The role of vascular biomarkers for primary and secondary prevention.

A position paper from the European Society of Cardiology Working Group on peripheral circulation Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society

 
Vlachopoulos C, Xaplanteris P, Aboyans V et al.
Atherosclerosis. 2015 Aug;241(2):507-32
 

Introduction

Various risk scores exist to assess cardiovascular risk and to guide preventive strategies. Despite their wide use, risk scores are not perfect and a small but significant gap exists between predicted and actual event rates. Several factors may contribute to the limitations of risk scores, including extrapolation to populations or times different from the original cohort and the choice of factors included.
Biomarkers may further stratify patients’ risk. CV biomarkers reflect early functional or morphological changes, before overt disease manifests, which could offer opportunities for prevention of clinical CV disease through timely treatment.
 

Vascular biomarkers as surrogate endpoints

Changes in surrogate endpoints are detected earlier and at a lower cost than the clinical endpoint they are a substitute for, which facilitates diagnosis and clinical trials. A biomarker should satisfy several phases of evaluation, according to the American Heart Association (AHA), to be considered as a surrogate endpoint:

1. 1: Proof of concept
2. 2: Prospective validation
3. 3: Incremental value
4. 4: Clinical utility
5. 5: Clinical outcomes
6. 6: Cost-effectiveness

In addition, a biomarker should be relatively easy to measure, according to a well-defined protocols, and it should distinguish individuals at risk. The current article proposes to add three additional steps for a vascular biomarker to qualify as a clinical surrogate endpoint:

1. 7: Ease of use
2. 8: Methodological consensus
3. 9: Reference values (or cut-off values).

 
This document gives a methodological outline, and discusses all 9 criteria for each vascular biomarker, revealing that many steps have not been established for all of them, and cost-effectiveness data are almost uniformly lacking.
Most biomarkers considered fit within the concept of early vascular aging, in which a cumulative measure of the impact of CV risk factors on the arterial wall, in association and interaction with the individual genetic background, has the potential to accurately predict a person’s overall CV risk. This document investigates the role of peripheral (non-coronary circulation) noninvasive vascular biomarkers for primary and secondary CV disease prevention. This document should help clinicians in selecting the appropriate index to be measured in different clinical and research scenarios.
 
Carotid ultrasonography, ankle-brachial index (ABI), arterial stiffness, central haemodynamics/wave reflections, endothelial function and circulating biomarkers related to vascular wall biology are discussed in detail according to the criteria mentioned above.
 

Interplay between macro and microvascular disease

Disruption of vasculoelastic properties of large arteries, which smoothen out the pulsatile pressure that is the consequence of ventricular ejection, can lead to end-organ damage. The structure of the microvasculature correlates with wave reflections, stiffness of large conduit arteries and blood pressure levels. Several such relationships indicate coupling and crosstalk between micro- and macrovascular arterial beds. The crosstalk can aggravate problems in either system, culminating in target organ damage.
 
The role of vascular biomarkers in specific subgroups is also discussed in detail. Prediction of hypertension in normotensives and CV risk stratification in hypertensive individuals in relation to vascular characteristics, of which arterial stiffness is the most relevant, is outlined. Similarly, identification of diabetes and dyslipidaemia in individuals not yet affected by these conditions is considered, as well as CV risk stratification in patients who are affected. Presence of peripheral artery disease (PAD) categorises patients in the highest risk group, and vascular biomarkers may further stratify risk in PAD patients. Stroke is also a strong predictor of further CV events and death, again a risk that may be refined by biomarkers. Moreover, renal impairment predicts CV risk, which can further be stratified by cfPWV (the velocity of the pulse as it travels from the heart to carotid and femoral artery).
 

Pharmacological modification of vascular biomarkers and CV risk

Although several drug classes can modify levels of vascular biomarkers, this does automatically imply that modification translates in reduced morbidity and mortality.
Effects of different pharmacological classes on endothelial functions vary widely, and are summarised. Arterial stiffness is more homogeneously decreased by most antihypertensive agents, either via an active or a passive effect. Anti-inflammatory drugs, lipid-lowering agents and phosphodi-esterase type 5 inhibitors can also lower arterial stiffness. Central systolic blood pressure and wave reflection have been shown to be favourably modified by some drugs, while other agents had the opposite or a neutral effect. Antihypertensive drugs have been shown to reduce cIMT, with superior effect of calcium channel blockers. It should be noted that it is unclear whether this larger reduction in cIMT represents a greater reduction in intima-media wall mass. Future applications of 3D imaging of the carotid plaque may aid developing interventions to reduce total plaque area or volume.
In addition to pharmacological modification, lifestyle changes and food supplements can also positively impact vascular biomarkers.
 

Conclusion

Biomarkers should not be routinely measured, but may be of added value beyond classical risk factors in patients classified as having moderate risk, and when therapeutic dilemma’s arise. Biomarkers can refine risk stratification and guide therapeutic decisions. Vascular biomarkers may be particularly informative as they integrate, predict risk and detect subclinical disease from different vascular beds.
It is currently unclear if one vascular biomarker is clearly superior. Choice of a biomarker or a combination depends on the clinical setting and present comorbidities, and may well differ for each individual patient. Although promising, vascular biomarker-driven therapeutic decisions need to be validated through randomised clinical trials.
 
- We refer to the article for details on the different vascular biomarkers and the extent to which they fulfil the 9 essential criteria –
 
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