Prognostic Value of Peripheral Arterial Tonometry in Patients with ...

Journal of Atherosclerosis and Thrombosis 　Vol. 21, No. 3

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Original Article

Prognostic Value of Peripheral Arterial Tonometry in Patients with Coronary Artery Disease and a High Cardiovascular Risk Profile Alois Suessenbacher, Jakob Dörler, Maria Wanitschek, Hannes F. Alber, Otmar Pachinger and Matthias Frick Innsbruck Medical University, Univ. Clinic for Internal Medicine Ⅲ-Cardiology, Innsbruck, Austria

Aim: Data regarding the prognostic value of peripheral endothelial function testing in patients with cardiovascular disease are conflicting. Peripheral arterial tonometry (PAT) is increasingly used to measure the peripheral endothelial function. The prognostic value of this method has not been investigated thus far in patients with cardiovascular disease and/or a high cardiovascular risk profile. Methods: In 96 patients with significant coronary artery disease (CAD) or ＜ 70% stenosis and ≥ three cardiovascular risk factors, reactive hyperemia was induced following upper arm occlusion and the PAT-ratio between baseline and hyperemia was calculated. The patients were followed for cardiovascular events (revascularization, acute coronary syndrome, ischemic stroke, cardiovascular death, repeat coronary angiography due to chest pain) for 44±14 months. The first event was included in the combined end point. Results: The study cohort was divided according to the median PAT-ratio (1.91). The combined end point occurred in 14 patients with a PAT-ratio below the median (1.91) and in 12 patients with a PAT-ratio of ≥ 1.91 (p = 0.65). In a subgroup of 76 patients, the PAT-ratio was reassessed after six months. No differences in the event rate were found between the patients who exhibited deterioration (n = 50) and those who exhibited an improvement in the PAT-ratio of ＞ 0.1 (n = 26; 22 vs. 32%, p = 0.32). The combined end point occurred earlier in the patients with a PAT-ratio within the 1st tertile than in those with a PAT-ratio within the 2nd/3rd tertile (11.3±11.0 vs. 27.5±18.6 months, p = 0.03). Conclusions: In patients with established CAD or a high cardiovascular risk profile, the PAT-ratio cannot be used to predict the risk of future cardiovascular events. However, a lower PAT-ratio may be associated with the earlier occurrence of cardiovascular events. J Atheroscler Thromb, 2014; 21:230-238. Key words: Peripheral endothelial function, Prognostic value, PAT-ratio

Introduction Data concerning the prognostic value of the peripheral endothelial function are conflicting. In patients without documented cardiovascular disease, several trials have demonstrated that peripheral endothelial dysfunction is related to increased cardiovascular risks 1-3). In contrast, studies in patients with established cardiovascular disease have demonstrated conAddress for correspondence: Matthias Frick, Innsbruck Medical University, Univ. Clinic for Internal Medicine ⅢCardioloy, Anichstrasse 35, A-6020 Innsbruck, Austria E-mail: [email protected] Received: July 19, 2013 Accepted for publication: September 18, 2013

flicting results 4-11). During the last few years, the EndoPAT ® device, a novel technique used to assess the peripheral endothelial function, has been increasingly used. With this device, peripheral arterial tonometry (PAT) can be used to measure the pulse wave amplitude during reactive hyperemia and calculate the ratio between the baseline and hyperemia values (PAT-ratio), which represents the endothelial function. A correlation between the values obtained using the PAT method and cardiovascular risk factors has been confirmed 12). However, compared to ultrasound based endothelial function testing conducted by measuring the flow-mediated vasodilation (FMD) of the brachial artery, the PAT technique provides distinct information regarding the vascular function in small,

Prognostic Value of the Endothelial Function

rather than conduit, vessels 13). Prognostic data regarding the EndoPAT technique are rare. To the best of our knowledge, only two studies have investigated the prognostic value of this parameter in a cohort of patients with unexplained chest pain 14) and in patients with heart failure with a preserved ejection fraction 15). Therefore, the purpose of the present study was to examine whether the PATratio can be used to predict future cardiovascular events in patients with angiographically proven coronary artery disease (CAD) or non-significant CAD with a high cardiovascular risk profile. Methods Study Population Ninety-six patients with significant CAD on coronary angiography (≥ 70% stenosis in at least one major coronary vessel), ＜ 70% stenosis and a high cardiovascular risk profile (≥ three cardiovascular risk factors, including arterial hypertension, diabetes mellitus, smoking, hypercholesterolemia, a positive family history of cardiovascular disease) and patients with diabetes mellitus and ＜ 70% stenosis were enrolled in this study. The exclusion criteria were as follows: planned coronary artery bypass surgery, significant valvular disease, symptoms of chronic heart failure, a left ventricular ejection fraction of ＜ 35%, the development of acute coronary syndrome within one week before inclusion, untreated severe arterial hypertension and atrial fibrillation. The study protocol was approved by the local ethics committee. Written informed consent was obtained from all study participants, and the study complied with the declaration of Helsinki. Study Protocol The total cholesterol, triglyceride, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were measured in the fasting state. Individuals with a plasma LDL cholesterol level of ＞ 130 mg/dL or who were receiving cholesterol-lowering therapy were classified as hypercholesterolemic patients 16). Arterial hypertension was defined as the use of antihypertensive medications or the presence of an elevated blood pressure (≥ 140/90 mmHg) before endothelial function measurement. A positive family history for cardiovascular disease was assumed if a first-degree male relative ≤ 55 years of age or female relative ≤ 65 years of age suffering from any cardiovascular disease was reported by the study participant. Patients were included after undergoing coronary angiography. The PAT-ratio was measured in the fasting state (at least 12 hours) between 08:00 and 10:00

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a.m. after withholding all vasoactive drugs on that day. All participants were asked not to smoke on the day of the examination. The peripheral endothelial function was assessed using the commercially available EndoPAT ® device (Itamar Medical Ltd, Caesarea, Israel), as previously described 17). With this device, a beat-to-beat plethysmographic record of the finger arterial pulse wave amplitude was captured using pneumatic probes placed on the index finger of each hand. For the assessment of the endothelial function, the reactive hyperemia technique was used: the measurements were obtained for five minutes at baseline (at rest), followed by five minutes of occlusion of the right upper arm with a sphygmomanometer cuff inflated to a suprasystolic level (50 mmHg above the initially measured systolic blood pressure). The cuff was then deflated to induce reactive (flow-mediated) hyperemia, which was measured for 10 minutes. The left hand remained unoccluded as a reference to correct for potential systemic changes. The PAT-ratio, which represents the endothelial function, was calculated as the ratio between the magnitude of the average postocclusive pulse wave amplitude (1.5-2.5 minutes after the release of arterial occlusion) and the average pulse wave amplitude observed over five minutes of preocclusion, corrected for systemic changes. Immediately after the first PAT measurement, treatment of cardiovascular risk factors was optimized (e.g. the adaptation of antihypertensive therapy or lipid-lowering therapy). The patients were invited to visit our outpatient department three months after inclusion for additional optimization of the treatment of cardiovascular risk factors. Furthermore, in patients who agreed to revisit the outpatient department, a second PAT measurement was obtained six months after study inclusion to evaluate whether a change in the PAT-ratio predicts future cardiovascular events. Follow-up data were obtained after 44±14 months using a review of hospital records and an official death registry, including all deaths occurring in Austria. Cardiovascular events were defined as follows: revascularization via either percutaneous coronary intervention or coronary artery bypass surgery, the presence of acute coronary syndrome (either ST elevation myocardial infarction or non-ST elevation acute coronary syndrome according to common definitions 18, 19)), ischemic stroke or cardiovascular death (death from myocardial infarction, stroke or other atherosclerotic diseases) and the use of coronary angiography due to chest pain. For the statistical analyses, the first event was included in the combined end point.

Suessenbacher et al .

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Table 1. Patient characteristics and medications

Age (years) Women (%) Arterial hypertension (%) Smoking (%) Positive family history (%) Hypercholesterolemia (%) Diabetes mellitus (%) Total-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) Creatinine (mg/dL) HbA1c (in those with diabetes) (%) Body-mass-index (kg/m2) Significant CAD (%) Modified Gensini Score PCI (%) Aspirin (%) Clopidogrel (%) Statin (%) ACE-Inhibitor (%) AT-Ⅱ blocker (%) Calcium channel blocker (%) Beta blocker (%) Diuretics (%) PAT-ratio

Overall (n = 96)

PAT-ratio ＜ 1.91 (n = 48)

PAT-ratio ≥ 1.91 (n = 48)

p-value (＜ 1.91 vs. ≥ 1.91)

62±8 25 87 21 20 88 26 195±50 119±43 53±17 166±118 0.96±0.19 7.6±1.6 27.5±4.6 81 6.8±3.5 68 97 79 91 63 15 13 66 12 2.0±0.6

61±7 29 85 19 25 88 23 201±57 124±49 51±15 176±142 0.95±0.19 8.1±2.0 27.6±5.3 77 6.3±3.7 65 100 77 88 65 17 10 63 10 1.6±0.2

62±9 21 88 23 15 88 29 190±42 113±36 53±18 158±91 0.97±0.19 6.9±0.75 27.5±4.0 85 7.4±3.3 71 94 81 94 60 13 15 69 12 2.4±0.5

0.56 0.35 0.77 0.62 0.2 1.0 0.49 0.27 0.24 0.58 0.79 0.61 0.25 0.9 0.30 0.17 0.51 0.08 0.62 0.29 0.67 0.56 0.54 0.49 0.75 ＜ 0.001

The plus-minus values indicate the mean±SD PAT: peripheral arterial tonometry, LDL: low-density lipoprotein, HDL: high-density lipoprotein, CAD: coronary artery disease, PCI: percutaneous coronary intervention, ACE = angiotensin converting enzyme, AT-Ⅱ= angiotensin Ⅱ, PAT: peripheral arterial tonometry

Statistical Analyses All analyses were conducted using a statistical software program (IBM ® SPSS ® Statistics, Version 20). The data are expressed as the mean±standard deviation or as frequencies (percentages). The normal distribution of the variables was tested using the Kolmogorov-Smirnov test, and accordingly continuous variables were compared using Student’s t -test, the Mann-Whitney U-test or the Wilcoxon test, as appropriate. For categorical variables, the chi-square test was used to compare differences between groups and McNemar’s test was applied to test for changes in medications in the subgroups with serial PAT-ratio measurements. In order to obtain groups of comparable size, the patient population was divided into two groups according to the median PAT-ratio, and the cumulative event rates were calculated according to the Kaplan-Meier method and log-rank test. Further-

more, in order to test whether the PAT-ratio can be used to predict the time to the first event, patients who reached the combined end point were divided into two groups according to PAT-ratio tertiles (first vs. 2nd/3rd tertiles). A subgroup of patients underwent serial PAT measurement. In order to investigate whether an improvement in the PAT-ratio is associated with a lower risk of cardiovascular events, the patients were divided into two groups according to the first tertile and 2nd/3rd tertiles. Cumulative event rates were calculated according to the Kaplan-Meier method and log-rank test. For all analyses, a two-sided p-value of ＜ 0.05 was considered to be statistically significant. Results The clinical characteristics are presented in Table


Fig. 1. Kaplan Meier curves for the PAT-ratio. The p-value was calculated using the log-rank test. ＊

Combined end point = revascularization, acute coronary syndrome, ischemic stroke, cardiovascular death, repeat coronary angiography due to chest pain.

1. In order to evaluate the prognostic value of the PAT-ratio, the patients were divided according to the median PAT-ratio (1.91). No differences in clinical characteristics were found between the groups, as presented in Table 1. Furthermore, no differences in medical pretreatment were found between the analyzed subgroups. The combined end point occurred in 14 patients with a PAT-ratio below the median (1.91) and in 12 patients with a PAT-ratio of ≥ 1.91 (p = 0.65). Fig. 1 shows Kaplan-Meier plots revealing no differences in event-free survival between the groups. In order to evaluate whether the PAT-ratio can be used to predict the time to the first cardiovascular event, patients who experienced an event were divided into two groups according to the first tertile and 2nd/3rd tertiles, which revealed that the combined end point occurred earlier in those with a lower PAT-ratio (Fig. 2). According to the study protocol, a patient was included only if diabetes mellitus was present. However, among the 25 patients with diabetes mellitus, only three had no CAD; however, these three individuals all had hypercholesterolemia as an additional cardiovascular risk factor. One of these patients was a smoker, and the other two had arterial hypertension as an additional risk factor. A subgroup of 76 patients agreed to undergo serial assessments of the PAT-ratio. Three months after study inclusion, the patients visited our outpatient department in order to optimize their treatment of cardiovascular risk factors (particularly with respect to

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Fig. 2. Error bars demonstrating the mean time to the first cardiovascular event according to the PAT-ratio tertiles.

adaption of antihypertensive treatment and lipid-lowering therapy). Six months after inclusion, the PATratio was reassessed. The mean PAT-ratio decreased from 2.0±0.6 to 1.8±0.6 (p = 0.02). The changes in the clinical parameters and medications during the six-month period are presented in Table 2. A decrease in the LDL-cholesterol levels and a trend towards lower HbA1c levels in the diabetics were observed. Concerning the medications, clopidogrel was less often used six months after study inclusion. In order to analyze whether an improvement in the PAT-ratio is associated with fewer cardiovascular events, the study population was divided into two groups: PAT-ratio “non-improvers” (no changes, a decrease or a ＜ 0.1 increase in the PAT-ratio, n = 50), and PAT-ratio “improvers” (an increase in the PATratio of ≥ 0.1, n = 26). The mean baseline PAT-ratio in the non-improvers decreased from 2.2±0.6 to 1.7± 0.3 after six months (p ＜ 0.001), whereas the baseline PAT-ratio in the improvers increased from 1.7±0.4 to 2.2±0.8 (p ＜ 0.001). No differences in the event rate (22 vs. 32%, p = 0.32) or event-free survival were observed between the groups (Fig. 3). Discussion In patients with angiographically proven CAD and/or with a high cardiovascular risk profile, the peripheral endothelial function assessed according to the PAT-ratio cannot be used to predict future cardio-

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Table 2. Changes in the clinical parameters and medications

Total-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) Creatinine (mg/dL) HbA1c (in those with diabetes) (%) Body-mass-index (kg/m2) Aspirin (%) Clopidogrel (%) Statin (%) ACE-Inhibitor (%) AT-Ⅱ blocker (%) Calcium channel blocker (%) Beta blocker (%) Diuretics (%) PAT-ratio

Baseline

3 Months

6 Months

195±50 119±43 53±17 166±118 0.96±0.19 7.6±1.6 27.5±4.6 97 79 91 63 15 13 66 12 2.0±0.6

174±36 98±30 51±13 152±93 0.98±0.18 6.2±0.9 27.4±4.0 94 67 88 58 17 11 67 14 n.a.

175±42 96±31 55±16 160±140 0.98±0.17 6.9±1.4 27.4±3.5 95 50 86 58 14 9 63 13 1.8±0.6

p-value (BL vs. 6 Months) ＜ 0.001 ＜ 0.001

0.13 0.22 0.88 0.06 0.42 0.5 ＜ 0.001 0.39 0.18 0.13 0.38 0.51 0.63 0.02

The plus-minus values indicate the mean±SD BL: baseline, LDL: low-density lipoprotein, HDL: high-density lipoprotein, ACE: angiotensin-converting enzyme, AT-Ⅱ: angiotensin Ⅱ, PAT: peripheral arterial tonometry

vascular events. These findings are consistent with our previously published data in a comparable patient cohort using the ultrasound based FMD method to measure the endothelial function 11, 20). Furthermore, our results represent the first analysis of the prognostic value of the PAT-ratio in patients with established cardiovascular disease. The most frequently used endothelial function testing method continues to be the assessment of the FMD of the brachial artery using high-resolution ultrasound 21). However, this method is prone to high interobserver variability. During the last few years, the EndoPAT ® device, a novel technique used to assess the peripheral endothelial function, became commercially available. As the endothelial function is measured using an automated software algorithm, this method has a low interobserver variability and can be used in large study cohorts 12). Regarding the FMD, data concerning the prognostic value of the peripheral endothelial function are clear in healthy individuals: several trials have demonstrated that peripheral endothelial dysfunction is related to increased cardiovascular risks 1-3). In contrast, studies of patients with established cardiovascular disease have demonstrated conflicting results 5-11). Regarding the EndoPAT technique, the prognostic value of the PAT-ratio was recently investigated in a cohort of patients with unexplained chest pain and low-risk findings during stress testing

and/or the absence of new obstructive lesions on coronary angiography (only 16% of included patients had known coronary artery disease, defined as previous myocardial infarction or revascularization) 14). A logarithmic PAT-ratio of ＜ 0.4 was found to be associated with more cardiovascular events after seven years of follow-up. In the present study, the prognostic value of the peripheral endothelial function assessed according to the PAT-method was investigated for the first time in patients with angiographically proven significant CAD or a high cardiovascular risk profile. Our results support previous findings in a comparable cohort evaluated using the FMD method 11, 20). As presented in Fig. 1, the PAT-ratio could not be used to predict future cardiovascular events in the investigated patient population. Some data suggest that conducting serial assessments of the peripheral endothelial function enhances the prognostic value of this parameter 9, 10). However, in our study cohort using the EndoPAT ® method, the patients who exhibited deterioration in the endothelial function after six months did not have a higher risk of cardiovascular events compared to those who demonstrated no changes or even an improvement in the PAT-ratio (Fig. 3). In order to evaluate whether the patients with the lowest PAT-ratios experience cardiovascular events earlier than those with a higher baseline PAT-ratio, we divided the patients who experienced a cardiovascular


Fig. 3. Kaplan Meier curves for the PAT-ratio improvers and the PAT-ratio non-improvers. The p-value was calculated using the log-rank test. ＊

Combined end point = revascularization, acute coronary syndrome, ischemic stroke, cardiovascular death, repeat coronary angiography due to chest pain.

event into two groups: those with a PAT-ratio in the lowest tertile, and those with a PAT-ratio higher than the lowest tertile ( = 2nd and 3rd tertiles). As presented in Fig. 2, the combined end point occurred earlier in the patients with a lower PAT-ratio, suggesting that a worse peripheral endothelial function is associated with the earlier occurrence of cardiovascular events. Almost three-fourths of the study participants agreed to visit our outpatient department to optimize their treatment of cardiovascular risk factors after three months and reassess their endothelial function after six months. Due to this intervention, a decrease in the LDL-cholesterol levels was found among all patients, and a trend towards lower HbA1C values was observed in the subjects with diabetes mellitus. However, no changes in the HDL-cholesterol levels or body mass index were noted, and the HDL-cholesterol levels were quite high among the patients with known cardiovascular disease. Concerning medications, no changes were observed during the six-month study period, with the exception of the use of clopidogrel, which was reduced after six months. This finding can be explained by the use of bare metal stents, with the indication for dual antiplatelet therapy for four weeks. A decrease in the PAT-ratio was noted after six months. However, the mean baseline PAT-ratio of 2.0 ±0.06 among the patients with CAD is high compared to the data reported by Bonetti et al.22) who described a PAT-ratio of 1.27±0.05 in patients with coronary endothelial dysfunction and 1.78±0.08 in

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those without CAD with a normal coronary endothelial function. The high PAT-ratio observed in our study cohort may be explained by the fact that many patients were receiving treatment with statins or ACE inhibitors at the time of study inclusion. For both classes of drugs, an improvement in the endothelial function has been described 23-25). Hovland et al.26) compared the PAT-ratios of patients with familial hypercholesterolemia under statin treatment with those of normal healthy controls and found no differences between the investigated groups, ascribing this finding to the use of statin pretreatment in the patients with familial hypercholesterolemia. The PATratios in the patients with familial hypercholesterolemia under statin treatment (1.93) were comparable to the mean PAT-ratio observed in our study cohort (2.0), in which 91% of the patients were taking a statin. Regarding clopidogrel, an improvement in the PAT-ratio was found after a single 600-mg loading dose 27). With respect to combination therapy consisting of the beta blocker carvedilol and the ACE inhibitor lisinopril, an improvement in the PAT-ratio of 0.74 has been reported in obese individuals with arterial hypertension 25). Our study cohort is not directly comparable to that cohort, as the mean body mass index in our study was 27 kg/m2, compared with 38 kg/m2 in the cited study, and all of the patients in the cited study were hypertensive, whereas, in our study, 87% of the patients suffered from arterial hypertension. However, extrapolating the findings of Kelly et al.25) to other ACE inhibitors and beta blockers may explain why the mean PAT-ratio observed in our study cohort was approximately 0.7 higher than that previously reported in patients with coronary artery disease (1.3) 22). In the subgroup with serial PAT measurements, the mean PAT-ratio decreased to 1.8 after six months. Although this deterioration was statistically significant, the clinical value of our finding must be discussed, as Heffernan et al.28) demonstrated that a PATratio of 2.0±0.1 is associated with “low-risk CAD,” a PAT-ratio of 1.6±0.07 is associated with “moderaterisk CAD” and a PAT-ratio of 1.3±0.04 is associated with “high-risk CAD.” The risk of CAD was stratified according to data from the Atherosclerosis Risk in Communities (ARIC) study, in which cardiovascular events were found to be independently associated with the levels of high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2.29) As the mean PAT-ratio of 1.8 found in our study is in between that observed in the low- and moderate-risk groups, we do think that the observed deterioration is unlikely to be clinically relevant as there is no clear shift to a higher risk group. Using the FMD measurement, an


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increased risk of cardiovascular events has been demonstrated in patients with CAD in whom no improvements of the peripheral endothelial function occurred in serial assessments 9, 10). However, this finding could not be confirmed in the present study using the EndoPAT technique. An important difference between the FMD and PAT methods is the fact that the FMD assesses the endothelial function of conduit arteries, whereas the PAT method measures the microvascular endothelial function. Study Limitations Women are underrepresented in this study, as only 25% of the included patients were female. A possible influence of the menstrual cycle can be excluded because all women were postmenopausal, and no sex differences were recently observed in the PAT-ratio, even in young individuals (mean age 37±5 years) 30). The mean PAT-ratio was quite high in the patients with cardiovascular disease. This finding may be explained by the pre-existing risk factor treatment administered before study inclusion. Vasoactive drugs can influence the endothelial function. As we withheld all vasoactive drugs on the day of PAT measurement, the last dose was administered at least 12 hours before PAT measurement. This is in accordance with previous studies investigating the peripheral endothelial function 9, 20). However, it cannot be excluded that vasoactive drugs with longer half-lives had an effect on the PAT measurement. In light of our findings, the PAT method is thus suggested to not be feasible for the cardiovascular risk assessment of unselected patients in daily clinical practice for the following reasons. First, in our study population of patients with established CAD or a high cardiovascular risk profile, which represented patients seen in daily clinical practice, the PAT-ratio could not be used to predict future cardiovascular events. Second, as discussed above, the mean PAT-ratio observed in our study was quite high among the patients with established cardiovascular disease, perhaps due to the effects of pre-existing cardiovascular drug treatment. One may suggest that the results would have been different if all vasoactive drugs had been withheld for more than 12 hours or even several days before the PAT-ratio assessment. However, this is not possible in daily clinical (and of course scientific) practice due to the risk of hypertensive emergencies. Whether the PAT-ratio is a predictor of outcomes in more selected populations, such as patients with early coronary atherosclerosis 22), obstructive sleep apnea 31) or pulmonary hypertension 32) and children with diabetes mellitus 33),

deserves further study. Conclusion In patients with established CAD or a high cardiovascular risk profile, the peripheral endothelial function assessed according to the PAT method cannot be used to predict the risk of future cardiovascular events; however, a lower PAT-ratio may be associated with the earlier occurrence of cardiovascular events. In light of our findings, PAT measurement is not considered to be an additional useful tool for assessing cardiovascular risks in unselected patients. Grant Support Österreichischer Herzfonds, Vienna, Austria Conflicts of Interest All authors disclose no financial relationships with any biotechnology manufacturers, pharmaceutical companies or other commercial entities with an interest in the subject matter or materials discussed in this manuscript. References 1) Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM: Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multiethnic study of atherosclerosis. Circulation, 2009; 120: 502-509 2) Shimbo D, Grahame-Clarke C, Miyake Y, Rodriguez C, Sciacca R, Di Tullio M, Boden-Albala B, Sacco R, Homma S: The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis, 2007; 192: 197-203 3) Hirsch L, Shechter A, Feinberg MS, Koren-Morag N, Shechter M: The impact of early compared to late morning hours on brachial endothelial function and long-term cardiovascular events in healthy subjects with no apparent coronary heart disease. Int J Cardiol, 2011; 151: 342-347 4) Venneri L, Poggianti E, Jambrik Z, Varga A, Palinkas A, Picano E: The elusive prognostic value of systemic endothelial function in patients with chest pain syndrome. Int J Cardiol, 2007; 119: 109-111 5) Karatzis EN, Ikonomidis I, Vamvakou GD, Papaioannou TG, Protogerou AD, Andreadou I, Voidonikola PT, Karatzi KN, Papamichael CM, Lekakis JP: Long-term prognostic role of flow-mediated dilatation of the brachial artery after acute coronary syndromes without ST elevation. Am J Cardiol, 2006; 98: 1424-1428 6) Chan SY, Mancini GB, Kuramoto L, Schulzer M, Frohlich J, Ignaszewski A: The prognostic importance of


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