Curator & Reporter: Aviva Lev-Ari, PhD, RN
C-Reactive Protein, Fibrinogen, and Cardiovascular Risk
N Engl J Med 2013; 368:84-86 January 3, 2013DOI: 10.1056/NEJMc1213688
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To the Editor:
Kaptoge and colleagues (Oct. 4 issue)1 suggest that C-reactive protein (CRP) and fibrinogen, two biomarkers of inflammation, have a significant though limited incremental prognostic value when added to conventional risk factors. However, the implied ordering of risk factors on the basis of the chronology of their identification as risk factors should be challenged and replaced by an ordering that is based on their effect on prognostic accuracy. The hazard ratios for cardiovascular events (Table 1 of the article) for CRP or fibrinogen levels are in the range of those for established lipid risk factors and even blood pressure. Moreover, data shown in the Supplementary Appendix only (Table S4 and Fig. S4 in the Supplementary Appendix, available with the full text of the article at NEJM.org) reveal that adding the CRP or fibrinogen level to or omitting it from various risk-factor combinations produces differences in the C-index similar to those obtained when diabetes, the total cholesterol level, or the high-density lipoprotein (HDL) cholesterol level is added to or omitted from risk-factor combinations. These data call for an unbiased view of risk factors for cardiovascular disease that place the significance of biomarkers of inflammation such as CRP concentrations at the same level as conventional risk factors, rather than as a final low-impact increment.
Thomas M. Stulnig, M.D.
Medical University of Vienna, Vienna, Austria
thomas.stulnig@meduniwien.ac.atNo potential conflict of interest relevant to this letter was reported.
To the Editor:
In the Emerging Risk Factors Collaboration study involving 246,669 participants, Kaptoge et al. find that, on average, the CRP level was associated with a significant improvement in the prediction of cardiovascular disease, beyond that observed with classical risk factors. However, it was not predictive among women and in the analysis of the risk of stroke, indicating that the CRP level cannot be used as a one-size-fits-all marker of cardiovascular risk.
The prognostic value of the CRP level was first reported in patients with severe unstable angina1and subsequently also in healthy populations. Genetic studies did not support a pathogenetic role for CRP level in cardiovascular disease.2 A CRP cutoff point of at least 2 mg per liter has been proposed for the initiation of statin therapy,3 but in three ethnic groups, 41% of patients with ST-segment elevation myocardial infarction had CRP levels below this threshold.4 Thus, they would not have been eligible for such a preventive strategy.
The limited specificity and sensitivity of CRP measurements for predicting global cardiovascular disease risk suggest the need for appropriate studies of benefit in individual patients before the adoption of one-size-fits-all paradigms, which can be statistically relevant for study populations, with considerable health care costs, but not for the treatment of individual patients.
Enrico Ammirati, M.D.
San Raffaele Scientific Institute, Milan, ItalyAttilio Maseri, M.D.
Heart Care Foundation, Florence, Italy
amaseri@heartcarefound.orgNo potential conflict of interest relevant to this letter was reported.
To the Editor:
Kaptoge et al. report that the measurement of CRP or serum fibrinogen levels would identify 13,199 patients who could potentially benefit by a reduction of 30 events (fatal or nonfatal) over the course of 10 years, owing simply to a reclassification of risk and application of statin therapy. Were the test to have no cost, statin therapy to have neither side effects nor no excess cost of follow-up, and drug costs to be limited to $1,000 over the period of 10 years (all unreasonably low assumptions), the cost per event avoided would be greater than $15 million, or more than $500,000 per event. Not reporting the expected effect of such an approach on costs abrogates our responsibility to the community. I propose that an additional step be added that requires that we (as authors and journals) analyze the financial implications of our scientific observations.
Larry A. Weinrauch, M.D.
Harvard Medical School, Boston, MA
lweinrauch@hms.harvard.eduNo potential conflict of interest relevant to this letter was reported.
Author/Editor Response
In the Emerging Risk Factors Collaboration study, a meta-analysis of individual participant data from almost 250,000 people in 52 prospective studies, we found that information on biomarkers of inflammation such as CRP or fibrinogen level improved the prediction of first-onset cardiovascular disease outcomes when added to conventional risk factors. We conclude that the assessment of CRP or fibrinogen level in persons classified as being at intermediate risk (i.e., a predicted 10-year risk of cardiovascular disease of 10% to <20% on the basis of conventional risk factors alone) could help prevent one additional cardiovascular disease event over a period of 10 years for every 400 to 500 people so screened, assuming initiation of statin therapy according to the Adult Treatment Panel III guidelines.
We agree with Stulnig that the sequence in which risk factors are included in prediction models can influence their comparative effect. Our report focuses on the incremental value of biomarkers of inflammation, because current guidelines debate the value of adding them to conventional risk factors. However, as Stulnig notes, we also provide information showing that the separate predictive values for CRP, fibrinogen, total cholesterol, and HDL cholesterol levels were similar in analyses that did not depend on the sequence in which they were used. The order in which risk factors should be considered may depend on various factors (e.g., convenience, cost, and promotion of lifestyle changes to reduce the risk of cardiovascular disease).
Ammirati and Maseri suggest that the scoring for cardiovascular disease risk needs to be refined. Partly for this reason, we present findings for a range of clinically relevant subgroups, suggesting improvement in the prediction of cardiovascular disease with inflammation biomarkers that is apparently lower in women than in men. However, because these subgroup analyses were exploratory in nature, we believe that they require cautious interpretation until they can be confirmed in independent studies.
Weinrauch makes a rough estimate of the financial implications of our findings, assuming that only drug costs of $1,000 per person over a period of 10 years apply. Unfortunately, his calculations are overestimates by a factor of 20, since, according to the results of our study, drug costs would be limited to the 690 people treated after the additional assessment of CRP level, rather than all the 15,025 people initially classified as being at intermediate risk. Using Weinrauch’s figures, the cost would be $23,000 per cardiovascular disease event prevented over the course of 10 years, not $500,000. More generally, since simplistic financial calculations may be misleading, we encourage detailed cost-effectiveness evaluation,1 as stated in our report.
Stephen Kaptoge, Ph.D.
Simon G. Thompson, D.Sc.
John Danesh, M.D.
University of Cambridge, Cambridge, United Kingdom
erfc@phpc.cam.ac.ukfor the Emerging Risk Factors Collaboration
Since publication of their article, the authors report no further potential conflict of interest.
SOURCE:
http://www.nejm.org/doi/full/10.1056/NEJMc1213688?goback=%2Egde_72923_member_200638106
Other articles related to this subject matter appeared on this Open Access Online Scientific Journal:
PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity
Assessing Cardiovascular Disease with Biomarkers
http://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/
What is the role of plasma viscosity in hemostasis and vascular disease risk?
Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.
A second look at the transthyretin nutrition inflammatory conundrum
Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment
Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.