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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
Open AccessPublished:May 16, 2015DOI:https://doi.org/10.1016/j.atherosclerosis.2015.05.007

      Highlights

      • Risk scores are used in clinical decision-making but can under- or overestimate risk.
      • Biomarkers can further stratify the risk of patients at an individual level.
      • Biomarkers may prevent the occurrence of clinical disease by timely treatment.
      • Nine criteria should be met for a biomarker to be a surrogate endpoint.
      • Carotid ultrasonography, ABI and cfPWV fulfill most of the criteria.

      Abstract

      While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required.

      Keywords

      1. Introduction

      Accurate assessment of cardiovascular (CV) risk is essential for clinical decision-making; the benefits, risks and costs of management strategies must be weighed to choose the best individually tailored preventive strategy. Many scores have been developed over the years to classify patients into low, medium or high CV risk groups. In Europe, the HeartScore and its online version, Systemic Coronary Risk Evaluation (SCORE), have been introduced for the prediction of the total fatal 10-year CV risk [
      • Conroy R.M.
      • Pyorala K.
      • Fitzgerald A.P.
      • et al.
      Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project.
      ]. In the U.S.A., a number of different risk scores have been validated. The most widely used ones come from the Framingham Heart Study group that has proposed an array of 14 risk equations [], while the most recently proposed risk equation by the American College of Cardiology/American Heart Association (ACC/AHA) [
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the american college of Cardiology/American heart association task force on practice guidelines.
      ] has been the subject of controversy.
      Risk scores are not, however, flawless and their head-to-head comparison opens many questions [
      • Siontis G.C.
      • Tzoulaki I.
      • Siontis K.C.
      • Ioannidis J.P.
      Comparisons of established risk prediction models for cardiovascular disease: systematic review.
      ]. Moreover, a small, yet significant gap exists between predicted and actual event rates, leading to under- and over-prediction, thus raising the issue of calibration. The extrapolation to populations different from the original cohort, the choice of traditional risk factors that are included, the changes in population characteristics because of the time delay between observational studies and application of risk scores, as well as the omission of novel indices relating to CV pathophysiology may partly explain the limitations of risk scores [
      • Cooney M.T.
      • Dudina A.L.
      • Graham I.M.
      Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians.
      ].
      Additional tools to further stratify the risk of patients are biomarkers. According to the National Institutes of Health definition, a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [
      • Biomarkers Definitions Working G
      Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.
      ]. In essence, and in the setting of prevention, CV biomarkers reflect early functional or morphological changes, well before overt disease manifests. This identification of subclinical disease may open a window of opportunity to prevent the occurrence of clinical CV disease by timely treatment.
      Vascular biomarkers as surrogate endpoints:
      A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. Changes in surrogate endpoints are detected earlier and at a lower cost than clinical endpoints (e.g. morbidity and mortality). Thus, diagnosis and clinical trials are facilitated. A surrogate endpoint is expected to predict clinical benefit/harm or lack thereof, based on epidemiologic, therapeutic, pathophysiological or other scientific evidence. In order to be considered as a “surrogate endpoint” of CV events, a biomarker should satisfy several steps. According to the AHA, the 6 phases of evaluation of a novel risk marker include: 1. Proof of concept: Do novel biomarker levels differ between subjects with and without outcome? 2. Prospective validation: Does the novel biomarker predict development of future outcomes in a prospective cohort or nested case-cohort study? 3. Incremental value: Does it add predictive information over and above established, standard risk markers? 4. Clinical utility: Does it change predicted risk sufficiently to change recommended therapy? 5. Clinical outcomes: Does the use of the novel biomarker improve clinical outcomes, especially when tested in a randomized clinical trial? 6. Cost-effectiveness: Does the use of the biomarker improve clinical outcomes sufficiently to justify the additional costs? [
      • Hlatky M.A.
      • Greenland P.
      • Arnett D.K.
      • et al.
      Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.
      ].
      On top of the aforementioned criteria, a biomarker should be relatively easy to measure, in a non-invasive manner, according to a well-defined protocol and the obtained metric should distinguish individuals at risk, in order to be deemed suitable for use in clinical practice. Therefore, 3 additional steps (not present in the AHA scientific statement) [
      • Hlatky M.A.
      • Greenland P.
      • Arnett D.K.
      • et al.
      Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.
      ] should be added in the assessment of vascular biomarkers to qualify as clinical surrogate endpoints: 7. Ease of use: this will allow widespread application, 8. Methodological consensus: necessary to allow comparisons between studies and 9. Reference values: or, at least, cut-off values.
      Fulfilment of the 9-step criteria for each vascular biomarker (Table 1) will be subsequently discussed in relevant sections. Though all have a sound proof of concept and have been prospectively validated (steps 1 and 2), the incremental value, clinical utility and clinical outcomes (steps 3–5) have only been established for few of them; cost-effectiveness data (step 6) are almost uniformly lacking. The majority of them are easily measured (step 7), methodological consensus (step 8) has been reached for some, yet reference values (step 9) exist for only a few vascular biomarkers.
      Table 1Criteria for vascular biomarkers to qualify as clinical surrogate endpoints.
      1Proof of conceptDo novel biomarker levels differ between subjects with and without outcome?
      2Prospective validationDoes the novel biomarker predict development of future outcomes in a prospective cohort or nested case-cohort study?
      3Incremental valueDoes it add predictive information over and above established, standard risk markers?
      4Clinical utilityDoes it change predicted risk sufficiently to change recommended therapy?
      5Clinical outcomesDoes the use of the novel biomarker improve clinical outcomes, especially when tested in a randomized clinical trial?
      6Cost-effectivenessDoes the use of the biomarker improve clinical outcomes sufficiently to justify the additional costs?
      7Ease of useIs it easy to use, allowing widespread application?
      8Methodological consensusIs the biomarker measured uniformly in different laboratories? Are study results directly comparable?
      9Reference values (or cut-off values)Are there published reference values, or, at least, cut-off values?
      Modified from: Hlatky et al. Circulation 2009. Criteria 7–9 constitute additional essential criteria to the original criteria 1–6 proposed by Hlatky and coworkers
      • Hlatky M.A.
      • Greenland P.
      • Arnett D.K.
      • et al.
      Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.
      .
      Most of the biomarkers analyzed in this document fit within the concept of early vascular aging. According to this concept, a cumulative measure of the impact of CV risk factors on the arterial wall, in association and interaction the individual genetic background, has the potential to accurately gauge a person's overall CV risk [
      • Nilsson P.M.
      • Boutouyrie P.
      • Laurent S.
      Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and prevention.
      ]. The aim of this document is to scrutinize the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary CV disease prevention. The most widely used biomarkers related to vascular structure and function are presented; a uniform approach has been followed, including a brief methodological presentation, the current role, potential use as a surrogate endpoint, advantages/disadvantages and future perspectives. Regarding the order of presentation, the date of publication of the first outcome study for each vascular biomarker was used; those with the oldest outcome studies are presented first. The role of vascular biomarkers in the setting of comorbidities is presented, as well as their potential for guiding treatment. The Tables, as well as a dedicated section of the document provide detailed comparisons between vascular biomarkers at a glance; these should help clinicians in selecting the appropriate index to be measured in different clinical and research scenarios.

      2. Carotid ultrasonography

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): IIa/A.
      Infiltration of the subintimal layer of arteries by lipids and inflammatory cells constitutes an early process in the atherosclerotic continuum. Imaging techniques with adequate spatial resolution can assist in the timely detection and quantification of structural changes in the arterial wall that are associated with atheroma, fibrosis and the aging process. A thick intima-media complex, and carotid plaque as its extreme manifestation, serves as a proxy of generalized atherosclerosis. Though often regarded as two distinct phenotypes and biomarkers with different usefulness for risk prediction, both carotid intima-media thickness (cIMT) and plaque presence are assessed during imaging and provide complementary prognostic information, thus they cannot be viewed in isolation. The most commonly and easily accessed site is the common carotid artery and its bifurcation, though the femoral artery has also been studied.
      Methodology:
      cIMT is measured with transcutaneous ultrasound in B-mode images of the carotid tree as the distance of the intimal to the adventitial layer (visible as a typical double line of the arterial wall). cIMT is measured most easily in the segment of the distal common carotid artery based on the Mannheim consensus [
      • Touboul P.J.
      • Hennerici M.G.
      • Meairs S.
      • et al.
      Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.
      ], but risk prediction should be based on a thorough scan of the carotid arteries to detect the presence of plaques and on the measurement of the cIMT of the common carotid artery [
      • Stein J.H.
      • Korcarz C.E.
      • Hurst R.T.
      • et al.
      Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine.
      ]. The intra- and inter-observer agreement, as well as the accuracy of measurements of the mean cIMT was found to be highest in the common carotid artery, followed by the carotid bifurcation and inner carotid artery [
      • O'Leary D.H.
      • Polak J.F.
      • Wolfson Jr., S.K.
      • et al.
      Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group.
      ,
      • Espeland M.A.
      • Hoen H.
      • Byington R.
      • Howard G.
      • Riley W.A.
      • Furberg C.D.
      Spatial distribution of carotid intimal-medial thickness as measured by B-mode ultrasonography.
      ,
      • Montauban van Swijndregt A.D.
      • De Lange E.E.
      • De Groot E.
      • Ackerstaff R.G.
      An in vivo evaluation of the reproducibility of intima-media thickness measurements of the carotid artery segments using B-mode ultrasound.
      ,
      • Riley W.A.
      • Barnes R.W.
      • Applegate W.B.
      • et al.
      Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis. The Asymptomatic Carotid Artery Plaque Study.
      ,
      • Teynor A.
      • Caviezel S.
      • Dratva J.
      • Kunzli N.
      • Schmidt-Trucksass A.
      An automated, interactive analysis system for ultrasound sequences of the common carotid artery.
      ]. The optimal reproducibility obtained by scanning the common carotid artery is due to the ease of acquiring good quality images at an insonification angle of 90°; this, however, comes at the cost of missing disease that more often develops at the carotid bulb/internal carotid artery [
      • Sillesen H.
      Carotid intima-media thickness and/or carotid plaque: what is relevant?.
      ]. Reading should be done with semi-automated reading software (better than automated) [
      • Molinari F.
      • Meiburger K.M.
      • Saba L.
      • et al.
      Ultrasound IMT measurement on a multi-ethnic and multi-institutional database: our review and experience using four fully automated and one semi-automated methods.
      ] over a 1-cm segment because of the ease of use, potential to improve ultrasound quality, and probably lower variability compared to manual measurements [
      • Teynor A.
      • Caviezel S.
      • Dratva J.
      • Kunzli N.
      • Schmidt-Trucksass A.
      An automated, interactive analysis system for ultrasound sequences of the common carotid artery.
      ,
      • Rossi A.C.
      • Brands P.J.
      • Hoeks A.P.
      Automatic localization of intimal and adventitial carotid artery layers with noninvasive ultrasound: a novel algorithm providing scan quality control.
      ,
      • Selzer R.H.
      • Mack W.J.
      • Lee P.L.
      • Kwong-Fu H.
      • Hodis H.N.
      Improved common carotid elasticity and intima-media thickness measurements from computer analysis of sequential ultrasound frames.
      ]. An alternative method with better spatial and temporal resolution is the measurement of cIMT using echo-tracking [
      • Hoeks A.P.
      • Willekes C.
      • Boutouyrie P.
      • Brands P.J.
      • Willigers J.M.
      • Reneman R.S.
      Automated detection of local artery wall thickness based on M-line signal processing.
      ], however, a possible advantage of B-mode based analysis is that it can be easily used with standard high-resolution ultrasound equipment. The reproducibility of echo-tracking and B-mode based measurement of cIMT was shown to be similar in patients with increased risk factor burden and/or manifest atherosclerotic disease [
      • Schreuder F.H.
      • Graf M.
      • Hameleers J.M.
      • Mess W.H.
      • Hoeks A.P.
      Measurement of common carotid artery intima-media thickness in clinical practice: comparison of B-mode and RF-based technique.
      ,
      • Bianchini E.
      • Bozec E.
      • Gemignani V.
      • et al.
      Assessment of carotid stiffness and intima-media thickness from ultrasound data: comparison between two methods.
      ]. A value above the 75th percentile of a reference population is generally accepted as a threshold for increased cIMT [
      • Stein J.H.
      • Korcarz C.E.
      • Hurst R.T.
      • et al.
      Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine.
      ]. A value of 0.9 mm is set as a cut-off in the European Society of Cardiology (ESC) guidelines [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ,
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ]; this simplification may, however, lead to misclassification in different populations and age groups where similar values may be within the normal range [
      • Homma S.
      • Hirose N.
      • Ishida H.
      • Ishii T.
      • Araki G.
      Carotid plaque and intima-media thickness assessed by b-mode ultrasonography in subjects ranging from young adults to centenarians.
      ].
      Carotid plaque may represent a later stage or a different phenotype of atherosclerosis than increased cIMT [
      • Touboul P.J.
      • Hennerici M.G.
      • Meairs S.
      • et al.
      Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.
      ,
      • Sakakura K.
      • Nakano M.
      • Otsuka F.
      • Ladich E.
      • Kolodgie F.D.
      • Virmani R.
      Pathophysiology of atherosclerosis plaque progression.
      ]. However, this cannot be differentiated by ultrasound; many studies do not discriminate between plaque or cIMT and incorporate plaque thickness into cIMT measurements [
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
      ]. As a consequence, maximum cIMT (in contrast to mean cIMT) is close to plaque thickness if the Mannheim consensus is not used and cIMT is considered as a continuous parameter; this causes some confusion in the interpretation of the studies. Carotid plaque may be measured with ultrasound in 2D and in 3D-images. Several characteristics of plaques are currently examined, like the dissemination within the carotid tree, echogenicity (echolucent, echogenic, mixed echogenicity), echogenic distribution pattern (homogeneous versus inhomogeneous) and evaluation of surface structure (regular versus irregular [
      • Makris G.C.
      • Lavida A.
      • Griffin M.
      • Geroulakos G.
      • Nicolaides A.N.
      Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis.
      ]). Recently, plaque vascularization on contrast-enhanced ultrasound has been developed to optimize cardiovascular risk prediction [
      • Staub D.
      • Partovi S.
      • Schinkel A.F.
      • et al.
      Correlation of carotid artery atherosclerotic lesion echogenicity and severity at standard US with intraplaque neovascularization detected at contrast-enhanced US.
      ]. Among these plaque characteristics, total plaque volume was the most commonly evaluated parameter showing good inter- and intra-observer reproducibility (>90%) [
      • Makris G.C.
      • Lavida A.
      • Griffin M.
      • Geroulakos G.
      • Nicolaides A.N.
      Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis.
      ,
      • Landry A.
      • Spence J.D.
      • Fenster A.
      Quantification of carotid plaque volume measurements using 3D ultrasound imaging.
      ]. However, it is unclear whether different 3D techniques could be sufficiently standardized between laboratories, thus allowing widespread clinical usage [
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
      ]. Robust data upon superiority of 3D ultrasound over 2D is pending [
      • Makris G.C.
      • Lavida A.
      • Griffin M.
      • Geroulakos G.
      • Nicolaides A.N.
      Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis.
      ]. At present, the assessment of carotid plaque in population studies is mainly done in B-mode images of the carotid tree. In the clinical setting, easy to assess and reproducible plaque-based parameters (presence vs. absence or number of plaques), and simple definitions (plaque: maximum cIMT >1.5 mm) are advocated [
      • Polak J.F.
      • Szklo M.
      • Kronmal R.A.
      • et al.
      The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis.
      ]. At the moment, no generally accepted continuous parameter has been introduced into guidelines.
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept:
      cIMT: Multiple studies – by far more than for any other imaging biomarker - have shown higher cIMT in subjects with higher risk factor burden or manifest atherosclerotic disease [
      • Touboul P.J.
      • Hennerici M.G.
      • Meairs S.
      • et al.
      Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.
      ].
      Carotid plaque: A similar relation is true for carotid plaque but in a far lower number of publications [
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
      ,
      • Polak J.F.
      • Szklo M.
      • Kronmal R.A.
      • et al.
      The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis.
      ] (Table 2).
      Table 2Sensitivity to detect changes and guide for pharmacological treatment.
      Guide for pharmacological therapySensitivity for changesTime to changePrognostic value of changes
      Carotid ultrasonography++LowSlowNo
      Ankle-brachial index++LowNo dataModerate
      Arterial stiffness
      Carotid-femoral pulse wave velocity+++HighModerateModerate
      Brachial-ankle pulse wave velocity++HighModerateNo data
      Central haemodynamics/Wave reflections+++HighFastGood guide for therapy, with the exception of patients with heart failure and a low ejection fraction
      Endothelial function
      Flow mediated dilatation+++Very highFastModerate
      Endothelial peripheral arterial tonometry+Very highFastNo data
      Circulating biomarkers related to vascular wall biology
      High sensitivity C- reactive protein+++ModerateFastNo data
      2. Prospective validation and 3. Incremental value:
      cIMT: The prediction of future outcomes in prospective cohorts has been proved in several studies (Table 3). A meta-analysis of 16 studies with 36,984 participants showed an increase in risk for future CV events of 16% per 0.1 mm difference in baseline cIMT [
      • Lorenz M.W.
      • Polak J.F.
      • Kavousi M.
      • et al.
      Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.
      ].
      Table 3Risk prediction improvement.
      StudyOutcomeMarkers addedΔ C-statistic
      Change in C-statistic from addition of the novel marker to a classical risk factor model.
      Overall net reclassification indexClinical net reclassification index
      Net reclassification index calculated only for individuals at intermediate risk according to the Framingham Risk Score.
      Reference
      Carotid ultrasonographyUSE-IMT meta-analysis (n = 45,828)

      Framingham Offspring Study (n = 2965)

      Prog-IMT meta-analysis (n = 36,984)

      Shijingshan district and Peking University community cohort (n = 3258)
      First time MI or stroke

      Incident CVD

      Future CV events

      Future CV events
      Common cIMT

      Mean common cIMT, maximum internal cIMT, plaque presence

      Mean common cIMT

      Carotid plaque
      0.757 → 0.759

      Non-significant for mean common cIMT, 0.009 for maximum internal cIMT, 0.014 for plaque presence



      0.742 → 0.751
      0.8%

      Non-significant for mean common cIMT, 7.6% for maximum internal cIMT, 7.3% for plaque presence



      10.5%
      3.6%

      12.7% for maximum internal cIMT



      Den Ruijter et al., 2012

      Polak et al., 2011

      Lorenz et al., 2012

      Xie et al., 2011
      Ankle-brachial indexMultiethnic Study of Atherosclerosis (n = 1330)
      Only individuals at intermediate risk for cardiovascular events, according to the Framingham Risk Score, were included from the original cohort; in this case the overall and clinical net reclassification index are the same.


      Ankle Brachial Index Collaboration meta-analysis (n = 48,294)
      Incident CHD, CVD

      Total mortality
      ABI

      ABI
      0.623 → 0.650 (CHD), 0.623 → 0.650 (CVD)

      0.646 → 0.655 (men), 0.605 → 0.658 (women)
      3.6% (CHD), 6.8% (CVD)

      3.6% (CHD), 6.8% (CVD)Yeboah et al., 2012

      Ankle Brachial Index Collaboration 2008
      Arterial stiffness
      Carotid-femoral pulse wave velocityIndividual data meta-analysis (n = 17,635)

      Meta-analysis (n = 15,877)
      Total/CV mortality, CV/CHD events, stroke

      Total/CV mortality, CV events
      Log (aortic PWV)

      Carotid-femoral PWV


      8.34% (CV mortality)

      24.27% (CV mortality)

      Ben-Shlomo et al., 2013

      Vlachopoulos et al., 2010
      Brachial-ankle pulse wave velocityMeta-analysis (n = 8169)CV eventsBrachial-ankle PWVVlachopoulos et al., 2012
      Central haemodynamics/Wave reflectionsMultiethnic Study of Atherosclerosis (n = 5960)

      Taiwanese cohort (n = 1272)

      Meta-analysis (n = 5648)
      CV events

      CV and all-cause mortality

      CV events
      PPA, RM, AIx

      Central systolic BP and PP

      AIx, central PP
      0.002 (PPA), 0.002 (RM)



      10% (PPA), 15% (RM)







      Chirinos et al., 2012

      Wang et al., 2009

      Vlachopoulos et al., 2010
      Endothelial function
      Flow mediated dilationMeta-analysis (n = 14,753)

      Multiethnic Study of Atherosclerosis (n = 1330)
      Only individuals at intermediate risk for cardiovascular events, according to the Framingham Risk Score, were included from the original cohort; in this case the overall and clinical net reclassification index are the same.


      Meta-analysis (n = 5547)

      Multiethnic Study of Atherosclerosis (n = 2843)
      CV events

      Incident CHD, CVD

      CV events

      Incident CV events
      FMD

      FMD

      FMD

      FMD


      Non-significant for both CHD and CVD



      Non-significant


      2.4% (CHD), 2.3% (CVD)



      29%


      2.4% (CHD), 2.3% (CVD)



      28%
      Ras et al., 2013

      Yeboah et al., 2012

      Inada et al., 2012

      Yeboah et al., 2009
      Endothelial peripheral arterial tonometryLow-risk outpatients with chest pain (n = 270)CV eventsLog (RHI)Rubinshtein et al., 2010
      Circulating biomarkers related to vascular wall biology
      High sensitivity C- reactive proteinEmerging Risk Factors Collaboration meta-analysis (n = 166,596)

      Multiethnic Study of Atherosclerosis (n = 1330)
      Only individuals at intermediate risk for cardiovascular events, according to the Framingham Risk Score, were included from the original cohort; in this case the overall and clinical net reclassification index are the same.
      First CV event

      Incident CHD, CVD
      Log (CRP), total and HDL cholesterol

      hsCRP
      0.0039

      0.623 → 0.640(CHD), 0.623 → 0.640 (CVD)
      1.52%

      7.9% (CHD), 3.7% (CVD)


      7.9% (CHD), 3.7% (CVD)
      Emerging Risk Factors Collaboration 2012

      Yeboah et al., 2012
      ABI: ankle-brachial index; AIx: augmentation index; CHD, coronary heart disease; cIMT: carotid intima-media thickness; CV: cardiovascular; CVD, cardiovascular disease; FMD: flow mediated dilation; HDL: high density cholesterol; hsCRP: high sensitivity C-reactive protein; MI: myocardial infarction; PP: pulse pressure; PPA: pulse pressure amplification; PWV: pulse wave velocity; RHI: reactive hyperemia index; RM: reflection magnitude; SD: standard deviation.
      a Change in C-statistic from addition of the novel marker to a classical risk factor model.
      b Net reclassification index calculated only for individuals at intermediate risk according to the Framingham Risk Score.
      c Only individuals at intermediate risk for cardiovascular events, according to the Framingham Risk Score, were included from the original cohort; in this case the overall and clinical net reclassification index are the same.
      A recent meta-analysis based on data from 14 cohort studies (45,828 individuals from the general population) showed that common cIMT measurements do not add significantly to the Framingham Risk Score (FRS) regarding the prediction of first-time myocardial infarction or stroke [
      • Den Ruijter H.M.
      • Peters S.A.
      • Anderson T.J.
      • et al.
      Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.
      ]. Another study did not show any predictive value of common cIMT measurement in subjects with diabetes mellitus [
      • den Ruijter H.M.
      • Peters S.A.
      • Groenewegen K.A.
      • et al.
      Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.
      ]. However, it should be mentioned that this holds true only for common cIMT. Data for carotid bifurcation and internal cIMT have not been analysed so far. Furthermore, different definitions of the common carotid segment and tracing methods might have weakened the power of the analysis; in addition, the study population consisted mainly of Caucasian individuals, so results cannot be extrapolated to other ethnicities.
      Carotid plaque: Carotid plaque confers a superior diagnostic accuracy for future myocardial infarction compared to cIMT according to a recent meta-analysis (n = 54,336) [
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis.
      ] and this was corroborated by a systematic review [
      • Peters S.A.
      • den Ruijter H.M.
      • Bots M.L.
      • Moons K.G.
      Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review.
      ]. The presence of carotid plaques predicted CV mortality independently of the SCORE stratification and increased the risk for CV death by 2–4 times in intermediate risk and low risk individuals, respectively [
      • Sehestedt T.
      • Jeppesen J.
      • Hansen T.W.
      • et al.
      Risk prediction is improved by adding markers of subclinical organ damage to SCORE.
      ]. An incremental CV disease risk prediction with increasing number of plaques (1 site = 1.5; 95% confidence interval [CI]: 1.0–2.2; ≥2 sites = 2.2; 95% CI: 1.6–3.1), but not with increasing cIMT has been shown in the Three-City Study [
      • Plichart M.
      • Celermajer D.S.
      • Zureik M.
      • et al.
      Carotid intima-media thickness in plaque-free site, carotid plaques and coronary heart disease risk prediction in older adults. The Three-City Study.
      ]. In the Atherosclerosis Risk In Communities (ARIC) study, both cIMT and presence of plaque contributed to improved CV disease risk prediction [
      • Nambi V.
      • Chambless L.
      • Folsom A.R.
      • et al.
      Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk in Communities) study.
      ]. Similarly, ultrasound-derived plaque metrics improved risk prediction in the Multiethnic Study of Atherosclerosis (MESA) cohort [
      • Polak J.F.
      • Szklo M.
      • Kronmal R.A.
      • et al.
      The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis.
      ]. In general, studies on carotid plaque are in smaller cohorts than those on cIMT; similarly, they consist of Caucasians mostly, so again results cannot be extrapolated to other ethnicities.
      4. Clinical utility:
      cIMT: The meta-analysis by Den Ruijter et al. demonstrated that cIMT had a small, yet significant potential for reclassification only in intermediate risk individuals, with a clinical net reclassification index (NRI) of 3.2% in men and 3.9% in women (overall NRI: 0.8%), with a wide range among studies [
      • Den Ruijter H.M.
      • Peters S.A.
      • Anderson T.J.
      • et al.
      Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.
      ]. Given the small reclassification potential of cIMT, which is only evident in intermediate risk individuals, its clinical utility is open to question.
      Carotid plaque: In contrast to cIMT, studies that include assessment of plaque in general improve reclassification; the NRI for plaque presence was slightly higher and ranged from 5.6% for individuals with prior CV disease to 8.1% for individuals without CV disease at baseline [
      • Plichart M.
      • Celermajer D.S.
      • Zureik M.
      • et al.
      Carotid intima-media thickness in plaque-free site, carotid plaques and coronary heart disease risk prediction in older adults. The Three-City Study.
      ]. In the MESA cohort, cIMT plus plaque together resulted in an overall NRI of 9.9%; when only intermediate risk subjects were considered, the clinical NRI was 21.7% [
      • Polak J.F.
      • Szklo M.
      • Kronmal R.A.
      • et al.
      The value of carotid artery plaque and intima-media thickness for incident cardiovascular disease: the multi-ethnic study of atherosclerosis.
      ]. Similar results were reported from the Framingham Offspring Study cohort and a large Chinese population [
      • Polak J.F.
      • Pencina M.J.
      • Pencina K.M.
      • O'Donnell C.J.
      • Wolf P.A.
      • D'Agostino Sr., R.B.
      Carotid-wall intima-media thickness and cardiovascular events.
      ,
      • Xie W.
      • Wu Y.
      • Wang W.
      • et al.
      A longitudinal study of carotid plaque and risk of ischemic cardiovascular disease in the Chinese population.
      ] (Table 3).
      5. Clinical outcomes: The question if a cIMT-driven therapy leads to better outcomes has not been answered yet. In practice, high cIMT values and/or presence of plaque are considered as target organ damage and call for aggressive risk factor modification. Though there are no studies to support such practices, carotid ultrasound scanning for detection of increased cIMT or carotid plaque may lead to increased prescription of aspirin and statins by physicians [
      • Korcarz C.E.
      • DeCara J.M.
      • Hirsch A.T.
      • et al.
      Ultrasound detection of increased carotid intima-media thickness and carotid plaque in an office practice setting: does it affect physician behavior or patient motivation?.
      ] and intensified goal setting for LDL-cholesterol levels [
      • Johnson H.M.
      • Turke T.L.
      • Grossklaus M.
      • et al.
      Effects of an office-based carotid ultrasound screening intervention.
      ]. However, conflicting results have been reported regarding the impact of carotid ultrasound scanning on patient motivation [
      • Korcarz C.E.
      • DeCara J.M.
      • Hirsch A.T.
      • et al.
      Ultrasound detection of increased carotid intima-media thickness and carotid plaque in an office practice setting: does it affect physician behavior or patient motivation?.
      ,
      • Rodondi N.
      • Collet T.H.
      • Nanchen D.
      • et al.
      Impact of carotid plaque screening on smoking cessation and other cardiovascular risk factors: a randomized controlled trial.
      ]. Lipid-lowering drugs can reduce carotid plaque volume [
      • Makris G.C.
      • Lavida A.
      • Nicolaides A.N.
      • Geroulakos G.
      The effect of statins on carotid plaque morphology: a LDL-associated action or one more pleiotropic effect of statins?.
      ]; nevertheless, cIMT and plaque are biomarkers that change slowly over time, therefore patients may be on optimal medical therapy for a prolonged period of time and, yet, have increased cIMT values and/or plaques. In spite of the aforementioned issues, cIMT has been used as an intermediate endpoint in randomised clinical trials of novel drugs [
      • Bots M.L.
      • Visseren F.L.
      • Evans G.W.
      • et al.
      Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
      ]. Importantly, it has been demonstrated that cIMT changes do not have prognostic implications; in a large meta-analysis of 36,984 participants, cIMT progression was not linked to future CV events [
      • Lorenz M.W.
      • Polak J.F.
      • Kavousi M.
      • et al.
      Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.
      ].
      6. Cost-effectiveness:
      cIMT: One study simulated the cost-effectiveness of cIMT screening over a 20–30 year period on the basis of the ARIC study data using a Markov model [
      • den Ruijter H.M.
      • Vaartjes I.
      • Sutton-Tyrrell K.
      • Bots M.L.
      • Koffijberg H.
      Long-term health benefits and costs of measurement of carotid intima-media thickness in prevention of coronary heart disease.
      ]. Based on a 1% lower absolute risk of myocardial infarction in men and of 1–3% lower risk in women respectively, cIMT measurements increased quality-adjusted life years (QALYs) by 0.01–0.02 in men and 0.03–0.05 in women. The corresponding costs were an additional $100 per man, and a cost-saving of $200–300 per woman.
      Carotid plaque: No studies on cost-effectiveness for measurement of carotid plaque are available to date.
      7. Ease of use: Experienced sonographers are required for reliable image acquisition, especially for plaque detection. Automated systems have facilitated cIMT measurements and 3D ultrasound may help to quantify atherosclerotic plaque volume and characteristics.
      8. Methodological consensus: Strict standardization of ultrasound and reading protocols is required; the existing Mannheim consensus [
      • Touboul P.J.
      • Hennerici M.G.
      • Meairs S.
      • et al.
      Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.
      ], American Society of Echocardiography consensus statement [
      • Stein J.H.
      • Korcarz C.E.
      • Hurst R.T.
      • et al.
      Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine.
      ], and Prog-IMT procedures [
      • Lorenz M.W.
      • Polak J.F.
      • Kavousi M.
      • et al.
      Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.
      ] are steps towards standardization.
      9. Reference values:
      cIMT: Reference values for common cIMT measured with the echotracking system have been reported [
      • Engelen L.
      • Ferreira I.
      • Stehouwer C.D.
      • Boutouyrie P.
      • Laurent S.
      Reference values for arterial measurements C. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors.
      ].
      Carotid plaque: Reference values for carotid plaque number, volume and other characteristics are still lacking. It is still unclear if the normal value should be “no carotid plaque”, as plaques are frequently present in the elderly [
      • Homma S.
      • Hirose N.
      • Ishida H.
      • Ishii T.
      • Araki G.
      Carotid plaque and intima-media thickness assessed by b-mode ultrasonography in subjects ranging from young adults to centenarians.
      ]. The concept of carotid plaque burden, based on a 3D ultrasound approach, may constitute a better metric of subclinical atherosclerosis [
      • Sillesen H.
      • Muntendam P.
      • Adourian A.
      • et al.
      Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage Study.
      ,

      L. Fernandez-Friera, J.L. Penalvo, A. Fernandez-Ortiz, et al., Prevalence, vascular distribution and multi-territorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of early subclinical atherosclerosis) study, Circulation. Published online before print April 16, 2015, http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014310.

      ,
      • Baber U.
      • Mehran R.
      • Sartori S.
      • et al.
      Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study.
      ].
      Taken together, cIMT meets some of the 9 essential criteria to classify as a clinical surrogate endpoint, whereas carotid plaque meets most of them (Table 4, Table 5).
      Table 4Assessment of vascular biomarkers.
      Proof of conceptProspective validationIncremental valueClinical utilityClinical outcomesCost-effectivenessEase of useMethodological consensusReference values
      Carotid ultrasonography+++++++++++++/−+++++Yes, for cIMT measured with the echotracking method.
      Ankle-brachial index+++++++++++++++/−++++++++Diagnostic thresholds for PAD (cutoff value: 0.90)
      Arterial stiffness
      Carotid-femoral pulse wave velocity++++++++++++++++++++++Yes
      Brachial-ankle pulse wave velocity+++++++++++++++++Yes, for Asian populations.
      Central haemodynamics/Wave reflections+++++++++++++++++++Yes
      Endothelial function
      Flow mediated dilatation++++++++++/−+++No
      Endothelial peripheral arterial tonometry++++++++++No
      Circulating biomarkers related to vascular wall biology
      High sensitivity C- reactive protein+++++++++++++++++++++Cutoff value: 2 mg/L.
      Table 5Usefulness of vascular biomarkers for primary and secondary CVD prevention.
      RecommendationLevel of evidenceComments
      Carotid ultrasonographyIIaAModerate usefulness for risk stratification. Concomitant identification of plaque presence.
      Ankle-brachial indexIIaAUseful for risk stratification, especially women.
      Arterial stiffness
      Carotid-femoral pulse wave velocityIIaAUseful for risk stratification.
      Brachial-ankle pulse wave velocityIIbB
      Central haemodynamics/Wave reflectionsIIbB
      Endothelial function
      Flow mediated dilatationIIIBRequires skilled, trained operator. Reactive hyperaemia is stressful. Methodological problems are not resolved. Added value is not proven.
      Endothelial peripheral arterial tonometryIIICReactive hyperaemia is stressful.

      Added value is not proven.
      Circulating biomarkers related to vascular wall biology
      High sensitivity C- reactive proteinIIbB
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      Carotid ultrasound allows the simultaneous assessment of both cIMT and plaques. cIMT is validated by a substantial number of prospective long-term outcome studies. These have been performed in the general population, with sufficient number of events (myocardial infarction and stroke) and have included individuals at risk from various ethnic groups. Carotid plaque has incremental value to cIMT in risk assessment. Carotid ultrasound is relatively easy to use and can be applied to daily practice given the widespread availability of ultrasound devices [
      • Aldridge M.E.
      • Do K.
      • Oo T.
      • Naqvi T.Z.
      Carotid intima-media thickness and plaque assessment by trained medical residents: validation and preliminary testing of a training protocol.
      ].
      The main disadvantage of cIMT is its low, yet significant, independent predictive power for future CV events over established risk scores. Increased cIMT values may not be solely attributed to atheromatosis of the intima; hypertension results in thickening of the media and, thus, in thicker cIMT. Nevertheless, the combined assessment of cIMT and plaque presence improves risk prediction. The meta-analyses suggest that cIMT measurements should not be routinely performed in the general population. The initial cost of the ultrasound device, probe and software, as well as training of sonographers should also be considered. Methodological issues pertaining to the site of measurements impede comparisons of cIMT values from different laboratories. Structured training and certification of sonographers should be sought, as well as certification for centres performing cIMT measurements by reference centres. The calibration of different ultrasound devices on the basis of a common phantom would be an additional step towards standardization; this approach has already been used for strain analysis in echocardiography (“The Leuven approach”). The cost-effectiveness of cIMT measurements and concomitant treatment should be assessed in depth. Regarding plaques, these are mainly prevalent in the elderly, which limits or even excludes their assessment in younger subjects below the age of 40–50 years. Currently, the low availability of 3D ultrasound, which can quantify total plaque volume and other plaque characteristics hampers detailed plaque characterization.
      Current status in clinical practice guidelines:
      The European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension have endorsed ultrasound scanning of the carotid arteries for cIMT measurement and plaque detection [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ]; this is also the case in the ESC guidelines for CV disease prevention in individuals at intermediate risk (class IIa/B recommendation in both guidelines) [
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ]. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines propose a IIa/B recommendation for risk assessment in individuals with intermediate risk (10-year risk for CV events of 6–20%) [
      • Greenland P.
      • Alpert J.S.
      • Beller G.A.
      • et al.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ]. The most recent ACC/AHA guidelines for the assessment of CV risk in asymptomatic adults have given cIMT a class III/B recommendation for predicting a first atherosclerotic CV disease event; plaque assessment was not reviewed in these guidelines [
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the american college of Cardiology/American heart association task force on practice guidelines.
      ] (Table 6).
      Table 6Implementation of vascular biomarkers in guidelines.
      ESC/EASD guidelines on diabetes, pre-diabetes and cardiovascular diseases (2013)ESC/ESH guidelines for the management of arterial hypertension (2013)ESC guidelines on cardiovascular disease prevention in clinical practice (2012)ESC/EAS guidelines for the management of dyslipidaemias (2011)ACC/AHA guideline on the assessment of cardiovascular risk (2013)ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults (2013)ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults (2010)
      Carotid ultrasonographyMay be considered as useful cardiovascular marker, adding predictive value to the usual risk estimate.Class IIa/level of evidence: B
      • -
        Asymptomatic adults at moderate risk: Class IIa/level of evidence: B
      It is indicated to screen for dyslipidaemias in the presence of increased cIMT or carotid plaques.Class III/level of evidence: BClass IIa/level of evidence: B
      Ankle-brachial indexMay be considered as useful cardiovascular marker, adding predictive value to the usual risk estimate.Class IIa/level of evidence: BPAD is a high risk condition, and lipid-lowering therapy (mostly statins) is recommended: Class I/level of evidence: AClass IIb/level of evidence: BClass IIa/level of evidence: B
      Arterial stiffness
      Carotid-femoral pulse wave velocityMay be considered as useful cardiovascular markers, adding predictive value to the usual risk estimate.Class IIa/level of evidence: BClass III/level of evidence: C
      Brachial-ankle pulse wave velocityMay be considered as useful cardiovascular markers, adding predictive value to the usual risk estimate.Class III/level of evidence: C
      Central haemodynamics/Wave reflections
      Endothelial function
      Flow mediated dilationClass III/level of evidence: B
      Endothelial peripheral arterial tonometry
      Circulating biomarkers related to vascular wall biology
      High sensitivity C- reactive protein
      • -
        As part of refined risk assessment in patients with an unusual or moderate CVD risk profile: Class IIb/level of evidence: B
      • -
        Asymptomatic low-risk individuals and high-risk patients: Class III/level of evidence: B
      • -
        Individuals with increased hsCRP have a higher risk level than that calculated from the SCORE chart
      • -
        Not recommended as a secondary target of therapy for everybody; however, it may be useful in people close to the high risk category to better stratify their total CV risk.
      Class IIb/level of evidence: BHigh sensitivity-CRP level >2 mg/L is an additional factor to be considered during treatment decision making for individuals without atherosclerotic disease
      • -
        Men ≥50 years old or women ≥60 years old with low-density lipoprotein cholesterol less than 130 mg/dL; not on lipid-lowering, hormone replacement, or immunosuppressant therapy; without clinical CHD, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins: Class IIa/level of evidence: B
      • -
        Asymptomatic intermediate-risk men ≤50 years old or women ≤60 years old: Class IIb/level of evidence: B
      • -
        Asymptomatic high-risk adults: Class III/level of evidence: B

      3. Ankle-brachial index (ABI)

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): IIa/A.
      In healthy individuals, systolic BP levels are physiologically higher in the lower extremities as compared to the arms; this is a combined effect of pulse wave reflections and amplification, as well as changes in vessel wall thickness attributed to hydrostatic pressure. This relationship can be quantified by the ratio of ankle-to-brachial systolic pressure, termed ABI; a decrease of this ratio heralds a late stage of atherosclerosis with hemodynamic compromise attributed to obstructive lesions. First described as a non-invasive method to diagnose lower extremity peripheral artery disease (PAD) [
      • Yao S.T.
      • Hobbs J.T.
      • Irvine W.T.
      Ankle systolic pressure measurements in arterial disease affecting the lower extremities.
      ], ABI has been subsequently scrutinized as a marker of CV disease prognosis, once the high risk of mortality and morbidity of patients with PAD was evidenced [
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      ].
      Methodology:
      Its mode of measurement and calculation has recently been harmonized [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ]. The standard mode of measurement requires a (handheld) continuous wave Doppler device and a manual blood pressure (BP) cuff. From this respect, it is one of the less expensive and most available methods to detect atherosclerosis and stratify CV risk. While ABI is traditionally calculated at each ankle by taking the highest pressure between the systolic BPs of the posterior tibial and dorsalis pedis artery divided by the highest systolic BP between both arms, the lower of the 2 lower limbs ABI is retained to assess CV risk of the subject [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ]. In healthy subjects at low risk for PAD, trivial intrinsic differences of ABI values have been reported between men and women, and in subjects of African descent versus other ethnic groups [
      • Aboyans V.
      • Criqui M.H.
      • McClelland R.L.
      • et al.
      Intrinsic contribution of gender and ethnicity to normal ankle-brachial index values: the Multi-Ethnic Study of Atherosclerosis (MESA).
      ]. While these small differences (<0.02) may impact the estimation of PAD in these different groups, they are not clinically relevant at an individual level, so similar normal values are accepted.
      The ABI threshold to diagnose PAD is commonly at 0.90. At higher levels (>1.40) ABI identifies medial calcinosis, i.e. calcification of the tunica media without affecting the arterial lumen, a condition distinct from atherosclerosis. Stiffened arteries due to this disease are mostly observed in aged population, especially in case of diabetes and/or end-stage renal failure.
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: This is intuitive, as PAD (i.e. a low ABI) is causally linked to CV risk factors (Table 2).
      2. Prospective validation and 3. Incremental value: Several longitudinal studies in the general population have demonstrated the predictive ability of ABI for overall and CV mortality and morbidity (Table 3). In an individual-based meta-analysis collecting data of >48,000 men and women through 16 studies, it has been demonstrated that an ABI <0.90 is associated with increased risk of mortality (hazard ratio [HR]: 3.33 in men and 2.71 in women) [
      • Fowkes F.G.
      • Murray G.D.
      • Butcher I.
      • et al.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ]. Actually the risk of mortality (or CV events) increases when ABI values fall below 1.10, but becomes more significant and consistent below 0.90. Subjects with an ABI between 1.10 and 1.40 are at the lowest risk levels of CV events. In case of high (>1.40) ABI, the risk of total and CV mortality is also increased [
      • Fowkes F.G.
      • Murray G.D.
      • Butcher I.
      • et al.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ]. However, in this case, the intra-arterial pressure of leg arteries cannot be accurately estimated by the cuff. In approximately half of these cases, occlusive artery disease due to atherosclerosis coexists [
      • Aboyans V.
      • Ho E.
      • Denenberg J.O.
      • Ho L.A.
      • Natarajan L.
      • Criqui M.H.
      The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects.
      ]. Two studies support the hypothesis that in patients with very high ABI, only those with concomitant medial calcinosis and occlusive disease are at increased risk of death [
      • Aboyans V.
      • Lacroix P.
      • Tran M.H.
      • et al.
      The prognosis of diabetic patients with high ankle-brachial index depends on the coexistence of occlusive peripheral artery disease.
      ,
      • Suominen V.
      • Uurto I.
      • Saarinen J.
      • Venermo M.
      • Salenius J.
      PAD as a risk factor for mortality among patients with elevated ABI–a clinical study.
      ]. Hence, in case of an ABI >1.40, further tests (e.g. toe-brachial index, or Doppler flow analysis) is mandatory to refine the risk estimation.
      4. Clinical utility: Owing to its diagnostic role for PAD (values <0.9 or >1.4), ABI can change predicted risk sufficiently to change recommended therapy. The ARIC study reported modest risk prediction improvement with use of ABI in addition to the FRS; this needs further evaluation, especially because ABI was measured only in one leg, so that it is estimated that 1/4th of PAD cases were not detected [
      • Murphy T.P.
      • Dhangana R.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      Ankle-brachial index and cardiovascular risk prediction: an analysis of 11,594 individuals with 10-year follow-up.
      ]. In addition, the oscillometric method was used to determine limb pressures [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ,
      • Verberk W.J.
      • Kollias A.
      • Stergiou G.S.
      Automated oscillometric determination of the ankle-brachial index: a systematic review and meta-analysis.
      ]. The validity of this method to estimate accurately ankle artery pressure is still a matter of controversy, since it presents uncertain validity and reproducibility in case of PAD [
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      ,
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ].
      The ABI collaboration meta-analysis showed that 19% of men and 36% of women can have their risk estimation reclassified if the ABI is performed in addition to the FRS [
      • Fowkes F.G.
      • Murray G.D.
      • Butcher I.
      • et al.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ]. In predicting events, the C-index increased modestly in men, from 0.672 when using the FRS alone to 0.685 when adding ABI to FRS, and improved dramatically in women, from 0.578 to 0.690, with NRI of 4.3% in men and 9.6% in women. Restricting the analysis in those at intermediate 10-year risk of 10–19% resulted in higher NRIs, both in men (15.9%) and women (23.3%) [
      • Fowkes F.
      • Murray G.
      • Butcher I.
      • et al.
      Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.
      ]. In an intermediate-risk subgroup from the Framingham Offspring Study, an NRI of 7.9% for coronary heart disease was reported [
      • Yeboah J.
      • McClelland R.L.
      • Polonsky T.S.
      • et al.
      Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.
      ] (Table 3).
      5. Clinical outcomes: Whether the use of ABI can ultimately lead to improved prognosis after prompt intervention requires further investigation in randomized controlled trials. One open trial comparing aspirin 100 mg vs. placebo in patients with ABI <0.90 detected after a large population screening failed to show any benefit after 8 years of follow-up [
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      ]. In another double-blinded trial limited to diabetic patients with ABI <1.0, aspirin 100 mg was not superior to placebo to decrease mortality or CV events [
      • Belch J.
      • MacCuish A.
      • Campbell I.
      • et al.
      The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease.
      ]. However, an analysis for the NHANES cohort [
      • Pande R.L.
      • Perlstein T.S.
      • Beckman J.A.
      • Creager M.A.
      Secondary prevention and mortality in peripheral artery disease: National Health and Nutrition Examination Study, 1999 to 2004.
      ] study suggests better outcome in individuals with an ABI <0.90 who were at least on two out of three major CV protective drugs (i.e. antiplatelet agents, angiotensin-converting enzyme inhibitors [ACE-Is]/angiotensin receptor blockers and/or statins), but this merits confirmation with an appropriately designed trial. A meta-analysis (n = 11,686) reported that various drug classes improve walking distance in patients with an ABI<0.90, albeit with limited benefits; statins were the most efficient among them [
      • Gasecki D.
      • Rojek A.
      • Kwarciany M.
      • et al.
      Pulse wave velocity is associated with early clinical outcome after ischemic stroke.
      ].
      Apart from single measurements, ABI change over time can also provide predictive information (except when revascularization is performed, which usually leads to an ABI increase when successful). An ABI decrease of more than 0.15 within 3 years was associated with a 2.4-fold risk increase of death, and 2.8-fold risk increase of CV mortality [
      • Criqui M.H.
      • Ninomiya J.K.
      • Wingard D.L.
      • Ji M.
      • Fronek A.
      Progression of peripheral arterial disease predicts cardiovascular disease morbidity and mortality.
      ]. With respect to its ability to monitor and guide therapy, intra- and inter-observer reproducibility is acceptable (at best ±0.10) but not sufficient to detect individual small values change during follow-up [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ]. At population level, ABI changes slowly over time, so that this marker is not highly sensitive to risk factor modification or pharmacological intervention.
      6. Cost-effectiveness: At present, no data regarding cost-effectiveness have been published. Nonetheless, the initial cost of the equipment is relatively low.
      7. Ease of use: ABI can be easily measured after an initial training regarding the use of the Doppler device.
      8. Methodological consensus: The measurement and interpretation of the ABI has been standardized [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ].
      9. Reference values: Cutoff points for PAD have been ascertained, as mentioned above. The same cutoff points (values <0.90 or >1.40) are used to detect individuals at increased risk for CV events independently of the presence of symptoms of PAD and other risk factors [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ,
      • Fowkes F.G.
      • Murray G.D.
      • Butcher I.
      • et al.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      ].
      In summary, ABI meets most of the 9 essential criteria to classify as a clinical surrogate endpoint (Table 4, Table 5).
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      A unique advantage is that ABI is the only biomarker that has both a diagnostic (for PAD) and prognostic (for CV disease and mortality) role. An additional advantage is its wide availability, so that it can currently be considered as the first-line vascular biomarker to be used in the setting of primary care; however, skilled operators are required for consistent, accurate results. The low cost of the equipment and the extensive validation are also ranked among the strengths of the method.
      The disadvantages of the ABI include false negative results in patients with medial calcinosis because stiff arteries produce falsely elevated ankle pressure (see above). Resting ABI is insensitive to mild PAD; treadmill tests are sometimes used to increase sensitivity, but this increases assessment duration and is unsuitable for patients who are obese or have co-morbidities. Measurement of the ABI can be time-consuming in the setting of PAD.
      A number of issues are open. Devices using non-Doppler based methodology should be accredited. Further research should explore potentially easier and faster alternative methods for ABI measurement that would likely be implemented more broadly in primary care. Finally, the optimal method of ABI calculation for predicting CV events and PAD merits additional investigation [
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      ].
      Current status in clinical practice guidelines:
      The ESH/ESC guidelines for the management of hypertension state that ABI should be considered for detecting PAD in hypertensives (class IIa/B recommendation) [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ]; the same holds true in the ESC guidelines for CV disease prevention in individuals at intermediate risk (class IIa/B recommendation) [
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ]. The European Society of Cardiology/European Association for the Study of Diabetes (ESC/EASD) guidelines for diabetes and pre-diabetes state that ABI may be considered as a useful marker that adds predictive value to the usual risk estimate [
      • Ryden L.
      • Grant P.J.
      • et al.
      ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
      ]. The U.S. Preventive Services Task Force concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for PAD and CVD risk assessment with the ABI [
      • Moyer V.A.
      Force USPST. Screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index in adults: U.S. Preventive Services Task Force recommendation statement.
      ]. According to the ACCF/AHA guidelines, measurement of ABI is reasonable for the assessment of CV risk in asymptomatic adults (class IIa/B recommendation) [
      • Greenland P.
      • Alpert J.S.
      • Beller G.A.
      • et al.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ]. The most recent ACC/AHA guidelines state that ABI measurement may be considered if, after quantitative risk assessment, a risk-based treatment decision is uncertain (class IIb/B recommendation) [
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the american college of Cardiology/American heart association task force on practice guidelines.
      ] (Table 6).

      4. Arterial stiffness

      Arterial stiffening results primarily from arteriosclerosis (principally a disease of the media, related to normal or accelerated aging) rather than from atherosclerosis (principally a disease of the intima, affecting the vessel in a patchy and not uniform manner). Because waves travel faster in a rigid tube, loss of compliance results in increased velocity of pulse waves; therefore, a high pulse wave velocity is a hallmark of arteriosclerosis. CV risk factors alter the composition and mechanical properties of arterial walls making them eventually less compliant. Elastic-type arteries, such as the aorta, are primarily affected, as opposed to muscular arteries.
      A multitude of invasive and non-invasive methods measuring arterial stiffness have been described. The most widely used and validated techniques involve the assessment of pulse waves as they travel over a significant portion of the arterial tree; regional (over shorter arterial segments) and local (carotid or femoral) arterial stiffness are emerging as promising biomarkers [
      • van Sloten T.T.
      • Schram M.T.
      • van den Hurk K.
      • et al.
      Local stiffness of the carotid and femoral artery is associated with incident cardiovascular events and all-cause mortality - the Hoorn Study.
      ]. Carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle PWV (baPWV) are dealt with herein. Cardio-ankle vascular index (CAVI) has been recently introduced. CAVI is primarily used in Japan and has the theoretical advantage to be less dependent on BP levels. CAVI had been correlated with several arteriosclerotic and atherosclerotic diseases [
      • Shirai K.
      • Hiruta N.
      • Song M.
      • et al.
      Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives.
      ].

      4.1 Carotid-femoral pulse wave velocity (cfPWV)

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): IIa/A.
      cfPWV, i.e. the velocity of the pulse as it travels from the heart to the carotid and the femoral artery, remains the most commonly used non-invasive method and is considered as the “gold standard” [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ]. Data regarding risk prediction are less consistent concerning local stiffness, i.e. carotid stiffness measured with high-resolution echotracking systems, or arterial stiffness measured at other arterial sites such as carotid-radial PWV and femoro-tibial PWV.
      Methodology:
      cfPWV is usually measured using the “foot-to-foot” velocity method from a number of waveforms. These are usually obtained using surface tonometry probes at the right common carotid artery and the right femoral artery and the time delay (Dt, or transit time) is measured between the “foot” of the two waveforms [
      • Asmar R.
      • Benetos A.
      • Topouchian J.
      • et al.
      Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies.
      ]. The “foot” of the wave is defined at the end of diastole, when the steep rise of the wavefront begins. The transit time is the time of travel of the “foot” of the wave over a known distance. A variety of different waveforms can be used including pressure [
      • Asmar R.
      • Benetos A.
      • Topouchian J.
      • et al.
      Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies.
      ], distension [
      • Van Bortel L.M.
      • Laurent S.
      • Boutouyrie P.
      • et al.
      Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.
      ] and flow [
      • Cruickshank K.
      • Riste L.
      • Anderson S.G.
      • Wright J.S.
      • Dunn G.
      • Gosling R.G.
      Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function?.
      ]. The distance D covered by the waves is usually assimilated to the skin distance between the two recording sites, i.e. the common carotid artery and the common femoral artery. PWV is calculated as PWV = D/Dt (m/s).
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: A large number of studies have reported the various physiological and pathophysiological conditions associated with increased arterial stiffness [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ]. Apart from the dominant effect of BP and aging, these include genetic background, CV risk factors and diseases, and also primarily non-CV diseases (such as end-stage renal disease [
      • London G.M.
      • Blacher J.
      • Pannier B.
      • Guerin A.P.
      • Marchais S.J.
      • Safar M.E.
      Arterial wave reflections and survival in end-stage renal failure.
      ]) and chronic inflammatory diseases (such as inflammatory bowel disease [
      • Zanoli L.
      • Cannavo M.
      • Rastelli S.
      • et al.
      Arterial stiffness is increased in patients with inflammatory bowel disease.
      ]). Arterial stiffness is a cumulative measure of their damaging effects on the arterial wall (Table 2).
      2. Prospective validation and 3. Incremental value: The predictive value of arterial stiffness has been largely demonstrated. Currently, numerous studies in patients with uncomplicated essential hypertension [
      • Boutouyrie P.
      • Tropeano A.I.
      • Asmar R.
      • et al.
      Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study.
      ,
      • Laurent S.
      • Boutouyrie P.
      • Asmar R.
      • et al.
      Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients.
      ,
      • Laurent S.
      • Katsahian S.
      • Fassot C.
      • et al.
      Aortic stiffness is an independent predictor of fatal stroke in essential hypertension.
      ], type 2 diabetes mellitus [
      • Cruickshank K.
      • Riste L.
      • Anderson S.G.
      • Wright J.S.
      • Dunn G.
      • Gosling R.G.
      Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function?.
      ], end-stage renal disease [
      • Blacher J.
      • Guerin A.P.
      • Pannier B.
      • Marchais S.J.
      • Safar M.E.
      • London G.M.
      Impact of aortic stiffness on survival in end-stage renal disease.
      ], elderly subjects [
      • Meaume S.
      • Benetos A.
      • Henry O.F.
      • Rudnichi A.
      • Safar M.E.
      Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age.
      ,
      • Sutton-Tyrrell K.
      • Najjar S.S.
      • Boudreau R.M.
      • et al.
      Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults.
      ] and the general population have prospectively validated cfPWV [
      • Mattace-Raso F.U.
      • van der Cammen T.J.
      • Hofman A.
      • et al.
      Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study.
      ]. The independent predictive value of arterial stiffness has also been demonstrated for neurologic functional outcome after stroke [
      • Gasecki D.
      • Rojek A.
      • Kwarciany M.
      • et al.
      Aortic stiffness predicts functional outcome in patients after ischemic stroke.
      ]. Arterial stiffness is a robust predictor of all-cause and CV mortality, fatal and non-fatal coronary events and fatal strokes [
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.
      ,
      • Vlachopoulos C.
      • Aznaouridis K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
      ], thus it can be considered as an intermediate endpoint for CV events [
      • Laurent S.
      • Briet M.
      • Boutouyrie P.
      Arterial stiffness as surrogate end point: needed clinical trials.
      ]. In an individual data meta-analysis, CV disease events increased by 30% per 1-standard deviation (SD) increase of cfPWV (95% CI: 1.18–1.43) after adjustment for traditional risk factors [
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.
      ]. The independent association with all-cause mortality merits attention, as it indicates that the role of arterial stiffness extends beyond diseases of the CV system. Moreover, it should be noted that the independent predictive value of arterial stiffness has been demonstrated after adjustment for classical CV risk factors, including brachial pulse pressure. In addition, arterial stiffness retains its predictive value for CV events after adjustment for the FRS [
      • Boutouyrie P.
      • Tropeano A.I.
      • Asmar R.
      • et al.
      Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study.
      ] or SCORE [
      • Sehestedt T.
      • Jeppesen J.
      • Hansen T.W.
      • et al.
      Risk stratification with the risk chart from the European Society of Hypertension compared with SCORE in the general population.
      ], suggesting that it has an added value to a combination of CV risk factors (Table 3).
      4. Clinical utility: Two studies and an individual data meta-analysis showed that patients at intermediate risk could be reclassified into a higher or lower CV risk category when arterial stiffness was measured [
      • Mattace-Raso F.U.
      • van der Cammen T.J.
      • Hofman A.
      • et al.
      Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study.
      ,
      • Sehestedt T.
      • Jeppesen J.
      • Hansen T.W.
      • et al.
      Risk stratification with the risk chart from the European Society of Hypertension compared with SCORE in the general population.
      ,
      • Mitchell G.F.
      • Hwang S.J.
      • Vasan R.S.
      • et al.
      Arterial stiffness and cardiovascular events: the Framingham Heart Study.
      ]. Specifically, in the Framingham study 15.7% of patients at intermediate risk could be reclassified into a higher (14.3%) or lower (1.4%) risk category [
      • Mitchell G.F.
      • Hwang S.J.
      • Vasan R.S.
      • et al.
      Arterial stiffness and cardiovascular events: the Framingham Heart Study.
      ]. In a recently published individual data meta-analysis (n = 17,635 participants), the 5-year overall NRI for coronary heart disease and stroke in intermediate risk individuals was 14.8% and 19.2% respectively [
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.
      ]. Finally, 29% of patients with chronic kidney disease were reclassified into lower or higher risk for all-cause mortality when arterial stiffness was taken in to account [
      • Karras A.
      • Haymann J.P.
      • Bozec E.
      • et al.
      Large artery stiffening and remodeling are independently associated with all-cause mortality and cardiovascular events in chronic kidney disease.
      ] (Table 3).
      5. Clinical outcomes: No study or randomized controlled trial has yet assessed the potential of cfPWV as a target for therapy and whether such a strategy would result in better clinical outcomes. One study in end-stage renal disease patients showed a better outcome for those that decreased their arterial stiffness [
      • Guerin A.P.
      • Blacher J.
      • Pannier B.
      • Marchais S.J.
      • Safar M.E.
      • London G.M.
      Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure.
      ]; this remains to be validated in a larger population of patients at lower CV risk. Such a study is currently underway [
      • Laurent S.
      • Briet M.
      • Boutouyrie P.
      Arterial stiffness as surrogate end point: needed clinical trials.
      ].
      6. Cost-effectiveness: No data are currently available. Wide adoption of the technique leads to continuous reduction of device cost; the potential for cost saving is high given the low cost of individual examination and high reclassification.
      7. Ease of use: Accurate recording of carotid and femoral pulses is easily performed after a short learning period; exposure of the inguinal region is, however, a drawback.
      8. Methodological consensus: An expert consensus document for the measurement of cfPWV in daily practice has been published [
      • Van Bortel L.M.
      • Laurent S.
      • Boutouyrie P.
      • et al.
      Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.
      ].
      9. Reference values: Reference values for PWV have been established in 1455 healthy subjects and a larger population of 11,092 subjects with CV risk factors [
      Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'establishing normal and reference values'.
      ]. These are reported according to age and BP levels. Although the relationship between cfPWV and CV events is continuous, a threshold of 12 m/s had been initially suggested as a conservative estimate of significant alterations of aortic function in middle aged hypertensives [
      • Laurent S.
      • Cockcroft J.
      • Van Bortel L.
      • et al.
      Expert consensus document on arterial stiffness: methodological issues and clinical applications.
      ], and included in the ESH/ESC guidelines for the management of hypertension. This threshold was based on cfPWV using the full direct carotid-to-femoral distance and has been revised in a recent consensus document to 10 m/s [
      • Van Bortel L.M.
      • Laurent S.
      • Boutouyrie P.
      • et al.
      Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.
      ], in order to normalise PWV values according to the arterial pathway. Accordingly, the investigator should preferentially use the direct carotid-femoral distance and multiply by 0.8 only marginally overestimating the real travelled distance by 0.4% [
      • Van Bortel L.M.
      • Laurent S.
      • Boutouyrie P.
      • et al.
      Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity.
      ,
      • Vermeersch S.J.
      • Rietzschel E.R.
      • De Buyzere M.L.
      • et al.
      Distance measurements for the assessment of carotid to femoral pulse wave velocity.
      ]. The new threshold is included in the 2013 ESH/ESC guidelines for the management of hypertension [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ].
      In sum, cfPWV meets most of the 9 essential criteria to classify as a clinical surrogate endpoint (Table 4, Table 5).
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      Aortic stiffness, as measured by cfPWV, integrates the damage of risk factors on the aortic wall over a long period, whereas BP, glycaemia, and lipids can fluctuate and their values, recorded at the time of risk assessment, may not reflect the average values damaging the arterial wall. Nevertheless, cfPWV is strongly influenced by age and BP levels, while the influence of other risk factors is weaker [
      • Cecelja M.
      • Chowienczyk P.
      Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review.
      ]. Its non-invasive nature, fast learning curve, the wide choice of available devices/no absolute need for a proprietary device, relatively low cost, extensive validation in large population studies and established reference values are among its advantages. On the other hand, exposure of the inguinal region for measurements and a calibration of the measured travelled distance are needed.
      cfPWV meets most of the criteria to qualify as a surrogate endpoint for CV disease. Currently, studies that address its ability to monitor and guide therapy and eventually improve outcomes are in progress; though it cannot be considered yet as a surrogate endpoint, it is at an advanced stage of validation.
      Current status in clinical practice guidelines:
      At present, the ESC guidelines for individuals at intermediate risk acknowledge the added value of cfPWV for the stratification of patients [
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ]. Moreover, it should be considered for hypertensives (class IIa/B recommendation) [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ], and it can add predictive value to the usual risk estimate of diabetics [
      • Ryden L.
      • Grant P.J.
      • et al.
      ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
      ]. In contrast, it is not recommended by the ACCF/AHA guidelines for the assessment of CV risk in asymptomatic adults (class III/B recommendation) [
      • Greenland P.
      • Alpert J.S.
      • Beller G.A.
      • et al.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ]; nevertheless, these need to be reappraised in the light of recent data [
      • Ben-Shlomo Y.
      • Spears M.
      • Boustred C.
      • et al.
      Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.
      ]. (Table 6)

      4.2 Brachial-ankle pulse wave velocity (baPWV)

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): IIb/B.
      baPWV is a method for assessing arterial stiffness. Though it shares the same theoretical background with cfPWV, baPWV capitalizes on the concept that measurements over a longer arterial length may provide additional information and be easier, as it only involves wrapping of a pressure cuff in each of the four exposed extremities [
      • Yamashina A.
      • Tomiyama H.
      • Takeda K.
      • et al.
      Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement.
      ]. The method has is being primarily used in Japan.
      Methodology:
      baPWV is measured using a volume-plethysmographic apparatus. Occlusion cuffs, connected to both plethysmographic and oscillometric sensors, are wrapped around both upper arms and ankles of the subjects lying in the supine position. The brachial and posterior tibial arterial pressure waveforms are recorded by the plethysmographic sensor. The path lengths from the suprasternal notch to the brachium (Lb) and from the suprasternal notch to the ankle (La) are obtained from superficial measurements and corrected for the height of the individual using validated equations. baPWV is then calculated according to the equation: baPWV = (La−Lb)/ΔTba, where ΔTba is the time interval between the wavefront of the brachial waveform and that of the ankle waveform [
      • Tomiyama H.
      • Hashimoto H.
      • Hirayama Y.
      • et al.
      Synergistic acceleration of arterial stiffening in the presence of raised blood pressure and raised plasma glucose.
      ].
      Considering the results of published prospective studies, a baPWV value of 18 m/s may be used as a cutoff value in the assessment of the risk for CV disease [
      • Ninomiya T.
      • Kojima I.
      • Doi Y.
      • et al.
      Brachial-ankle pulse wave velocity predicts the development of cardiovascular disease in a general Japanese population: the Hisayama Study.
      ,
      • Tomiyama H.
      • Koji Y.
      • Yambe M.
      • et al.
      Brachial – ankle pulse wave velocity is a simple and independent predictor of prognosis in patients with acute coronary syndrome.
      ]. Due to the fact that age and BP are major determinants of baPWV, a nomogram describing the correlation of the three variables is available [
      • Yamashina A.
      • Tomiyama H.
      • Arai T.
      • et al.
      Nomogram of the relation of brachial-ankle pulse wave velocity with blood pressure.
      ].
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: baPWV has been well validated as a CV risk marker, as it is closely correlated not only with cfPWV, but also with aortic PWV assessed by the invasive method [
      • Yamashina A.
      • Tomiyama H.
      • Takeda K.
      • et al.
      Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement.
      ,
      • Tomiyama H.
      • Yamashina A.
      Non-invasive vascular function tests: their pathophysiological background and clinical application.
      ]. Similarly to cfPWV, the presence of CV risk factors is linked to elevated baPWV values [
      • Yamashina A.
      • Tomiyama H.
      • Arai T.
      • et al.
      Brachial-ankle pulse wave velocity as a marker of atherosclerotic vascular damage and cardiovascular risk.
      ] (Table 2).
      2. Prospective validation and 3. Incremental value: For primary prevention, several prospective studies have reported that baPWV may be a useful predictor of future CV events in patients with end-stage renal disease, hypertension and in the general population [
      • Ninomiya T.
      • Kojima I.
      • Doi Y.
      • et al.
      Brachial-ankle pulse wave velocity predicts the development of cardiovascular disease in a general Japanese population: the Hisayama Study.
      ,
      • Kitahara T.
      • Ono K.
      • Tsuchida A.
      • et al.
      Impact of brachial-ankle pulse wave velocity and ankle-brachial blood pressure index on mortality in hemodialysis patients.
      ]. For secondary prevention, baPWV has been suggested as a useful predictor of the prognosis in patients with acute coronary syndromes and heart failure [
      • Tomiyama H.
      • Koji Y.
      • Yambe M.
      • et al.
      Brachial – ankle pulse wave velocity is a simple and independent predictor of prognosis in patients with acute coronary syndrome.
      ,
      • Meguro T.
      • Nagatomo Y.
      • Nagae A.
      • et al.
      Elevated arterial stiffness evaluated by brachial-ankle pulse wave velocity is deleterious for the prognosis of patients with heart failure.
      ]. Some prospective studies also demonstrated that an elevated baPWV is a predictor of progression of pathophysiological abnormalities in the early stages of hypertension and chronic kidney disease [
      • Tomiyama H.
      • Yamashina A.
      Non-invasive vascular function tests: their pathophysiological background and clinical application.
      ]. A meta-analysis demonstrated that an increase in baPWV by 1 m/s was associated with an increase by 12%, 13% and 6% in CV events, CV mortality, and all-cause mortality, respectively; the independent predictive value of baPWV was established when studies that had controlled for most CV risk factors were subsequently analyzed [
      • Vlachopoulos C.
      • Aznaouridis K.
      • Terentes-Printzios D.
      • Ioakeimidis N.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with brachial-ankle elasticity index: a systematic review and meta-analysis.
      ]. The potential clinical advantage of baPWV over traditional risk scores has not been, however, formally proven (Table 3).
      4. Clinical utility: No data exist regarding the potential of the method for reclassification and subsequent implications for therapy. Despite that, an improvement in baPWV following drug therapy for hypertension, dyslipidaemia and diabetes mellitus and lifestyle modifications (exercise, weight reduction, smoking cessation) has been shown [
      • Toyama K.
      • Sugiyama S.
      • Oka H.
      • et al.
      Combination treatment of rosuvastatin or atorvastatin, with regular exercise improves arterial wall stiffness in patients with coronary artery disease.
      ].
      5. Clinical outcomes: No studies exist to date to substantiate the prospect that treatment according to baPWV values can lead to better clinical outcomes.
      6. Cost-effectiveness: The cost-effectiveness of this method has not been addressed yet.
      7. Ease of use: The technique is easy to use, as measurements are automatically performed after cuff placement at the extremities.
      8. Methodological consensus: Measurements are performed according to manufacturer's instructions; however, a consensus paper has not been published.
      9. Reference values: Reference values have been published for Chinese populations [
      • Ai Z.S.
      • Li J.
      • Liu Z.M.
      • et al.
      Reference value of brachial-ankle pulse wave velocity for the eastern Chinese population and potential influencing factors.
      ,
      • Wang X.
      • Xie J.
      • Zhang L.J.
      • Hu D.Y.
      • Luo Y.L.
      • Wang J.W.
      Reference values of brachial-ankle pulse wave velocity for Northern Chinese.
      ]; no data exist for non-Asian populations. Similar to cfPWV, these are reported according to age and BP levels.
      In conclusion, baPWV meets some of the 9 essential criteria in order to be considered a clinical surrogate endpoint (Table 4, Table 5).
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      Simplicity and concurrent ABI measurement (albeit with the oscillometric method; see section 3. ABI) with the same device are considerable advantages. The disadvantages of the method include issues pertaining to calculation of travelled distance (height-based formulas), need for validation in diverse populations and lack of reference values. Importantly, applicability may be limited when arteries of smaller calibre are affected, such as in diabetes mellitus or in distal PAD.
      It should be emphasized that cfPWV data (which assess predominantly elastic type arteries) are not automatically extrapolated to baPWV, which reflects the stiffness of the large-to middle-sized arteries, and therefore, elastic arteries are assessed along with muscular and mixed-type arteries [
      • Yamashina A.
      • Tomiyama H.
      • Takeda K.
      • et al.
      Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement.
      ].
      Comparisons with the “gold standard” method of cfPWV are needed. Despite the fact that the incremental value of baPWV over and above traditional risk factors has been demonstrated in high-risk populations, prospective studies are needed to examine its incremental value over risk scores in the general population. Moreover, it is currently unknown whether improvement of baPWV with interventions might also translate into successful prevention of CV events.
      Current status in clinical practice guidelines:
      At present, baPWV has not been endorsed by guidelines (Table 6).

      5. Central haemodynamics/wave reflections

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): IIb/B.
      Left ventricular afterload is dependent on aortic valve and peripheral circulation properties (steady-state component) and on the elasticity of the aorta and the large arteries (pulsatile component). Different models allow quantification of systemic circulation mechanics. In the most realistic ones, pressure and flow waves are generated with each heartbeat and are propagated towards the periphery where they are reflected backwards (towards the heart) for various reasons (stiffness gradient, presence of bifurcations, abrupt diameter gradient in arterioles). On their return, the reflected waves merge with the antegrade wave and amplify it [
      • Nichols W.W.
      • ÓRourke M.F.
      • Vlachopoulos C.
      McDonald's Blood Flow in Arteries.
      ]. As a result of this (but not exclusively), peripheral BPs are higher compared to central (aortic) BPs to a varying degree, a phenomenon named “amplification” [
      • Avolio A.P.
      • Van Bortel L.M.
      • Boutouyrie P.
      • et al.
      Role of pulse pressure amplification in arterial hypertension: experts' opinion and review of the data.
      ]. Central BPs are more relevant than peripheral ones, as the heart, brain and kidneys are directly exposed to them [
      • Namasivayam M.
      • McDonnell B.J.
      • McEniery C.M.
      • O'Rourke M.F.
      Anglo-Cardiff Collaborative Trial Study I. Does wave reflection dominate age-related change in aortic blood pressure across the human life span?.
      ]. With aging, the arrival of reflected waves in the ascending aorta is shifted into systole due to earlier wave return; this is largely attributed to increased aortic stiffness/PWV and the resulting wave changes shape. With vasoconstriction, the amplitude of the reflected pressure waves increases. Both these processes lead to increased central systolic pressure (increased cardiac load and oxygen consumption), lower diastolic pressure (decreased myocardial perfusion pressure) and promotion of degeneration of the elastic components of the arterial wall. The net result is an imbalance towards myocardial ischaemia and an impairment of (mainly diastolic) left ventricular function. Of note, in the presence of systolic heart failure the forward wave is of lesser magnitude and as a result, wave reflections are reduced.
      Methodology:
      Central haemodynamic indices are either central BP parameters and derivatives (central systolic BP, pulse pressure, augmented pressure and amplification) or indices that quantify wave reflections [augmentation index (AIx), forward and backward wave, wave intensity analysis]. Invasive recordings provide accurate measurements of central pressures and wave reflection. In clinical studies, however, non-invasive methods are used for quantification. Classical pulse wave analysis [
      • Nichols W.W.
      • ÓRourke M.F.
      • Vlachopoulos C.
      McDonald's Blood Flow in Arteries.
      ] involves analysis of pressure waves alone, from the carotid, radial, or brachial artery. The subsequent use of a transfer function (or special algorithms) and calibration to non-invasively measured pressure yields parameters of the central waveforms, such as central (aortic) pressure, augmentation pressure (measure of the enhancement of central aortic pressure by the reflected pulse wave) and AIx (augmentation pressure to pulse pressure ratio). From pressure waves and simultaneously acquired or estimated flow waves [
      • Kips J.G.
      • Rietzschel E.R.
      • De Buyzere M.L.
      • et al.
      Evaluation of noninvasive methods to assess wave reflection and pulse transit time from the pressure waveform alone.
      ], wave separation analysis (assumes a set forward wave, a limitation of the approach) has been used to acquire amplitudes of forward (Pf) and backward (Pb) waves and their ratio, termed reflection magnitude. It should be emphasized that indices and their individual validation for clinical use are not interchangeable; for example, augmented pressure and reflection magnitude have a better predictive ability than the AIx [
      • Verbeke F.
      • Marechal C.
      • Van Laecke S.
      • et al.
      Aortic stiffness and central wave reflections predict outcome in renal transplant recipients.
      ,
      • Chirinos J.A.
      • Kips J.G.
      • Jacobs Jr., D.R.
      • et al.
      Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis).
      ].
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: Increased wave reflection is related to the extent of myocardial ischaemia in patients with [
      • Kingwell B.A.
      • Waddell T.K.
      • Medley T.L.
      • Cameron J.D.
      • Dart A.M.
      Large artery stiffness predicts ischemic threshold in patients with coronary artery disease.
      ] and without [
      • Nichols W.W.
      • Denardo S.J.
      • Johnson B.D.
      • Sharaf B.L.
      • Bairey Merz C.N.
      • Pepine C.J.
      Increased wave reflection and ejection duration in women with chest pain and nonobstructive coronary artery disease: ancillary study from the Women's ischemia Syndrome Evaluation.
      ] obstructive coronary artery disease. Moreover, it is directly related to left ventricular hypertrophy [
      • Hashimoto J.
      • Nichols W.W.
      • O'Rourke M.F.
      • Imai Y.
      Association between wasted pressure effort and left ventricular hypertrophy in hypertension: influence of arterial wave reflection.
      ] and its regression with treatment [
      • Hashimoto J.
      • Imai Y.
      • O'Rourke M.F.
      Indices of pulse wave analysis are better predictors of left ventricular mass reduction than cuff pressure.
      ], to left atrial size [
      • Weber T.
      • Wassertheurer S.
      • O'Rourke M.F.
      • et al.
      Pulsatile hemodynamics in patients with exertional dyspnea: potentially of value in the diagnostic evaluation of suspected heart failure with preserved ejection fraction.
      ], and is inversely related to left ventricular diastolic function at rest [
      • Weber T.
      • Wassertheurer S.
      • O'Rourke M.F.
      • et al.
      Pulsatile hemodynamics in patients with exertional dyspnea: potentially of value in the diagnostic evaluation of suspected heart failure with preserved ejection fraction.
      ] and during exercise [
      • Holland D.J.
      • Sacre J.W.
      • Leano R.L.
      • Marwick T.H.
      • Sharman J.E.
      Contribution of abnormal central blood pressure to left ventricular filling pressure during exercise in patients with heart failure and preserved ejection fraction.
      ]. Measures of wave reflection can improve the diagnostic accuracy in patients with suspected heart failure with preserved ejection fraction [
      • Weber T.
      • Wassertheurer S.
      • O'Rourke M.F.
      • et al.
      Pulsatile hemodynamics in patients with exertional dyspnea: potentially of value in the diagnostic evaluation of suspected heart failure with preserved ejection fraction.
      ]. An increase in wave reflection has been associated with a decreased renal function [
      • Verbeke F.
      • Van Biesen W.
      • Peeters P.
      • Van Bortel L.M.
      • Vanholder R.C.
      Arterial stiffness and wave reflections in renal transplant recipients.
      ] and with an impaired outcome following acute ischemic stroke [
      • Gasecki D.
      • Rojek A.
      • Kwarciany M.
      • et al.
      Aortic stiffness predicts functional outcome in patients after ischemic stroke.
      ] (Table 2).
      2. Prospective validation and 3. Incremental value: Measures of wave reflection have consistently been reported to be independent predictors of either CV events or CV mortality in high risk populations: patients with impaired renal function [
      • Weber T.
      • Ammer M.
      • Gunduz D.
      • Bruckenberger P.
      • Eber B.
      • Wallner M.
      Association of increased arterial wave reflections with decline in renal function in chronic kidney disease stages 3 and 4.
      ], renal transplant recipients [
      • Verbeke F.
      • Marechal C.
      • Van Laecke S.
      • et al.
      Aortic stiffness and central wave reflections predict outcome in renal transplant recipients.
      ], dialysis patients [
      • London G.M.
      • Blacher J.
      • Pannier B.
      • Guerin A.P.
      • Marchais S.J.
      • Safar M.E.
      Arterial wave reflections and survival in end-stage renal failure.
      ], patients undergoing coronary interventions [
      • Weber T.
      • Auer J.
      • O'Rourke M.F.
      • et al.
      Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions.
      ], patients undergoing coronary angiography [
      • Chirinos J.A.
      • Zambrano J.P.
      • Chakko S.
      • et al.
      Aortic pressure augmentation predicts adverse cardiovascular events in patients with established coronary artery disease.
      ], and patients hospitalized due to acute heart failure [
      • Sung S.H.
      • Yu W.C.
      • Cheng H.M.
      • et al.
      Excessive wave reflections on admission predict post-discharge events in patients hospitalized due to acute heart failure.
      ]. Results are less consistent in broader populations: in most [
      • Chirinos J.A.
      • Kips J.G.
      • Jacobs Jr., D.R.
      • et al.
      Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis).
      ,
      • Wang K.L.
      • Cheng H.M.
      • Sung S.H.
      • et al.
      Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study.
      ], but not all [
      • Mitchell G.F.
      • Hwang S.J.
      • Vasan R.S.
      • et al.
      Arterial stiffness and cardiovascular events: the Framingham Heart Study.
      ] community-based studies an independent predictive value of measures of wave reflections has been shown. Results are heterogeneous in studies on hypertensive patients [
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • et al.
      Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.
      ] and in geriatric patients [
      • Benetos A.
      • Gautier S.
      • Labat C.
      • et al.
      Mortality and cardiovascular events are best predicted by low central/peripheral pulse pressure amplification but not by high blood pressure levels in elderly nursing home subjects: the PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness in institutionalized Very Aged Population) study.
      ]. In almost all studies, the predictive value was additional to that of brachial BP.
      In a meta-analysis of 5648 subjects, central systolic BP, central pulse pressure and central AIx were independent predictors of CV events; of interest, central AIx also independently predicted all-cause mortality, a finding that extends its role beyond the CV system. Central pulse pressure had a marginally significant (P = 0.057) better predictive ability for clinical events when compared with peripheral pulse pressure [
      • Vlachopoulos C.
      • Aznaouridis K.
      • O'Rourke M.F.
      • Safar M.E.
      • Baou K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis.
      ]; when one study with methodological shortcomings was excluded, statistical significance was reached [
      ,
      Central pulse pressure versus peripheral pulse pressure: case still open?.
      ] (Table 3).
      4. Clinical utility: In the largest population study, wave reflections (expressed as reflection magnitude) predicted the occurrence of heart failure and severe CV events [
      • Chirinos J.A.
      • Kips J.G.
      • Jacobs Jr., D.R.
      • et al.
      Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis).
      ]. Several novel indices of clinical utility and reclassification were computed, showing an NRI of 13% for hard CV events and of 38% for heart failure, as compared to models that included brachial systolic and diastolic BP among other traditional risk factors (Table 3).
      5. Clinical outcomes: Antihypertensive drug trials have demonstrated an improvement in intermediate endpoints, such as left ventricular mass, following a reduction of wave reflections and central pressures [
      • de Luca N.
      • Asmar R.G.
      • London G.M.
      • O'Rourke M.F.
      • Safar M.E.
      • Investigators R.P.
      Selective reduction of cardiac mass and central blood pressure on low-dose combination perindopril/indapamide in hypertensive subjects.
      ,
      • Hashimoto J.
      • Westerhof B.E.
      • Westerhof N.
      • Imai Y.
      • O'Rourke M.F.
      Different role of wave reflection magnitude and timing on left ventricular mass reduction during antihypertensive treatment.
      ]. Evidence showing that an improvement in wave reflection will lead to a reduction in CV events was provided by the Conduit Artery Functional Evaluation (CAFÉ) study, where, despite a similar reduction in peripheral systolic BP, a calcium-channel blocker regimen was more effective in lowering central systolic BP, and reduced future CV events compared to a beta-blocker regimen [
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • et al.
      Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.
      ].
      6. Cost-effectiveness: No studies so far have investigated the cost effectiveness of measures of central haemodynamics/wave reflections. Nevertheless, the use of central BPs, compared to peripheral BPs, for guiding antihypertensive treatment led to less use of medications [
      • Sharman J.E.
      • Marwick T.H.
      • Gilroy D.
      • et al.
      Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study.
      ]. The assessment of central haemodynamics is valuable in the evaluation of young persons with isolated systolic hypertension by identifying those who do not have concurrently increased central pressures, a common pattern, thus obviating the need for further investigations and drug treatment [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ,
      • O'Rourke M.F.
      • Vlachopoulos C.
      • Graham R.M.
      Spurious systolic hypertension in youth.
      ].
      7. Ease of use: Assessment of wave reflections/central BPs with peripheral tonometry can be made by validated, non-invasive devices. Cuff-based techniques are more easy to use and offer simultaneous assessment of both brachial and aortic BP, as well as the opportunity of 24-h recordings; they predict left ventricular hypertrophy more accurately than peripheral ambulatory blood pressure monitoring [
      • Protogerou A.D.
      • Argyris A.A.
      • Papaioannou T.G.
      • et al.
      Left-ventricular hypertrophy is associated better with 24-h aortic pressure than 24-h brachial pressure in hypertensive patients: the SAFAR study.
      ]. Nevertheless, the technical validation of these latter devices is ongoing and needs to be done at rest and with exercise [
      • Weber T.
      • Wassertheurer S.
      • Rammer M.
      • et al.
      Validation of a brachial cuff-based method for estimating central systolic blood pressure.
      ,
      • Pucci G.
      • Cheriyan J.
      • Hubsch A.
      • et al.
      Evaluation of the Vicorder, a novel cuff-based device for the noninvasive estimation of central blood pressure.
      ].
      8. Methodological consensus: It is yet unclear which index will prove to be the most useful for clinical practice and how this should be measured. A consensus statement on central BP measurements and antihypertensive therapy has been published; an updated version is warranted [
      • Agabiti-Rosei E.
      • Mancia G.
      • O'Rourke M.F.
      • et al.
      Central blood pressure measurements and antihypertensive therapy: a consensus document.
      ].
      9. Reference values: Reference values for central haemodynamics have been recently published [
      • Herbert A.
      • Cruickshank J.K.
      • Laurent S.
      • Boutouyrie P.
      Reference values for arterial measurements C. Establishing reference values for central blood pressure and its amplification in a general healthy population and according to cardiovascular risk factors.
      ].
      As a result, wave reflections and central haemodynamics meet some of the 9 essential criteria to classify as a clinical surrogate endpoint (Table 4, Table 5)
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      Advantages include the strong physiological background and the clinical value in high-risk patients. The incremental value of wave reflections/central haemodynamics has been shown to some degree; however, more data are needed regarding clinical utility, improvement of clinical outcomes and cost-effectiveness.
      Because peripheral pressure is necessary to calibrate central pressure, their respective clinical values cannot be easily disentangled. It needs to be clarified, which is the ideal measure of wave reflections (pulse wave analysis-based indices: AIx, augmented pressure; wave separation analysis-based indices: amplitude of backward wave, reflection magnitude; wave intensity analysis-based indices: wave reflection index, intensity of forward compression and expansion waves) and central pressures. Simplifications of systems for assessment that facilitate adoption by clinicians are welcome.
      Current status in clinical practice guidelines:
      The ESH/ESC guidelines for the management of arterial hypertension state that central BPs/AIx can be helpful when assessing young patients with isolated systolic hypertension; however, more data are required before central haemodynamic indices are recommended for routine use in hypertensives in general [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ] (Table 6).

      6. Endothelial function

      A multitude of techniques for assessing endothelial function have been described. The focus of this document is on non-invasive methods owing to their ease of use that permits implementation in clinical practice beyond vascular laboratories. Invasive methods and laboratory techniques requiring high levels of technical expertise remain outside the scope of this document and will not be addressed. Such methods (coronary endothelial function, venous occlusion plethysmography, pulse wave analysis for endothelial function assessment, laser Doppler flowmetry, biochemical markers and bioassays, endothelial microparticles, progenitor cells and glycocalyx) have been previously reviewed in a position statement by the ESC Working Group on Peripheral Circulation [
      • Lekakis J.
      • Abraham P.
      • Balbarini A.
      • et al.
      Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.
      ].

      6.1 Flow-mediated dilation (FMD)

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): III/B.
      The endothelium regulates all aspects of vascular homeostasis by releasing vasoactive molecules in response to physical and chemical stimuli. Endothelium-derived nitric oxide (NO) is the main mediator of all vasoprotective effects; NO is a very potent vasodilator but also has anti-inflammatory, anti-proliferative and antithrombotic properties. Reduced NO bioavailability, due to reduced production and/or increased inactivation, results from altered redox and inflammatory state. Endothelial dysfunction is present very early in the atherosclerotic process, long before structural changes in vessel wall are evident [
      • Balletshofer B.M.
      • Rittig K.
      • Stock J.
      • et al.
      Insulin resistant young subjects at risk of accelerated atherosclerosis exhibit a marked reduction in peripheral endothelial function early in life but not differences in intima-media thickness.
      ]. This dysfunction contributes to the development and progression of atherosclerosis and even plaque rupture [
      • Lekakis J.
      • Abraham P.
      • Balbarini A.
      • et al.
      Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.
      ].
      Endothelial function was initially assessed using invasive methods and pharmacological stimuli in the coronary arteries and in the peripheral resistance arteries (venous occlusion plethysmography). Brachial artery FMD was the first non-invasive technique to assess endothelial function in the peripheral conduit arteries [
      • Celermajer D.S.
      • Sorensen K.E.
      • Gooch V.M.
      • et al.
      Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
      ] and remains today the most widely applied method [
      • Lekakis J.
      • Abraham P.
      • Balbarini A.
      • et al.
      Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.
      ].
      Methodology:
      FMD is an endothelium-dependent, NO-mediated process that uses high-resolution ultrasound in the brachial artery by means of a high frequency linear transducer to monitor changes in arterial diameter in response to increased blood flow, an important physiological stimulus for endothelial NO production [
      • Corretti M.C.
      • Anderson T.J.
      • Benjamin E.J.
      • et al.
      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      ]. In brief, images are acquired at baseline and after deflation of a cuff inflated to at least 50 mmHg above systolic BP [
      • Corretti M.C.
      • Anderson T.J.
      • Benjamin E.J.
      • et al.
      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      ] or at about 250 mmHg [
      • Doshi S.N.
      • Naka K.K.
      • Payne N.
      • et al.
      Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide.
      ] for a set length of time, usually 4–5 min. Placement of the cuff above or below the elbow has been the subject of controversy; upper versus lower cuff placement maximizes hyperaemic response but distorts the brachial artery and introduces variability in results. FMD is defined as the maximum percent increase in arterial end-diastolic diameter during the first minutes of hyperaemia compared with the diameter at rest [
      • Doshi S.N.
      • Naka K.K.
      • Payne N.
      • et al.
      Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide.
      ]. To assess the endothelium-independent smooth muscle capacity to dilate, nitrate-mediated dilation is also determined as the percent increase in brachial artery diameter 4 min after administering sublingual glyceryl trinitrate. FMD has been closely correlated with endothelial function assessed in the coronary circulation [
      • Celermajer D.S.
      • Sorensen K.E.
      • Gooch V.M.
      • et al.
      Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
      ,
      • Anderson T.J.
      • Uehata A.
      • Gerhard M.D.
      • et al.
      Close relation of endothelial function in the human coronary and peripheral circulations.
      ]; variability across laboratories and reproducibility over the short and medium term are vey good [
      • Wang T.J.
      Multiple biomarkers for predicting cardiovascular events: lessons learned.
      ].
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: Endothelial dysfunction, assessed by impaired FMD, has been extensively associated with most of the established and emerging CV risk factors (e.g. dyslipidaemia, hypertension, smoking, diabetes mellitus, family history of premature atherosclerosis, elevated plasma homocysteine), as well as with the presence and extent of structural arterial disease and prevalent CV disease. Assessment of endothelial dysfunction using FMD appears to complement other imaging endpoints of structural arterial disease burden, probably preceding their occurrence [
      • Bechlioulis A.
      • Kalantaridou S.N.
      • Naka K.K.
      • et al.
      Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.
      ] (Table 2).
      2. Prospective validation and 3. Incremental value: FMD has been prospectively validated in predicting future CV events. Its prognostic value has been demonstrated in patients with advanced atherosclerosis, in subjects at high CV risk and more recently also in low-risk subjects, although this was not a consistent finding in all studies. Three meta-analyses showed an independent prognostic value [
      • Inaba Y.
      • Chen J.A.
      • Bergmann S.R.
      Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.
      ,
      • Ras R.T.
      • Streppel M.T.
      • Draijer R.
      • Zock P.L.
      Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis.
      ,
      • Xu Y.
      • Arora R.C.
      • Hiebert B.M.
      • et al.
      Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis.
      ]; for each 1% increase in FMD, risk was decreased by 13% (relative risk [RR]: 0.87; 95% CI: 0.83–0.91), 8% (RR: 0.92; 95% CI: 0.88–0.95) and 10% (RR: 0.90; 95% CI: 0.88–0.92) respectively. The correlation of FMD with risk was stronger in populations with overt CV disease.
      The incremental value of FMD in addition to classical CV risk factor evaluation using risk scores such as the SCORE and FRS has not been established. Few studies so far have reported on the incremental value of FMD using the change in the area under the curve with conflicting results [
      • Peters S.A.
      • den Ruijter H.M.
      • Bots M.L.
      The incremental value of brachial flow-mediated dilation measurements in risk stratification for incident cardiovascular events: a systematic review.
      ]. (Table 3) Of note, invasive methods for assessment of endothelial function have shown incremental value over the FRS [
      • Lind L.
      • Berglund L.
      • Larsson A.
      • Sundstrom J.
      Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease.
      ].
      4. Clinical utility: The reclassification potential of FMD has been examined in the MESA cohort; in intermediate risk individuals the NRI was 2.4% for incident coronary heart disease [
      • Yeboah J.
      • McClelland R.L.
      • Polonsky T.S.
      • et al.
      Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.
      ]. (Table 3)
      5. Clinical outcomes: Numerous studies have incorporated FMD measurements because it improves rapidly with physiological and pharmacological interventions (e.g. statins, ACE-Is, calcium channel blockers, exercise, weight loss, estrogen, antioxidants, vitamins, dietary constituents). This reinforces the concept that endothelial dysfunction, the earliest stage of atherosclerosis, is a reversible process [
      • Charakida M.
      • Masi S.
      • Luscher T.F.
      • Kastelein J.J.
      • Deanfield J.E.
      Assessment of atherosclerosis: the role of flow-mediated dilatation.
      ,
      • Briet M.
      • Collin C.
      • Laurent S.
      • et al.
      Endothelial function and chronic exposure to air pollution in normal male subjects.
      ]. Nevertheless, whether an improvement in FMD with treatment may also translate into improved clinical outcomes has not been tested in a randomized controlled trial. In non-randomized controlled studies, FMD improvement was associated with a reduction in events in hypertensive postmenopausal women [
      • Modena M.G.
      • Bonetti L.
      • Coppi F.
      • Bursi F.
      • Rossi R.
      Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women.
      ], whereas persistent FMD impairment despite optimized therapy was associated with an increase in CV events [
      • Landmesser U.
      • von Eckardstein A.
      • Kastelein J.
      • Deanfield J.
      • Luscher T.F.
      Increasing high-density lipoprotein cholesterol by cholesteryl ester transfer protein-inhibition: a rocky road and lessons learned? The early demise of the dal-HEART programme.
      ,
      • Kitta Y.
      • Obata J.E.
      • Nakamura T.
      • et al.
      Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease.
      ].
      6. Cost-effectiveness: The cost-effectiveness of FMD has not been studied so far.
      7. Ease of use: FMD measurements require significant technical expertise; guidelines propose a minimum number of 100 supervised scans prior to scanning independently and at least 100 scans/year to maintain competency [
      • Corretti M.C.
      • Anderson T.J.
      • Benjamin E.J.
      • et al.
      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      ].
      8. Methodological consensus: Published guidelines have facilitated uniform FMD measurements [
      • Corretti M.C.
      • Anderson T.J.
      • Benjamin E.J.
      • et al.
      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      ]. Nevertheless, methodological differences have been reported regarding the level of inflation pressure to cause ischaemia, duration of ischaemia, brachial versus wrist cuff inflation and the time point at which the effect of reactive hyperaemia is assessed.
      9. Reference values: Currently there are no reference values for FMD.
      In conclusion, FMD does not fulfill the 9 essential criteria in order to be considered a clinical surrogate endpoint (Table 4, Table 5).
      Advantages/disadvantages, issues remaining to be addressed and future perspectives:
      FMD is an integrative marker of the damage from risk factors on the arterial wall and a valuable research tool in the study of the role of risk factors in atherosclerosis [
      • Corretti M.C.
      • Anderson T.J.
      • Benjamin E.J.
      • et al.
      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      ]. The most important role of FMD appears to be its ability to monitor the effect of a treatment or an intervention on endothelial function. Its rapid response to treatment stirred the anticipation that it may replace studies of traditional CV outcomes that take longer time and are more expensive. The method is completely non-invasive and safe, easy to use, reliable and repeatable in expert laboratories. FMD is limited mainly by technical difficulties and methodological shortcomings. Extensive training of the operator is needed resulting in a long learning curve, and image analysis may be labor-intensive. Potential environmental/physiological influences (e.g. food, caffeine, temperature, stress) need to be controlled for. Methodological standardization is needed (cuff positioning, timing of response, edge detection, software analysis, stereotactic probe-holding devices) to reduce operator-dependence, improve reproducibility and allow comparison among laboratories [
      • Ghiadoni L.
      • Faita F.
      • Salvetti M.
      • et al.
      Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study.
      ]. Normal and reference values are yet to be established.
      Evolution of the methodology is sought to establish applicability in daily practice and acceptable cost/benefit ratio. Furthermore, the reclassification of subjects at intermediate risk is still open to question. Therefore, currently FMD remains mainly a valuable research tool.
      Current status in clinical practice guidelines:
      The ESC guidelines have not endorsed FMD for clinical use either for refinement of risk stratification [
      • Perk J.
      • De Backer G.
      • Gohlke H.
      • et al.
      European guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).
      ] or for monitoring the effect of treatment [
      • Mancia G.
      • Fagard R.
      • et al.
      2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ]. FMD has a class III/B indication in the ACCF/AHA guidelines for the assessment of CV risk in asymptomatic adults [
      • Greenland P.
      • Alpert J.S.
      • Beller G.A.
      • et al.
      2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      ]. (Table 6)

      6.2 Endothelial function assessed by recordings at the finger

      Usefulness for primary and secondary CV disease prevention (Recommendation/Level of evidence): III/C.
      Noninvasive, finger probe-based methods exist for endothelial function assessment: digital thermal monitoring (DTM), digital volume photoplethysmography (DVP) and, the most widely used, endothelial peripheral arterial tonometry (EndoPAT). DTM (Endothelix Inc., Houston, TX, U.S.A.) is a technique that shares the same pathophysiological background with FMD using temperature as a surrogate marker of blood flow; nevertheless few studies with small sample sizes have been published to date [
      • Schier R.
      • Marcus H.E.
      • Mansur E.
      • et al.
      Evaluation of digital thermal monitoring as a tool to assess perioperative vascular reactivity.
      ,
      • Ahmadi N.
      • Nabavi V.
      • Nuguri V.
      • et al.
      Low fingertip temperature rebound measured by digital thermal monitoring strongly correlates with the presence and extent of coronary artery disease diagnosed by 64-slice multi-detector computed tomography.
      ], Similarly, DVP has been used for endothelial function assessment on top of its use for pulse wave analysis [
      • Millasseau S.C.
      • Ritter J.M.
      • Takazawa K.
      • Chowienczyk P.J.
      Contour analysis of the photoplethysmographic pulse measured at the finger.
      ], but there are limited published data to date [
      • Gordon S.E.
      • Cartwright N.
      • Griffiths M.J.
      Investigation of endothelial function by pulse contour analysis: a protocol for drug administration and timing of pulse contour assessment.
      ].
      The pathophysiological background of EndoPAT is similar to that of brachial FMD, since both assess endothelial function. Nevertheless, several studies have reported low to moderate correlation between the two methods, suggesting that FMD and EndoPAT provide distinct information regarding vascular function [
      • Hamburg N.M.
      • Palmisano J.
      • Larson M.G.
      • et al.
      Relation of brachial and digital measures of vascular function in the community: the Framingham heart study.
      ,
      • Schnabel R.B.
      • Schulz A.
      • Wild P.S.
      • et al.
      Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods.
      ,
      • Kuvin J.T.
      • Patel A.R.
      • Sliney K.A.
      • et al.
      Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude.
      ]. These findings may be explained by the corrections implemented in the EndoPAT (see Methodology section below), whilst no such correction is incorporated in the brachial FMD method, and by the difference in type of vessels measured – small arteries and microcirculation in the case of EndoPAT versus single conduit vessel in the case of brachial FMD [
      • Hamburg N.M.
      • Palmisano J.
      • Larson M.G.
      • et al.
      Relation of brachial and digital measures of vascular function in the community: the Framingham heart study.
      ,
      • Schnabel R.B.
      • Schulz A.
      • Wild P.S.
      • et al.
      Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods.
      ,
      • Flammer A.J.
      • Anderson T.
      • Celermajer D.S.
      • et al.
      The assessment of endothelial function: from research into clinical practice.
      ].
      Methodology:
      EndoPAT is based on the noninvasive measurement of pulsatile volume changes at the fingertip by peripheral arterial tonometry using a patented device (Itamar Medical, Caesarea, Israel). Essentially, the method is a modification of volume plethysmography. Tests can be carried out with the patient positioned either sitting or supine, with the sensors placed on the index finger of each arm. The endothelium-mediated changes in the finger vasculature elicited by a 5-min occlusion of the brachial artery are quantified, using a standard BP cuff inflated to a suprasystolic pressure. When the cuff is abruptly released, the surge of blood flow causes an endothelium-dependent FMD. The dilation is captured by the device as an increase in amplitude of the peripheral arterial tonometry signal. A post-occlusion to pre-occlusion ratio is calculated. Because the signal is also affected by additional, non-endothelial dependent factors, those are corrected by measurements in the contralateral arm. An additional correction is performed for baseline values. Thus, the corrected values characterize the bioavailablity of NO and therefore represent endothelial function. A score is provided in either linear or logarithmic scale.
      Fulfilment of surrogate endpoint criteria:
      1. Proof of concept: EndoPAT has been incorporated in numerous population-based studies such as the Framingham, the Gutenberg Heart and Heart Strategies Concentrating on Risk Evaluation (HeartSCORE) study where it was shown to correlate with conventional risk factors of atherosclerosis and diabetes [
      • Hamburg N.M.
      • Palmisano J.
      • Larson M.G.
      • et al.
      Relation of brachial and digital measures of vascular function in the community: the Framingham heart study.
      ,
      • Schnabel R.B.
      • Schulz A.
      • Wild P.S.
      • et al.
      Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods.
      ,
      • Hamburg N.M.
      • Keyes M.J.
      • Larson M.G.
      • et al.
      Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study.
      ,
      • Mulukutla S.R.
      • Venkitachalam L.
      • Bambs C.
      • et al.
      Black race is associated with digital artery endothelial dysfunction: results from the Heart SCORE study.
      ]. In coronary artery disease, it distinguished high from moderate and low risk patients [
      • Heffernan K.S.
      • Karas R.H.
      • Patvardhan E.A.
      • Jafri H.
      • Kuvin J.T.
      Peripheral arterial tonometry for risk stratification in men with coronary artery disease.
      ]. In patients referred to diagnostic angiography, the calculated score was worse in patients with coronary artery disease than in patients without [
      • Toggweiler S.
      • Schoenenberger A.
      • Urbanek N.
      • Erne P.
      The prevalence of endothelial dysfunction in patients with and without coronary artery disease.
      ]; the score predicted both obstructive and non-obstructive ischemic heart disease [
      • Matsuzawa Y.
      • Sugiyama S.
      • Sugamura K.
      • et al.
      Digital assessment of endothelial function and ischemic heart disease in women.
      ]. Similarly to FMD, EndoPAT score is very sensitive in response to risk factors or, conversely, upon initiation of treatment. (Table 2)
      2. Prospective validation and 3. Incremental value: EndoPAT was predictive of outcomes in 2 studies in heart failure patients with preserved ejection fraction followed for 5 and 20 months respectively [
      • Matsue Y.
      • Suzuki M.
      • Nagahori W.
      • et al.
      Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction.
      ,
      • Akiyama E.
      • Sugiyama S.
      • Matsuzawa Y.
      • et al.
      Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction.
      ]. With respect to primary prevention, there is, to date, one published study demonstrating the ability to predict future CV events during a 7-year follow-up period [
      • Rubinshtein R.
      • Kuvin J.T.
      • Soffler M.
      • et al.
      Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.
      ]. In the aforementioned study, a score (natural logarithmic-scaled reactive hyperaemia index) < 0.40 was shown to have added prognostic value after adjustment for the FRS (HR: 1.68; 95% CI: 1.02–2.78) [
      • Rubinshtein R.
      • Kuvin J.T.
      • Soffler M.
      • et al.
      Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events.
      ]. (Table 3)
      4. Clinical utility: The clinical utility of the method is largely unknown; no studies have so far examined whether they can change predicted risk sufficiently to change recommended therapy.
      5. Clinical outcomes: In a similar fashion to FMD, EndoPAT can be modified with drug and lifestyle interventions [
      • Hamilos M.
      • Muller O.
      • Ntalianis A.
      • et al.
      Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel.
      ,
      • Koska J.
      • Schwartz E.A.
      • Mullin M.P.
      • Schwenke D.C.
      • Reaven P.D.
      Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes.
      ,
      • Aversa A.
      • Vitale C.
      • Volterrani M.
      • et al.
      Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes.
      ,
      • Kim J.Y.
      • Paik J.K.
      • Kim O.Y.
      • et al.
      Effects of lycopene supplementation on oxidative stress and markers of endothelial function in healthy men.