PWV (r 2 U 0.36, P U 0.002) but not AIx correlated with pulse pressure. Journal of Hypertension 2006, 24:

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1 Original article 2085 Pulse wave velocity is increased in patients with transient myocardial ischemia Johannes Baulmann a, Rami Homsi a, Sakir Uen a, Rainer Düsing a, Rolf Fimmers b, Hans Vetter a and Thomas Mengden a Objective We have recently shown that mean pulse pressure is higher in patients with transient myocardial ischemia. Pulse pressure elevation might be an important consequence of increased arterial stiffness. The aim of this study was to prove if arterial stiffness is changed in patients with transient myocardial ischemia who bear a high cardiovascular risk. Additionally we investigated whether arterial stiffness or wave reflection is the best indicator for transient myocardial ischemia. Aortic pulse wave velocity (PWV) is a measure of arterial stiffness, and augmentation index (AIx) an indication of arterial wave reflection. Both are indicators for cardiovascular risk. Methods PWV (carotid femoral) and AIx (SphygmoCor) were assessed in 74 hypertensive patients. Transient myocardial ischemia was detected using an ST-triggered 24-h ambulatory blood pressure monitoring device. Results ST-segment depressions were recorded in 30 of 74 patients. There were no significant differences with regard to age, mean arterial pressure, systolic blood pressure, diastolic blood pressure or heart rate. PWV was seen to be higher in patients with transient myocardial ischemia (10.6 versus 9.5 m/s, P U 0.036). There was no significant difference in AIx between the two groups. PWV (r 2 U 0.36, P U 0.002) but not AIx correlated with pulse pressure. Conclusions PWV is higher in hypertensive individuals (age > 60 years) with transient myocardial ischemia, suggesting that PWV is an indicator of increased cardiovascular risk. Although AIx is known to be associated with several cardiovascular diseases, it was not seen to be associated with silent myocardial ischemia. Our results suggest that the clinical significance of parameters of arterial stiffness and arterial wave reflection change with age, with a higher clinical importance of PWV indicated in patients over the age of 60. J Hypertens 24: Q 2006 Lippincott Williams & Wilkins. Journal of Hypertension 2006, 24: Keywords: arterial hypertension, arterial stiffness, augmentation index, cardiovascular risk, pulse wave velocity, transient myocardial ischemia a Medizinische Poliklinik, University of Bonn and b Institute for Medical Statistics, University of Bonn, Germany Correspondence and requests for reprints to Johannes Baulmann MD, University of Bonn, Medizinische Poliklinik, Division of Hypertension and Vascular Medicine, Wilhelmstraße 35-37, D Bonn, Germany Tel: +49 (0) ; fax: +49 (0) ; johannes.baulmann@ukb.uni-bonn.de Received 11 July 2005 Revised 21 April 2006 Accepted 28 May 2006 Introduction Silent myocardial ischemia is defined as an objectively confirmable, temporary disturbance of myocardial blood supply not accompanied by corresponding pain symptoms [1]. Mortality is increased 1.9 to 5.9-fold in hypertensive patients with silent myocardial ischemia, even when there is no known coronary heart disease [2 4]. The prognostic significance of silent myocardial ischemia is also well established in survivors of myocardial infarction, patients with chronic stable angina and those with unstable angina [4 7]. Thus, patients with silent myocardial ischemia bear a very high cardiovascular risk. Arterial stiffness is a cardiovascular risk factor that has been increasingly the focus of much research. Many studies have shown that pulse wave velocity (PWV) is a marker of arterial stiffness, and that augmentation index (AIx) is a marker of arterial wave reflection [8,9]. PWV is widely accepted as a marker for aortic stiffness, and is therefore representative of the stiffness of the arterial tree wall [10,11]. Increased PWV has been shown to be a cardiovascular risk factor predicting mortality in the elderly [12], in patients with end-stage renal failure [13] and in patients with type 2 diabetes and impaired glucose tolerance [14]. In addition, PWV is associated with the occurrence of coronary events in hypertensive patients [15]. The central aortic pressure wave is composed of the initial wave, which is generated from left ventricular ejection, and the later arriving reflected wave [16,17]. The effect of wave reflection on the second systolic peak can be described as augmenting the initial wave and thus the AIx (augmented pressure as a percentage of pulse pressure) is a measure of the additional load that the left ventricle faces [18]. It is important to note that augmentation is influenced by the timing and the amplitude of the reflected wave, which again depends on microcirculation [16,19]. In patients with end-stage renal failure, the AIx is also an independent predictor of mortality [20] ß 2006 Lippincott Williams & Wilkins

2 2086 Journal of Hypertension 2006, Vol 24 No 10 Augmentation also correlates well with left ventricular mass in hypertensives and in normotensive young men [21]. In a recent publication, Weber et al. [22] identified AIx as an independent risk marker for premature coronary artery disease in men younger than 60 years. Nevertheless, PWV and AIx do not correlate as well as initially thought. PWV and AIx both increase with age, but it was shown in a multivariate analysis of 50 healthy men that AIx correlated independently with age, but not with PWV [23]. This was confirmed in a later publication [24]. Kelly et al. [23] concluded that AIx is more likely to be related to the intensity of the reflected wave than to its velocity. Several reviews discuss these issues further [25 27]. However, evidence-based data indicating to what extent PWV and AIx represent prognostic significance, are rare. Recently we found that pulse pressure (PP) > 60 mmhg is a predictor of silent myocardial ischemia [28], and this was confirmed in a later study of 1240 patients [29]. High PP, among other factors, might be an important consequence of increased arterial stiffness. The aim of this study was to show whether arterial stiffness is changed in patients with transient myocardial ischemia, accompanied by an increase of cardiovascular risk. Additionally, we investigated whether arterial stiffness or wave reflection is the best indicator for transient myocardial ischemia. Methods Patients In the cardiological outpatient clinic of the University of Bonn, ambulatory 24-h blood pressure measurement (ABPM) devices with ST-triggering are used for patients with arterial hypertension within the framework of clinical examinations. Basically these patients were similar compared to those in the previous study of Uen et al. [28] but patients were matched for age and mean arterial pressure. Hypertensive patients were recruited consecutively with the following inclusion and exclusion criteria. The protocol was approved by the medical ethics committee of Nordrhein/NRW, Germany. Inclusion criteria All hypertensive patients were included in the study, regardless of whether they were on antihypertensive medication at the time of examination. Included patients were aged between 50 and 80 years. Exclusion criteria Patients with conditions that may have interfered with the ST analysis, such as those with valvular defects, pericarditis, cardiomyopathies, intraventricular conduction abnormalities in their resting electrocardiogram (ECG) recordings, serum electrolytes disturbances, pre-excitation syndromes, atrial fibrillation, frequent ventricular extrasystoles, pacemaker ECG, digitalis medication or heart failure [New York Heart Association (NYHA) III IV], were excluded from the study. ST-triggered 24-h ambulatory blood pressure monitoring ST-triggered ABPM examinations were performed in all patients while continuing anti-anginal and antihypertensive medication. The device used in the ST-triggered ABPM was the CardioTens-01 (Meditech, Budapest, Hungary). This device is capable of continuous ST analysis, storage of ECG registrations and ambulatory blood pressure (BP) monitoring. The ECG unit of the device performed routine ECG registration via two independent channels, producing a strip with two leads (CM5 and CC5) of 30 s duration every 5 min. The BP unit of the device measured BP oscillometrically every 15 min in the period between 1000 and 2200 h, every 30 min between 2200 and 0600 h, and every 10 min between 0600 and 1000 h. The BP monitoring unit was validated in accordance with the British Hypertension Society protocol [30]. In the case of one of the following events, a 60 s ECG strip was recorded and an additional BP measurement was made: (1) ST event according to the rule (horizontal or descending ST depression by 1 mm, 1 min duration, 1 min interval since previous episode); (2) cardiac rhythm changes by 30 beats/min or a heart rate outside the range of beats/min; (3) asystole 2.5 s; (4) if the patient event button was pressed. The patients recorded a standardized patient protocol throughout the monitoring, covering physical activities, symptoms experienced and the time at which antihypertensive medication was taken. Both the BP and the ECG recordings were analyzed using the Medibase software program Version 1.34 (Meditech) with visual display control. Individual settings included the isoelectric reference point (PQ segment), the J point and the L point [60 or 80 ms after the J point, depending on heart rate (HR)]. An individual reference segment at a 3-mm interval was established to compensate for the effect of any position changes and to eliminate a constant ST depression from the overall evaluation. The population was subdivided into two groups: one with and one without episodes of ST-segment depression. ECG A resting echocardiogram with 12 standard leads was recorded for all patients while they were lying at rest. Registration was done with the device Hellige

3 Arterial stiffness and myocardial ischemia Baulmann et al (Marquette Electronic Inc., Freiburg, Germany). The parameters evaluated were the standard ECG times, cardiac dysrhythmias and the Sokolow index. Pulse wave analysis and velocity All measurements were performed following the recommendations for user procedures of clinical applications of arterial stiffness, task force III [31], using the Sphygmo- Cor device (AtCor Medical, Sydney, Australia). Using applanation tonometry, the radial artery pulse contour was assessed and recorded simultaneously. The waveforms were calibrated against oscillometrically measured brachial pressure (BPTRUE). The measure of arterial wave reflection (AIx) [32] was calculated by the system software. To determine aortic PWV, pressure waveforms were recorded sequentially at the carotid and femoral artery. With a simultaneous ECG recording of the R wave as a reference frame, the system software calculated the pulse wave transit time [33]. Statistics The evaluation of ECG, ABPM, PWV and AIx examinations was performed in a blind fashion by an investigator unfamiliar with the patients data. Differences between two groups were analyzed using the two-sample t-test or the x 2 -test. P < 0.05 was considered to be significant. Statistical analyses were performed with SPSS 12.0 for Windows (SPSS Inc., Chicago, Illinois, USA). To investigate whether the differences in arterial stiffness were dependent on age, gender, body height and mean arterial pressure, we adjusted PWV and AIx for those characteristics. Results Episodes of ST depression were seen in 30 of 74 patients. According to a standardized patient protocol specifying palpitations and symptoms of ischemia (e.g. angina or dyspnea) all ST events were clinically silent. The patients were subdivided into two groups: those with and those without episodes of ST-segment depression. There were no significant differences between the groups in the following: sex, body mass index, body height, weight, age, smoking status, creatinine, dyslipoproteinemia, cholesterol, history of myocardial infarction, stroke, angina pectoris, coronary heart disease and peripheral occlusive disease (Table 1). With regard to medication, only calcium-channel blockers were administered significantly more frequently in the group with silent myocardial ischemia (56 versus 32%) (Table 1). The office measured hemodynamic characteristics (Table 2) of mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and pulse pressure (PP) were not significantly different, and although there was a trend towards higher PP in patients with ST events, this difference also failed to reach a significant level. PWV was significantly higher in patients with transient myocardial ischemia ( versus m/s, P ¼ 0.036) (Fig. 1) and remained significant when Table 1 Clinical characteristics of the studied population With silent myocardial ischemia (n ¼ 30) Without silent myocardial ischemia (n ¼ 44) P value Age (years) 66 (6.9) a 65 (9.0) a 0.59 Male 18 (60%) 25 (57%) 0.79 BMI (kg/m 2 ) 27.6 (4.1) a 26.3 (3.5) a 0.18 Height (m) 1.70 (0.1) a 1.70 (0.1) a 0.80 Weight (kg) 79.7 (16) a 76.6 (14.3) a 0.41 Smokers 2 (7%) 9 (20%) 0.08 Diabetes mellitus 5 (17%) 5 (11%) 0.53 Creatinine 0.9 (0.2) a 1.0 (0.2) a 0.67 Dyslipoproteinemia 19 (63%) 26 (59%) 0.72 Cholesterol (mmol/l) 5.6 (1.2) a 5.6 (1.2) a 0.99 Myocardial infarction 7 (23%) 9 (20%) 0.77 Stroke 2 (7%) 4 (9%) 0.70 Revascularization 9 (30%) 11 (25%) 0.58 Known coronary heart disease 10 (33%) 11 (28%) 0.44 Peripheral arterial occlusive disease 4 (13%) 7 (16%) 0.76 Medication b-blockers 16 (53%) 27 (61%) 0.50 Diuretics 13 (43%) 21 (48%) 0.71 Calcium-channel antagonists 17 (56%) 14 (32%) 0.04 ACE inhibitors 15 (50%) 14 (32%) 0.13 AT 1 antagonist 4 (13%) 10 (23%) 0.30 Nitrates 9 (30%) 10 (23%) 0.50 Anti-aggregation 21 (70%) 24 (55%) 0.18 Statins 16 (53%) 18 (41%) 0.30 No medication 1 (3%) 2 (5%) 0.79 a Mean SD. BMI, body mass index; ACE, angiotensin-converting enzyme; AT 1, angiotension II type 1 receptor.

4 2088 Journal of Hypertension 2006, Vol 24 No 10 Table 2 Hemodynamic characteristics of the studied population With silent myocardial ischemia Without silent myocardial ischemia) P value Office MAP (mmhg) (12.5) (16.8) 0.61 SBP (mmhg) (24.3) (23.7) 0.77 DBP (mmhg) 80.0 (8.0) 82.4 (12.0) 0.31 Heart rate 64.8 (10.9) 62.6 (9.5) 0.37 Pulse pressure (mmhg) 64.9 (21.1) 60.8 (17.9) h ABPM MAP (mmhg) 91.6 (8.6) 93.6 (12.4) 0.42 SBP (mmhg) (12.5) (16.0) 0.81 DBP (mmhg) 72.3 (8.2) 73.8 (12) 0.54 Heart rate 71.0 (10.4) 69.5 (8.9) 0.52 Pulse pressure (mmhg) 60.1 (11.6) 57.4 (9.7) 0.30 The values are mean average ( SD). MAP, mean arterial pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure monitoring. adjusted for age, gender, body height and mean arterial pressure (P ¼ 0.042). AIx was not significantly different. PWV but not AIx was significantly correlated with PP (r 2 ¼ 0.36 PWV versus PP, P ¼ 0.002). Discussion The main finding of the present observational study is that aortic pulse wave velocity is significantly higher in patients with the cardiovascular risk factor of silent myocardial ischemia (10.6 versus 9.5 m/s). No other parameters of pulse wave analysis reached statistical significance. Clinical and hemodynamic parameters were also not significantly different. The importance of 24-h Holter ECG monitoring in detecting silent myocardial ischemia and the criteria for detection are well known [34]. Factors that have been shown potentially to lead to false-positive ST events [35] were excluded from our investigation. Episodes of ST depression were detected in 30 (40.5%) of 74 of our patients. According to the literature, the frequency of ST events in hypertensive patients is 15 72% [36 38]. Long-term observations have revealed that patients with silent myocardial ischemia have a much more negative prognosis than those without ST-depression episodes [39]. The functional disturbance of silent myocardial ischemia is often associated with regional contractile disturbances [40]. Only half of the patients suffering from cardiac events, including death, develop angina pectoris prior to death [39]. In a previous study including 1240 patients, pulse pressure was significantly higher in patients where ST events were recorded [29]. If pulse pressure is influenced by arterial stiffness, then the identification of more valid parameters of arterial stiffness would be useful in early detection of patients at an increased risk [19]. Our main finding is that in those hypertensive patients with a very poor prognosis (silent myocardial ischemia), PWV is increased, but other parameters of pulse wave analysis are not. This finding suggests that PWV is an significant indicator of increased cardiovascular risk. PWV remains significantly higher after adjustment for age, body height, gender and 24-h mean arterial pressure (P ¼ 0.042). The increased PWV in hypertensive patients with silent myocardial ischemia is in line with other studies where it was found that an increased PWV is an indication of high cardiovascular risk [41 43]. Thus, a high correlation between PWV and mortality was found in patients with end-stage renal failure [44]. Even when blood pressure was decreased to the same extent, PWV independently predicted mortality [44]. In another study, hypertensives with high Framingham Risk Scores showed a significant increase of primary coronary events and cardiovascular complications, correlating with increased PWV [15]. PWV was the strongest predictor of cardiovascular mortality in every age group. In 2002 Kingwell et al. [45] showed that the ischemic threshold in patients with coronary artery disease (mean age of 62 years) was predicted by stiffer large arteries (carotid femoral PWV, r ¼ 0.26). This is in line with our findings. The fact that PWV bears prognostic importance even in the early stages of cardiovascular disease still needs to be proven; however, our study supports this hypothesis. Fig. 1 Augmentation index (%) PWV (m/s) *P = Pulse wave characteristics of the studied population: shaded bars, with silent myocardial ischemia; white bars, without silent myocardial ischemia. PWV, aortic pulse wave velocity.

5 Arterial stiffness and myocardial ischemia Baulmann et al AIx is a marker of arterial wave reflection [46]; it represents the increased pressure on the left ventricle, mainly influenced by cardiac action, arterial stiffness and the distance of wave reflection points from the heart [46]. These reflection points are largely sites where substantial change in impedance is observed [17]. In hemodialysis patients, AIx is associated with the development of left ventricular hypertrophy [21]. Additionally, other studies point to the correlation between AIx and cardiovascular risk [20,47]. Weber et al. [22] indicated that a higher AIx is associated with an increased risk of coronary artery disease. However, in our study, AIx was not significantly related to the presence of silent myocardial ischemia. This could be explained by the fact that the association between coronary artery disease and AIx was only seen in age groups under 60. The mean age in our study population was 66. This is in line with another recently published study, in which AIx did not significantly correlate with proximal coronary artery plaque volume [48]. Conversely, carotid femoral PWV did show a correlation with proximal coronary artery plaque volume (P ¼ 0.07); however, the study population was relatively small (n ¼ 35) with a mean age of 61 years. Coronary plaque load is a structural feature that relates to silent myocardial ischemia, whereas the presence of myocardial ischemia is a functional parameter associated with high cardiovascular risk. In the group of patients from our cardiologic outpatient clinic who have silent myocardial ischemia, AIx was not altered. Thus, whereas AIx was not able to indicate high cardiovascular risk in patients with transient myocardial ischemia, PWV may. 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