|Year : 2019 | Volume
| Issue : 1 | Page : 2-6
Ankle–Brachial Index, plasma homocysteine, and brachial-ankle pulse wave velocity are important indicators in the diagnosis of early stage lower-extremity arterial occlusive disease
Tan Li, Yang Zhang, Wangde Zhang
Department of Vascular Surgery, Beijing Chao Yang Hospital Capital Medical University, Beijing, China
|Date of Submission||08-Apr-2019|
|Date of Acceptance||26-Apr-2019|
|Date of Web Publication||8-May-2019|
Department of Vascular Surgery, Beijing Chao Yang Hospital Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chao Yang District, Beijing
Source of Support: None, Conflict of Interest: None
Background: This study evaluated noninvasive methods for the diagnosis and classification of lower-extremity arterial occlusive disease (LEAOD), specifically, plasma homocysteine (pHcy), ankle–brachial index (ABI), and brachial-ankle pulse wave velocity (baPWV). Materials and Methods: The study involved 102 patients with intermittent claudication treated at Beijing Chao Yang Hospital from 2010 to 2011. The affected arteries were assessed by computed tomography angiography (CTA) and categorized depending on the degree of occlusion as normal, stenotic, or occluded. ABI, pHcy, and baPWV were measured and compared among the groups. Factors that can affect ABI readings were analyzed. Results: Compared with patients in the normal group, the stenotic and occluded patients had significantly higher pHcy and baPWV, and lower ABI levels. The pHcy levels of the stenotic and occluded groups were similar. While statistically significant different ABI and baPWV levels were shown between the stenotic and occluded groups. The t values were 9.43 and 3.76, and the P < 0.001 and 0.001, respectively. Hypertension, diabetes mellitus, and blood cholesterol, C-reaction protein, and pHcy levels can influence the ABI value. Conclusion: ABI, pHcy, and baPWV values correlated with the results of the CTA examination with regard to LEAOD classification. ABI and baPWV may be useful for the categorical diagnosis of the disease. These findings contribute to the early diagnosis of LEAOD using noninvasive methods.
Keywords: Ankle–brachial pressure index, atherosclerosis, brachial-ankle pulse wave velocity, lower-extremity arterial occluded disease, plasma homocysteine
|How to cite this article:|
Li T, Zhang Y, Zhang W. Ankle–Brachial Index, plasma homocysteine, and brachial-ankle pulse wave velocity are important indicators in the diagnosis of early stage lower-extremity arterial occlusive disease. Transl Surg 2019;4:2-6
|How to cite this URL:|
Li T, Zhang Y, Zhang W. Ankle–Brachial Index, plasma homocysteine, and brachial-ankle pulse wave velocity are important indicators in the diagnosis of early stage lower-extremity arterial occlusive disease. Transl Surg [serial online] 2019 [cited 2019 Jul 22];4:2-6. Available from: http://www.translsurg.com/text.asp?2019/4/1/2/257803
| Introduction|| |
Lower-extremity arterial occlusive disease (LEAOD) is a peripheral arterial disease or arteriosclerosis obliterans,,, with occlusive lesions in the iliac, infrainguinal, femoropopliteal, and tibioperoneal arteries of the legs. Peripheral arterial diseases and LEAOD are primarily caused by the accumulation of plaques composed of macrophage-based atheroma and cholesterol in the lumen of the arteries. Eventually, these arterial plaques lead to the calcification of blood vessels, and arteriosclerosis, arterial stenosis, and arterial occlusion. Many risk factors for cardiovascular disease also contribute to the pathogenesis of both peripheral arterial diseases and LEAOD, including smoking, diabetes, hypertension, high cholesterol, and lipidemia.,
The prevalence of peripheral arterial diseases varies depending on the world region. In the United States, it is more than 10%, while in China, it is about 18% in people older than 69 years. About 75% of patients with peripheral arterial disease initially show symptoms of LEAOD, including fatigue, discomfort, pain, or achiness in the muscles of the lower extremities, and intermittent claudication.,, Without proper treatment, ischemic ulcers and tissue gangrene or even loss of limbs may occur., The available nonsurgical treatments are antiplatelet agents and anticoagulation medications, together with pain relievers. Surgical procedures include bypass grafting, angioplasty and stenting, atherectomy, and amputation.,,
Early diagnosis and proper early intervention are crucial for the treatment and prognosis of LEAOD. The current diagnostic methods for LEAOD may be considered noninvasive or invasive. Noninvasive methods include the ankle–brachial index (ABI), which indicates the ratio of the blood systolic pressure in the lower legs to that in the arms (left or right). Additional noninvasive methods include measuring the plasma homocysteine (pHcy) level and the brachial-ankle pulse wave velocity (baPWV);,, the latter by magnetic resonance angiography and computed tomography angiography (CTA)., Compared with angiographic methods, those noninvasive approaches for diagnosing early LEAOD are lower in cost, simpler to perform, and more practical in clinics.
Homocysteine is a nonprotein amino acid that is present in excessive amounts (hyperhomocysteinemia) under some pathological conditions. In 1969, McCully identified a link between hyperhomocysteinemia and atherosclerosis. Subsequently, hyperhomocysteinemia has been found to be associated with a variety of vascular and cardiovascular diseases. However, the mechanism of the association between hyperhomocysteinemia and stenosis or occlusion in LEAOD has not been determined.
As a parameter that reflects the extensibility of arteries, baPWV has been widely used in the diagnosis of peripheral arterial diseases and even coronary arterial diseases. It measures the velocity of pulses transmitted between two preset positions, which depends on the extensibility and thickness of the blood vessels: The faster the velocity, the less extensible the arteries. Thomas Young initiated the concept of PWV in 1808. Since then, a variety of modifications has been made to increase the accuracy of PWV for determining the condition of arteries, and make it easier to measure. In 2002, Yamashina et al. described baPWV as a simple and noninvasive measurement of PWV to analyze patients with coronary artery disease that has high accuracy and reproducibility. Now, the method has been widely applied to examine many kinds of arterial diseases and become an index of arterial stiffness that shows prognostic predictability independently., However, the use of baPWV in LEAOD has scarcely been reported.
The ABI test is widely used for the assessment of coronary and peripheral arterial diseases, and results correspond well with angiography. Although an association between ABI and arterial stenosis or occlusion in LEAOD has been established by many researchers, this measurement has limitation itself.
Although ABI, pHcy, and baPWV have been used in the diagnosis of LEAOD, it is not known how well each of these noninvasive methods correlates with the severity of LEAOD as categorized by angiography. Although ABI is now commonly used to screen for LEAOD, baPWV, and pHcy are rarely applied., The delineation of these correlations should contribute to the proper use of these methods in the diagnosis of LEAOD.
In the present study, we investigated 102 patients who suffered from intermittent claudication for any associations between ABI, pHcy, and baPWV and the results obtained from CTA. We also discuss how data obtained by these methods can be interpreted to indicate the progression of LEAOD.
| Materials and Methods|| |
One hundred and two patients (57 men and 45 women; 59.35 ± 18.79 years old) with intermittent claudication and examined by CTA at Beijing Chao Yang Hospital from January 2010 to December 2011 were selected for this study. All participants provided letters of consent for involvement in the present study. Patients with any of the following diseases were excluded: atrial fibrillation, abnormal thyroid functions, dyslipidemia, cancer, infection or severe liver or kidney disease, hemorrhagic or thrombotic diseases, or a history of taking multivitamins. All patients were screened and classified in accordance with the Fontaine classification of ischemia.
For all patients, serum albumin, prealbumin, total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, blood urea nitrogen, blood creatinine, and high-sensitivity C-reactive protein were analyzed by Roche biochemical analyzer.
For the pHcy assay, 3 mL of fasting whole blood was obtained and transferred into ethylenediaminetetraacetic acid anticoagulant tubes. Plasma was obtained by centrifugation and stored at −70°C. The pHcy levels were detected using a homocysteine ELISA kit purchased from Axis-Shield (Dundee, UK). Tests were performed in accordance with the manufacturer's protocol, with pHcy <15 mol/L considered normal.
The baPWVs of patients were measured using the Complior SP (Artech Medical, Pantin, France). Sixteen consecutive values were recorded from each patient. The 3 highest and 3 lowest readings were excluded from the analysis, and the middle value of the remaining 10 readings was used to calculate the mean value of baPWV. The reference for normal baPWV was <14.00 m/s. Light peripheral atherosclerosis was considered at baPWV from 14.00 to 18.00 m/s, and baPWV >18.00 m/s was considered peripheral atherosclerosis.
The ABI was calculated as the ratio of the systolic blood pressure in the lower legs to the systolic blood pressure in the arms, with 1.0–1.3 taken as normal.
Classification of lower-extremity arterial occlusive disease based on computed tomography angiography
CTA was performed with a Siemens SOMATOM Definition dual-source (two X-ray tubes) CT scanner (Munich Germany). Optiray (Ioversol) was used at 350 mg/mL as the nonionic contrast medium. The scanning was performed starting from lumbar-2 to the toes. The threshold for the region of interest was set at 100 Hounsfield units, above which the images were automatically captured and saved.
Based on the CTA images, patients were categorized as normal, stenotic, or occluded. The normal group was defined as 0%–50% occluded in the following selected major arteries: the iliac, femoral, anterior tibial, and posterior tibial. The stenotic group was defined as 50%–95% occluded in one or multiple arteries. The occluded group was >95% occluded in multiple arteries.
Analyses were conducted with SPSS 13.0 software from IBM (IBM SPSS®, SPSS Inc. Chicago, USA). The normal distribution value is presented as the mean ± standard deviation. The skewed distribution is given as the median. All measurement data comparisons were performed using the independent t-test and single factor variance analysis. All counted data were compared using Chi-squared analyses.
Risk factors were first screened with single factor variance analysis, and then further characterized with multiple linear regression analysis to find independent factors that influence the target analyte. We also performed multiple regression analyses of other factors that may affect the value of ABI. The categorical variables were analyzed by the Chi-squared method, while numerical variables were analyzed by t-test.
| Results|| |
Comparisons of clinical characteristics among the three groups
All patients were classified as normal (n = 62), arterial stenotic (n = 29), or arterial occluded (n = 11) based on the CTA images [Figure 1]. The patient groups were not significantly different with regard to age, body mass index (BMI), smoking history, or alcoholic drink history [Table 1].
|Figure 1: Computed tomography angiography was performed with SOMATOM definition computed tomography scanner. Optiray (ioversol) was used at 350 mg/mL as the nonionic contrast medium. Normal, stenotic, and occluded were classified by the level of arterial occlusion at 0%–50%, 50%–95%, and >95%. The stenotic and occluded sites are indicated by red arrows|
Click here to view
Comparisons of plasma homocysteine, brachial-ankle pulse wave velocity, and ankle–brachial index values among the three groups
The pHcy levels of both the stenotic and the occluded groups were significantly higher than that of the normal group [Table 2]. The t values were 2.92 and 3.19, respectively, and the P = 0.005 and 0.002, respectively. However, there was no significant difference between the stenotic and occluded groups with regard to pHcy levels. The t value was 0.65 and the P = 0.519.
|Table 2: Comparisons of plasma homocysteine, brachial-ankle pulse wave velocity, and ankle-brachial index in groups classified for lower-extremity arterial occlusive disease by computed tomography angiography|
Click here to view
The baPWV values of both the stenotic and the occluded groups were significantly higher than that of the normal group [Figure 1] and [Table 2]. The t value were 12.89 and 11.04 respectively and the P value was all <0.001 in two groups. Additionally, it also had a statistically significant difference between the stenosis and the occlusive groups. The t value was 3.76 and the P = 0.001.
The ABI values were significantly lower in the stenotic and occluded groups compared to that in the normal group [Table 2], the t values were 9.64 and 7.37, respectively, and the P value was all <0.001 in two groups. In addition, the ABI value was lower in the stenotic group than in the occluded group, the t value was 9.43 and the P < 0.001.
Factors influencing ankle–brachial index values
The results of the multiple regression analyses indicated that the following factors affected the ABI value: hypertension, history of diabetes mellitus, systolic pressure of the lower limb, lower limb diastolic blood pressure, total cholesterol, pHcy, high-density lipoprotein, plasma creatinine, high sensitivity C-reactive protein, and baPWV [Table 3]. No correlation was found between ABI and gender, BMI, blood hemoglobin level, blood albumin level, or prealbumin level (data not shown).
Associations of probable risk factors with abnormal ABI were analyzed, and the odds ratios suggested that the following are independent variables: history of hypertension, history of diabetes mellitus, total cholesterol, high sensitivity C-reaction protein, and pHcy [Table 3].
| Discussion|| |
LEAOD constitutes a significant proportion of systemic atherosclerotic and peripheral arterial diseases and is accompanied by substantial systemic morbidities.,,, It has been demonstrated that patients with LEAOD with ABIs ≤0.9 are predisposed to complications of renal dysfunction, heart failure, and cerebrovascular disease. Since the lower extremities are responsible for a major portion of body movements or exercise, the arteries in the lower extremities may have unique characteristics that are important to know when conducting a diagnosis. Upon movement of the legs, arteries in the lower extremities are dilated, and those in the upper extremities are constricted. This suggests that limbs involved in ambulatory movements may have a specialized mechanism for blood flow dynamics; an effective collateral blood supply to the lower extremity seems more important than to the upper extremity. Insufficient blood flow for an extended period may not only affect limb viability but also cause potential tissue damage, limb loss, or even mortality.,, Thus, proper noninvasive diagnostic methods may enable clinicians to perform an earlier diagnosis and intervention for LEAOD.
In the present study, we evaluated ABI, pHcy, and baPWV, all noninvasive methods, for the diagnosis of LEAOD, using CTA as the reference. ABI and baPWV values closely correlated with the CTA findings, and either may serve to differentiate arterial stenosis from occlusion. However, while pHcy levels could differentiate between normal and diseased arteries, pHcy levels of stenotic and occluded arteries were similar. Nevertheless, these methods can all be used as general indicators of LEAOD.
Noninvasive examination is usually the first choice method for early diagnosis and surveillance of LEAOD. Currently, ABI is the most commonly used method for the diagnosis of peripheral arterial and coronary diseases, with high sensitivity and reproducibility. However, ABI may not be suitable for patients with artery calcification, which can interfere with the measurement of artery velocity and cause misleadingly high ankle pressure. Furthermore, ABI values may vary by examiner, or they may be influenced by hypertension, diabetes mellitus, or high levels of high-sensitivity C-reactive protein, pHcy, or baPWV.
Since baPWV was first used as a noninvasive method, many studies have been conducted to characterize its accuracy, compared with the conventional PWV test. In the current study, the data suggest that baPWV is also an accurate diagnostic tool for the diagnosis of LEAOD, with little or no interference from spurious arterial hypertension., It has been shown that ABI and baPWV can be used in combination to reflect more accurately the health of arteries, and especially for the early diagnosis of arteriosclerosis and arterial occlusive diseases. Our study further supports that both ABI and baPWV are useful for the diagnosis and categorization of arterial stenosis and occlusion in LEAOD.
It has long been known that hyperhomocysteinemia is related to atherosclerosis and cardiovascular diseases, but the mechanism(s) is not fully understood. It has been suggested that homocysteine may degrade or inhibit the formation of artery components such as elastin, proteoglycans, and collagen. Our study supports that pHcy is associated with vascular pathology, and parallels damage of the artery in degree.
| Conclusion|| |
Our analysis confirms ABI, baPWV, and pHcy for the diagnosis and classification of LEAOD by pathological stage, and we identified risk factors that contribute to the progression of the disease. This study may help clinicians use noninvasive methods to classify and therefore properly treat LEAOD. Further research is planned to include more healthy volunteers of different ages into the investigation of baPWV and pHcy, to establish a guideline for the primary prevention of LEAOD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gandhi S, Weinberg I, Margey R, Jaff MR. Comprehensive medical management of peripheral arterial disease. Prog Cardiovasc Di
s 2011;54 (1):2-13.
Dosluoglu HH, Lall P, Cherr GS, Harris LM, Dryjski ML. Role of simple and complex hybrid revascularization procedures for symptomatic lower extremity occluded disease. J Vasc Surg
Cassar K. Peripheral arterial disease. BMJ Clin Evid
2011. pii: 0211.
Maseri A, Fuster V. Is there a vulnerable plaque? Circulation
Alexopoulos N, Raggi P. Calcification in atherosclerosis. Nat Rev Cardiol
Shammas NW. Epidemiology, classification, and modifiable risk factors of peripheral arterial disease. Vasc Health Risk Manag
Bartholomew J R, Olin J W. Pathophysiology of peripheral arterial disease and risk factors for its development[J]. Cleve Clin J Med
2006, 73 Suppl 4 (Suppl_4): S8-14.
Wang Y, Xu Y, Li J, Wei Y, Zhao D, Hou L, Hasimu B, Yang J, Yuan H, Hu D. Characteristics of prevalence in peripheral arterial disease and correlative risk factors and comorbidities among female natural population in China. Vasa
Almahameed A, Bhatt D L. Contemporary management of peripheral arterial disease: III. Endovascular and surgical management[J]. Cleve Clin J Med
2006, 73 Suppl 4(Suppl_4): S45-51.
Kröger K, Bock E, Hohenberger T, Moysidis T, Santosa F, Pfeifer M. German Union of PAD Self-Help Groups. ABI derived from the highest and lowest ankle pressure. What is the difference? Int Angiol
Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: Systematic review and meta-analysis. Eur J Vasc Endovasc Surg
Amoh-Tonto CA, Malik AR, Kondragunta V, Ali Z, Kullo IJ. Brachial-ankle pulse wave velocity is associated with walking distance in patients referred for peripheral arterial disease evaluation. Atherosclerosis
Dellegrottaglie S, Sanz J, Macaluso F, Einstein AJ, Raman S, Simonetti OP, Rajagopalan S. Technology insight: Magnetic resonance angiography for the evaluation of patients with peripheral artery disease. Nat Clin Pract Cardiovasc Med
Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJ. Diagnostic performance of computed tomography angiography in peripheral arterial disease: A systematic review and meta-analysis. JAMA
Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, Koji Y, Hori S, Yamamoto Y. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res
Shimamoto K, Ando K, Fujita T, Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ishimitsu T, Ito M, Ito S, Itoh H, Iwao H, Kai H, Kario K, Kashihara N, Kawano Y, Kim-Mitsuyama S, Kimura G, Kohara K, Komuro I, Kumagai H, Matsuura H, Miura K, Morishita R, Naruse M, Node K, Ohya Y, Rakugi H, Saito I, Saitoh S, Shimada K, Shimosawa T, Suzuki H, Tamura K, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Umemura S. Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension. The Japanese Society of Hypertension guidelines for the management of hypertension. Hypertens Res
Ramakrishnan S, Sulochana KN, Lakshmi S, Selvi R, Angayarkanni N. Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys
Ostergren J, Sleight P, Dagenais G, Danisa K, Bosch J, Qilong Y, Yusuf S; HOPE Study Investigators. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J
Muster AJ, Kane B, Kim H, McPherson DD. Brachial arterial dynamics during staged lower extremity exercise: Utility and comparison in physically active versus sedentary subjects. Echocardiography
Ato D, Sawayama T. Factors associated with high brachial-ankle pulse wave velocity in non-hypertensive and appropriately treated hypertensive patients with atherosclerotic risk factors. Vasc Health Risk Manag
Yamasa T, Ikeda S, Koga S, Kawano H, Kaibara S, Maemura K. Comparison of the brachial-ankle pulse wave velocity between patients with acute coronary syndrome and effort angina pectoris and effort angina pectoris. Intern Med
[Table 1], [Table 2], [Table 3]