New Risk Markers for Cardiovascular Prevention
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- De Backer, G.G. Curr Atheroscler Rep (2014) 16: 427. doi:10.1007/s11883-014-0427-z
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The importance of total cardiovascular (CV) risk estimation before management decisions are taken is well established. Models have been developed that allow physicians to stratify the asymptomatic population in subgroups at low, moderate, high, and very high total CV risk. Most models are based on classical CV risk factors: age, gender, smoking, blood pressure, and lipid levels. The impact of additional risk factors is discussed here, looking separately at the predictive increments of novel biomarkers and of indicators of subclinical atherosclerotic disease. The contribution of biomarkers to the total CV risk estimation is generally modest, and their usage should be limited to subjects at intermediate total CV risk. Detection of subclinical vascular damage may improve total CV risk estimation in asymptomatic subjects who are close to a threshold that could affect management decisions and in whom the chances of re-classification in a different risk category are great. There is, however, an urgent need for trials in which the value of using total CV risk estimation models is tested.
KeywordsCardiovascular diseasePreventionRisk factorsPrediction
For many years, different expert committees have recommended using estimates of total cardiovascular (CV) risk for the prevention of cardiovascular disease (CVD)[1, 2, 3•, 4, 5•]. The reason for that is to tailor the preventive strategy in accordance with the total CV risk of the individual: the higher the patient’s total CV risk, the more intense should be the preventive approach. For particular patient groups it is known that the CV risk is high or very high and no special risk estimation models are needed to know that; this is the case for patients with established CVD, for patients with diabetes mellitus or with chronic kidney disease, or for subjects with severe elevation of single CV risk factors, such as familial hypercholesterolaemia or severe arterial hypertension.
Why should one estimate total CV risk?
Total CV risk estimation is of fundamental importance because:
CVD is multifactorial in origin
CV risk factors interact synergistically
Clinicians treat patients, not isolated risk factors
Preventive actions should be guided in accordance to the total CV risk level.
To estimate the total CV risk in these apparently healthy asymptomatic people, risk estimation models are needed and have been developed on the basis of observations in large cohort studies. Tools based on results from the Framingham study in the US [6, 7] have been developed first, but have some limitations related to numbers, to the study population on which the models are based, and in some models to the ‘soft’ character of some outcome measures.
Several other models have been developed in recent years [8–13], among which the SCORE model  in Europe, with the advantage that it is based on a very large population base and that it estimates the chances of developing fatal CV events which can be reproduced, and allows the calibration of the model at the level of the nation on the condition of the existence of reliable mortality statistics. All these models include non-modifiable CV risk factors (age and gender) and modifiable risk factors such as smoking habits, blood pressure, and total cholesterol; in other models additional factors have been included such as family history, diabetes, HDL cholesterol ( HDL-C), high-sensitivity C-reactive protein (hs-CRP), or indicators of social deprivation [9–11].
The question can be raised if the risk estimation that is obtained with these models is fit for purpose, should we aim for better predictive tools using additional risk markers? What “added value” can we expect by including novel risk markers in the existing risk scores? How to address all these questions has been well summarized by M.Romanens et al .
In approaching these questions we should not lose sight of the original aim of using these risk estimation models: to stratify the apparently healthy population in subgroups according to their total CV risk; preventive strategies should be different for people at low, moderate, high, or very high total CV risk. But these risk estimation models should not be used to estimate the total CV risk at the level of an individual person. CV risk estimation of a given person and expressed in terms of absolute risk remains hazardous and very approximate; risk models are not crystal balls for prophesying .
To improve total CV risk estimation, one could start by including in the model an average of multiple measures of the traditional risk factors (total cholesterol and blood pressure) rather than results based on a single measurement [16, 17].
Among the novel risk markers that could improve risk estimation are several candidates related to lifestyles, to lipid metabolism, inflammation, thrombosis, genetic predisposition, vascular function, or neurohumoral activity.
Quality criteria to evaluate new risk markers for the estimation of total CV risk in the asymptomatic population
- The measurement of the risk marker should be easy, accurate and reliable
- The risk marker should predict CVD independently of other risk factors in persons free of CVD
- The risk marker should provide incremental information beyond what can be obtained with existing risk estimation models.
- Adding the risk marker should influence management strategies in a way that CVD prevention becomes more efficacious and more cost-effective.
It is insufficient to demonstrate the predictive value of these factors, independent of the conventional CV risk factors. This on its own is no proof of the incremental value of the marker in the risk estimation tool.
Novel biomarkers should add reliably to the predictive power of traditional CV risk factors; it should also lead to a better calibration with no significant differences between predicted and observed CVD event rates. It should result in a significant net reclassification improvement index (NRI), particularly in the large group of subjects at intermediate CV risk in whom the clinical NRI (CNRI) can be estimated. Particular interest should go into modifiable novel risk markers that could become part of an intervention program; the latter should then be tested in a randomized controlled trial (RCT)regarding its potential in preventing clinical outcomes, safety as well as cost-effectiveness. Although it must be admitted that the application of the existing risk estimation tools has also never been tested in an RCT as to its value in preventing ‘hard’ CVD events compared to standard of care.
Predictive Increments of Novel Biomarkers at the Level of the Community
For the estimation of the total CV risk, the incremental value of new biomarkers that can be measured on easily obtainable material such as blood or urine has been examined in numerous large population studies. This has been studied by adding new markers to different existing risk estimation models that have been reviewed by G. Siontis et al. . One can reasonably assume that biomarkers improving the predictive power of one model will also do so for other models that are based on similar traditional CV risk factors. For appraising the improved predictive value of adding a biomarker to an established risk estimation model, different statistics should be used as proposed by others [14, 19••]. These include changes in C-statistics derived from the area under the receiver operating curve (AUROC), indices of calibration, the NRI, and the CNRI. The C-statistic on its own is of limited value in models that already have a substantial AUROC. The SCORE model with age, gender, smoking, systolic blood pressure, and total cholesterol resulted already in a C-statistic of 0.81. This leaves little room for improvement through the introduction of new biomarkers. It has been suggested that a reasonable improvement in discrimination can only be expected for variables that are strongly associated with CVD with an odds ratio of 16 or more .
The Case of HDL-C
Net reclassification improvement (% reclassified into high [ > = 5 %] or low [<5 %] total CV risk) by adding HDL-C to the SCORE model
High risk countries
Low risk countries
High risk countries
Low risk countries
In women from high-risk countries, a significant proportion was correctly re-classified by introducing HDL-C; the NRI in them was 11.5 % (p = 0.015), and this was mainly due to a re-classification towards higher risk categories .
From this exercise with HDL-C in SCORE it looks as if including novel risk markers may be useful in estimating the total CV risk in the subgroup at intermediate risk just below the threshold for intensive risk modification of the middle-aged population. SCORE charts incorporating different levels of HDL-C are included in the EAS/ESC guidelines on the management of dyslipidaemias .
The role of elevated triglycerides as a predictor of CVD has been discussed for many years. Fasting triglycerides relate to risk in univariate analyses but the effect is attenuated by adjustment for other factors, especially HDL-C . More recently, attention has focused on non-fasting triglycerides, which may be more strongly related to risk independent of the effects of HDL-C .
In a collaborative analysis of 58 studies adding body mass index (BMI) to the Framingham Risk Score (FRS) did not improve risk prediction of CVD (NRI: -0.19) . However, in the Dutch MORGEN project, adding obesity (BMI > =30 kg/m2) and a parental history of myocardial infarction to a model based on classical risk factors, yielded in a significant NRI of 5.5 % in men and a non-significant NRI of 3.3 % in women when a 10-year estimated risk of total CV events was categorized using 10 % cut-off values; the improvements were mainly due to obesity . Therefore, it may well be that by including BMI as a continuous variable does not improve the NRI while it does with the BMI dichotomized into those who are obese or not.
The Belgian Health Care Knowledge Centre (KCE) published a report in 2013 on ‘novel serum biomarkers for the prediction of CV risk’ . Based on a systematic review of the literature from 2008 to 2012, 167 references were identified and 16 studies were included in the review. Studies that were published before 2008 had been discussed in the excellent overview published by MJ. Pencina et al. in 2008 .
Based on the results in these 16 studies, the predictive increments of various biomarkers were tested among which markers of inflammation: (hs-CRP, fibrinogen), markers of lipid metabolism (apolipoprotein A1, apolipoprotein B100, phospholipase A2, HDL cholesterol), and a variety of markers such as N-terminal proB-type natriuretic peptide (NT-proBNP), uric acid, homocysteine, and troponin.
hs-CRP had been investigated in a majority of identified studies. Two of these were systematic reviews of the addition of hs-CRP to risk estimation models which partially overlapped [29, 30]; the first included 23 studies the other 31. In addition, they identified 12 original studies published since 2008.
In the first review , it was demonstrated that hs-CRP was associated with CVD, independently from the risk factors that were included in the Framingham model and there was evidence of a dose-response gradient. But in only one study risk reclassification was calculated. In that study , 14 % of all participants originally stratified into the Framingham risk group of 10 - 20 % chances of developing CVD/10 years, were re-classified as low-risk (<10 %), and 5 % were re-classified as high risk (>20 %).
In the second review , 13 studies reported on the effect on the AUROC of adding hs-CRP to the Framingham model; five reported no change and eight reported an improvement of the C-statistic varying from +0.01 to +0.15 points.
From the 12 original studies published since 2008 it could be concluded that adding hs-CRP to the Framingham or the ASSIGN models resulted in a significant but modest reclassification of participants (NRI ranging from 1.52 to 11.8 %). CNRI was consistently greater than NRI. This may partially be explained by the fact that, in intermediate-risk persons, other risk factors such as smoking or advanced age are less prevalent leaving more room for a larger contribution of hs-CRP. The NRI was also consistently higher when coronary heart disease (CHD) was considered an outcome compared with CVD.
In the intermediate-risk participants of the MESA study, the addition of hs-CRP to the FRS resulted in an increase of the C statistic from 0.623 to 0.640(p = 0.03) and in an NRI of 8 % for the incidence of coronary events [32•].
In the report of the KCE , two studies were identified regarding the predictive increments of fibrinogen [22, 33]; the findings were to a certain extent comparable to what was observed for hs-CRP: a modest overall NRI and a greater CNRI, although the latter was mainly due to down-reclassification. Adding fibrinogen to the model on top of hs-CRP did not result in a change in C-statistic more than when either marker was used alone .
Among other biomarkers the systematic review of the KCE  retained six original studies which assessed the predictive increment of NT-proBNP, homocysteine, uric acid, and troponin. NT-proBNP was the only one to improve substantially discrimination and reclassification when added to the Framingham model in five studies out of six [33–35].
In the cardiovascular cohort of the Malmo Diet and Cancer study , the NT-proBNP was added to a model with the conventional CV risk factors; NT-proBNP predicted CV and coronary events but the changes in C-statistics were small; the NRIs were not significant. By limiting the analyses to participants at moderate CV risk the NRI was 7 % for CV events and 15 % for coronary events, but this was mainly a re-classification towards lower risk groups with limited clinical relevance .
In a systematic overview published in 2009, of the predictive increments of nine emerging risk factors, among which there were five biomarkers (hs-CRP, Lp(a), homocysteine, leukocyte count, fasting glycaemia), it was concluded that the current evidence did not support the routine use of any of these risk factors for further stratification of intermediate-risk persons .
In the Scottish Heart Health Extended Cohort (SHHEC) study it was possible to measure troponin I levels in nearly 75 % of the study population using a high-sensitivity assay. In models adjusted for sex, cohort, and all risk factors from the ASSIGN model, troponin I improved the prediction of new CV events significantly over a 20-year period; the NRI was estimated at 3.2 % (p = 0.0005) for CV events and at 4.5 % (p = 0.012) for coronary death. The C-statistics improved also significantly [37•].
Predictive Increments of Multiple Novel Biomarkers Together
In the Women’s Health Initiative, a moderate improvement in CHD risk prediction was observed when an 18-biomarker panel was added to different prediction models, including the Framingham Risk Score (FRS), in post-menopausal women; five out of the 18 new risk markers improved the C-statistic with 0.02 and an NRI of 6.5 % .
In the Framingham Heart Study, a multimarker score including NT-proBNP and urinary albumin/creatinine ratio moderately improved the C-statistic by 0.01 in the prediction of CVD events .
In the Cardiovascular Health Study, the addition of six biomarkers – CRP, fibrinogen, factor VIIIc, interleukin-6, Lp(a), and Hgb – did not improve discrimination beyond established risk factors .
In the prospective Atherosclerosis Risk in Communities ( ARIC) Study, the basic model included traditional risk factors; the hs-CRP did not add significantly to the AUROC and neither did most of the 19 other novel markers that were tested .
In the Uppsala Longitudinal Study of adult men, the C statistic for CVD death prediction increased by 0.06 when four markers – troponin, N-BNP, cystatin-C and CRP– were added to established markers in the subgroup free of CVD at baseline .
In the MORGAM study, 30 novel biomarkers were examined in two cohort studies; several of them were associated with the incidence of CVD, but this was only consistent in both cohorts and in men and women for NT-proBNP, hs-CRP, and troponin I; with these three markers, a score was developed and the addition of this score to a conventional risk model resulted in improved C-statistics (from 0.67 to 0.69, p = 0.004) and in an NRI of 11 % ( p < 0.0001), approximately half of which was due to correct up-classification of events .
In the Framingham Heart Study, the predictive increments of biomarkers that are supposed to be more cardio-specific were studied . A multimarker score was constructed with soluble ST2, growth differentiation factor-15, and tropinin I; these markers were associated with death and CV events but not with coronary events. Adding this multimarker score to a model containing the classical CV risk factors, hs-CRP, and NT-proBNP resulted in a significant improvement of the C-statistic (p = 0.005) and in a significant NRI (p = 0.001), and CNRI (p = 0.002). The absence of an association with coronary events suggests that these biomarkers are more related with myocardial stress than with inflammation or vascular stress.
In the Study of Health in Pomerania, the predictive increment of a multimarker approach including endocrine and metabolic parameters was examined in a model including the classical CV risk factors. Hs-CRP, HbA1c, and insulin-like growth factor-1 (IGF-1) remained significant predictors of CV death; the C-statistic for CV death improved by adding these biomarkers to the model from 0.898 to 0.910 (p = 0.02); the NRI was 10.6 % .
From all of this one may conclude that the addition of novel biomarkers, even when taken together, improves risk estimation moderately, and the ability to improve risk prediction models is rather inconsistent from study to study.
Predictive Increments of Indicators of Subclinical Atherosclerotic Disease in Asymptomatic Patients
Some new risk markers that are more related to disease development may be of interest not primarily to improve risk prediction in general, but in order to identify particular groups of interest in the large cohort of apparently healthy people at moderate risk according to the existing risk estimation models.
Imaging preclinical CVD may help in reclassifying people who are considered at intermediate total CV risk on the basis of the existing tools into higher risk categories where a more intense preventive strategy is indicated.
Different non-invasive techniques are now available; carotid ultrasound, computed tomography imaging, ankle-brachial blood pressure ratios, and different tests of vascular function have been studied in asymptomatic persons as to their ability to improve CV risk prediction.
The indications for applying these novel techniques are not yet well defined in algorithms; generally, these techniques could be of value in persons at intermediate total CV risk according to the existing tools, but in whom there is reasonable expectation of reclassification by searching for subclinical disease. Other techniques such as magnetic resonance imaging are of value in the cardiology clinic, but are at this moment not indicated for total CV risk estimation in the asymptomatic apparently healthy population.
The Ankle-Brachial Index ( ABI)
The measurement of the ABI is a simple and cheap method to detect peripheral artery disease as a surrogate of systematic atherosclerosis. Its prognostic value in predicting coronary and cerebrovascular disease has been documented . In a recently published report, the ABI was related to CV events independent of the Framingham Risk Score (FRS). The C-index increased slightly, but the NRI was 4.3 % (p = 0.05) in men and 9.6 % (p < 0.001) in women; in the subgroup at intermediate risk according to the FRS, the NRI was even 16 % in men and 23 % in women [46•].
Using carotid ultrasound, subclinical atherosclerosis can be detected based on the measurement of the intima-media thickness (IMT) and of the presence of plaques and their characteristics.
Subjects free of CVD with an increased IMT are at increased CV risk, independent of the presence of classical CV risk factors .
In the Rotterdam study, IMT was added to the FRS and resulted in an NRI of 8.2 % in women, less in men . In the ARIC study, an NRI of 9.9 % was observed in both genders . One of the limitations of applying this technique in daily practice relates to high variability and low reproducibility. In good hands carotid ultrasound may add to total CV risk estimation and help to adapt preventive actions accordingly.
Tests of Vascular Function
Flow-Mediated Vasodilation (FMD)
Atherosclerosis affects the endothelial function from its early stages. Therefore, the assessment of the endothelial-dependent vasodilator function of peripheral arteries is used to detect early abnormalities of endothelial health. The predictive value of brachial artery FMD has been largely studied . The incremental value of FMD measurements, independent of the FRS or the SCORE model, has been examined in only a few studies .
In one study in male intermediate-risk subjects, the addition of FMD using 4.75 % as a cut-off value increased the AUC (C-statistic) from 0.68 to 0.76. In the intermediate-risk individuals of the Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis (MESA), no changes in the C-statistic were reported after the addition of FMD to the basic prediction model; in that study it was shown that the addition of FMD to the model resulted in a low NRI (32). Different methods exist to measure FMD; they are prone to large inter-observer and intra-observer variability and need improvements in that respect before they can be implemented in clinical practice.
The measurement of arterial stiffness as a tissue biomarker has been studied using pulse wave analyses. Based on results from a meta-analysis it was concluded that the measurement of regional aortic pulse wave velocity (PWV) had incremental predictive value beyond classical CV risk factors . In the Rotterdam study, PWV had an independent prognostic value over and beyond the FRS. The added value of the PWV was largest in subjects with the lowest FRS .
Computed Tomography Imaging
Calcifications of the coronary arteries are indicators of atherosclerosis in the absence of chronic renal failure. The presence and the extent of calcification have mainly been examined using the Agatston score . Attention is now also paid to estimates of calcium volume and density.
In the Rotterdam Coronary Calcification Study, the risk of developing a myocardial infarction was 12 times greater in the upper percentile range of coronary calcium, independently of the traditional CV risk factors . In the Heinz Nixdorf Recall Study  and in the MESA study  it was demonstrated that the presence of coronary calcium can reclassify subjects who were considered to be at low or moderate total CV risk based on classical models into high or very high risk categories. In a recent report from the MESA study it was demonstrated that coronary artery calcium volume and density were independently associated with coronary and CV risk .
Results with the multislice CT with decreased radiation level also indicate effective reclassification of patients at intermediate risk according to classical models, into low or high risk groups .
Combining Different New Risk Markers
In the recent 2013 ACC/AHA guideline on CV risk assessment [5•], the question was raised on the evidence of reclassification or contribution to risk assessment when hs-CRP, apo B, creatinine of estimated glomerular filtration rate, microalbuminuria, coronary calcium, IMT , ABI, family history, or cardiorespiratory fitness are considered in addition to the traditional CV risk factors present in existing models. This was tested using 13 systematic reviews and meta-analyses, and on the basis of additional tests in the Pooled Cohort Equations that was newly developed. The conclusion from the working group is, “if, after quantitative risk assessment, a risk-based treatment decision is uncertain, assessment of one or more of the following – family history, hs-CRP, coronary artery calcium score or ABI – may be considered to inform treatment decision making.”
Different models have been developed to estimate the total CV risk of an asymptomatic person; these models are based on traditional CV risk factors and they should remain the mainstay of CV risk estimation at the level of the community. Which model to use may differ from country to country; the clinician should use the model that is based on recent observations in a population that resembles as close as possible the community where the patients come from.
The addition of novel risk markers such as HDL-C and hs-CRP can usefully reclassify individuals who are in the intermediate-risk category and close to a threshold for intervention.
Adding additional tests to detect subclinical vascular damage may improve risk estimation in persons where the chances are great that the results from these tests may reclassify the person in another risk category that may influence management decisions. However, it should be remembered that the actual problem with primary prevention of CVD is not the need for more personalized strategies but the failure to act in those who have the potential to benefit. Furthermore, there is an urgent need for intervention trials testing the value of using total CV risk estimation models in strategies for the primary prevention of CVD.
Compliance with Ethics Guidelines
Conflict of Interest
Guy G. De Backer
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.