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Keywords:

  • Arterial stiffness;
  • Atherosclerosis;
  • Biomarker;
  • Cardiovascular risk;
  • Endothelial dysfunction;
  • Mechanism;
  • Methodology;
  • Therapeutics

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

Aims: Stiffening of the large arteries is a common feature of aging and is exacerbated by a number of disorders such as hypertension, diabetes, and renal disease. Arterial stiffening is recognized as an important and independent risk factor for cardiovascular events. This article will provide a comprehensive review of the recent advance on assessment of arterial stiffness as a translational medicine biomarker for cardiovascular risk.

Discussions: The key topics related to the mechanisms of arterial stiffness, the methodologies commonly used to measure arterial stiffness, and the potential therapeutic strategies are discussed. A number of factors are associated with arterial stiffness and may even contribute to it, including endothelial dysfunction, altered vascular smooth muscle cell (SMC) function, vascular inflammation, and genetic determinants, which overlap in a large degree with atherosclerosis. Arterial stiffness is represented by biomarkers that can be measured noninvasively in large populations. The most commonly used methodologies include pulse wave velocity (PWV), relating change in vessel diameter (or area) to distending pressure, arterial pulse waveform analysis, and ambulatory arterial stiffness index (AASI). The advantages and limitations of these key methodologies for monitoring arterial stiffness are reviewed in this article. In addition, the potential utility of arterial stiffness as a translational medicine surrogate biomarker for evaluation of new potentially vascular protective drugs is evaluated.

Conclusions: Assessment of arterial stiffness is a sensitive and useful biomarker of cardiovascular risk because of its underlying pathophysiological mechanisms. PWV is an emerging biomarker useful for reflecting risk stratification of patients and for assessing pharmacodynamic effects and efficacy in clinical studies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

Aging of the arterial system is accompanied by progressive structural changes, consisting of fragmentation and degeneration of elastin, increases in collagen, thickening of the arterial wall, endothelium damage, and progressive dilation of the arteries [1,2]. These changes are often accompanied by progression of atherosclerotic plaques in the arterial wall, leading to severe morbidity and mortality due to rupture of atherosclerotic plaques [3]. The structural changes in the arterial system are invariably associated with vascular stiffness as represented by increase in the velocity of the pressure wave as it travels conduit vessels. In a normal elastic aorta, the pressure wave reflects from the periphery and returns to the heart during diastole. As the aorta stiffens, the velocity of the pressure wave increases, and the reflected pressure wave eventually reaches the heart earlier, that is, at the end of systole instead of diastole, causing augmentation of the systolic blood pressure (SBP) and increased cardiac afterload. Arterial stiffening is associated with a widened pulse pressure (PP) that eventually manifests itself as isolated systolic hypertension, which affects 30% of adults at 80 years of age [4,5].

Recent epidemiological studies have shown that the arterial stiffness has an independent predictive value for cardiovascular events in several populations, including patients with uncomplicated essential hypertension [6,7] and type II diabetes [8]. Arterial stiffness is thus an intermediate endpoint for cardiovascular events, predicting cardiovascular events independently of and beyond peripheral PP [9]. The mechanisms producing arterial stiffness have been associated with altered endothelium and vascular smooth muscle cell (SMC) functions, systemic and vascular inflammation, over the background of genetic predisposition. Literature was gathered mainly through PubMed (1975–2008) search on the topics related to arterial stiffness, methodology, mechanism, biomarker, cardiovascular risk, atherosclerosis, endothelial dysfunction, and therapeutics. Therapeutic agents are also searched using the http://www.iddb3.com database. Literatures leading the field of arterial stiffness as a biomarker for cardiovascular risk are selected and reviewed. This article summarizes the most recent advances in the assessment of arterial stiffness, the contributing mechanisms, and the use of PWV as an emerging biomarker useful for reflecting risk stratification of patients and for assessing pharmacodynamic effects and efficacy in clinical studies.

Measurement of Arterial Stiffness

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

In clinical practice, methodologies used to measure arterial stiffness can be categorized into (i) analysis of pulse transit time, (ii) wave contour of the arterial pulse, and (iii) direct measurement of arterial geometry and pressure, corresponding to regional, systemic, and local determination of stiffness [10,11]. Representatives of the most commonly used methods for arterial stiffness and their advantages and limitations are described here and summarized in Table 1, in comparison with key noninvasive methods for endothelial dysfunction and atherosclerosis.

Table 1.  Methods of noninvasive assessment of arterial stiffness, endothelial function, and atherosclerosis
MethodApplicationAdvantageLimitation
Pulse wave velocityArterial stiffnessMost reliable measurement, with prognostic value; clinical experience; low costLocation- and blood pressure-dependent; no data on arterial geometry
Change in vessel diameter to pressureArterial stiffness; endothelial dysfunctionDirect measurement of arterial stiffness and standard to assess endothelial dysfunction; reliable; low costHeavily depend on blood pressure measurement
Augmentation indexesArterial stiffness; endothelial dysfunctionEase of use; clinical experience; low costAffected by other variables such as heart rate and vasomotor tone, and relatively poor to predict outcome
Ambulatory artery stiffness indexArterial stiffnessSimple and straight forward measurementTo be validated to predict clinical outcome
Flow-mediated dilationEndothelial dysfunctionReliable and correlated with invasive measurement of endothelial function; clinical experienceTechnically demanding; variability of the methodology (require a standardized protocol)
Carotid intima-media thicknessArtherosclerosisReliable and direct measurement of atherosclerotic plaque by ultrasound; clinical experience; ease of useUnable to provide lipids and other vulnerable plaque composition; technical demanding
Computed tomographyArtherosclerosisCalcified plaque detectionLack of clinical experience for plaque assessment; radiation exposure
Magnetic resonance imagingArtherosclerosis; arterial stiffnessAnatomic and functional characterization of plaques; high resolution assessment of vessel wall for plaque and arterial stiffnessLack of clinical experience for plaque and vessel wall assessment; high cost

Pulse Wave Velocity (PWV)

PWV is a parameter that is a derivative of pulse transit time. Arterial PWV, especially the aortic PWV, has emerged as an important independent predictor of cardiovascular events [7,12,13]. Figure 1 illustrates one of the most commonly used noninvasive aortic PWV measurements. The arterial pulse wave is recorded at a proximal artery, such as the common carotid, as well as at a more distal artery, such as the femoral. Thus, PWV = D (meters)/Δt (seconds), where D is the distance between the two recording sites and Δt is the time delay between the arrival of a predefined part of the pulse wave at these two points relative to the peak of the R-wave of the ECG (Fig. 1). The value of PWV increases with arterial stiffness. Factors that affect the value of PWV are defined by the Moens-Korteweg equation, PWV =√(Eh/2ρR), where E is Young's modulus of the arterial wall, h is wall thickness, R is arterial radius at the end of diastole, and ρ is blood density [14]. Large clinical data sets demonstrate that aortic stiffness measured by carotid-femoral PWV is an independent predictor for all cause and cardiovascular mortality, fatal and nonfatal coronary events, and fatal strokes in patients with uncomplicated essential hypertension, type II diabetes, and end-stage renal disease [15]. Similar findings have also been extended to elderly subjects and the general population [16].

image

Figure 1. Illustration of arterial PWV. The arterial pulse wave is recorded at a proximal artery (the common carotid, labeled as M1 on the left penal) and at a more distal artery (the femoral, labeled as M2). PWV is calculated as D (meters)/ΔT (seconds), where D is the distance between the two recording sites and ΔT is the time delay between the arrival of the pulse wave at these two points and compared using the R-wave of the ECG shown here. A number of devices can automatically calculate the PWV between any two-user selected/defined locations.

Download figure to PowerPoint

In addition to carotid-femoral, other regions have also been measured for PWV, such as brachial-ankle, aorta-femoral, and femoral-tibial. Brachial-ankle PWV (baPWV) has brought considerable attention as a biomarker to monitor advanced clinical and subclinical atherosclosis largely based on clinical studies in Japanese populations [17]. While significantly correlated between baPWV and aortic PWV, aortic PWV has been most widely used due to its reflection of large elastic artery stiffness in comparison of baPWV determined partly by peripheral artery stiffness [17,18]. In addition, baPWV measurement is closely dependent on blood pressure. Recently, a new method, termed the cardio-ankle vascular index (CAVI), has been proposed using modified baPWV measurement that is independent of blood pressure [19,20]. However, the clinical significance of both baPWV and CAVI remains to be validated in a large-scale study. More recently, a single pulse recording method to determine the aortic PWV has been described [21]. This new method was validated with independent noninvasive measurements of carotid-femoral transit time and suggested as an alternative means for aortic PWV [21].

Relating Change in Vessel Diameter (or Area) to Distending Pressure

The change in diameter of a number of arteries, such as the carotid, brachial, radial, and aorta, can be related to the distending pressure, providing a series of direct measures of arterial stiffness. The vessel diameter is frequently measured noninvasively by ultrasound and less frequently by MRI. The change in diameter is calculated relative to distending pressure measured at the brachial artery in most cases. The curvilinear relationship between pressure and diameter is approximated with a logarithmic transformation, resulting in the beta index reflecting the stiffness. Diameter–pressure relationship can also be accurately determined invasively with simultaneous measurement of dimensions by using intravascular ultrasound and arterial pressure by a luminal pressure transducer [10,14].

Arterial Pulse Waveform (Augmentation Indexes)

Augmentation index (AIx) calculated from the pressure waveform of an artery is widely used to quantify the arterial stiffness and evaluate the cardiovascular risk. The forward-moving pressure wave generated with each cardiac pulse is partially reflected back toward the proximal aorta at points of impedance mismatch along the arterial tree (mainly arterioles). AIx is the percentage of central pulse pressure attributable to the secondary systolic pressure rise, produced by overlap of the forward and early reflected pressure waves. AIx is determined from carotid or radial artery pressure waves recorded by applanation tonometery, the procedure has mainly been used in the diagnostic evaluation of patients with cardiovascular risk factors and hypertension [22]. AIx also depends on other variables such as heart rate and vasomotor tone of the arterial system, which can result in considerable variability and thus may limit its use as a surrogate measure of arterial stiffness, especially if a drug under investigation changes the heart rate, for example, beta blockers [23, 24].

Ambulatory Arterial Stiffness Index (AASI)

AASI derived from 24-h ambulatory blood pressure monitoring has recently been described for its use to determine arterial stiffness [25] even though its use as a surrogate measure of arterial stiffness has been debated [9]. AASI studies the dynamic relationship between diastolic blood pressure (DBP) and SBP in an ambulatory blood pressure monitoring setting throughout the day and calculates a novel index as 1, the regression of DBP on SBP, on the basis that average distending BP varies during the day and that the relation between DBP and SBP with this changing distending BP largely depends on the structural and functional characteristics of the large arteries [26]. Three recent clinical studies showed close relationship between AASI and aortic PWV and AIx, and thus the investigators suggested that AASI could predict cardiovascular mortality and morbidity, in particular stroke [13,25,26]. In contrast, another study concluded that AASI is not a specific biomarker for reduced arterial compliance, with little association with PWV readout [27].

Mechanisms of Arterial Stiffness

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

Recent science suggests that arterial stiffness is associated with endothelial dysfunction, expression of modified vascular wall matrix proteins, altered vascular SMC number, structure and functions, inflammation, and potential genetic determinants.

The Role of Endothelial Cells in Arterial Stiffness

Endothelial cells are involved in many aspects of vascular biology, including (i) vasoconstriction and vasodilation, and hence the control of blood pressure, (ii) blood clotting (thrombosis & fibrinolysis), (iii) vascular inflammation and atherosclerosis, (iv) formation of new blood vessels (angiogenesis), and (v) fluid retention and edema [28]. Endothelial dysfunction is a hallmark for vascular diseases and contributes to atherosclerosis, which is very common in patients with type 2 diabetes, hypertension, or other chronic pathophysiological conditions [29,30]. One of the main mechanisms of endothelial dysfunction is the diminishing of nitric oxide (NO) bioactivity, a key endothelium-derived relaxing factor that plays a pivotal role in maintaining vascular tone and reactivity [31]. Blocking NO synthesis results in acute increase in local arterial stiffness in healthy volunteers [31,32,33]. Endothelial dysfunction may increase arterial stiffness by inducing the contraction of vascular SMCs or by promoting atherosclerosis [34]. Several studies provided direct co-relationship between arterial stiffness and endothelial dysfunction in both coronary and forearm vascular beds [35,36,37,38].

The Role of Vascular SMC in Arterial Stiffness

Vascular SMCs are essential for vascular function and compliance. By contraction and relaxation, vascular SMCs control the luminal diameter and enable blood vessels to maintain an appropriate blood pressure. In addition, vascular SMCs synthesize large amounts of extracellular matrix (ECM) components and increase proliferation and migration. Because of these properties, SMCs are involved not only in short-term regulation of the vessel diameter, but also long-term adaptation, via structural remodeling by changing cell number and connective tissue composition. SMCs release a number of inducible matrix metalloproteinases (MMPs) such as MMP-9, which can degrade elastin. Loss of elastin or elastic lamellae from the vascular media contributes to arterial stiffness. Similarly, a recent study showed that in patients with MYH11 gene mutation (a dominant-negative effect) that affects the C-terminal coiled-coil region of the smooth muscle myosin heavy chain (a specific contractile protein of SMCs), aortic stiffness was increased in parallel with large areas of arterial medial degeneration and very low content of SMCs in aorta, providing direct evidence for a role of vascular SMCs in arterial stiffness [39].

The Role of Inflammation in Arterial Stiffness

Inflammation has been recognized as one of the key risk factors contributing to atherosclerosis and stiffening of the large arteries. Inflammation may stiffen the large arteries by a number of mechanisms that ultimately change the functional and structural components of the arteries [40]. First, inflammation is associated with reduced endothelial-derived NO half-life because increased oxidative stress produced by inflammation inactivates NO, and thus induces endothelial dysfunction (vide supra). Second, chronic inflammation is known to play a critical role in development and progression of atherosclerosis and the close relationship between atherosclerosis and arterial stiffness was demonstrated. Inflammatory mediators can promote leukocyte infiltration and activate vascular SMCs, which in turn increase the expression and activity of MMPs and contribute to arterial stiffening. Recently, significant co-relationship was demonstrated between arterial stiffening (assessed by PWV) and inflammation as evidenced by elevated levels of circulating high sensitive C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNFα), and interleukin-6 in essential hypertension [41,42].

Genetic Basis of Arterial Stiffness

Recent studies suggest that arterial stiffness may be associated with genetic predisposition, which is largely independent of the influence of blood pressure and other cardiovascular risk factors [43]. An early study revealed that the arterial stiffness was greater in adolescents with a parental history of myocardial infarction or diabetes than with no such parental history [44]. In a recent study, arterial stiffness was found to be higher in offspring of families with hypertension than in control subjects [45]. However, hypertension-induced vascular wall thickening is not associated with an increase in arterial stiffness in patients with essential hypertension and in rat models of hypertension [43]. Using candidate gene approach, the renin-angiotensin-aldosterone system (RAAS), which is involved in blood pressure control and hypertension, was shown to play a key role in arterial stiffness [46,47]. In addition, polymorphysms of matrix proteins, such as elastin and MMP-3, have also been associated with arterial stiffness [48,49].

Therapeutic Agents that Modify Arterial Stiffness

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

Arterial stiffness is not only a risk factor for cardiovascular diseases but also an emerging biomarker of therapeutic interventions. Nonpharmacological interventions are shown to reduce arterial stiffness, including exercise training, dietary changes, and hormone replacement therapy in recent onset menopause [16]. Pharmacological treatment of arterial stiffness can be divided into several categories based on the mechanism of action, mainly including (i) antihypertensive, (ii) agents against congestive heart failure, (iii) antihyperlipidemic agents, and (iv) antidiabetic agents. Representatives of each category of agents are listed in Table 2.

Table 2.  Representative pharmacological agents for the prevention of arterial stiffness.
AgentsEffect on arterial stiffnessReferences
Antihypertensive
 Diuretics
  IndapamideReduction in BP but no effect on PWV[50]
  HydrochlorthiazideReduction in BP but no effect on PWV[51]
 β-blockers
 BisoprololDecreased PWV[52]
 NebivololDecreased PWV[53]
 ACE inhibitors
  CaptoprilDecreased PWV and AIx[53]
  ClazaprilDecreased PWV[54]
 ATII receptor antagonists
  LosartanDecreased PWV and aortic AIx[53]
  ValsartanDecreased PWV and aortic AIx[55]
 Calcium channel antagonists
  NitrendipineDecreased PWV and BP[56]
  VerapamilDecreased PWV[57]
Agents for congestive heart failure
 Aldosterone antagonists
  SpironolactoneDecreased PWV and AIx[58]
  EplerenoneDecreased PWV[59]
Hyperlipidemic agents
 PravastatinDecreased PWV[60]
 FluvastatinDecreased PWV[61]
Antidiabetic agents
 RosiglitazoneDecreased PWV[62]

Antihypertensive Drugs

The effects of antihypertensive drugs on arterial stiffness are complex and variable [53]. These agents could have both short-term functional (direct and indirect) and long-term structural effects on the arterial wall. The direct functional effects are mediated by smooth muscle relaxation. The indirect effects are the result of attenuation of wave reflections and decrease in arteriolar tone [53]. The structural effects of antihypertensive drugs may involve vascular remodeling and the change of elastic protein distribution in the arterial wall. A large number of antihypertensive drugs have been investigated in both clinical and preclinical conditions and demonstrated their varied effects on arterial stiffness, including diuretics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II (ATII) receptor antagonists, and calcium channel antagonists [14,53,63] (Table 1). For example, in the Conduit Artery Function Evaluation (CAFE) study, two antihypertensive drug treatments, one with calcium channel blocker regimen (amlodipine ± perindopril) and another β-blocker-based regimen (atenlol ± thiazide), produced substantial different effects on central aortic pressures and hemodynamics but with little different effect on systemic blood pressure [64]. Importantly, cardiovascular event reduction better mirrored the effect on central BP than on peripheral BP, suggesting that the central BP effects of a new drug ought to be a better way to predict whether a new drug will reduce cardiovascular events than peripheral arm BP.

Drugs for Treatment of Congestive Heart Failure

A relationship between arterial stiffness and congestive heart failure has been demonstrated [65,66]. Spironolactone and eplerenone are aldosterone antagonists and demonstrated to be life-saving agents in patients with advanced heart failure and may benefit patients with mild heart failure. A significant relationship between the aldosterone-to-renin ratio (ARR) and aortic systolic BP and arterial stiffness in untreated hypertensive subjects [58]. In this randomized controlled study, only spironolactone reduced arterial stiffness in comparison with bendroflumethiazide [59]. Similarly, eplerenone have been shown to reduce arterial stiffness in hypertensive patients [59] and this therapeutic benefit of eplerenone may be associated with decreased collagen/elastin ratio and a reduction in circulating inflammatory mediators [67] or by means of endothelial protection [68]. Likewise, ACE inhibitors and β-blockers, which are also shown to be effective in congestive heart patients, are effective in reducing arterial stiffness (Table 2).

Drugs for Management of Dyslipidemia

Statins, the key contemporary cholesterol lowering agents, are effective in improving endothelial dysfunction and arterial stiffness [63]. The mechanism by which statins improve endothelial function may involve enhancing NO bioactivity by virtue of their antiinflammatory activities. This assertion is supported by evidence suggesting that effects of statin treatment on arterial stiffness are rather early and partly independent of cholesterol [60, 61].

Drugs for Treatment of Type 2 Diabetes

Epidemiological data suggest that insulin resistance and arterial stiffness are interrelated. In healthy insulin sensitive-subjects, insulin acutely decreases the augmentation index as measured using PWV. In insulin-resistant subjects, this effect of insulin is blunted implying that insulin resistance involves also large arteries and not only the microcirculation. This may provide one mechanism linking insulin resistance and cardiovascular disease [69]. Interestingly, one recent study compared normal subjects with offspring of diabetic parents and showed that subjects with predisposition to diabetes had carotid artery stiffening even in the absence of metabolic and blood pressure alterations [70]. While clinical data are limited on therapeutics of arterial stiffness with antidiabetic approach, rosiglitazone, an antidiabetic agent that improves insulin sensitivity, was shown to be effective in reducing arterial stiffness in patients with prediabetes or nondiabetic metabolic syndrome [62], suggesting that rosiglitazone may have an antiatherogenic effect in these patients. Furthermore, pioglitazone has also demonstrated favorable trends for cardiovascular disease risk reduction in the PROactive study, the largest cardiovascular disease outcome trial of glucose-modifying therapy completed to date [71]. On the other hand, however, data from recent large-scale clinical trials drawn particular attention on increased risk of heart failure and possibly myocardial infarction in patients with type 2 diabetes treated with thiazolidinedione drugs [72], challenging the overall role of this class in delivering cardiovascular benefits.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References

While there is considerable evidence suggesting that arterial stiffness is an independent cardiovascular risk factor and probably the best prognostic index for cardiovascular events, some important questions remain to be addressed.

First, is arterial stiffness a useful surrogate for cardiovascular risk or just a disease risk biomarker? The answer is probably both. Clinical studies demonstrated that arterial stiffness measured by aortic PWV and wave reflections could be used as a surrogate for various therapeutic interventions (Table 2). However, further studies are required to validate the predictive value of arterial stiffness in predicting cardiovascular risk reduction as a surrogate biomarker for registration of drug.

Second, which method of arterial stiffness may provide the most reliable assessment? A number of methods are currently available to assess arterial stiffness, of which peripheral/central pulse pressure and Alx (for wave reflection) are considered “surrogates” of arterial stiffness. Because pulse pressure is amplified across central and peripheral arteries, brachial pulse pressure might be an inaccurate surrogate for aortic or carotid pulse pressure. Central pulse pressure and Alx are dependent on the speed of wave, the reflectance point, and the duration and pattern of ventricular ejection, and thus only indirect surrogate measures of arterial stiffness. Central pressure and Alx may provide additional information concerning wave reflection for the measurement of arterial stiffness. In contrast, it has been demonstrated in clinical studies that aortic PWV, which measures the speed of wave travel and represents intrinsic arterial stiffness, provides an intermediate endpoint for cardiovascular events. Likewise, various modifications of PWV measurement, such as baPWV and AASI, have been shown their values in clinical studies of Japanese populations. While it appears that aortic PWV might be the best method to date to assess arterial stiffness, further clinical studies are required to validate it as a surrogate in predicting cardiovascular risk.

Third, how does arterial stiffness as a surrogate compare with those of endothelial dysfunction and atherosclerosis? There is sufficient evidence demonstrating that pathophysiology of arterial stiffness involves endothelial dysfunction, altered SMC function, and vascular inflammation, which overlap in a large degree with atherosclerosis. In spite of considerable similarities in the mechanisms and final outcome, differences clearly exist among arterial stiffness, endothelial dysfunction, and atherosclerosis. Aortic PWV, as a surrogate for arterial stiffness measurement, relies in part on changes of vessel structure and elastic function, which is distinct from the endothelial function. Endothelial dysfunction is associated with decreased production of NO, resulting in reduced vasorelaxation, prothrombotic activities, and proinflammatory action of oxidative stress. Assessment of endothelial function could represent a “barometer” of vascular health to gauge cardiovascular risk. Considerable clinical evidence suggests that testing endothelial function, either by invasive methods such as coronary and forearm circulation by intraarterial acetylcholine-induced vasodilation or by noninvasive measurement of flow-mediated dialation, could also be a useful surrogate to predict cardiovascular events. Atherosclerosis is a complex vascular disease initially triggered by endothelial dysfunction and inflammation, and later involved in lipids deposition, chronic local vascular inflammation, altered vascular SMCs function and extracelluar remodeling, and calcification in atherosclerotic plaques. Atherosclerotic plaques will ultimately lead to rupture, erosion, and occlusion of the vessel by thrombosi. Several invasive (such as angiography and intravascular ultrasound) and noninvasive technologies (such as ultrasound of carotid intima-media thickness, computed tomography assessment of coronary artery calcium, and MRI for composition and functional assessment of plaques) have been developed to assess the high-risk atherosclerotic plaques. While some technologies such as intravascular ultrasound and intima-media thickness have shown to be of values in clinical studies, much remains to be learned for their use as a surrogate of therapeutic intervention due to either the quality to assess plaque vulnerability or lack of clinical experience.

Finally, as clinical studies suggest that arterial stiffness, endothelial dysfunction, or direct plaque imaging assessment might be served as an independent surrogate for cardiovascular risk, combined assessment of all three variables might be a better surrogate to predict cardiovascular risk. Alternatively, because all of these pathophysiological conditions share some common mechanism such as endothelial dysfunction and vascular inflammation, the combined assessments of arterial stiffness, endothelial dysfunction, or vulnerable plaque along with circulatory biomarkers (e.g., C-reactive protein, inflammatory cytokines) might provide a more predictive surrogate of disease progression and regression in response to therapy. For example, statins have been demonstrated to benefit vascular health by reduction of arterial stiffness, improve endothelial function, and reduce the progression of atherosclerosis. The prospect arises that assessment of arterial stiffness, possibly together with endothelial function testing, vascular imaging or circulatory biomarker measurement, may become a better surrogate/biomarker to assess the efficacy of new therapeutic agents and whether they will reduce cardiovascular risk at an earlier stage of the disease process.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Measurement of Arterial Stiffness
  5. Mechanisms of Arterial Stiffness
  6. Therapeutic Agents that Modify Arterial Stiffness
  7. Conclusion
  8. Conflict of Interest
  9. References
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