Tailor-made therapy for the prevention of acute coronary syndromes: future role of biomarkers in risk stratification and disease management

Due to the ongoing global increase in the prevalence of coronary artery disease (CAD), this chronic and progressive illness is projected to become the largest single cause of disease-burden worldwide by the year 2020 [1]. ‘Globalization’ of dietary habits and urbanization in the developing world are thought to be among the protagonists of this development [2]. Parallel to its impact on the general health of the global community, CAD will also burden the different healthcare systems of the world to an increasing extent. Currently, the annual cost of coronary heart disease in the UK already ranks highest of all diseases for which comparable analyses have been performed [3]. Bearing this perspective in mind, together with the current knowledge of traditional risk factors for the development of CAD, a serious responsibility, both in the field of primary and secondary prevention, lies ahead for policy makers in developed nations as well as in upcoming economies. On the other hand, despite all preventive measures, the occurrence of CAD and its manifestation in the form of acute coronary syndrome (ACS) cannot be expelled totally. Consequently, the cardiovascular research field will remain challenged towards expansion of their pathophysiologic and therapeutic knowledge-base for the purpose of tertiary prevention; reduction of mortality and morbidity, and improvement of the quality of life for those patients who have experienced an ACS.

In conformity with current therapeutic aims [4,5], prevention of myocardial reinfarction will remain of vital importance in the management of these patients with CAD. As commonly acknowledged, the surge for tertiary prevention and, in particular, prevention of myocardial reinfarction has previously already led to several milestone achievements. Worth mentioning are the introduction of fibrinolytic therapy [6,7] and primary percutaneous coronary intervention [8] in order to obtain early reperfusion in the acute phase, as well as the many separate pharmacologic developments that have contributed towards validated, long-term post-ACS pharmacotherapeutic treatment strategies [4,5]. Undoubtedly, the future will continue to reveal crucial aspects of coronary pathophysiology, disease management and individual risk stratification for the occurrence of major adverse cardiac events.

Having stated this, it can also be concluded that in our quest for better understanding and management, paradigm shifts have taken place both in the realm of the pathophysiology of ACS, as well as in our general thinking about ideal disease management. With respect to the pathophysiology, the framework of our former belief that ACS result from a primarily chronic and progressive metabolic process, has shifted towards a concept in which the combination of distorted lipid metabolism, vascular inflammation, endothelial dysfunction, decreased endothelial regenerative capacity and increased thrombogenicity plays a dominant role [9–11]. Further improvement in our understanding of pathophysiology could lead to a substantial and desirable shift in terms of disease management, in which ACS patients are no longer considered to be a homogeneous group requiring more or less the same long-term pharmacotherapeutic preventive treatment. Instead ACS patients could be regarded as a more heterogeneous population in which we acknowledge that these patients differ on the basis of a different composition of the aforementioned dynamic pathophysiologic constituents and are, therefore, also individually exposed to different risks over time.

In this context, the major future paradigm shift in ACS management implies the identification of the individual patient who is at high risk of experiencing a (repeat) coronary event within a precise and short timeframe. Identification of such a ‘vulnerable period’ and subsequent therapeutic adjustment could then lead to prevention of the imminent event. This framework, in which the vulnerable plaque will have to be actively sought as part of a vulnerable artery, the vulnerable arterial bed and the vulnerable patient at large, will perfectly fit in the future era of ‘personalized medicine’ [12].

Major progress will have to be made, though, before combined individual and dynamic risk prediction of coronary events will come of age and find clinical application. A key role in this process could be reserved for biomarkers. Since the primary demonstration in 1954 that serum transaminase is increased in acute myocardial infarction [13], biomarker development has impressively evolved towards the current status in which established and specific biomarkers, including Troponin-T, play an essential role in diagnostics and risk stratification. Apart from these established biomarkers, novel biomarkers (e.g., placental growth factor) have also proven to be effective risk predictors [14]. Equally important, many within the vast range of novel markers hold the promise to reflect the various components of CAD quite specifically, such as vascular inflammation, endothelial dysfunction, diminished endothelial regenerative capacity, hypercoagulability, myocardial ischemia and necrosis [11,15]. Besides the fact that these biomarkers possess an inherent ability to individually reflect the pathophysiologic process (e.g., vascular inflammation, endothelial dysfunction and increased thrombogenicity) and its consequences (e.g., ischemia and necrosis), they also possess the ability to reflect disease dynamics through varying plasma values. Compared with dynamic biomarkers with changing values over time, a traditional risk factor such as a confirmed positive familial history of cardiovascular disease, can be considered ‘static’ information. Once it has been determined to be a patient characteristic, it will pose a lifelong and more or less constant risk and will therefore not be able to predict the occurrence of an ACS in a specific and short future timeframe. However, biomarkers of vascular inflammation for instance, or a combination of markers for that matter, that are found to adequately reflect pathophysiologic alterations in the arterial bed, might fluctuate prior to an event and therewith indicate that the patient is in a ‘vulnerable period’ for the development of an acute coronary syndrome.

Obviously, this (yet uninvestigated) scenario raises a very attractive hypothesis for individual, dynamic risk stratification and subsequent clinical decision making. Biomarker properties, at least in theory, perfectly suit monitoring short-term risks of a dynamic pathophysiologic process, like CAD essentially is. Realistically, testing of such a hypothesis requires further understanding of biomarker kinetics, patterns, appropriate cut-off values and prediction characteristics (such as timeframes), particularly briefly prior to the actual occurrence of an ACS. Furthermore, clinical application also requires biomarker measurement standardization and selection of assays that have adequate precision in the appropriate ranges for CAD [16]. In an ideal future setting, however, obtained knowledge of biomarker patterns prior to coronary events could lead to simple point-of-care testing, in which patients with CAD, but without cardiac complaints, could both assess their short-term future risk, as well as monitor therapeutic efficacy at home using bedside tests. Vulnerable patients could benefit from a tailor-made and individual therapeutic plan with intensification of pharmacologic treatment or possibly even an immediate coronary angiography with intra-vascular ultrasound-derived techniques for the assessment of unstable, vulnerable plaques.

Besides their potential in diagnostics and risk assessment, biomarkers could also find an application in monitoring and validating the efficacy of future pharmacotherapeutic agents for the treatment of CAD (e.g., research on the effects of anti-inflammatory drugs). Additionally, biomarkers could contribute to the expansion of knowledge on the pharmacokinetics of currents drugs, for example, through monitoring the anti-inflammatory effects of various statins, assessing the effects of angiotensin-converting enzyme-inhibitors on endothelial function, or mapping variable responses to antiplatelet therapy at a more specific biochemical level than possible solely with functional tests, such as bleeding time and turbidometric platelet aggregometry. The recent US FDA approval of one particular bedside monitor of antiplatelet therapy preludes an era in which patients will progressively be able to monitor therapeutic efficacy at home and inform clinicians in case of divergence [17]. This sort of point-of-care monitoring of therapy obviously has the potential to spare some patients the disadvantages of generalized dosing and subsequent over- or undertreatment. In a final, but yet to be properly investigated scenario, cytokines themselves, as well as their receptors, might represent therapeutic options in CAD management [14,18]. Monoclonal antibodies that block TNF-α or integrin-dependent leukocyte adhesion have already been proven to reduce inflammation in patients with rheumatoid arthritis, multiple sclerosis and Crohn’s disease [18].

In conclusion, the tremendous momentum that biomarkers have gained over time as relatively cheap, noninvasive, easily-accessible and yet specific diagnostic tools, may merely prove to be the beginning of the exploration of these very challenging and versatile biochemical structures. Due to the presence of gaps and conflicting evidence within our current knowledge base, serious challenges can be identified that will have to be confronted in order to investigate the aforementioned possible applications. It is the authors’ conviction, however, that given the rationally assumed potential for superior clinical decision making and disease management, biomarker research for diagnostic, risk assessment as well as therapeutic applications will not loose momentum within the foreseeable future.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.