomarkers of the same family, such as carboxy terminal propeptide of procollagen type-I or the N-terminal propeptide of type I collagen, may be associated with incident hypertension.38–40 Additional prospective studies with larger sample sizes and longer follow-up durations and that measure other TIMPs, MMPs, and markers of collagen turnover are required to confirm the present findings and better characterize the contributions of extracellular matrix turnover to BP progression in the community.
We used a single measurement of the biomarkers, and their levels may vary over time.41 Such analyses using single-occasion measurements would result in an underestimation of the true strength of the association of biomarkers with the outcomes studied. It is also noteworthy that prior investigators have reported minimal short-term11 and long-term42,43 variability over time for the matrix biomarkers studied in the present investigation in individuals without cardiovascular diseases11 and in some referral samples from individuals with disease.42,43 A majority of participants in the present study were white individuals of European ancestry, which limits the generalizability of our findings to other ethnicities.
Conclusions
In the present community-based sample, higher plasma TIMP-1 and MMP-9 concentrations were associated with greater risk of progression to a higher BP level and development of hypertension on follow-up. Overall, these data support the concept that higher circulating levels of matrix remodeling biomarkers may predate the onset of hypertension, perhaps because these markers reflect vascular remodeling that accompanies the evolution of high BP. PIIINP levels were not associated with BP progression or with incident hypertension.
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Acknowledgments |
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Sources of Funding
This work was supported through National Heart, Lung, and Blood Institute contracts RO1 HL67288, HL080124, and 2K24HL04334 (Dr Vasan) and 1R01AG028321 and RO1HL076784 (Dr Benjamin).
Disclosures
None.
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The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.821769/DC1.
Guest Editor for this article was Paolo Verdecchia, MD.
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