Subclinical atherosclerosis, inflammation and events

"Preclinical ATS" is an early stage of atherosclerotic disease. The term indicates that “something is beginning to change" in vascular walls. The damage is still minimal, and can still potentially be corrected.
Carotid artery ultrasonography and measures of carotid intima-media thickness (IMT) are emerging technologies that may be useful in identifying a patient who may benefit from more aggressive preventive therapy. Recent data have improved our understanding of the application of CIMT as a screening tool for cardiovascular disease. This non-invasive, reproducible, inexpensive and radiation-free screening test provides a measurement that can place an individual into a higher or lower risk category, thus allowing for appropriate implementation of preventive strategies. (1)

Markers of subclinical atherosclerosis

Beyond intima-media thickness, other markers of subclinical atherosclerosis have been described in the last decade, such as evaluation of endothelial dysfunction and ankle-brachial index.

1) Endothelial dysfunction may affect cardovascular outcome

Advances in the understanding of vascular biology of atherosclerosis have improved our approach to its clinical management. The normal endothelium is an autocrine, paracrine, and endocrine organ that plays a key role in protection against atherosclerosis. Endothelium regulates vascular tone, lipid breakdown, inflammation, vessel growth and thrombogenesis. Conventional risk factors, however, can promote atherosclerosis by inducing endothelial dysfunction, through the decrease of bioavailability of nitric oxide (NO), the main mediator of the abovementioned endothelial functions. (2)
Evidence suggests that endothelial dysfunction is on the casual pathway for both atherogenesis and destabilisation of established plaques. A dysfunctional endothelium may lose its ability to exert its protective effect on the vascular system, and thus can be an important factor in the development and progression of the atherosclerotic process as well as outcome. (2 - 4) Endothelial function, as assessed by flow-mediated dilation (FMD), has been shown to be affected by cardiovascular risk factor, related to arterial diseases and to cardiovascular outcome, validating its use for studying the atherosclerotic disease. (5)

2) Intima Media Thickness to enter into risk calculation and as surrogate marker to monitor effects of drugs

Intima-media thickness is a marker of subclinical atherosclerosis at the level of the carotid arteries. It is measured by high-frequency (≥ 8 MHz) ultrasound transducers in both carotid arteries, on the distal straight 1 cm off the common carotid arteries, the carotid bifurcations and the proximal artery and 1 cm of the internal carotid arteries.
According to the joint ESH/ESC guidelines we considered normal values < 0.9 mm, intima-media thickness (IMT) values ranging from 0.9 mm to 1.5 mm and asymptomatic carotid plaque (ACP) values > 1.5 mm. (6)
Measurement of IMT has the potential to improve the assessment of global cardiovascular risk (GCVR), as it is currently possible by using the common score systems (Framingham, SCORE and the Italian “Progetto Cuore”). Indeed, these traditional risk prediction schemes need improvement as the majority of the CV events seems to occur in the “low” and “intermediate” GCVR groups. It has recently demonstrated that IMT (such as other markers of preclinical atherosclerosis: pulse wave velocity and left ventricular mass) predicts cardiovascular death independently of SCORE and the combination may improve risk prediction.
In a median 13-year follow-up of 1968 asymptomatic subjects, broaden primary prevention from subject with SCORE ≥ 5% to include subjects with 1% ≤ SCORE < 5% together with IMT, sensitivity increased from 72% to 89% (P = 0.006) (7). Similarly, in another study on 13145 subjects without pre-existing cardiovascular disease, it has been evaluated whether carotid IMT and the presence (or absence) of plaques improve risk prediction, stratified according to the Framingham risk score. The 23% of population was reclassified: the CIMT plus traditional risk factors plus plaque model provided the most improvement in the area under the curve (AUC), which increased from 0.742 (RF only) to 0.755 (95% confidence interval for the difference in adjusted AUC: 0.008 to 0.017). (8) Furthermore, we recently reported that in an Italian population with a low-intermediate global cardiovascular risk (as defined according to the equations of the Progetto Cuore), total events occurred in the 8% of subjects with normal carotid ultrasound findings, in the 13% (n = 14) with increased IMT and in the 15% (n = 23) with ACP (p < 0.012) (9 - 10). Finally, carotid IMT can be used as a surrogate marker in order to monitor the effects of different drugs, such as statins or calcium-antagonists, on the regression of the atherosclerotic process. (11)

3) Ankle-brachial blood pressure index (ABI) potentially can also be included in risk scoring systems

Ankle-Brachial Index (ABI) is a ratio of systolic blood pressure at dorsalis pedis and/or posterior tibial arteries to that in the brachial artery. It is an easy-to-perform, inexpensive, reproducible and non-invasive test. (12)
The technical requirements consist in a blood pressure cuff and a Doppler ultrasonic sensor. In normal conditions, blood pressure at the ankle is slightly higher than that one at the upper arms, so that ABI is usually > 1.00; high values (> 1.40) could be related to poor arterial compressibility resulting from stiffness and calcification, which may occur more commonly in patients with diabetes. Instead, lower values indicate reduced flow in the iliac-femoro-popliteal arterial vascular bed. ABI is used in vascular practice to detect and assess the severity of peripheral artery disease (PAD). Even in asymptomatic patients, values < 0.90 are widely accepted as a reasonable cut point to confirm the diagnosis of preclinical atherosclerosis of arteries supplying the legs. (13) ABI is an indicator of generalised atherosclerosis because lower levels have been related to higher rates of concomitant disease in other arteries (such as carotid and coronary arteries). Important results also suggest that GCVR is similar in patients with instrumental evidence of arterial stiffness or with low ABI. (14 - 15) Consequently, any abnormal ABI (< 0.9 or > 1.4) or evidence of arterial stiffness should be considered a marker of higher CV risk. Interestingly, from the first confidential results of the PANDORA study (16) it appears that approximately 20% of the population with a GCVR < 20% (according to the cards of risk) have an asymptomatic PAD. These subjects are then predisposed to poly-vascular atherosclerotic disease and need aggressive prevention, as do patients with asymptomatic carotid lesions (increased IMT or ACP). Therefore, ABI has the potential of being included into the cardiovascular scoring systems.

INFLAMMATION: cytokines and cytokine-inducible inflammatory molecules and circulating levels of C-reactive protein to potentially become biomarkers of increased risk.

Beyond traditional risk factors (RF), novel biomarkers have been investigated as possible indicators of increased risk. (17 - 18) Ample evidence, indeed, has suggested the pivotal causal role of inflammation in the atherosclerotic process from endothelial dysfunction to plaque rupture and thrombosis. Atherothrombosis of the coronary and cerebral vessels could then be a disorder of inflammation and innate immunity, as well as a disorder of lipid accumulation. (19) As a consequence, the various cytokines and cytokine-inducible inflammatory molecules are progressively becoming markers of ATS. Information on circulating levels of C-reactive protein (CRP) has generated interest in CRP as a potential biomarker of systemic inflammatory conditions and cardiovascular risk. According to current statements, subjects with CRP < 1 mg/l were considered at low risk, while those ones with CRP between 1 and 3 mg/l and between 3 and 10 mg/l were respectively considered at moderate and high risk. (20) In healthy males, CRP levels often increase in proportion to the prevalence of RF. In a previous prospective study we demonstrated that low values of CRP at baseline in healthy subjects were associated, after a five-year follow-up, to a lower incidence of cardiovascular events than high values. (21)  Risk-prediction models that incorporate hsCRP, such as the Reynolds Risk Score, have been developed. They improve risk classification and the accuracy for global risk prediction, particularly for those deemed at “intermediate risk” by usual algorithms, such as the Framingham Risk Score. Recent guidelines published by the joint European Society of Hypertension/European Society of Cardiology have suggested the inclusion of C-reactive protein (CRP) in the standard assessment of cardiovascular risk in hypertensive patients. (6)

Subclinical carotid atherosclerosis and inflammation:

Elevated CRP concentrations may significantly influence the occurrence of cerebro- and cardiovascular events. Several studies have suggested that inflammation may be important for accelerated progression of atherosclerosis, but few data are available on subjects with early stages of atherosclerosis. We recently investigated the predictive role of CRP in subjects with early stages of atherosclerosis, beyond the traditional cardio- and cerebrovascular RF. The hypothesis has been tested in two subgroups of patients: with and without hypertension. (22) The hypertensive subjects showed “at baseline” a higher proportional frequency of carotid lesions and “after a five-year follow-up” a higher incidence of clinical events than without it. In the no-hypertensive group an independent predictive role was shown just for the presence of preclinical lesions, whereas in the hypertensive group both elevated CRP and baseline carotid lesions influenced clinical events. We also found a strong correlation between events and quintiles of CRP concentrations in patients with hypertension, but not in those without it. Thus, our findings seem to highlight the role of inflammation in accelerated atherosclerotic development and progression in patients with hypertension. Other studies have not yet shown the association between inflammation and degree of carotid ATS. (26-27) The strong relationship between hs-CRP and IMT that we amply demonstrated may potentially account for the complex role of hs-CRP and IMT in the pathogenesis of cardiovascular events. Beyond the utility of high-sensitivity CRP levels in the prediction of early and late stages of atherosclerosis and subsequently in its association with clinical events, the therapeutic implications of these results still need to be evaluated by further studies. These data could support the hypothesis that patients with increased levels of inflammatory markers should be more aggressively managed.

Conclusion:

Recent investigations on atherosclerosis have focused on inflammation, providing new insight into mechanisms of disease. Inflammatory markers involved in vascular inflammation stimulate the generation of endothelial adhesion molecules, proteases, and other mediators, which may enter the circulation in soluble form. Contemplation of the clinical use of biomarkers in the context of atherosclerotic cardiovascular disease however requires considerable care. The example of inflammation in atherosclerosis illustrates rapid translation of basic science understanding to the clinic. Further studies, both in progress and for the future, will help evaluate the role of novel and emerging biomarkers in the clinical management of atherosclerosis and targeting of therapies. (21)
Although the circulating concentrations of several inflammatory mediators correlate with increased cardiovascular risk, few are ready for clinical practice. As a downstream biomarker, hs-CRP attracts particular attention. It provides functional integration of overall upstream cytokine activation. Adiponectin, soluble CD40 ligand, IL-18 and MMP-9 are additional biomarkers that have emerged in the search for predictors of a primary adverse cardiovascular event based on clinical data supported by broad experimental evidence. In addition, CRP, sCD40L (29), and adiponectin may serve as targets for pharmacologic therapy. With the exception of CRP, however, none of the established and emerging novel biomarkers for cardiovascular risk have demonstrated an independent additive value in the score systems. Furthermore, few commercial assays, currently available, achieve adequate levels of standardisation and accuracy for clinical use.