|Year : 2021 | Volume
| Issue : 3 | Page : 146-152
Arterial stiffness – A measurable vascular marker in clinical practice
Nagaraj Desai1, CR Venkatesh2, Prabhakar Koregol3
1 Department of Cardiology, JSS Medical College and Hospital, JSS Academy Higher Education and Research, Mysuru, Karnataka, India
2 Department of General Medicine, JSS Medical College and Hospital, JSS Academy Higher Education and Research, Mysuru, Karnataka, India
3 Namana Medical Centre, Bengaluru, Karnataka, India
|Date of Submission||30-Nov-2020|
|Date of Acceptance||29-Mar-2021|
|Date of Web Publication||16-Jul-2021|
Prof. Nagaraj Desai
JSS Medical College, Hospital and JSS Academy Higher Education and Research, Mysuru, Karnataka
Source of Support: None, Conflict of Interest: None
Arterial stiffness results from the changes in the walls of the large vessels and aorta. It has been incriminated in the pathogenesis of cardiovascular disorders. Its association with the major risk factors and atherosclerosis has been explored. Pulse wave velocity (PWV) is generally measured to evaluate it. Noninvasive methods of its measurement, which have been found to be satisfactory inaccuracy, make it a very attractive tool for cardiovascular risk assessment. In clinical practice, probe-based or cuff-based systems are commonly used to measure arterial stiffness. It may well be suited for the detection of vascular abnormality of an intermediate clinical phenotype and has been shown to be a marker of poorer prognosis in some diseases like chronic kidney disease. It has also been found to be reversible in clinical studies, although in the early stages. Given the global burgeoning cardiovascular diseases, it may serve as an attractive clinical screening tool that may be applied to a large population to implement early preventive strategies and utilize the limited resources to those with abnormal findings. Region-specific guidelines do recommend measurement of PWV. However, in the real world, the measurement of arterial stiffness remains underutilized as yet.
Keywords: Arterial stiffness, cardiovascular risk, pulse wave velocity
|How to cite this article:|
Desai N, Venkatesh C R, Koregol P. Arterial stiffness – A measurable vascular marker in clinical practice. APIK J Int Med 2021;9:146-52
|How to cite this URL:|
Desai N, Venkatesh C R, Koregol P. Arterial stiffness – A measurable vascular marker in clinical practice. APIK J Int Med [serial online] 2021 [cited 2021 Jul 29];9:146-52. Available from: https://www.ajim.in/text.asp?2021/9/3/146/321666
| Introduction|| |
Of the non-communicable diseases, cardio and cerebrovascular diseases (CCVD) account for a large number of deaths in India. Unlike in the west, it has been observed that these diseases tend to occur at an earlier age with increased morbidity and mortality.,
Significant energies including fiscal resources are spent on the diagnosis and management of the CCVD after they clinically manifest with aggressive advocacy from several quarters including clinical guidelines, scientific societies, and backed by the results of clinical trials. While such an approach has its own clinical merits and importance, one cannot overemphasize the need for an early diagnosis and prevention of vascular diseases considering the finite resources available to the society and the huge task of reducing the burden of burgeoning CCVD. The implications for the clinical practice are obvious. One should be targeting at an early diagnosis of vascular disorders. Widespread implementation of such strategies in the population for diagnosis and therapeutic intervention may mitigate the devastating clinical outcomes.
Atherosclerosis has been noted to be the most common cause of CCVD with other etiologies trailing it distantly.
Yet another vascular abnormality, which may be present in a given individual is arteriosclerosis. Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events. Furthermore, newfound interest and measurement of aortic and large artery hemodynamics are emerging. This has been driven principally by the accumulating evidence that aortic stiffness is an independent predictor of future cardiovascular risk in a variety of populations.
This effect is postulated to be due to its effect on cardiac afterload, atherosclerosis plaque formation or progression, or both. A recent large study has tried to explore this relationship, using a cardiovascular magnetic resonance (CMR) and whole-body CMR angiogram in a low – intermediate-risk group population. The aim of the study was to examine the association between arteriosclerosis, atherosclerosis, and ventricular remodeling. The authors conclude that systemic arteriosclerosis is associated with left ventricular remodeling but not atherosclerosis. They suggest that future efforts in cardiovascular risk prevention should thus seek to address both arteriosclerosis and atherosclerosis individually. Although the techniques of measuring vascular stiffness have been around for nearly 100 years, only in the past 20–25 years, pragmatic noninvasive approaches have allowed the incorporation of arterial stiffness measurements, usually in the form of aortic pulse wave velocity (PWV), into the clinical assessment of patients. In this review, the authors propose to review the concept of arterial stiffness and its clinical utility.
| Definition|| |
Arterial stiffness may be defined as a vascular phenotype caused by the changes in the walls of large arteries, especially the aorta, resulting from the loss of elasticity over time. An increase in the stiffness may portend increased cardiovascular risk.
| Pathophysiology of Arterial Stiffness|| |
Arterial stiffening, at least in part, reflects gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the arterial wall. Arterial stiffness is a concept that refers to the material properties of the arterial wall, which in turn has functional consequences for the artery because it affects the manner in which pressure, blood flow, and arterial diameter change with each heartbeat. In addition to the passive mechanical properties of the load-bearing structures, arterial stiffness can be modulated by the functional components related to cellular processes. The wall stiffness can be affected by endothelial function through the modulation of smooth muscle tone or by alterations in the integrity of the extracellular matrix. Decreased vascular compliance of the large arteries manifests as increased arterial pulse pressure with higher systolic pressures and lower diastolic pressures without a significant change in the mean pressure. The clinical consequences of higher systolic pressure include an increased risk of stroke and myocardial infarction. Vascular stiffness increases left ventricular afterload and decrease coronary perfusion, leading to CVD. Further, it is reported that increased vascular stiffness, as measured by PWV, is associated with increased cardiovascular and all-cause mortality in dialysis patients.
There may be a variable period of months to years and even decades of 'asymptomatic/quiescent phase when the vascular abnormalities and atherosclerosis is building up in a segment of a vessel wall causing some preclinical abnormalities in the vascular tree [Figure 1]. Recognizing these abnormalities with imaging or nonimaging techniques has been a subject of great interest.
|Figure 1: Progression of arteriosclerosis over time. CRP: C-reactive protein, ABI Ankle brachial index, CCVD: Cardio and cerebrovascular diseases|
Click here to view
It is useful, at this stage, to add a small note on the relationship between the arteriosclerosis and atherosclerosis vis-a-vis CVD. The debate about the nature of the relationship between arterial stiffness and cardiovascular disease: Is arterial PWV (aPWV) a measure of arteriosclerosis truly an independent risk factor or simply a marker? A number of hypothetical relationships have been proposed. It is possible that the CVD is primarily driven by the aortic stiffness independent of well-known major risk factors. Although some outcome data is reported, it still requires more evaluation. Alternately, the risk factors themselves might have caused changes in the vessel wall which is measured as stiffness. Nevertheless, aPWV could still be more closely related to future events than a single “snapshot” measure of individual risk factors in isolation. Third, if the presence of atheroma alters the mechanical properties of the arterial wall, then aPWV could simply be a measure of the amount of plaque between the carotid and femoral arteries. Nonetheless, PWV is used to measure arterial stiffness.
| Methods of Studies of Arterial Stiffness|| |
Many experimental animal models and human epidemiological studies support the importance of the relationship between arterial stiffness and hypertension., The animal models studied include dietary manipulation models, genetic models, salt-sensitive rat models, and diabetes type 2 models. The Framingham heart cohort study also has suggested a temporal association between arterial stiffness and hypertension, the former preceding the latter.
| Measurement of Arterial Stiffness|| |
Our understanding of changes in vascular mechanics and its effect on blood pressure has grown as technology has improved our ability to quantify the vascular stiffness in man. A recent scientific statement by the American heart association, lead by Townsend et al., evaluating the status of vascular stiffness discusses the status and recommends, comprehensively, further improvements and refinements in the research. Improvements in the standards of measurements and further research are expected to result in its widespread clinical use.
| Methods of Measurement of Arterial Stiffness|| |
The pulse-wave velocity (PWV; measured in meters per second) and variations such as carotid-femoral PWV (cfPWV; measured in meters per second) are used to measure arterial stiffness. PWV without modification is used in the general sense of arterial stiffness. The addition of lower case modifiers such as “cf” is used when speaking of specific segments of the arterial circulation. This is a valid measure, justified by equations such as the Moens-Korteweg and Bramwell Hill equations with which these measures agree.
The measurement of the vascular stiffness can be done in both longitudinal as well as cross-sectional manner over muscular as well as elastic arteries. Usually, arterial stiffness is evaluated as the velocity of pulse-wave travel across an artery segment for example, aorta and other vessels. Arterial stiffness can also be derived by using complex formulae given certain parameters like pressure. Other methods to measure arterial stiffness include the assessment of arterial compliance or distensibility or measures of characteristic impedance (relating pressure changes to flow changes). When arterial geometry (size and wall thickness) is known, it can be used to compute the arterial wall elastic modulus, a direct expression of the stiffness of the wall. Confusion arises when measures such as systolic pressure augmentation, which compares the first and second systolic peaks in the central aortic waveform and is sometimes reported as an augmentation index, are presented as “stiffness” parameters. Such measures are the result of several factors, including, but not limited to, arterial stiffness.
| How to Measure Arterial Stiffness?|| |
Devices used to measure pulse wave velocity
Several methods have been used to measure PWV. Use of tonometry, ultrasonography, Oscillometry, Magnetic Resonance (MR) techniques have been reported. Point measurements like MR or ultrasound-derived distensibility, regional measures like transit time PWV, and indirect measures derived from analysis of features of pressure waveforms recorded in the arm using a standard blood pressure cuff have been used. cfPWV and conventional pulse pressure have the strongest evidence base supporting the clinical value and are the best studied.,
Direct assessment is by measuring the transit time of pressure waveform from probes placed on carotid and femoral arteries or cuffs on brachial and femoral arteries [Figure 2]a and [Figure 2]b or it can be derived from flow waveforms recorded by Doppler or MR. Probe-based devices are user dependent and require skilled appropriately trained personnel to obtain repeatable cfPWV values using relatively inexpensive equipment. Cuff-based measurements though require less training, may be less accurate, particularly at high values of cfPWV, possibly limiting its use in any of the major outcome studies. Although MR provides more accurate estimation of path length it requires expensive equipment and has a much lower temporal resolution. In addition, flow-based (Doppler or MR) as compared with pressure-based assessments of transit time have opposite sensitivities to wave reflection. As a result, aortic PWV assessed by MR or Doppler flow will have systematically lower values than tonometry-based PWV. Alternatively, cfPWV can be estimated indirectly from a single pressure waveform recorded in the brachial artery using a standard blood pressure cuff, and proprietary algorithms. Although cuff-based methods are more appealing for clinical use, because of their ease of use, concerns regarding accuracy of these methods suggest that they cannot be viewed as interchangeable with direct cfPWV measurements. Probe-based cfPWV is the current gold standard measure of vascular stiffness, can be easily assessed in a clinic or hospital setting and has the most outcome data. It also seems that expensive and time-consuming techniques such as MR, without substantial outcome data, will very unlikely enter the clinical setting any time soon. Pulse pressure depends on a variety of factors, including aortic geometry and peak aortic flow, whereas CFPWV is largely a measure of aortic wall stiffness which makes CFPWV the gold standard measure of aortic stiffness. Thus, at present, direct, probe-based CFPWV measurement seems most appropriate for clinical use.
|Figure 2: (a-c) The recordings obtained from a patient who has multiple risk factors. The periscope™ system (Genesis Medical Systems, USA) obtains the data by using simultaneous recordings of blood pressures from both arms and thighs using cuffs and four lead ECG recordings. Its output includes pulse-wave velocities, arterial stiffness index, ankle brachial index, mean arterial pressure, pulse pressure, also, it derives data on central aortic pressure, carotid femoral pulse wave velocity, presence of peripheral artery disease, and framingham risk score|
Click here to view
The authors have been using the cuff-based systems for a decade. [Figure 2]a, [Figure 2]b, [Figure 2]c illustrates the data obtained from a system.
| Devices Used to Measure Pulse Wave Velocity|| |
Recommendations for measurement
- Arterial stiffness should be determined noninvasively by measurement of cfPWV (Class I; Level of Evidence A)
- PWVs measured in other vascular segments such as ankle-brachial or the determination of the cardiac-ankle vascular stiffness index is useful in cardiovascular outcome predictions in Asian populations, but longitudinal studies in the United States and Europe by these methods are lacking (Class I; Level of evidence B)
- Single-point estimates of PWV are not recommended because there is a lack of evidence of cardiovascular outcome prediction in longitudinal studies. Measurement of PWV in other arterial segments such as carotid-radial is not recommended because it does not predict outcomes (Class III; Level of Evidence B).
| Caveats of Interpretation of Carotid-femoral Pulse Wave Velocity|| |
According to the guidelines,, it is preferable to avoid prediction of prognosis based on a single point estimate as long-term data are not reported. One should pay attention while interpreting the significance of a value of cfPWV. Thresholds and Normative Values for Risk Assessment cfPWV were included in the 2007 European Society of Hypertension/European Society of Cardiology guidelines for the management of hypertension in which a fixed cutoff of 12 m/s was proposed, indicating subclinical organ damage.
This was modified by a recent expert consensus, which took into consideration a new distance calculation methodology and recommended a new 10 m/s threshold (derived by multiplying 12 m/s by 0.8 and then rounding up). Although attractive because of the simplistic approach, risk estimation based on fixed thresholds has several limitations, including variable elasticity of the aorta. The relationship of the increase in PWV to aging is not inevitable. It has been shown that increase in cfPWV is not steep in low-risk population; suggesting that a major part of stiffness may be pathological and that therefore, it may not be appropriate to use age-specific thresholds for risk estimation.
Heart rate and mean arterial pressures influence PWV measurements. To minimize such confounding effects, arterial stiffness should be assessed in a quiet, temperature-controlled environment. Participants should also refrain from alcohol, vasoactive medications, and vigorous physical activity ideally for 12 h and large meals, caffeine-containing food and drinks, and smoking for at least 2–4 h before the measurements. It is important that participants are allowed to rest in the supine position for at least 10 min to ensure hemodynamic stability.
| Methodological Confounders|| |
Although cfPWV is recognized as the gold standard for the noninvasive assessment of arterial stiffness, arterial stiffness often is measured in alternative (or additional) vascular beds. For example, several noninvasive commercial devices assess baPWV. Compared with the carotid-femoral vascular bed, the brachial-ankle vascular bed encompasses additional arterial territories with different characteristics, different determinants of stiffness, and different influences of atherosclerosis. Indexes are not necessarily interchangeable, either physiologically or prognostically. This must be taken into account for not only research but also clinical work.
| Measurement of Central Aortic Hemodynamics|| |
Central aortic hemodynamics measurements, which reflect its elastic property (and stiffness) are found to be abnormal in several clinical conditions, which may have bearing on their prognosis. With the advent of noninvasive technologies, it has been possible to measure it. It is the mechanical afterload imposed by the systemic circulation to the contracting left ventricle. In the presence of a normal aortic valve, LV afterload is determined largely by the elastic properties (arterial stiffness), arteriolar caliber, and wave reflection characteristics of the arterial tree (arterial load). There are reports of its correlation to prognosis in certain cohort of patients like end-stage renal disease; that increased aortic stiffness determined by measurement of aortic PWV is a strong independent predictor of all-cause and mainly cardiovascular mortality. The central aortic pressure is derived and reported. Hashimoto reviews its importance and implications underscoring its utility in clinical practice. Indeed, its measurement, which is derived by device-specific algorithm [Figure 2c] could be a useful parameter to obtain and could be correlated to the cardiovascular prognosis.
| Arterial Stiffness as a Risk Factor|| |
Reference to the association between arterial stiffness and disease is found in ancient literature. Several pointers suggest that it may be considered a risk factor. Its ability to discriminate and reclassify beyond traditional Framingham risk factors is an important one. The biological basis which contributes to the abnormality of cardiovascular functioning also support such a possibility. Additional favorable points include it being noninvasive, repeatable, easily available, and economical. The data on its ability to predict prognosis has also been documented albeit in selected cohorts like hypertension, chronic kidney disease. A recently published meta-analysis reported more detailed individual participant data from 17,635 participants drawn from 16 individual studies, the majority of which used handheld probes to assess cfPWV. After adjustment for age and sex, a 1SD difference in log-transformed PWV was associated with 45% higher CVD events in 5-year follow-up. After additional adjustments for SBP, cholesterol or lipids, smoking, diabetes mellitus, and hypertension, it was still associated with 35% higher CVD events in 5-year follow-up. The addition of cfPWV to standard Framingham risk factors in group at intermediate risk improved classification of those who experience CVD events in 10-year follow-up by 13%. All these points suggest vascular stiffness is a true risk factor rather than the marker.
Further, in a meta-analysis of genome-wide association studies involving most of the same cohorts by the same group, demonstrated that a locus associated with cfPWV was also associated with a proportional increase in risk for developing various CVD endpoints, including myocardial infarction and heart failure, suggesting that excessive aortic stiffness, as assessed by cfPWV, is a true risk factor, rather than just a marker of risk, for CVD.
Large scale data retrospectively analyzed or prospective studies are needed in low- and intermediate-risk groups to ascertain the value of measurement of arterial stiffness in these population of various regions and ethnicity. Once available, this could serve as an important fillip for the widespread clinical use of measurement of arterial stiffness.
| What Stiffness May add to Our Understanding|| |
Aortic versus peripheral pulse wave velocity
PWV can be evaluated in any segment of circulation. However, two reasons why aortic PWV is favored:
- Vessels to all organs which are the target of vascular disease are connected to the aorta
- Aortic stiffness is more predictive of CV death.
PWV is independent prediction of cardiovascular endpoints, Health ABC study showed clear association of CV events with Aortic PWV at each quartile of increasing velocity independent of age, gender, SBP, race, or known previous CVD.,,
| Is Vascular Stiffness Reversible?|| |
Both human and animal models have suggested arterial stiffness is potentially reversible.,, It is not surprising that antihypertensive drugs have repeatedly demonstrated efficacy to lower arterial stiffness. This is because blood pressure reduction unloads the stiff components of the arterial wall, such as collagen. Whether different classes of antihypertensive agents vary in their efficacy to affect arterial structure and thus influence arterial compliance via a pressure-independent mechanism is more controversial. However, ACE inhibitors could be possibly of some benefit. Evaluation in large scale trials or meta-analysis of smaller studies is necessary to provide further clarity.
Many treatment modalities have been suggested as possible candidates for treatment for reversing vascular stiffness. However, treatment of obesity and hypertension remain the cornerstone of reversibility. Exercise healthy diet, weight loss, and antihypertensive medications are considered positive modifiers of vascular stiffness. ACE-inhibitors, angiotensin II receptor blockers, aldosterone antagonists, and calcium antagonists have favorable effects in improving arterial elasticity, while beta-blockers have an inverse effect. Diuretics have not been evaluated. Lipid-lowering therapy, some antidiabetic therapy have shown to reduce arterial stiffness.
| Is Vascular Stiffness a Target for Therapy?|| |
Favorable effects in improving arterial elasticity, while beta-blockers have an inverse effect. Diuretics have not been evaluated. Lipid-lowering therapy, some antidiabetic therapy have shown to reduce arterial stiffness.
ACE-inhibitors, angiotensin II receptor blockers, aldosterone antagonists, and calcium antagonists have favorable effects in improving arterial elasticity, while beta-blockers have an inverse effect. Diuretics have not been evaluated. Lipid-lowering therapy, some antidiabetic therapy have shown to reduce arterial stiffen. However, for all the interventions, there seems to be a critical time zone, so following healthy vascular aging they becomes important and has been recommended by ACC/AHA as well as ESC 2013.
- Younger individuals at intermediate risk. Little point in established CVD
- Borderline or white coat hypertension
- Early recognition of cardiovascular toxicity in a patient receiving cancer chemotherapy is important to mitigate the unfavorable clinical outcomes. Arterial stiffness may manifest or progress in patients receiving cancer chemotherapies. A recently published systematic review and meta-analysis support the measurement of arterial stiffness to identify early cardiovascular injury and subsequent care. It possibly opens up a potential opportunity to evaluate arterial stiffness in the cohort of patients receiving chemotherapy.
| Arterial Stiffness and Therapies|| |
Many therapeutic agents which work on the arterial wall have potential to reduce arterial stiffness. These drugs belonging to different classes include antihypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta-blockers, diuretics, and nitrates), statins, peroral antidiabetics, advanced glycation end-products cross-link breakers, anti-inflammatory drugs, endothelin-A receptor antagonists, and vasopeptidase inhibitors. However, clinical studies evaluating the influence of decrease in arterial stiffness on major adverse cardiovascular and cerebrovascular events are needed.,
What remains to be done before measurement of arterial stiffness can be recommended routinely for clinical practice.
- Large prospective study/retrospective meta-analysis to test the hypothesis that PWV has a meaningful impact on clinical outcome and facilitates decision making in medium-risk individuals and subjects with borderline hypertension
- Cost-effectiveness of the strategy needs to be proven
- The prospective demonstration of the clinical utility is particularly important as threshold for treatment is lowered and many more people are asked to take lifelong medications with known risk and uncertain personal benefits.
| Conclusions|| |
Measurement of arterial stiffness provides a clinician with a simple noninvasive tool to recognize the vascular abnormality even before overt clinical manifestation. This may enable him to intervene and mitigate the adverse consequences especially in those who are at low and intermediate risk for cardiovascular disorders. Given the huge population which falls into this category across the globe, one cannot overemphasize the utility of such a simple approach. Before it can be put into routine practice, systematic evaluation in large clinical studies of the strategy of integrating measuring of vascular stiffness with other well-known parameters is in order. Arterial stiffness should be seen as a complimentary to risk factors including blood pressure measurement and should be considered when calculating risk or making treatment decisions. While the evaluation of atherosclerosis has occupied the clinician's mind and all efforts are made by him to evaluate it, the arterial stiffness seems to receive poor attention though both these processes affect the biology of the arterial system possibly “together in association.” This mindset needs to change as the clinical guidelines also recommend the measurement of arterial stiffness. The availability of regional longitudinal data in various cohorts of population should only, indeed, improve the enthusiasm to measure it.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]