Reimagining the Value of Brachial-Ankle Pulse Wave Velocity as a Biomarker of Cardiovascular Disease Risk—A Call to Action on Behalf of VascAgeNet

Abstract

This review critiques the literature supporting clinical assessment and management of cardiovascular disease and cardiovascular disease risk stratification with brachial-ankle pulse wave velocity (baPWV). First, we outline what baPWV actually measures—arterial stiffness of both large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb. Second, we argue that baPWV is not a surrogate for carotid-femoral pulse wave velocity. While both measures are dependent on the properties of the aorta, baPWV is also strongly dependent on the muscular arteries of the lower extremities. Increased lower-extremity arterial stiffness amplifies and hastens wave reflections at the level of the aorta, widens pulse pressure, increases afterload, and reduces coronary perfusion. Third, we used an established evaluation framework to identify the value of baPWV as an independent vascular biomarker. There is sufficient evidence to support (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. However, there is limited or no evidence to support (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values. Fourth, we address future research requirements. The majority of the evaluation criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets, whereas the (5) clinical outcomes and (6) cost-effectiveness criteria require prospective investigation. The (8) methodological consensus criteria will require an expert consensus statement. Finally, we finish this review by providing an example of a future clinical practice model.

Cardiovascular disease (CVD) risk management may be improved by incorporating arterial stiffness (AS), a measure of biological vascular aging, within standard clinical practice. Brachial-ankle pulse wave velocity (baPWV, see Figure 1), a composite measure of central and peripheral AS,¹ has been widely adopted in parts of East Asia, with the Japanese Society of Hypertension Guidelines recommending the use of baPWV for hypertension management.² Despite incorporation within the 2023 European Society of Hypertension guidelines,³ in which it is recommended as a screening tool for hypertension-mediated organ damage, baPWV has received sparse attention in Western countries. This review focuses on the use of baPWV as a vascular biomarker to aid in the clinical management of CVD risk. Definitions for key terms and concepts used throughout the review are provided in Table 1. After reading this review, readers should be able to better understand:

Figure 1.

Comparison of wall composition and changes in pulse wave velocity with age between central and peripheral arterial regions. Brachial-ankle pulse wave velocity (baPWV; composite measure) summates the arterial properties between the descending aorta at the level of the brachial artery and the ankle, comprising of arteries or arterial regions (eg, the aorta) with different structural and mechanical characteristics. cfPWV indicates carotid-femoral pulse wave velocity (central); crPWV, carotid-radial pulse wave velocity; and faPWV, femoral-ankle pulse wave velocity (lower-limb). VSMC indicates vascular smooth muscle cell.

Table 1.

Key Terminology Definitions

1. The physiological principles of baPWV;

2. baPWV is a unique vascular biomarker and not a surrogate for carotid-femoral pulse wave velocity (cfPWV) or other measures of AS;

3. The evidence supporting the use of baPWV as a vascular biomarker;

4. Future research requirements.

VASCULAR AGING AND ARTERIAL STIFFENING

The deterioration in vascular structure and function over time are the hallmarks of vascular aging. Vascular aging is attributable to atherosclerosis, the narrowing of the artery by the deposition of atheromatous plaque, and arteriosclerosis, the stiffening and thickening of the arterial wall.^4,5 Although vascular aging is a natural phenomenon associated with chronological age, there is wide interindividual variability as a function of lifestyle, environmental and genetic factors.⁶

AS describes the resistance of the arterial wall to deformation. The arterial wall comprises endothelial cells, vascular smooth muscle cells, and connective scaffolding proteins—principally collagen and elastin (see Figure 1). Elastin predominates in central arteries, ensuring a high elastic potential and the capacity to cushion the flow and pressure oscillations caused by intermittent cardiac left-ventricular ejection.⁷ Collagen fibers and vascular smooth muscle cells predominate in muscular peripheral arteries, which means a lower elastic potential but a greater propensity for alterations in tone. The transition from a compliant aorta to relatively stiffer muscular arteries generates an impedance mismatch or stiffness gradient.^7,8 The stiffness gradient attenuates the cyclical forward pressure wave into a smooth consistent blood flow, prevents transmission of pulsatile energy to the microcirculation, and moderates wave reflection and, therefore, cardiac workload.^7,8

Arterial stiffening is an arteriosclerotic process resulting from the gradual fragmentation, calcification, and loss of elastin fibers, the accumulation of stiffer collagen fibers, calcification and senescence of vascular smooth muscle cells, inflammation, and endothelial dysfunction contributing to a loss of elasticity or increase in the myogenic tone of the vessel wall.^7,9 Central arteries are susceptible to stiffening, whereas the stiffening of peripheral arteries is less pronounced (see Figure 1).¹⁰ Arterial stiffening, particularly of the aorta, increases systolic and pulse blood pressure and the pulsatile load on the left ventricle, as well as the transmission of pulsatile energy to the microcirculation, leading to damage of target organs.⁷ The differing impact of age, lifestyle factors, and risk factors on central and peripheral arteries leads to progressive attenuation of the physiological impedance mismatching, with attenuation or reversal of the stiffness gradient.^10,11 This amplifies and hastens wave reflection, increasing cardiac workload and the impairment of coronary perfusion.⁸

OVERVIEW OF BAPWV

Measurement of baPWV

Pulse wave velocity is the speed at which the forward pressure wave propagates along the arterial tree and is calculated as arterial path length divided by pulse transit time (PTT). A higher PWV indicates a greater (detrimental) AS. The PTT for baPWV is commonly measured using blood pressure cuffs equipped with oscillometric and volume-plethysmographic sensors. The cuffs are secured around the upper arm (s; brachial artery) and ankle (s; tibial and peroneal arteries) and used to simultaneously record the underlying pulse pressure waveforms (Figure 2). The PTT is then calculated as the time interval between the brachial and ankle waveforms using the foot-to-foot method, where the foot is detected using the intersecting tangent method. The arterial path length is typically estimated automatically via height-based equations but can be estimated using body surface measurements and calculated as the path length from the suprasternal notch to the ankle minus the suprasternal notch to the brachium.¹²

Figure 2.

Schematic for the measurement of brachial-ankle pulse wave velocity (baPWV). baPWV is estimated as the length between the sternal notch and the ankle (L_SA) minus the sternal notch to brachium (L_SB), as determined by body surface measurements or height-based formulas, divided by the time delay between brachial and ankle waveforms (∆T_BA). Note: solid line denotes effective path length.

What Physiological Construct Does baPWV Measure?

There is a prevalent, but mistaken, view that baPWV solely reflects the stiffness of peripheral arteries.¹³ baPWV not only incorporates the medium-sized muscular peripheral arteries of the lower limbs but also the elastic descending aorta (Figure 1). The proximal portion of the aorta is excluded from baPWV, at least theoretically, which can be attributed to the use of the brachial artery as the proximal measurement site. Following the ventricular ejection, pulse pressure waves simultaneously propagate along the heart-brachial and heart-descending aorta arterial segments. It is assumed that the distance propagated and PTT for these pulse pressure waves are equitable. This theoretically results in the descending aorta serving as the starting point for baPWV.^1,14 This assumption is made for cfPWV, as the heart-carotid arterial segment is inconsistent with the path of blood flow for the region of interest. While the starting point of baPWV is the descending aorta, it is still influenced by the preceding segments and the heart-brachial arterial segment. The importance of upper-limb PWV is often overlooked as it is expected to change little with age,¹⁵ but an increase or decrease in heart-brachial PWV may bias the baPWV outcome by increasing or decreasing the brachial-ankle PTT.

Disadvantages of baPWV

Measurement of baPWV May Be Inappropriate in Some Patient Populations

The presence of cardiovascular pathology can impact the accuracy of baPWV measures. Stenosis in the lower limbs, aortic stenosis, aneurysm, or regurgitation may lead to a pseudo-underestimation of baPWV.^16,17 Stenosis in the subclavian arteries may lead to a pseudo-overestimation of baPWV. Measurement of baPWV may be inappropriate if the patient presents with one of the aforementioned conditions.

Height-Based Formulas to Estimate Arterial Path Length Are Inaccurate

The arterial path length is typically estimated using height-based formulas, which may be advantageous for clinical practice but lack accuracy. compared with magnetic resonance imaging, height-based formulas overestimated path length by ≈11%.¹⁸ This contributes to absolute values of baPWV being substantially higher than all other regional PWV measures. Magnetic resonance imaging and height-based path lengths are highly correlated, indicating this problem may be rectified with an appropriate adjustment factor, but population-specific validation is required.¹⁸

Advantages of baPWV

Measurement of baPWV Is Simple and Automated

A prominent advantage of baPWV is its ease of assessment, with PPT being determined noninvasively and automatically using oscillometry. Limited training is needed for the baPWV operator, since the technique does not differ from any cuff-based blood pressure measurement. This simplicity, combined with an inherent low-patient burden, means baPWV may be easily applied in clinical practice.

Measures of baPWV Can Be Determined With Accuracy and Precision

baPWV has shown good agreement (r=0.87) with central PWV obtained by invasive recording.¹⁹ baPWV can be determined with good reliability (intraobserver, between-visit day to day) and good reproducibility with low-operator bias (interobserver, same day).²⁰ Comparative studies have reported higher between-day intraclass-correlation coefficients for baPWV (0.84) compared to cfPWV (0.70).²⁰

Ankle Brachial Index, Systolic Interarm Blood Pressure Difference, and Pulse Wave Analysis Can Be Determined Concurrently With baPWV

The ankle brachial index (ABI) is the ratio of the systolic blood pressure measured at the ankle to that measured at the brachial artery, with a threshold of ≤0.9 typically indicating significant stenosis and lower-extremity peripheral artery disease (PAD) or >1.4 indicating vascular calcification.²¹ An interarm blood pressure difference (IAD) of ≥10 mm Hg indicates significant upper extremity stenosis and PAD.²² ABI and IAD can identify the presence of stenosis and inform the suitability of baPWV measurement. Pulse wave analysis (PWA) entails using a generalized transfer function to estimate the aortic pressure waveform, from which central hemodynamic variables such as central blood pressure and arterial wave reflection indices are derived.^23,24 These complimentary outcomes will be further discussed in the Potential Clinical Practice Model section.

BAPWV IS A STANDALONE MARKER OF CVD RISK

baPWV is commonly perceived as a surrogate of the referent PWV measure, cfPWV. baPWV and cfPWV do reflect overlapping regional arterial properties and functions and share similar associations with CVD risk factors (Figure 1).^25,26 However, baPWV also incorporates the medium-sized muscular arteries of the lower extremities,²⁶ the stiffness of which can increase with age^16,27 and predicts stroke and CVD, including heart failure and myocardial infarction.²⁸ Increased stiffness of the muscular lower-limb arteries may principally contribute to CVD by amplifying and hastening wave reflections at the level of the aorta. This increases systolic blood pressure and widens pulse pressure, augmenting cardiac workload and increasing afterload while reducing coronary perfusion. The inclusion of this larger vascular territory means baPWV can provide additional, or at least different, cardiovascular information. Compared with cfPWV, baPWV is more strongly associated with cardiovascular structure and function, including left-ventricular mass and diastolic function.^29,30 Although, whether this translates to differentiation of hard outcome prognosis over the longer term between PWV measures is unclear.

EVIDENCE SUPPORTING USE OF BAPWV AS A VASCULAR BIOMARKER

Within this section, we critique whether there is evidence to support the use of baPWV as an intermediate outcome. An intermediate outcome is a surrogate measure for a clinical end point, for example, CVD morbidity or mortality. A vascular biomarker can be considered an intermediate outcome if it is associated with the intended clinical end point and is on the causal pathway between exposure (eg, behavior or treatment) and effect (ie, predicts clinical benefit/harm).³¹ A vascular biomarker can be considered suitable for clinical use if it satisfies the aforementioned, confers meaningful prediction of clinical benefit/harm superior beyond existing biomarkers (eg, lipids) and is practical for use in the intended setting (ie, can be implemented). Below, we consider the 9 criteria for the evaluation of novel biomarkers of CVD risk presented by the American Heart Association³² and endorsed by the European Society of Cardiology and the Association for Research into Arterial Structure and Physiology Society.³³ For each of the 9 criteria, we provide a definition, an overview of the key evidence, and indicate important gaps in the literature.

Proof of Concept

Definition

Capacity to distinguish between subjects with and without CVD morbidity. Commonly tested with a cross-sectional study and quantified by determining whether the difference between groups is significant. Ideally, these findings are replicated in independent study populations.

Evidence

Compared with nondiseased controls, baPWV is greater in patients with CAD,¹⁹ heart failure with preserved ejection fraction,³⁴ target organ damage (cardiac, arterial, chronic kidney disease),³⁵ CVD risk factors,^36,37 and abnormal cardiovascular structure and function.^29,30,34

Gaps

The existing research has predominantly been conducted in East Asia, particularly Japan. Confirmatory research is required, but there is no evidence to suggest the utility of baPWV may differ between countries and ethnicities.

Prospective Validation

Definition

Ability to predict the development of future CVD morbidity or mortality. Typically tested with a prospective cohort, nested case-cohort, or case-control study and quantified as an odds ratio, risk ratio (RR), or hazard ratio (HR) adjusted for risk factors including age and blood pressure.

Evidence

Several meta-analyses have been published summarizing the capacity of baPWV to predict cardiovascular events and mortality.^38–40 In 2017, Ohkuma et al³⁸ estimated the pooled HR using individual data from 14 673 Japanese adults (across 8 studies) without a history of CVD. Following a mean follow-up of 6.4 years, participants in the fifth quintile (≥18.8 m/s) versus the first quintile (<12.9 m/s) had a 3.5-fold (95% CI, 2.1–5.7) greater risk of developing CVD. These findings by Ohkuma et al³⁸ mostly corroborate the 2012 report by Vlachopoulos et al³⁹ who calculated the pooled RR from 18 cohort studies (total n=8169). Following a mean follow-up of 3.6 years, participants with high versus low baPWV (using high/low cut-points specified by each study) were at a greater risk for total cardiovascular events (RR, 3.0 [95% CI, 1.6–5.3]) and cardiovascular mortality (RR, 5.4 [95% CI, 2.2–13.3]). Contrary to the findings by Ohkuma et al,³⁸ Vlachopoulos et al³⁹ reported that participants with a high baPWV were also at greater risk for all-cause mortality (RR, 2.5 [95% CI, 1.6 -3.9]). In 2021, Sang et al⁴⁰ focused on patients with atherosclerotic CVD: compared with low baPWV, participants with high baPWV (using high/low cut-points specified by each study) were at greater risk for cardiovascular events (HR, 2.6 [95% CI, 1.6–4.0]) and cardiovascular mortality (HR, 2.7 [95% CI, 1.9–3.8]).

Gaps

baPWV is consistently associated with cardiovascular events in participants with and without a history of CVD.^38–40 Prospective validation studies are required to confirm the applicability of these findings beyond East Asia.

Incremental Value

Definition

Capacity of a novel biomarker to add predictive information beyond established biomarkers or models, such as the American College of Cardiology/American Heart Association atherosclerotic cardiovascular disease risk score. Typically tested with a prospective cohort study, in which the participants are followed over time and the number of outcome events (ie, CVD morbidity or mortality) is recorded. The incremental value of the new biomarker can be quantified by comparing the change in odds ratio, RR, HR, or the global chi squared (χ²). Although, it should be noted that these statistics are not standardized and can be misleading for prognosis analysis. An alternative statistic is the C index, which is used to determine how well a risk marker discriminates between individuals at different risk levels. For binary outcome variables, the C index is equivalent to the area under the receiver operating characteristic curve.

Evidence

In the largest study to date,⁴¹ 6359 Korean adults (40–79 years) without a documented history of CVD were followed for a median period of 4 years. The area under the receiver operating characteristic curve for cardiovascular events was superior for baPWV (area under the receiver operating characteristic curve, 0.70 [95% CI, 0.68–71]) compared with the 2013 American College of Cardiology/American Heart Association risk score (area under the receiver operating characteristic curve, 0.62 [0.61–0.63]). baPWV also conferred incremental value to the 2013 American College of Cardiology/American Heart Association risk score, improving the χ² from 21 to 50.⁴¹ For patients with a history of CVD or suspected CAD, baPWV also conferred additional prognostic value to computed tomography angiography,⁴² single-photon emission computed tomography,⁴³ flow-mediated dilation (endothelial function),^44,45 hs-CRP,⁴⁶ and ABI.⁴⁷

Gaps

Only 2 prospective studies have investigated the general population. Additional prospective studies are warranted, particularly in general populations beyond East Asia.

Clinical Utility

Definition

Usefulness to clinical practice, in particular, the ability of the new biomarkers to move patients from 1 risk category to another and thereby modify treatment. As a more powerful alternative to the C statistic, the integrated discrimination improvement and net reclassification improvement tests are often used to test whether the new biomarker improves the ability to discriminate between groups.

Evidence

Among a general population of 4251 Chinese adults, with and without a history of CVD, baPWV was added to a model which included mean arterial pressure as the initial exposure variable and fatal/nonfatal cardiovascular and cerebrovascular end points as the outcomes.⁴⁸ The addition of baPWV improved discrimination (integrated discrimination improvement, 1.6%, [95% CI, 0.2–2.9]) and net reclassification (net reclassification improvement, 52% [95% CI, 29–75]). This supports the findings from previous individual-participant data meta-analysis by Ohkuma et al.³⁸ While no known studies have investigated whether baPWV measurements can improve disease management, a limited number of studies have investigated the baPWV response to treatment. A meta-analysis of 17 randomized controlled clinical trials reported nonsignificant changes in baPWV or cfPWV following treatment with angiotensin-converting enzyme inhibitors.⁴⁹ However, baPWV improved (ie, decreased) by 1.3 m/s (95% CI, −2.1 to −0.5) when Japanese adults (n=80) with type 2 diabetes were treated for 2 years with a sodium-glucose cotransporter 2 inhibitor (tofogliflozin) when compared with a usual care group (n=74).⁵⁰ A meta-analysis (n=6, baPWV studies)⁵¹ reported that diet plus exercise therapy had a moderate effect on baPWV (standardized mean difference, −0.5 [95% CI, −0.8 to −0.2]), a systematic review (n=7 studies)⁵² reported that combined resistance and aerobic training in postmenopausal women (n=16–101; mean age, 54–79 years) reduced baPWV by 0.6 to 2.1 m/s, and a 20-week quasiexperimental study⁵³ reported that combined exercise plus statin treatment decreased baPWV from 17.5 m/s (SD, 3.6) to 16.3 m/s (SD, 2.7) despite a nonsignificant change in blood pressure.

Gaps

Additional prospective studies, in independent populations and beyond East Asia, are required to quantify whether baPWV improves risk stratification.

Clinical Outcomes

Definition

Whether the use of the biomarker improves clinical outcomes. Optimally tested with a randomized controlled clinical trial and quantified by comparing outcomes for participants who are clinically managed using a new biomarker versus participants who are managed using standard care.

Evidence

No known direct evidence exists to support the clinical outcomes criteria. However, the 2019 Japanese Society of Hypertension Guidelines for the Management of Hypertension recommends the measurement of baPWV for managing hypertension.² The recommendation was based on the available research supporting the predictive ability (ie, prospective validation) and incremental value of baPWV.³⁸ baPWV was also included in the 2023 European Society of Hypertension guidelines.³

Gaps

Clinical trials are required to determine whether treatment strategies based on baPWV measurement improve clinical outcomes.

Cost-Effectiveness

Definition

Whether the use of the biomarker improves clinical outcomes sufficiently to justify the additional costs. Typically determined by comparing the incremental cost to the incremental benefit. The incremental benefit is typically quantified as the change in life expectancy, the quality-adjusted life-years, and the incremental cost-effectiveness ratio. The incremental costs include the downstream costs that can be attributed to the new biomarker, including follow-up testing and therapies prescribed.

Evidence

No known studies have investigated the cost-effectiveness of baPWV. Cost-effectiveness is likely high, considering clinical utility and low operation costs, namely: (1) a single oscillometric device could be used to simultaneously measure blood pressure, ABI, IAD, and baPWV; (2) consumable requirements are minimal, including reusable cuffs; and (3) minimal operator training requirements—akin to ABI. While baPWV cost-effectiveness data is unavailable, data are available for ABI. A recent Markov model⁵⁴ focused on 10-year cardiovascular event risk among women in the general Italian population. The additional cost associated with ABI screening, when added to the Framingham Risk Score, was €110/patient, the incremental quality-adjusted life-year was 0.0039/patient, and the incremental cost-effectiveness ratio was €27.99/quality-adjusted life-years.

Gaps

baPWV-specific cost-effectiveness is required.

Ease of Use

Definition

Whether measurement procedures are simple enough to permit widespread adoption.

Evidence

The most prominent advantage of baPWV is its simplicity of use, with automated measurement following cuff placement.

Gaps

Implementation studies are warranted to determine best practice guidelines for implementing baPWV within clinical practice.

METHODOLOGICAL CONSENSUS

Definition

Uniformity of biomarker measurements in different clinics. Required to compare obtained measurement values against reference values.

Evidence

Though some scientific societies have provided guidelines on the clinical use of different techniques assessing AS,⁵⁵ no specific guidelines exist to standardize baPWV methodology.

Gaps

A consensus statement is required to help ensure measurement procedures are uniform across clinics, including consideration of the following: the required operator training; quality control; subject preparation; testing environment; data collection; cuff placement; outcome reporting; and path length determination.

Reference Values

Definition

The availability of published reference or cutoff values.

Evidence

Reference values, relative to age and blood pressure, have been published for the Japanese population.³⁶ Several East Asian studies have suggested cut-points for cardiovascular risk assessment, albeit the cut-point range is wide, 14 to 18 m/s, and a limited number of adults older than 70 years of age have been included.^36,56,57

Gaps

Additional studies, including in non-Asian populations, are required to determine the expected change in baPWV with age, with respect to biological sex and blood pressure.

FUTURE DIRECTION

Below, we summarize the important gaps in the literature, provide suggestions for addressing the gaps, then finish with an example of a potential clinical practice model.

Gaps in the Literature

As summarized above and in Table 2, there is sufficient evidence to support criteria (1) to (4). The priority scores were driven up (worse) by the need for data beyond East Asia and moderated by the fact that between-country differences in the association between baPWV and cardiovascular outcomes are likely attributable to modifiable risk factors rather than race/ethnicity.

Table 2.

Summary of Evidence, Gaps in Knowledge, and Research Priorities

There is limited or no evidence to support (5), (6), (8), and (9). Studies are required to discern the usefulness of baPWV in guiding treatment decisions and to determine whether the baPWV-guided treatment improves life expectancy and quality of life. Additionally, to guide clinical management with baPWV, data are required to generate reference values that apply to diverse populations. However, the reference values will only be of true value if there is measurement conformity across clinics. As such, a consensus statement is required to standardize the way baPWV is measured. The priority for addressing the cost-effectiveness criteria has been scored 2 (low), considering the expected clinical utility and low operating costs. The priority for addressing clinical outcomes, methodological consensus, and reference values have been scored 4 (high) to 5 (very high), considering that these are major impediments for persuading clinicians to change their clinical practice.

Criteria (7) has been scored a 3 (medium). The score was driven up due to the low-operator training requirements and moderated by the lack of best practice guidelines for clinical practice adoption. Adopting a new clinical management tool is disruptive to existing clinical practices and many barriers may exist, including but not limited to where/how the new tool fits within existing workflow models, potential changes to infrastructure, and alterations to clinical decision-making. To address this gap, the current focus on evidence-based research needs to extend to implementation science. Most evidence-based research is not incorporated into routine clinical practice. Implementation science is a discipline, which seeks to understand the barriers and facilitators to clinical practice adoption and design and test different strategies to scale evidence-based practices.

Addressing the Gaps in the Literature

This section has been broken down into 2 parts. Part 1 (short term) considers research that can be conducted to address the evaluation criteria. Part 2 (long term) goes beyond the evaluation criteria, considering future refinement of the methodology itself.

Short Term

A number of the evaluation criteria, particularly (1) to (4) and (9), can be further supported using existing cohort datasets. Example datasets include the ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), JHS (Jackson Heart Study), HCHS (Hispanic Community Health Study)/SOL (Study of Latinos), FHS (Framingham Heart Study), NAKO (German National Cohort), SHIP (The Study of Health in Pomerania), the COmPLETE Health Study, and The SAPALDIA 3 Study (Swiss Study on Air Pollution and Lung Disease in Adults).

The (8) methodological consensus criteria can largely be addressed by bringing together an expert team and adapting guidelines, which have been developed for cfPWV. However, there are some unique considerations for baPWV, which may require additional research, including a path length formula suited to Western populations. The NAKO study,⁵⁸ which calculated baPWV using direct body surface measurements in >200 000 adults, may assist with validating a path length formula.

The (5) clinical outcomes and (6) cost-effectiveness criteria will require prospective investigation, whereby primary care clinicians are randomized to adopt baPWV or to persist with usual patient care for a defined period. This will facilitate determination of the impact of baPWV on clinical management, including therapeutic prescription, and cardiovascular outcomes.

Long Term

The above (short term) discussion considers baPWV as a standalone biomarker, which may not be the best approach for clinical management. Consider that the same device can be used to measure blood pressure, ABI, IAD, and baPWV, each of which provides different cardiovascular information. Further research is required to determine whether the combined use of these biomarkers improves risk stratification and clinical management. There is also scope for utilizing artificial intelligence/machine learning to distinguish cardiovascular phenotypes and more objective treatment recommendations.

Potential Clinical Practice Model

The intent of this section is not to make specific recommendations pertaining to the implementation of baPWV within clinical practice but rather to stimulate much-needed discourse. The simplicity and automation of measurement, low cost of the measurement device, and inherent low-patient burden means baPWV may be readily integrated into clinical practice and succeed where other PWV biomarkers have yet to gain traction. Nonetheless, in addition to satisfying the 9 evaluation criteria discussed above, thought needs to be afforded to how baPWV will be implemented. In this section, we present a theoretical model to indicate how baPWV may be used in clinical practice as part of a screening routine by a primary care physician to gain a holistic snapshot of a patient’s cardiovascular health. This model encompasses ABI, IAD, and PWA, and although the evidence supporting their use is not unequivocal,^59–62 these measures can be assessed concurrently with baPWV and may enhance reclassification beyond risk scores.^22,63,64 PWA-derived outcomes including central blood pressure and arterial wave reflection may be particularly useful for enhancing diagnostic accuracy of heart failure⁶⁵ and improving clinical care.⁶⁶

Figure 3 outlines a potential clinical practice model in the form of a decision tree. Traditional risk factors are initially used to stratify all-cause CVD risk, followed by the measurement of ABI and IAD. A positive (ie, unhealthy) ABI (<0.9 or >1.4) or IAD (≥10 mm Hg systolic BP) test would indicate advanced peripheral atherosclerosis and very high risk for myocardial infarction and stroke. A patient may be prescribed advanced imaging and then intensive treatment in the form of lifestyle behaviors, medication, and surgery. If the ABI and IAD are negative (healthy), additional information provided by baPWV and PWA will be considered. If the baPWV score is positive (see Reference Values section), the patient may be allocated to intensive preventive treatments for all-cause cardiovascular event risk, acute coronary syndrome, and target organ damage risk. A positive PWA score may indicate the need to prescribe medications to decrease cardiac afterload, such as antihypertensive medications.⁶⁶ If both the baPWV and PWA scores are negative, the patient may be sent home with a wearable patch, which continuously sends sensitive PWA and baPWV data to the cloud.⁶⁷ The in-clinic and ambulatory data will be harmonized in clinical management software and used to generate a cardiovascular phenotype and treatment plan. The first generation of the software may use a decision tree–based machine learning algorithm,⁶⁸ advancing to more complex algorithms or artificial intelligence with subsequent generations.

Figure 3.

Example of a potential future clinical practice model in the form of a decision tree. In this example, traditional risk factors will be measured and used to stratify all-cause cardiovascular disease (CVD) risk. Subsequently, ankle brachial index (ABI) and systolic interarm blood pressure difference (IAD) are measured. Positive ABI and IAD (ie, unhealthy, ABI score <0.9 or >1.4 and IAD≥10 mm Hg) scores indicates peripheral arterial disease (PAD) and increased myocardial infarction (MI) and stroke risk. If the ABI and IAD scores are negative (ie, healthy, ABI: between 0.9 and 1.4; IAD<10 mm Hg), the additional information provided by brachial-ankle pulse wave velocity (baPWV) and pulse wave analysis (PWA) will be considered. A positive baPWV indicates increased risk for all-cause cardiovascular events, acute coronary syndrome (ACS), and target organ damage (TOD) risk. A positive PWA score may indicate increased afterload and increased heart failure (HF) risk. If both the baPWV and PWA scores are negative, the participant is sent home with a wearable device to collect ambulatory PWA and baPWV data, from which a composite CVD risk score is derived.

Conclusions

The overarching goal of this article was to harmonize and critique the literature supporting the clinical management of CVD risk with baPWV. In the introduction, we listed 4 aims, each of which are restated and addressed below, related to a better understanding of:

Physiological Principles of baPWV

baPWV characterizes the AS of large central elastic arteries and medium-sized muscular peripheral arteries of the lower limb (see Figure 1).

baPWV Is a Unique Vascular Biomarker

While baPWV and cfPWV strongly agree, due to both incorporating the aorta,^25,26 baPWV is dependent on the medium-sized peripheral muscular arteries of the lower extremities (see Figure 2). Increased lower-extremity AS may principally contribute to cardiovascular by amplifying and hastening wave reflections at the level of the aorta, widening pulse pressure, increasing afterload, and reducing coronary perfusion. baPWV and cfPWV are distinct biomarkers and attempts to quantify baPWV as a surrogate for cfPWV undermine the true values of both measures.

Evidence Supporting the Use of baPWV as a Vascular Biomarker

To address this aim, we used the nine criteria presented by the American Heart Association³² and endorsed by the European Society of Cardiology and Association for Research into Arterial Structure and Physiology.³³ The evidence is summarized in Table 2. There is sufficient evidence to support the criteria: (1) proof of concept; (2) prospective validation; (3) incremental value; and (4) clinical utility. There is limited or no evidence to support the criteria: (5) clinical outcomes; (6) cost-effectiveness; (8) methodological consensus; or (9) reference values.

Future Research Requirements

The majority of framework criteria, (1) proof of concept, (2) prospective validation, (3) incremental value, (4) clinical utility and (9) reference values, can be supported using existing cohort datasets. Prospective investigation is required for criteria (5) clinical outcomes and (6) cost-effectiveness. The (8) methodological consensus will require expert consultation.

We finish this review by providing an example future clinical practice model (see Figure 3). This model assumes that the optimal value of baPWV will be extracted when it is not considered as a standalone biomarker but rather is incorporated with traditional risk factors and complementary outcomes.

ARTICLE INFORMATION

Sources of Funding

This article is based upon work from COST Action VascAgeNet CA18216 supported by COST (European Cooperation in Science and Technology; www.cost.eu). K. Stone is supported by the Health Care Research Wales funded National Cardiovascular Research Network, Wales. M.L. Meyer is supported by the National Institute for Health Grant R01AG061088. R.E. Climie is supported by the National Health and Medical Research Council of Australia (reference: 2009005) and by a National Heart Foundation Future Leader Fellowship (reference: 105636). L Stoner is supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Numbers R01HL157187 and R01HL162805

Disclosures

None.