PULSE WAVE VELOCITY AS A NEW ASSESSMENT TOOL FOR ATHEROSCLEROSIS

PULSE WAVE VELOCITY AS A NEW ASSESSMENT TOOL FOR ATHEROSCLEROSIS Introduction Hirohide Yokokawa, M.D., Ph.D.¹, Aya Goto, M.D., MPH, Ph.D. ², and Seiji Yasumura, M.D., Ph.D. ³, ¹assistant Professor, Department of Public Health, Fukushima Medical University School of Medicine, ²associate Professor, Department of Public Health, Fukushima Medical University School of Medicine, ³professor, Department of Public Health, Fukushima Medical University School of Medicine The World Health Organization reported in 2005 that cardiovascular disease was the most common cause of death worldwide, accounting for approximately 30% of all deaths [1]. Age-specific statistics show that the main cause of death between the ages of 15-59 was HIV/AIDS, followed by ischemic heart disease and tuberculosis [2]. Among elderly individuals, main causes of death were ischemic heart disease followed by cerebrovascular disease [2]. The data stress the importance of preventing and treating atherosclerotic disease. One of the most important factors contributing to the increase in atherosclerotic disease is aging. Over the past several decades, life expectancy at birth has increased globally by approximately 20 years, from 46.5 years in 1950-1955 to 65.2 years in 2002, and this trend is observed in both developed and developing countries [2]. Another factor that contributes to atherosclerosis is diabetes, which is increasing globally at an alarming rate. The International Diabetes Federation (IDF) predicts the prevalence of diabetes to increase from 5.1% (194 million people worldwide) in 2003 to 6.3% (333 million) in 2025 [3]. In response, the United Nations passed a resolution in December 2006 recognizing diabetes as a chronic, debilitating, and costly social burden [4]. Conventional and noninvasive tools for evaluating atherosclerosis have been recently developed and are currently in use [5,6]. Among these is pulse wave velocity (PWV), which depicts the velocity of a pulse wave between two arterial points and constitutes a clinical index of aortic stiffness. The use of PWV has received increasing attention as a non-invasive method to measure vascular injury [6]. PWV levels change with age, differ between sexes, and increase in the presence of atherosclerotic disease and associated risk factors [7]. In this commentary, we discuss the mechanisms of PWV and summarize recent studies that address a connection between PWV and atherosclerotic diseases [6-12]. Development of PWV PWV measures the speed of a blood pressure wave between two given sites of an artery, and is determined by arterial wall elasticity and thickness [7]. The first use of PWV was reported in 1922 in a study examining an association between age and arterial stiffness [13]. At the time, procedures for measuring PWV were complicated and not suitable for diagnostic purposes. During the 1960s, as new techniques were developed to assess pulse wave and pressure, reports on PWV increased. Initially, the carotid-femoral PWV (cfpwv) was identified for its usefulness as a marker of vascular damage, and its relationship to disease prognosis was confirmed in several studies [8-10]. However, this method proved impractical in the clinical setting, as patients were required to disrobe, which made screening many subjects in a short time frame difficult. To accommodate the demand for measuring arterial stiffness in the clinic, an automatic system to measure brachial-ankle PWV (bapwv) was developed and commercialized in Japan in

1999. Since then, about 10,000 devices have been sold in Japan, South Korea, China, and Taiwan. The reliability and validity of bapwv versus cfpwv has been confirmed. Importantly, bapwv does not require examiners to acquire specialized techniques, and measurements are made by wrap cuffs on the brachia and ankles [14]. Results of cfpwv and bapwv measurements are not equivalent because bapwv reflects sclerosis of both central elastic arteries and peripheral muscular arteries, while cfpwv reflects only the sclerosis of central arteries. However, a high correlation between the two has been reported (r = 0.87) [14]. PWV as an Atherosclerotic Disease Marker Following its commercialization in 1999, many reports on PWV have been published. These studies revealed that PWV increases with age, is higher among men as compared to women until age 60, and then becomes similar in both sexes in older age groups [7]. PWV has wide potential applications for predicting the prognosis of early vascular damage. Table 1 summarizes recent studies on PWV and associated risk factors following three stage categories: health behaviors, clinical indicators, and final outcomes. Smoking is considered as a health behavior reported to increase PWV level [15], and the duration of smoking cessation is known to have a significant linear relationship with improvement in cfpwv in ex-smokers [16]. Similarly, excessive alcohol consumption is associated with elevated PWV [17-18]. Furthermore, some reports suggest that physical activity has favorable effects on aortic stiffness assessed by PWV [19-20]. PWV also increases in the presence of atherosclerosis-related conditions such as diabetes mellitus [7,21], dyslipidemia [22], and hypertension [23]. In our previous reports, we showed that among health check-up attendants, blood pressure and glucose-related measurements, in addition to age and sex, were associated with PWV level [24]. Along with recent worldwide attention, evidence regarding metabolic syndrome and PWV are starting to accumulate. These studies suggest PWV as a predictor of metabolic syndrome and its synergetic increase in the presence of multiple components [25-27]. In relation to increasing attention on chronic kidney disease as an important risk factor of cardiovascular diseases as well as end stage renal disease, PWV is reported to correlate with proteinuria and renal function [28-30]. Finally, there have been a number of longitudinal studies reporting the effects of PWV on cardiovascular and cerebrovascular [31-32]. In the case of cardiovascular disease, a longitudinal study among middle-aged hypertensive patients in France demonstrated that relative risk increased by 1.4 times for each standard deviation (SD) increase in PWV (3.5 m/sec) [8]. Additionally, the same research group reported that PWV was an independent predictor of cerebrovascular diseases [10] and all-cause mortality [9] among hypertensive patients. The relative risk of stroke mortality was 1.7 for 4 m/sec PWV and that of all-cause mortality was 2.1 for 5 m/sec PWV. We also conducted a case-control study in a Japanese population to examine the association between PWV and cerebral infarction [11]. Subjects consisted of 92 pairs of cerebral infarction patients (cases) and healthy individuals (controls) admitted for a health check-up at a general hospital, matched for age and sex. In our analysis, family history of hypertension (OR = 8.6), cerebrovascular diseases (OR = 13.7), a high-density lipoprotein cholesterol of 40 mg/dl or higher (OR = 0.1), and PWV over 1600 cm/sec (OR = 2.9) remained significant in a multivariate conditional logistic regression model. Unique Applications of PWV Recently, unique assessments of the usefulness of PWV have been carried out. One study determined a relationship between PWV and obstructive sleep apnea syndrome (OSAS), which is

known to be a risk factor of cardiovascular morbidity and mortality through hypertension, abnormal metabolic parameters, and obesity [33-34]. A cross-sectional study among Japanese patients coming to a hospital for sleep apnea treatment revealed that PWV was significantly higher among those diagnosed with OSAS [33]. In addition, Kitahara et al. [34] treated patients with OSAS by using continuous positive airway pressure, and reported that the treatment effectively reduced PWV levels along with heart rate and blood pressure. Moreover, there are trials that have used PWV to evaluate the effectiveness of consuming green coffee bean extract [35], beta-carotene [36], beta-cryptoxanthin [36], and eicosapentaenoic acid [37] in preventing atherosclerotic vascular damage. Conclusion Atherosclerotic diseases are receiving public health attention due to a rapid increase in prevalence, their impact on individual mortality and morbidity, and their influence over national health policy. Here, we have indicated the potential value of using PWV, which is a convenient, inexpensive, and noninvasive test to identify vascular injury and predict vascular disease. The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) have added PWV measurement as an early index of large artery stiffening in the 2007 Guideline for the Management of Arterial Hypertension [38]. We recommend increased utilization and further evaluation of PWV as a screening tool for atherosclerotic diseases. References 1. Ten Statistical Highlights in Global Public Health. World Health Statistics 2006, World Health Organization. http://www.who.int/whosis/whostat2006_10highlights.pdf 2. Global health: today s challenges. The World Health Report 2003, World Health Organization. http://www.who.int/whr/2003/en/chapter1-en.pdf 3. The global burden of diabetes. Diabetes atlas (2 nd ed.). International Diabetes Federation, 2006: 7-12. 4. The UN Resolution on diabetes. http://www.unitefordiabetes.org/campaign/resolution.html. 5. O'Leary DH, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14-22. 6. Khoshdel AR, et al. Better management of cardiovascular diseases by pulse wave velocity: combining clinical practice with clinical research using evidence-based medicine. Clin Med Res 2007;5:45-52. 7. Tomiyama H, et al. Influences of age and gender on results of noninvasive brachial-ankle pulse wave velocity measurement a survey of 12517 subjects. Atherosclerosis 2003;166:303-9. 8. Boutouyrie P, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002;39:10-15. 9. Laurent S, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236-41. 10. Laurent S, et al. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003;34:1203-12. 11. Yokokawa H, et al. Evaluation of atherosclerosis-associated factors and pulse wave velocity for predicting cerebral infarction: a hospital-based, case-control study in Japan. Intern Med J 2007;37:161-67. 12. Blacher J, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434-39.

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velocity. Atherosclerosis 2006;184:363-69. 37. Tomiyama H, et al. Do eicosapentaenoic acid supplements attenuate age-related increases in arterial stiffness in patients with dyslipidemia?: A preliminary study. Hypertens Res 2005;28:651-55. 38. Mancia G,; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105-87. Please address correspondence to: Hirohide Yokokawa Department of Public Health Fukushima Medical University School of Medicine 1, Hikarigaoka, Fukushima City, 960-1295, Japan Tel: 81-24-547-1179 Fax: 81-24-548-4600 E-mail: yokokawa@fmu.ac.jp

Table 1. Pulse-wave velocity associated factors Groups Subgroups Results Reference numbers Health Behaviors Cigarette smoking Cigarette smoking increased blood pressure, heart rate and bapwv in both chronic smokers and non-smokers. 15 Current and ex-smokers had significantly higher cfpwv, 16 and in ex-smokers, the duration of smoking cessation had a significant linear relationship with improvement in cfpwv. Alcohol drinking A U-shaped association was found between alcohol 17 consumption and arterial stiffness in old women, but not in men. An excessive alcohol intake (more than 60g of 18 ethanol/day) was significantly associated with elevated bapwv. Physical activity Increased walking frequency over a 24-month period 19 predicted reduced vascular stiffness in women. Sports-related physical activity was inversely and 20 significantly associated with PWV. Clinical Metabolic Fasting blood glucose was closely related to bapwv, as 25 Indicators syndrome related well as age and systolic blood pressure. parameters High PWV appeared to exhibit a strong independent 26 association with the presence of metabolic syndrome, together with adiposity and insulin resistance. The estimated annual rate of increase in bapwv was 27 higher among subjects with raised blood pressure and plasma glucose than in those with either condition alone or neither. Proteinuria Brachial-ankle PWV was an independent and significant 28 factor for microalbuminuria in essential hypertension. Brachial-ankle PWV increased with a decrease in renal 29 function, or with proteinuria, independently of other risk factors. Final Cardiovascular Higher aortic PWV was associated with both total 31 Outcomes diseases mortality and cardiovascular mortality in the elderly. Aortic PWV was an independent predictor of primary coronary events in hypertensive patients. 8 Carotid-femoral PWV was an independent associated 9 factor for all-cause and cardiovascular mortality in hypertensive patients Cerebrovascular Carotid-femoral PWV was an independent predictor of 32 diseases coronary heart disease and stroke in healthy subjects. Aortic PWV was an independent predictor of the occurrence of stroke death in essential hypertensive patients. 10 A high bapwv might be independently associated with a higher risk of cerebral infarction 11