Biomarkers hold the promise of revealing the genetic predisposition of individuals for the development of various diseases, such as atherosclerosis. Yet genetic biomarkers in the field of cardiovascular disease have failed to display the same success as in predicting the risk of development of certain kinds of tumors. In contrast, circulating biomarkers are a promising approach as they reflect ongoing pathological processes, even though they have limited sensitivity and specificity for the prediction of disease development. Anatomical, morphological, and biological markers derived from different imaging modalities, such as computed tomography, positron emission tomography, and magnetic resonance imaging have also been extensively tested. One example is the coronary calcium score, derived from computer tomography scans. This score does not rely on the administration of contrast media and employs only low radiation doses. The coronary calcium score is among the most promising novel biomarkers, as it combines biological information—calcification of atherosclerotic lesions— with spatial location.

The reason such an intense focus is placed on identifying novel biomarkers is that traditional risk factors do not allow reliable and sufficient identification of all subjects at risk for the onset and development of cardiovascular disease. Even though many highly promising biomarkers have been introduced and tested in large patient populations over traditional risk scores like the Framingham risk score. The combination of different biomarkers has also failed to evidence significant improvement in the prediction of disease development. Some biomarkers have resulted in the reclassification of certain patient groups. However the true benefit of these biomarkers remains theoretical in the absence of confirmation by large randomized trials.

Even though no revolutionary novel biomarkers have yet been discovered and introduced into the field of cardiovascular diseases, some have shown great potential and are now being tested in large randomized trials. They include biomarkers from the fields of proteomics, metabolomics, and transcriptomics. However, these techniques do not allow spatial localization of the causative pathological process in the body. Several currently tested promising approaches are based on specific spatial localization. In this context, techniques combining the spatial or anatomical information derived from imaging with the biological information derived from molecular probes seem to be a particularly promising approach for improving the risk stratification of
patients. Among the most promising such techniques are novel hybrid molecular imaging modalities (eg, magnetic resonance imaging with positron emission tomography [MR-PET]) with novel in vivo molecular markers.

In the context of cardiovascular diseases, patients are increasingly stratified using risk-scoring systems. One example is the Framingham Risk Score, which classifies patients into categories of high. intermediate, and low risk for cardiovascular disease, This risk scoring system is based on 10-year absolute risk of coronary heart disease or cardiovascular disease. Risk-scoring systems, however, have been shown to have limited accuracy in certain patient populations like women and older patients. To improve risk stratification, additional tests extending predictive accuracy have been proposed. In the case of atherosclerotic disease, an assessment of carotid intima-media thickness has been proposed as an additional test to improve risk stratification. Studies have shown that addition of carotid intima-media thickness measurement to established risk-scoring systems can lead to a small, but significant, improvement in cardiovascular risk prediction.

In this large population-based study, the authors aimed to compare carotid intima-media thickness measurements to the traditionally used Framingham Risk Scoring System. The authors investigated a large population of more than 3500 nondiabetic subjects. aged 55 to 75 years. The ability of carotid intima-media thickness measurements to better classify people into categories of high, intermediate, and proven prediction of coronary heart disease or stroke. In older women, the addition of carotid intima-media thickness Framingham risk factors significantly improved risk classification Reclassification was most substantial in women at intermediate risk for coronary heart disease and for stroke. The discrepancy between this study and previously performed studies could at least be partially explained by the differences in included study populations This study is a good example that shows that even in cases in which a well-established association between a parameter (carotid intima-media thickness) and risk of future events exists, its additional predictive value within clinical risk categories based on traditional risk factors is not always clear.

A population of more than 6500 participants between the ages of 45 to 84 and free of clinical. cardiovascular disease at the time the study was initiated. The primary end point was prespecified and included myocardial infarction, re- suscitated cardiac arrest, cardiovascular death, and stroke. A secondary combined endpoint of coronary events excluded stroke.

Aortic valve calcification is a particularly interesting parameter, as it can be assessed with the standard coronary artery scan and is therefore available without the need for additional examinations or tests. It is commonly observed in older adults, with an estimated prevalence of 25% in individuals older than 65 years of age. Aortic valve calcification is now recognized as an actively regulated inflammatory process that shares many similarities with the development of coronary atherosclerosis. In older adults without known cardiovascular disease, aortic valve calcification was shown to be a strong marker for the occurrence of future cardiovascular events.

In summary, this study of a large population free of clinical cardiovascular disease at the time the study was initiated showed that aortic valve calcification is a valid biomarker for the risk assessment of cardiovascular and coronary events and that it is superior to traditionally assessed risk factors. It was also shown that even when risk associations are adjusted for inflammatory biomarkers, aortic valve calcification remains a strong predictor of cardiovascular and coronary events. This finding suggests that aortic valve calcification may be a helpful marker for the severity of sub-clinical atherosclerosis. It should, however, be mentioned that the risk associations were significantly attenuated after adjustment for coronary artery calcium. suggesting that both these parameters, at least to some extent, reflect comparable biological processes that occur concomitantly in the arterial wall. 

A surprising and highly important finding of the study was that, even when aortic valve calcification was adjusted for inflammation, subclinical atherosclerosis, and other risk factors, the association with excess cardiovascular mortality remained. This observation could not be fully explained by the authors, but was very interesting, as excess mortality may be unrelated to progressive heart valve disease.