Atherosclerosis is well recognized as a deadly and disabling systemic disease that affects the arterial wall. The process begins early in life and progresses unpredictably. Unfortunately, the causes are unknown and, therefore, there is at present no known cure. The risk factors for atherosclerotic disease have been appreciated for many years and clinicians have defined methods for prevention and palliation. Unfortunately, atherosclerotic lesions are not always recognized early and the treatment options for advanced lesions are limited to medical, surgical or endovascular procedures. Regardless of the method chosen, treatment is often quite expensive and sometimes too late for (therapeutic) revascularization or limb salvage. Prevention or early intervention may include medical treatment or recommended lifestyle changes. These approaches are less expensive than the methods used for established lesions and, most noticeably, more timely. However, it is easily recognized that in order to prevent or intervene in the early stages of atherosclerosis, clinicians must have the ability to identify the at-risk population. In recent years, investigators have sought noninvasive methods for identifying patients with risk factors for atherosclerotic disease who pose a need for aggressive preventive strategies.
In order to understand the focus of the noninvasive test procedures, it is important to review the issues related to cardiovascular risk and systemic vascular disease.
Approximately 8-10 million American adults, most often those over 60 years of age, have peripheral artery disease (PAD). The most common cause of PAD is atherosclerosis, affecting men and women equally and placing African Americans at twice the risk of Caucasians. Atherosclerosis is not only a disease of the elderly. Recent studies have indicated that elevated serum fibrinogen levels and evidence of coronary artery disease are reliable predictors of PAD in people younger than 60 years of age.
Peripheral arterial disease is recognized as a slow and progressive systemic disorder. Obstructions within the arterial system may prevent organs supplied by these vessels from receiving adequate blood flow, oxygen and nutrients, deficiencies that lead to disruption of normal tissue function. Investigators have shown that atherosclerosis may concomitantly affect multiple circulatory systems. It is suspected that 40% - 90% of patients with peripheral arterial disease also have coronary artery disease and 44% of patients may also have cerebrovascular disease. Based on this evidence, peripheral arterial disease is considered to be a major risk factor for not only coronary artery disease but for cardiac events! Patients with severe PAD have a 60% incidence of significant coronary artery disease (> 70% stenosis of at least one coronary artery) and close to one -third of those patients have triple-vessel coronary artery disease with depressed left ventricular function.1-5
Multiple risk factors have been identified for lower extremity atherosclerotic disease. The most notable of these include age, diabetes, impaired glycemic control, fibrinogen, hypertension, hyperlipidemia with elevated low-density lipoprotein (LDL), low high-density lipoprotein (HDL), homocysteine, lipoprotein (a), and possibly gender. 8-11 As expected, the major risk factors for peripheral arterial disease are smoking, diabetes, hypercholesterolemia and hypertension with smoking and diabetes playing a prominent role.12 The danger for development of arterial disorders is much higher when other risk factors are present. Smoking is the number one risk factor for PAD, elevating the risk to more than three times that of non-smokers.8 People with Type 2 diabetes have three to four times the normal risk for PAD; this is higher than the risk for heart disease. It is also recognized that the risk for peripheral arterial disease increases 10% for every 10 mg/dL elevation in total cholesterol levels with low HDL and high triglyceride levels contributing to the risk.13 As a result of trauma to the arterial wall, hypertensive patients have at least a two-fold risk of developing PAD compared to normotensive patients. The amount of damage is influence by the amount of pressure, volume of blood pumped, and the size and flexibility of the arteries. Studies have shown that the treatment of hypertension may unmask previously asymptomatic peripheral arterial disease by decreasing the pressure gradient across the narrowed arterial lumen.
Other vascular risk factors include family history and evidence of persistent arterial inflammation and/or damage, commonly indicated by elevated C-reactive protein, and elevated levels of homocysteine, an amino acid, which has been linked to increased risk of heart disease, stroke, and peripheral arterial disease. This condition may occur concomitantly with deficiencies of vitamins B6, B12, and folic acid.
Current Treatment Strategies
Since atherosclerosis cannot be cured, clinicians have focused on preventive or palliative methods to treat the risk factors for PAD. Because PAD is a marker for coronary and cerebrovascular arterial disease, these therapies should also reduce the risk for cardiac dysfunction and stroke. Risk factors that can be modified such as hypertension, hyperlipidemia, sedentary lifestyle, smoking, diabetes, and glycemic control are initially addressed. Promising results have been shown with use of antiplatelet agents, and new drugs for treatment of hypertension and hypercholesterolemia.
Antiplatelet agents have been used to lower the risk of thrombosis, thus reducing cardiac events. In the Heart Outcomes Prevention Evaluation (HOPE) trial, an absolute risk reduction of 3.8% in the composite primary outcome of myocardial infarction, stroke or death was achieved in cardiovascular disease patients with use of the angiotensin-converting enzyme inhibitor, ramipril, and other agents.14 Blood pressure is treated to a target level of 130/80 mmHg and increased interest has been shown in using statins to lower total and LDL cholesterol to target levels.
Vascular endothelial growth factor, basic fibroblast growth factor and rFGF-2 are being evaluated for their potential to improve growth of collateral vessels.15 Single intra-arterial rFGF-2 has shown promising value for short-term management of intermittent claudication.16
Vascular Laboratory Markers of Cardiovascular Risk
In addition to searching for new, effective treatment options for early atherosclerotic disease, investigators have sought methods for identifying the at-risk population. Several noninvasive vascular test procedures have been shown to have value as predictors of cardiovascular disease risk. Three stand out from among those most recently investigated. These are the ankle-brachial index (ABI), measurement of carotid intima-media thickness (IMT), and brachial artery reactivity testing (BART).
Measurement of ankle and brachial systolic pressures and calculation of the ankle-brachial index are perhaps the most commonly performed vascular laboratory test procedures. To appreciate the value of this study, a brief review of flow dynamics in the lower extremity is in order.
Blood pressure and flow in the lower extremity arterial system are influenced by several anatomical features. Each of these contributes to a significant loss in energy and an increase in systolic pressure as blood moves from the aorta to the lower limbs. The most important of these features include branching of the major peripheral arteries, the diameter of the aorta compared to the smaller caliber limb arteries and the difference in wall elasticity and compliance when comparing the two conduits. Resting muscle tissue requires only sufficient blood flow to meet its metabolic demands. As such, under normal conditions, vascular resistance in a resting lower extremity is elevated and, as a consequence, ankle systolic blood pressures are normally equal to or greater than the central aortic pressure measured at brachial level. Flow demand increases in exercising muscles or in muscle bodies distal to significant arterial obstruction. Given this, a decrease in ankle pressure compared to brachial pressure signifies the presence of pressure-reducing obstruction (> 50% to 60% stenosis or occlusion) in the more proximal arteries of the resting lower limb. This hemodynamic feature allows for a simple, accurate means for detecting the presence of peripheral arterial disease. Because ankle systolic pressures are normally equal to or greater than the brachial systolic pressure, a calculated ankle-brachial index (ABI) should be equal to or greater than 1.0 An ABI < 0.9 is 95% sensitive and 99% specific for detecting angiographically documented arterial disease.17-19 Brachial artery pressures are routinely measured bilaterally. Ankle systolic pressure measurements are obtained in the dorsalis pedis and posterior tibial arteries of both lower limbs (Figure 1A and B).
Figure 1A:Tibial artery systolic pressures are obtained in the dorsalis pedis artery, an extension of the anterior tibial artery (A),
Figure 1B:, Pressures are obtained in the posterior tibial artery, which is located posterior to the medial malleolus. (B)
As noted in the following equation, the calculated ABI is based on the higher of the tibial artery pressures compared to the higher of the brachial artery pressures.
ABI = Highest brachial artery pressure / Highest tibial artery pressure
For example, a patient has brachial artery pressures of 140 mmHg on the right and 150 mmHg on the left. In this case, the left arm pressure would be used for calculation of the ABI. The right dorsalis pedis pressure is 162 mmHg while the posterior tibial pressure on that side is 158 mmHg. On the left, the pressure in the dorsalis pedis artery is 134 mmHg; the posterior tibial pressure is 142 mmHg. Using the higher tibial pressure on each side, the resting ABI on the right is 1.08 and .95 on the left.
Hemodynamically significant disease is suggested when the ankle pressures decrease to values below the systemic pressure. The extent of the deterioration in pressure, as evident in the ABI, serves as an indicator of the severity of lower limb arterial disease. In general, patients with mild to moderate claudication have an ABI in the range of 0.5 to 0.8. Patients with severe claudication due to multi-segmental arterial obstruction most often have indices less than 0.5 while those with tissue loss due to critical ischemia
demonstrate ankle pressures less than 35 mmHg, and an ABI less than 0.3.20-22
Studies have indicated that the ankle-brachial index may serve as a valuable marker for not only PAD but also coronary artery disease. According to research published in the journal Vascular Medicine in 1997, Dr. Sikkink and colleagues established an association between the ABI and cardiovascular morbidity and mortality. 23 In their study of 154 patients with an ABI less than 0.9, the 5-year cumulative survival rate was 91% for those with an ABI in the range of 0.7 to 0.89. While that fact appears to be relatively non-threatening, it must be noted that the survival rate deteriorated to 71% for patients with an ABI in the range of 0.5 to 0.71 and was only 63% for those with an ABI less than 0.5 The study also revealed that patients with an ABI in the range of .91 to .99 (very mild disease) and those with an ABI exceeding 1.4 (calcification / diabetes) had a higher incidence of symptomatic peripheral arterial disease than normal patients (ABI of 1.0 - 1.4) and a high prevalence of subclinical atherosclerosis as defined by other noninvasive markers.
The Strong Heart Study24 assessed the association of low (.9) and high (> 1.4) ABI with risk of all-cause and cardiovascular disease mortality in American Indians. In this study, an ABI greater than 1.4 predicted mortality with similar strength as an ABI less than .9. While evaluating the results of this study, the likelihood of co-morbid conditions, e.g., diabetes and renal failure, in patients with an ABI > 1.4 must be considered. One-third of the men and one-quarter of the women with coronary artery disease were found to have PAD. The investigators demonstrated that patients with PAD had an increased incidence of not only coronary artery disease, but also cardiac events. Specifically, an ABI less than 0.67 was predictive of cardiac events and was independently associated with an increased risk of cardiac death by two thirds.
The Honolulu Heart Program25 investigators studied 3450 ambulatory, elderly Japanese American men. An ABI less than .9 was present in 27.4 % of the men who ranged in age from 85 to 93 years, in 13.6% of those greater than 80 years of age and in 8% of the patients in the age group 71-74 years. The findings of this study demonstrated that the ABI was a reliable marker for generalized atherosclerotic disease and coronary artery disease in the old and very old Japanese American men. Surprisingly, a low ABI in the absence of symptoms was a relatively common finding in this study group.
Based on a 5-year study of 1592 randomly chosen men and women aged 55-74 years from Edinburgh, Scotland, Leng and associates found the ankle-brachial index to be a good predictor of subsequent cardiovascular events.26 At baseline, 90 patients had a resting ABI < 0.7, 288 subjects demonstrated a value < 0.9 and 556 had an ABI < 1.0. After five years, patients with an index < 0.9 at baseline demonstrated an increased risk for non-fatal myocardial infarction, stroke, cardiovascular death and all-cause mortality. When the ABI was combined with other risk factors, the ability to predict subsequent events was greatly enhanced. In their study group, the positive predictive value was 25% for hypertensive smokers with normal cholesterol levels. That value was shown to decrease in patients with a normal index but increased dramatically to 43.8% in patients with a low index.
Based on evidence from these and other studies, the American College of Cardiology and the American Heart Association have established practice guidelines for assessment of peripheral arterial disease. These organizations recommend obtaining a resting ABI for the following groups: Individuals with exercise-related limb pain or non-healing wounds, people who are 70 years of age or older, and people between 50 and 70 years of age with a history of smoking or diabetes.
Measurement of Carotid Intima-Media Thickness (IMT)
Atherosclerotic cerebrovascular disease (ASCVD) involves the arterial wall, chiefly the arterial intima. Every risk factor known for ASCVD exerts its effect on the arterial wall, causing it to increase in thickness. Therefore, arterial wall thickness should correlate with ASCVD, perhaps even in its preclinical stages. This feature provides an excellent rationale for using IMT as a marker for cardiovascular risk.
The intima is the innermost layer of the arterial wall and is comprised of a single layer of endothelial cells. The media, the middle layer of the wall, is made up of smooth muscle cells and their extracellular matrix. Loose connective tissue, which holds the blood vessels and nerves that supply the artery, comprises the outer wall layer, the adventitia.
Figure 2: Diagram illustrating the three layers of the arterial wall. The intima and the media are separated by the internal elastic membrane. The external elastic membrane separates the media and the adventitia.
As early as 1969, investigators at the University of Washington used sonography to define the normal acoustic characteristics of the arterial wall.27 Intima media thickness has been defined as a double-line pattern visualized sonographically on both walls of the common carotid arteries when viewed in the longitudinal image plane (Figure 3 A and B).
Figure 3A:Longitudinal B-Mode image of a common carotid artery (A).
Figure 3B: Intima-media thickness is defined as the double-line acoustic pattern seen on the near and far walls of the artery when viewed in the longitudinal plane (B).
In the early 1980s, Paolo Pignoli and colleagues compared and validated the intima media thickness measured sonographically to the measurements determined histologically.28-29 Comparison of the B-Mode images and histology results revealed that the double line pattern was consistent with the acoustic appearance of the arterial intima and adventitia. These studies helped to lay the foundation for current protocols even though instrumentation was crude compared to modern standards.
Atherosclerotic plaque evolves sonographically from a combined thickening of the intimal and medial layers of the arterial wall into echogenic material that encroaches on the arterial lumen (Figure 4 A, B, C).30-31
Figure 4A :Longitudinal B-Mode image of a common carotid artery (A).
Figure 4B:Intimal thickening is apparent on the far wall of a common carotid artery (B).
Figure 4C:An increase of 0.5 mm or more in thickness of the arterial wall or a discrete area where the arterial wall thickness is 50% greater than the surrounding wall is considered to be consistent with atherosclerotic plaque (C).
Because plaque originates in the subendothelial layer of the arterial wall, its presence must be taken into consideration when performing measurements of IMT which include both the intima and media. Current protocols consider a measurement to represent plaque if there is an increase of 0.5 mm or if there is a discrete area of the arterial wall that is 50% higher than the surrounding IMT.
Several technical issues must be considered when measuring the IMT. While the "double line" pattern can be imaged in the common carotid artery, the carotid bulb, and the internal carotid artery,32-33 it appears to be most conspicuous in the common carotid artery where the vessel walls are parallel. 32, 34-36 This most often occurs 5-10 mm below the carotid bifurcation. Optimal images are obtained when high resolution ultrasound systems are used, the transducer frequency exceeds 5 MHz, and the angle of incidence is such that the sound beam strikes the artery perpendicular to the vessel wall. Enhanced image clarity is achieved when harmonic and/or real-time compound imaging is used. Careful attention should also be given to the timing of measurements. During systole, the diameter of the arterial lumen increases and, as a consequence, IMT decreases as a result of arterial wall thinning.37-38 While diameter measurements may be made at peak systole and end-diastole, the most accurate data has been achieved when end-diastolic measurements are used. Most examiners base their final measurement on the average of 3 separate measurements which can be performed by hand or with use of an automatic edge detector using software that is commercially available.
It is also recognized that IMT increases with age, is most commonly larger in men than in women,36,40 and may have racial variations. Some studies have indicated that African Americans have higher common carotid artery IMT values than Caucasians 36 or non-Hispanic whites.39
Distinguishing normal and abnormal IMT values based on the current literature is difficult as the spread of cut points is quite wide. Because of this, it is not possible to define a single value that confirms abnormality. A number of laboratories estimate the normal IMT based on the equation IMT (in mm) = 0.008 × age (in years). It seems acceptable to assume, however, that an intima-media thickness of 0.9 mm or more is abnormal and will, most likely, be associated with visible plaque.
Potential sources of error arise when color or power Doppler imaging are used because the color may overwrite the vessel wall. Care must be taken to avoid measurement in areas where acoustic enhancement or shadowing are apparent and at sites of arterial disease where there is evidence of atherosclerotic plaque.40 Using the above guidelines, several studies have demonstrated the reproducibility of the technique. In general, studies fall into three broad categories: correlation between IMT and other known cardiovascular risk factors; correlation between IMT and cardiovascular events, e.g., stroke, myocardial infarction, death; and use of IMT as a marker for cardiovascular disease in clinical trials.
The Asymptomatic Carotid Plaque Study (ACAPS) performed at Bowman-Gray School of Medicine, demonstrated the reproducibility of IMT measurements by assessing both within-sonographer and between-sonographer measurements. 41 B-Mode imaging was used to measure changes in IMT in 858 asymptomatic patients with moderately elevated lipids who were receiving either a lipid-lowering agent and/or a low-dose antithrombotic agent. All patients had some degree of thickening (1.5 - 3.5 mm) in at least one segment of the carotid artery at the onset of the study. Sonographers from four participating study centers were trained and certified to perform a standardized protocol for assessment of the carotid IMT. The ultrasound readers also received certification following satisfactory completion of a 3-month training program. The sonographers obtained paired B-Mode images 1-month apart from the near and far walls of the CCA, bifurcation, and ICA bilaterally. 405 patients were examined by the same sonographer at each visit and 453 were examined by different sonographers. The same reader assessed each pair of sonographic images following a standardized reading protocol. The results of this study indicate that reliable end-point measures of carotid atherosclerosis can be achieved with uniform training of sonographers and readers and adherence to standardized imaging and reading protocols.
Given the reliability of sonography to define the presence and extent of thickening of the arterial wall, O'Leary et al reported the results of the Cardiovascular Health Study which evaluated 5117 patients over 65 years of age with standard cardiovascular risk factors and events.42 The investigators performed a series of IMT measurements in the near and far walls of the common and internal carotid arteries bilaterally. In this study, the combined IMT measurements from both the CCA and the internal carotid artery (ICA) yielded minimally higher adjusted relative risks for subsequent stroke or myocardial infarction than either measurement alone. It is of interest, as illustrated in Table 1, that the IMT values were highest in the ICA in both male and female patients with cardiovascular disease. The adjusted relative risk for prediction of myocardial infarction was slightly higher in the internal carotid artery while the measurements from the common carotid artery were better at predicting stroke. At the present time, there is no evidence to suggest that measurement of a specific segment of the carotid artery yield better predictive results. The CCA measurements, however, have shown the best reproducibility and are favored due to the prevalence of bifurcation plaque.29,43
Table 1: Data from the Cardiovascular Health Study. Note that the IMT values are highest in the internal carotid arteries of both male and female patients with cardiovascular disease. Modified from O'Leary et al; N Engl J Med 340: 14-22, 1999.
The results of the Carotid Atherosclerosis Progression Study were reported in 2006.44 Using endpoints of stroke, myocardial infarction and death, Lorenz and colleagues studied 5056 patients aged 19 to 90 years with a mean age of 50.1 years. Considering carotid IMT and other vascular risk factors, they found that IMT was an independent risk factor for myocardial infarction and combined endpoint in all age groups.
The Muscatine Study tracked various cardiovascular risk factors and events in 725 men and women aged 33 to 42 years from childhood through middle age.45 The mean maximum carotid IMT was 0.79 +/- 0.12 mm for men and 0.72 +/- 0.10 for women. In this study, cholesterol levels, blood pressure and body mass index all correlated to IMT. The authors concluded that carotid IMT was a surrogate marker for atherosclerosis in adolescence and young adulthood.
Based on these and other studies, IMT measurement has become a popular noninvasive tool for assessment of cardiovascular risk in large part because of the distinct advantages that it offers. Even though reproducibility is still an issue, the combined thickness of the intima and media of the carotid artery can be accurately and reliably measured with B-Mode sonography. The American Society of Echocardiography and the Society of Vascular Medicine and Biology recommend that imaging protocols for measurement of IMT employ the following: 1) use of end-diastolic (minimum dimension) measurements; 2) separate categorization of plaque presence and IMT measurements; 3) avoidance of a single upper limit of normal for IMT due to the variation in diameter values associated with age, sex, and race; and 4) incorporation of lumen measurement to account for changes in distending pressure.46
Regardless of these positive features, a number of important questions remain unanswered. Does the pathology of the thickened carotid artery represent early atherosclerosis or is it an "adaptive change"? Are the IMT measurements from the CCA more optimal than those from the ICA and how many arterial segments should be measured? Should clinicians concentrate on predictive power or reproducibility of the study? And finally, is IMT measurement really useful in daily clinical medicine? Until the answers to these questions are known, insurers are likely to remain reluctant to reimburse for this test procedure.
Brachial Artery Reactivity Testing (BART)
The endothelium of arteries secretes numerous substances that regulate vascular tone, platelet and leukocyte interactions, cell growth, and thrombogenicity. As such, endothelial function is thought to play an important role in the development of atherosclerosis and, therefore, cardiovascular risk. A number of studies have shown that arterial dilation is impaired in patients with cardiovascular risk factors.47,48
It has been long recognized that blood vessels have the capacity to self-regulate vasomotor tone in response to physical and chemical stimuli. Many arteries respond to an increase in blood flow (shear stress) by dilating. Research has shown that flow-mediated vasodilation (FMD) prompts release of nitric oxide from the endothelium but the mechanism for recognition of shear stress and the resultant dilation are not well understood. It appears that when shear stress occurs, calcium-activated potassium channels open within the endothelial cell membrane.49-51 The opening hyperpolarizes the endothelial cell, allowing the entry of calcium. Calcium activates the enzyme, endothelial nitric-oxide synthase, with subsequent generation of nitric oxide.52-53
The function of the endothelium may be assessed noninvasively using a blood pressure cuff inflation-deflation technique and measurement of flow-mediated dilation of an artery in response to increased blood flow (reactive hyperemia or shear stress). Most vascular laboratories apply the test procedure to assessment of brachial artery reactivity. At a glance, the procedure appears to be rather straightforward. A blood pressure cuff is inflated on the forearm to a suprasystolic pressure. Occlusion of the brachial artery causes ischemia and a consequent flow demand in the tissues distal to the cuff. When the cuff is deflated, brachial artery flow increases briefly to meet the needs of the ischemic tissue. The subsequent increased shear stress causes the brachial artery to dilate (Figure 5).
Figure 5: Cartoon illustrating a normal pre-cuff inflation diameter of an artery and the subsequent post-cuff deflation increase in arterial diameter as a result of reactive hyperemia (shear stress).
The dilation can be quantified as an index of vasomotor function. It must be considered, however, that there are numerous factors that affect vascular reactivity including temperature, certain food, drugs, sympathetic stimuli, the menstrual cycle, age, and weight. In addition, meticulous attention must be given to patient preparation and technical applications in order to ensure accurate, reproducible results.
A high resolution ultrasound system with B-Mode, color and spectral Doppler capabilities and a multi-frequency (7-12 MHz) linear array transducer are required for imaging the brachial artery. For timing of each image frame with respect to the cardiac cycle, simultaneous electrocardiographic (ECG) monitoring capabilities are also necessary.
Given that temperature and food may affect flow-mediated vascular reactivity, patients should fast for at least 8 to 12 hours prior to the exam and should be studied in a quiet, temperature-controlled room. Patients should also refrain from taking any vasoactive medications, exercising, smoking, ingesting caffeine and/or high-fat foods and vitamin C for at least 24 hours before the study.
The patient is positioned supine with the arm in a comfortable position for accessing the brachial artery. A blood pressure cuff is placed on the forearm (Figure 6).
Figure 6: Patient position and procedure for performance of brachial artery reactivity testing.
A sagittal B-Mode pre-inflation image of the artery is obtained above the antecubital fossa and the image of the near and far walls and intimal interfaces is optimized. Time-averaged Doppler spectral waveforms are recorded simultaneously (Figure 6). It is important to note that the sagittal image of the brachial artery will be recorded continuously from 30 seconds prior to inflation to 2 minutes following deflation of the blood pressure cuff. The cuff is inflated to 50 mmHg above systolic pressure and remains in place for 5 minutes. The brachial artery Doppler velocity signal is recorded again immediately following cuff deflation (figure 7).
Figure 7: Color flow image of a brachial artery and the Doppler spectral waveforms obtained during inflation of the forearm occlusive blood pressure cuff and following cuff deflation. Note the change in vascular resistance and increased velocity associated with the post-occlusion reactive hyperemia.
Following the procedure, measurements of brachial artery diameter may be made off-line using manual techniques or edge-detection software (Figure 8 A and B).
Figure 8: Longitudinal B-Mode image of a brachial artery demonstrating a peak systolic measurement of the pre-inflation diameter (A). The measurement is repeated immediately following cuff deflation (B). The maximal increase in arterial diameter usually occurs within 60-90 seconds following cuff deflation.
The measurement of arterial diameter may be reported as baseline, absolute change or as a percent change but is always determined at peak systole using the ECG recording to track the cardiac cycle. The maximal increase in arterial diameter usually occurs 60-90 seconds following cuff deflation and, most often, is only a fraction of a millimeter.
Because of the technical challenges associated with brachial artery reactivity testing, this procedure is used at present as a research tool for determining the risk of future cardiovascular events. Numerous studies have demonstrated that risk factor modification and some current drug therapies improve brachial artery reactivity but whether an improvement in endothelial function translates into improved outcome remains unknown. Large scale studies are needed to determine the reproducibility of the test and whether it may be useful as a tool for measurement of cardiovascular risk in an individual or in large population sub-sets. As with other cardiovascular test procedures, accurate evaluation of endothelial function will require training, certification, and continuing medical education for those who are responsible for the performance and interpretation of the tests.
Future Trends to Watch
The use of physiologic testing and bioimaging as markers of cardiovascular risk has increased over the past decade. The definition of a "normal" ankle-brachial index is changing and cut-points are being defined for identification of the "at-risk" patient population. Ongoing advances in ultrasound imaging and computer technology now make it possible to record multiple images of the brachial artery automatically using the ECG trigger. Using computer-based edge detection technology, the alterations in arterial diameter may be measured continuously. With these modalities, the entire time course of flow-mediated brachial artery dilation can be examined thus providing insight into the duration and extent of dilation and, possibly, vessel wall compliance. These investigations are coupled with the development of research to reveal the morphology and ultrastructure of atherosclerotic lesions with the hope of more accurate prediction of major cardiovascular events.
- Criqui M: Peripheral arterial disease-epidemiological aspects. Vasc Med. 6 (suppl 1): 3-7, 2001.
- Gonzales ER, Kannewurf BS: Atherosclerosis: a unifying disorder with diverse manifestations. Am J Health Syst Pharm. 55 (19 suppl 1); S4-S7, 1998.
- Hirsch AT: Fam Practice Recertification. 15 (suppl): 6-12, 2000.
- Aronow WS, Ahn C: Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women < 62 years of age. Am J Cardiol 74: 64-65, 1994.
- CAPRIE Steering Committee: A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348: 1329-1339, 1996.
- Murphy JD (ed): Mayo Clinic Cardiology Review, Chapter 59; 1013-1024; Lippincott, Williams & Wilkins, Philadelphia, 2000.
- Hertzer NR: Clinical experience with preoperative coronary angiography. J Vasc Surg 2: 510-514, 1985.
- TASC Working Group: Management of peripheral arterial disease. J Vasc Surg 31 (1 suppl) : S1-S296, 2000.
- Leng GC, Papacosta O, Whincup P, et al: Femoral atherosclerosis in an older British population: Prevalence and risk factors. Atherosclerosis 152: 167-174, 2000.
- Djousse L, Levy D, Murabito JM et al: Alcohol consumption and risk of intermittent claudication in the Framingham Heart Study. Circulation 102: 3092-3097, 2000.
- Newman AB, Siscovick DS, Manolio TA et al: Ankle-arm index as a marker of atherosclerosis in the cardiovascular health study. Circulation 88: 837-845, 1993.
- Criqui MH, Langer RD, Fronek A et al: Large vessel and isolated small vessel disease. In: Fowkes FGR (ed). Epidemiology of Peripheral Vascular Disease. London, Springer-Verlag, 1991.
- Hirsch AT, Haskal ZJ, Hertzer NR, et al: ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease: a collaborative report. Circulation 113 (1): e463-654, 2006.
- The Heart Outcomes Prevention Evaluation Study Investigators: Effects of angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342: 145-153, 2000.
- Laperna L: Diagnosis and medical management of patients with intermittent claudication. J Am Osteopath Assoc. 100: S10-S14, 2000.
- Lederman RJ: TRAFFIC (therapeutic angiogenesis with rFGF-2 for intermittent claudication). American College of Cardiology 50th Scientific Session, Orlando, Florida
- Yao JST: Pressure measurement in the extremity. In: Bernstein EF (ed). Vascular Diagnosis, 4th edition. St. Louis; 1993.
- Criqui MH, Fronek A, Klauber MR et al: The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral arterial disease: Results from noninvasive testing in a defined population. Circulation 71:516-522, 1985.
- Carter SA: The role of pressure measurements in vascular disease. In: Bernstein EF (ed). Noninvasive Diagnostic Techniques in Vascular Disease. St. Louis; Mosby, 1985.
- Yao JST, Hobbs JT, Irvine WT: Ankle systolic pressure measurements in arterial diseases affecting the lower extremities. Br J Surg 56: 676-679, 1969.
- Neumyer MM: Nonimaging physiologic tests for assessment of lower extremity arterial disease. In: Pellerito JS, Polak JF (eds) Introduction to Vascular Ultrasonography, 6th edition, Elsevier, Inc., Philadelphia, 2012.
- Scissons R: Physiologic Testing-Techniques and Interpretation, Unetixs Educational Publishing, North Kingstown, Rhode Island, 2012.
- Sikkink CJ, van Asten WN, van 't Hof MA et al: Decreased ankle/brachial indices in relation to morbidity and mortality in patients with peripheral arterial disease. Vasc Med 2 (3): 169-173, 1997.
- Resnick HE, Lindsay RS, McDermott MM et al: Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality. The Strong Heart Study. Circulation 109 (6): 733-739-2004.
- Schatz IJ, Masaki K, Yano K et al: Cholesterol and all-cause mortality in elderly people the Honolulu Heart Program: a cohort study. Lancet 358 (9279): 351-355, 2001.
- Leng GC, Fowles FG, Lee AJ et al: Use of ankle brachial pressure index to predict cardiovascular events and death: a cohort study. BMJ 313 (7070): 1440 1444, 1996.
- Hartley CJ, Strandness DE, Jr.: The effects of atherosclerosis on the transmission of ultrasound. J Surg Res 9 (10): 575-582, 1969.
- Pignoli P: Ultrasound B-Mode imaging for arterial wall thickness measurement. Atherosclerosis Rev 12: 177, 1984.
- Pignoli P, Tremoli E, Poli A, et al: Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 74: 1399 - 1406, 1986.
- Bond MG et al: Detection and monitoring of asymptomatic atherosclerosis in clinical trials. Am J Med I 86: 33-36, 1989.
- Riley WA et al: Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis: the asymptomatic carotid artery plaque study. Stroke 23: 1062-1068, 1992.
- O'Leary DH, Polak JF, Wolfson SK Jr., et al: Use of sonography to evaluate carotid atherosclerosis in the elderly: the cardiovascular health study. Stroke 22:1155-1163, 1991.
- Chambless LE, Heiss G, Folsom AR, et al: Associattion of coronary artery disease incidence with carotid arterial wall thickness and major risk factors: the atherosclerosis risk in communities (ARIC) Study, 1987-1993. Am J Epidemiol 146: 483-494, 1997.
- Stensland-Bugge E, Bonaa KH, Joakimsen O: Reproducibility of ultrasonographically determined intima-media thickness is dependent on arterial wall thickness: the Tromso study. Stroke 28:1972-1980, 1997.
- Crouse JR III, Craven TE, Hagaman AP, Bond MG: Association of coronary disease with segment-specific intimal-medial thickening of the extracranial carotid artery. Circulation 92:1141-1147, 1995.
- Howard G, Sharrett AR, Heiss G, et al: Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-Mode ultrasound. Stroke 24: 1297-1304, 1993.
- Tardy Y, Hayoz D, MignotJP, et al: Dynamic noninvasive measurements of arterial diameter and wall thickness. J Hypertens 10: S105-109, 1992.
- Devereux RB, Waeber B, Roman MJ: Conclusions on the measurements of arterial wall thickness: anatomic, physiologic and methodologic considerations. J Hypertens 10: S 119-121, 1992.
- D'Agostino RB Jr., Burke G, O'Leary D, et al: Ethnic differences in carotid wall thickness: the insulin resistance atherosclerosis study. Stroke 27:1744 - 1749, 1996.
- Ebrahim S, Papacosta O, Whincup P, et al: Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British regional heart study. Stroke 30: 841-850, 1999.
- Riley WA, Barnes RW, Applegate WB, et al: Reproducibility of noninvasive ultrasonic measurement of carotid atherosclerosis. The Asymptomatic Carotid Artery Plaque Study. Stroke 23: 1062-1068, 1992.
- O'Leary DH, Polak JF, Kronmal RA, et al: Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340: 14-22, 1999.
- Persson J, Formgren J, Israelsson B, Berglund G: Ultrasound determined intima-media thickness and atherosclerosis. Atheroscler Thromb 14: 261-264, 1994.
- Lorenz MW, von Kegler S, Steinmetz H, et al: Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 37 (1): 87-92, 2006.
- Davis PH, Dawson JD, Riley WA, Lauer RM: Carotid intimal-medial thickness is related ti cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 104: 2815, 2001.
- Roman MJ, Naqvi TZ, Gardin JM, et al: Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: A report from the American Society of Echocardiography and the Society of Vascular Medicine and Biology. J Am Soc Echocardiogr 19: 943-954, 2006.
- Laurent S, Lacolley P, Brunel P, et al: Flow-dependent vasodilation of brachial artery in essential hypertension. Am J Physiol 258: H1004 - 1011, 1990.
- Celermajer DS, Sorensen KE, Gooch VM, et al: Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340: 1111-1115, 1992.
- Olesen SP, Clapham DE, Davies PF: Haemodynamic shear stress activates a K+ current in endothelial cells. Nature 331: 168-170, 1988.
- Cooke JP, Rossitch E, Jr., Andon NA, et al: Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 88: 1663-1671, 1991.
- Miura H, Wachtel RE, Liu Y, et al: Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels. Circulation 103: 1992-1998, 2001.
- Pohl U, Holtz J, Busse, R, Bassege E: Crucial role of the endothelium in the vasodilator response to flow in vitro. Hypertension 8: 37-44, 1985.
- Joannides R, Haefeli WE, Linder L, et al: Nitric oxide is responsible for flow-dependent dilation of human peripheral conduit arteries in vivo. Circulation 91: 1314-1319, 1995.