Vascular Ultrasound and Cardiovascular Risk Assessment

Kozakova M¹ and Palombo C²*

¹Department of Clinical and Experimental Medicine, University of Pisa, Italy

²Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Italy

*Corresponding author: Carlo Palombo, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Italy

Received: January 05, 2016; Accepted: February 02, 2016; Published: February 03, 2016

Abstract

Vascular ultrasound is able to detect endothelial dysfunction, arterial structural remodeling and increased arterial stiffness. These alterations have been shown to be associated with established and emerging cardiovascular risk factors and with incident cardiovascular events. Therefore, vascular ultrasound has been proposed to evaluate the role of different risk factors in the initiation and progression of atherosclerotic process, to study vascular aging and the relationship between arterial stiffness and atherosclerosis, to assess the efficacy of life-style and therapeutic interventions, and to improve the estimation of individual cardiovascular risk. The present paper provides a critical overview of the clinical evidence appraising the association of flow-mediated dilation, carotid and femoral intima-media thickness and plaque presence as well as local arterial stiffness with cardiovascular risk factors and cardiovascular events.

Keywords: Ultrasound; Biomarkers; Carotid artery; Cardiovascular risk; Intima-Media thickness; Arterial stiffness; Flow-Mediated dilation

Abbreviations

CV: Cardiovascular; D: Disease; US: Ultrasound; FMD: Flow- Mediated Dilation; CHS: Cardiovascular Health Study; MESA: Multi-ethnic Study on Atherosclerosis; NRI: Net Reclassification improvement; IMT: Intima-Media Thickness; CCA: Common Carotid Artery; ARIC: Atherosclerosis Risk in Communities Study; ICA: Internal Carotid Artery; 3-D: 3-Dimensional; FA: Femoral Artery; PWV: Pulse-Wave Velocity; CF: Carotid-Femoral

Introduction

Cardiovascular (CV) Disease (D) is the leading cause of death worldwide. In Europe, CVD is responsible for over 4 millions death per year, and causes 42% and 51% of deaths among men and women, respectively, compared with 23% and 19% for all cancers [1]. The medical cost of CVD has continuously increased in the past years, and in 2012 the overall CVD cost in Europe was estimated to be of €196 billion. In the next 20 years this cost is expected to further escalate.

Yet, CVD is largely preventable, and an early detection of individuals at increased risk followed by the implementation of life-style and therapeutic interventions can prevent disability and death, improve quality of life and reduce the global health-care cost. However, the accurate and cost-effective identification of subjects at risk is still a challenge. Various risk scores (Framingham Risk Score, SCORE Charts, and others) have been developed to guide the preventive strategies [2], yet these scores provide estimation of a population-based risk rather than quantification of the individual risk. Furthermore, a substantial part of population belongs to intermediate risk, where it is not clear whether and when an aggressive prevention strategy is beneficial and cost effective.

The use of CV biomarkers in conjunction with risk scores is expected to refine the risk stratification of an individual subject and to guide the preventive/therapeutic strategy. A “biomarker” was defined by the National Institutes of Health as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [3]. Therefore, biomarkers can be used to detect the burden of subclinical disease in order to apply preventive measures, and they should also enable to monitor the response of subclinical disease to preventive interventions. Yet, robust pathophysiologic, epidemiologic and therapeutic evidence is necessary to validate any new biomarker. According to a scientific statement from the American Heart Association, biomarker should differ between subjects with and without outcome, should predict the development of future events over and above established risk markers, and its use should improve clinical outcomes when tested in a randomized clinical trial [4].

Vascular measures might be particularly informative for the assessment of CV risk, as they detect organ damage in different parts of vascular bed, are measurable in a non-invasive way, and reflect both aging process and adverse impact of established CV risk factors, like plasma lipids, smoking, high blood pressure, diabetes, inflammation [5].Nowadays, several vascular biomarkers have been proposed. A position paper from the European Society of Cardiology Working Group on peripheral circulation suggests that the choice of vascular biomarker, or their combination, should depend on the clinical setting and present comorbidities, and may differ for each individual patient [5]. The widespread clinical use of biomarkers depends also on their cost-effectiveness, ease of use, clear methodological consensus and availability of reference values. From this perspective a vascular Ultrasound (US) is an interesting method, as it allows the composite evaluation of vascular structure and function in a non-invasive way at a relatively low cost (Table 1). Vascular ultrasound can be used to assess endothelial function, geometry and stiffness of elastic arteries (like carotid artery) and muscular arteries (like brachial and femoral artery).

Table 1: Vascular biomarkers obtained by ultrasound.




  
     
    Description 
    Method of measurement 
    Formulas 
    Clinical Utility 
    Recommendation/ 
      Level of evidence 
      for CV prevention 
    Reference 
      values 
  
  
    FMD 
    response of BA to
      reactive hyperemia
    B-mode US
      RF-based US
    direct
      measurement
    in intermediate risk subjects NRI=2.4% for CHD [17]
    III/B
    No
  
  
    Carotid IMT 
    thickness of the near/far wall of CCA/bulb/ICA
    B-mode US
      RF-based US
       
    direct
      measurement
    CCA IMT in intermediate risk subjects NRI=3.6% for MI or stroke [34]
      ICA IMT in general populationNRI=7% for CHD [36]
    IIa/A
    Yes
  
  
    Carotid Plaques 
    number
      thickness
      area
      volume
    B-mode US
       
    direct
      measurement
    IMT+plaque in general population NRI=9.9% for CHD [41]
      IMT+plaque in intermediate risk subjects NRI=21.7%for CHD [41]
      ICA plaque in general population NRI=7.3% for CVD [42]
      carotid plaque score in general population NRI=10.2% for CVD [43]
    IIa/A
    No
  
  
    Local stiffness 
    changes in vessel diameter/area to distending pressure
       
       
       
       
       
       
       
       
      local PWV
       
       
    B-mode US
      RF-based wall tracking
       
    distensibility:
      DD/(DP*D)
      compliance:
      DD/DP
      beta index:
      ln(Ps/Pd)*D / (DD)
      elastic modulus:
      (DP*D)/ DD
      Young’s modulus:
      (DP*D)/ (DD*h)
      Bramwell-Hill equation [71]
    --
    --
    Yes



Table 1:  Vascular biomarkers obtained by ultrasound.

Endothelial function

The vascular endothelium is a single layer of cells situated at the interface between the blood and the vascular wall and releasing a wide range of factors that play a central role in the maintenance of vascular health, as they regulate vascular tone, vascular growth, inflammation, cell adhesiveness and coagulation [6]. A loss of normal endothelial function is believed a key event in the initiation of atherosclerotic process [7]. Endothelial function can be measured by different techniques, yet the most widely applied technique is brachial artery Flow-Mediated Dilation (FMD). FMD is a nitric oxide-mediated process using high resolution US to monitor the response of arterial diameter to increase in blood flow, which represents a physiologic stimulus for endothelial nitric oxide release [8].

FMD has been shown to be adversely associated with CV risk factors, like hypertension, diabetes, dyslipidemia, smoking, inflammation and abdominal obesity [9-13]. The prognostic value of FMD for future CV events has been also tested. In the elderly population of the Cardiovascular Health Study (CHS) [14] as well as in the population-based cohort of the Multi-ethnic Study of Atherosclerosis (MESA) [15], FMD resulted an independent predictor for CV events, and in a recent meta-analysis of 23 studies including 14 753 subjects, for each 1% increase in FMD the overall CVD risk decreased by 13% in diseased population and by 4% in asymptomatic population [16]. However, the above-mentioned studies also demonstrated that FMD added little to the prognostic accuracy of traditional CV risk factors/scores. In the intermediate risk population of the MESA, the Net Reclassification Improvement (NRI) of FMD for incident coronary heart disease was only 2.4% (Table 1), being lower than that of carotid intima-media thickness (IMT; 10.2%) [17].

FMD has been also used to evaluate the effect of life-style and pharmacologic interventions on endothelial function, and numerous studies have demonstrated that endothelial dysfunction may improve with exercise, weight loss, vitamins, statins or antihypertensive treatment [18-21].

Although the concept of FMD is simple, the correct and reproducible measurement requires significant expertise, and published guidelines suggest a minimum of 100 supervised scans before the independent scanning, and at least 100 scans per year to maintain competency [22]. Additional methodological issues, like the level of inflation pressure, duration of ischemia, localization of inflation and the time point at which the effect of hyperemia on artery is measured, should be standardized and respected by all centers using this method [22-23].

Therefore, at the moment, FMD seems to be above all an interesting research tool that can be employed to study the role of emerging CV risk factors in the development of atherosclerosis and to monitor the effect of interventions and treatment on endothelial function, as the method is non-invasive, does not use pharmacologic stimuli, can be repeated several times and has an adequate reproducibility in expert laboratories [24]. On the other hand, its widespread clinical use for the risk stratification is not currently recommended by guidelines [25-26].

Carotid/Femoral artery IMT and plaques

Arterial wall is histologically constituted of three layers; 1) the inner layer, called tunica intima and composed of a monolayer of endothelial cells supported by internal elastic lamina; 2) the middle layer, called tunica media and consisting of longitudinal smooth muscle cells surrounded by connective tissue with elastic lamellae; 3) the outermost layer, called tunica adventitia and formed by connective tissue with collagen fibers.IMT is a combined measure of tunica intima and tunica media, and may be assessed by high-resolution US in different segments of extracranial carotid tree or in large muscular arteries as the distance between the intima-luminal and the medialadventitial interfaces of the arterial wall. With aging and the presence of CV risk factor, IMT increases and loses its double-line aspect (Figure 1). Plaque, a focal intima-media thickening, appears first in the plaque prone areas [27], i.e. areas with a particular hemodynamic pattern, like arterial branching, that is characterized by a low and oscillating shear stress and a cyclic reversal flow (Figure 2A). It is unclear, whether thickened intima-media complex and the presence of plaques represent two different stages or two different phenotypes of atherosclerotic process.

Figure 1: A) Thin intima-media complex in adolescent; B) Increased thickness of intima-media complex in elderly healthy subject; C) Diffuse thickening of intima-media complex with structural changes leading to the loss of a 3-layer aspect; D) Irregular and markedly thickened CCA wall - development of the plaque at the posterior wall.

    
    
    Figure 1:  A) Thin intima-media complex in adolescent; B) Increased thickness
of intima-media complex in elderly healthy subject; C) Diffuse thickening of
intima-media complex with structural changes leading to the loss of a 3-layer
aspect; D) Irregular and markedly thickened CCA wall - development of the
plaque at the posterior wall.

Figure 2: A) Small fibrotic plaque at carotid bifurcation (atherosclerotic prone area); B) Flat, lipid-rich plaque at the posterior wall of CCA; C) Fibrotic concentric plaque at carotid bulb; D) Irregular fibrotic plaque at carotid bulb and calcified plaque with an irregular surface at the origin of internal carotid artery (acoustic shadowing).

    
    
    Figure 2:  A) Small fibrotic plaque at carotid bifurcation (atherosclerotic
prone area); B) Flat, lipid-rich plaque at the posterior wall of CCA; C) Fibrotic
concentric plaque at carotid bulb; D) Irregular fibrotic plaque at carotid bulb
and calcified plaque with an irregular surface at the origin of internal carotid
artery (acoustic shadowing).

Numerous large prospective studies, like Kuopio Ischemic Heart Disease study, Atherosclerosis Risk in Communities (ARIC) study, CHS, Carotid Atherosclerosis Progression Study, Rotterdam Study, have demonstrated the association between carotid IMT and incident CVD risk [28-32]. A meta-analysis of 16 studies including 36.984 participants showed an increase in CV events risk of 16% per 0.1 mm difference in baseline common carotid artery (CCA) IMT [33]. However, the studies evaluating the predictive value of carotid IMT over and above established risk scores have been largely negative [17,31], and in a meta-analysis of 14 population-based studies (45.828 participants), the NRI of CCA IMT over Framingham risk score was small, being 0.8% for overall cohort and 3.6% for intermediate risk subjects [34] (Table 1). Still, the meta-analysis was affected by the variability in the IMT methodologies and reporting (number of projections, number of segments, mean or maximal IMT value), and the evaluation was limited only to CCA IMT, while IMT in carotid bifurcation or Internal Carotid Artery (ICA) was not included. It seems that IMT in different carotid segments could be associated with different CV risk factors and events. In the British Regional Heart Study, CCA IMT was strongly associated with risk factors for stroke (above all blood pressure) and with prevalent stroke, whereas bulb IMT and/or plaques were more associated with ischemic heart disease risk factors(smoking, plasma fibrinogen) and prevalent ischemic heart disease [35]. In the MESA, only the mean of maximum IMT in ICA, but not in CCA, has significant NRI (7.0%) for coronary heart disease events [36] (Table 1). The differences between carotid segments can be explained by the fact that the atherosclerotic process tends to develop initially in the areas of arterial branching (Figure 2A), and that increase in CCA IMT may represent not only the atherosclerotic process, but also arterial remodeling reflecting smooth muscle cells hypertrophy and hyperplasia responding to increase in wall tensile stress and pulsatile load [37-38], above all in hypertensive patients.

Carotid plaque (Figure 2 A-D), when compared to IMT, has been shown to have a higher diagnostic accuracy for the prediction of future coronary artery disease events [39], and the presence of carotid plaques predicted CV mortality independently of SCORE stratification [40]. In the ARIC population followed for 15.2 years, adding plaque and carotid IMT (an average of values obtained in 3 segments of both the left and right sides) to traditional risk factors improved coronary heart disease prediction (NRI= 9.9% in the entire population and 21.7% in the intermediate risk groups) [41]. Improvement of CVD risk estimation over Framingham risk score and traditional risk factors was observed for the plaque presence in the ICA (NRI=7.3%) and for the total plaque score (NRI=10.2%) in the Framingham Offspring Study cohort and in Chinese population [43], respectively (Table 1).

Altogether the published data indicate that extensive US examination of extracranial carotid tree is required to fully assess the degree of atherosclerotic burden. Indeed, the American Society of Echocardiography consensus statement specifies that carotidartery ultrasonography for CVD risk prediction should be based on a thorough scan to detect the presence of plaques, followed by measurement of IMT in the CCA [44], and Mannheim consensus recommends to image each carotid segment from multiple angels as atherosclerotic process is distributed asymmetrically within the vessel wall [45].

In healthy subjects, an average IMT ranges between 400-750 μm (according to age; Figure 1 A and B), IMT progression rate is small - between 1-32μm per year, and the differences between the 25th and 75^th percentile are < 1 mm [46-49]. Consequently, a high degree of precision is required for IMT measurement. A higher accuracy and better reproducibility of measurements can be achieved by applications of automated edge-tracking algorithms [50], or by the use of Radiofrequency (RF)-based echo tracking technology allowing automatic measurement of IMT directly from unprocessed RF signal (Figure 3) [51].

Vascular Ultrasound and Cardiovascular Risk Assessment

Abstract

Abbreviations

Introduction

Endothelial function

Carotid/Femoral artery IMT and plaques

Local arterial stiffness

The role of vascular biomarkers in pediatric populations

Conclusion

References