Brachial artery hyperaemic blood flow velocity and left ventricular geometry

(2011), 1 5 & 2011 Macmillan Publishers Limited All rights reserved 0950-9240/11 www.nature.com/jhh ORIGINAL ARTICLE Brachial artery hyperaemic blood flow velocity and left ventricular geometry SJ Järhult, J Sundström and L Lind Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden Cardiovascular risk factors and carotid atherosclerosis relate to blood flow velocity in the brachial artery during induced hyperaemia. This relation proved to be particularly strong when using the hyperaemic systolic to diastolic blood flow velocity (SDFV) ratio. In this study, we further investigated this ratio in relation to the left ventricular (LV) geometry in a cross-sectional analysis. In the Prospective Investigation of the Vasculature in Uppsala Seniors study, 1016 seventy-year-olds participated. Blood flow velocity during hyperaemia of the brachial artery by Doppler was analysed. Echocardiography was performed, allowing analysis of LV geometry, categorised into four different groups: normal, concentric remodelling, concentric and eccentric hypertrophy. The SDFV ratio increased in subjects with concentric LV-remodelling (P ¼ 0.006) or LV-hypertrophy (P ¼ 0.001), but not in those with eccentric hypertrophy (P ¼ 0.12) when compared with the group with normal LV geometry. These associations remained significant after adjustment for gender, blood pressure, blood glucose, body mass index and antihypertensive treatment. The SDFV ratio in the brachial artery was related to concentric geometry of the LV in an elderly population sample, suggesting this new hemodynamic variable as a marker of increased afterload. Future studies have to determine if the SDFV ratio is a powerful predictor of future CV events, in addition to LV geometry. advance online publication, 17 March 2011; doi:10.1038/jhh.2011.21 Keywords: brachial; blood; velocity; left ventricular; remodelling Introduction Left ventricular hypertrophy (LVH) is a well-known predictor of cardiovascular events and sudden death. 1,2 Although often developing gradually in response to increased afterload and other trophic stimuli, most patients with LVH are not diagnosed until clinical signs of heart failure are present. Impaired production or biological activity of nitric oxide in the aging endothelium due to inflammation, stress and hyperglycaemia are some of the factors proposed to cause endothelial dysfunction, held as an important causal factor for LVH. In studies evaluating endothelial function, hyperaemic blood flow velocities in systole and diastole are often treated as separate variables. As shown in a recent study using data from 1016 seventy-year-olds in the Prospective Investigation of the Vasculature in Uppsala Seniors study, the hyperaemic systolic and diastolic blood flow velocities in the brachial artery were related to coronary risk in divergent ways. An even closer association to coronary risk was found for the hyperaemic systolic to diastolic Correspondence: Dr SJ Järhult, Department of Medical Sciences, Uppsala University Hospital, Akademiska Sjukhuset Ing 40 Plan 5, Uppsala SE-751 85, Sweden. E-mail: susann.jarhult@medsci.uu.se Received 18 October 2010; revised 13 January 2011; accepted 6 February 2011 blood flow velocity (SDFV) ratio. 3 The SDFV ratio, mirroring both vascular stiffness and peripheral resistance, might therefore contain additional cardiovascular information of possible use. In the present study, we evaluated if the SDFV ratio, recently also shown to be related to atherosclerosis in the carotid arteries, 4 was related to altered LV geometry. The hypothesis tested in this cross-sectional study was that the SDFV ratio, as a possible marker of left ventricular (LV) afterload, was related to concentric remodelling of the LV. Materials and methods Participants This study used data from 1016 seniors included in the Prospective Study of the Vasculature in Uppsala Seniors. All subjects, 50.2% of whom women, were recruited by the register of community living and were invited within 2 months of their 70th birthday. The participation rate was 50.1%. Participants completed a questionnaire regarding their medical history, regular medication and smoking habits. Approximately 10% of the cohort reported a history of coronary heart disease, 4% reported stroke and 9% diabetes mellitus. Almost half the cohort reported use of cardiovascular medication (45%), with antihypertensive medication being the most prevalent (32%). In all, 15% reported use of statins,

2 whereas use of insulin and oral antiglycemic drugs were reported by 2 and 6%, respectively (Table 1, for details, see Lind et al. 5 ). The study was approved by the Uppsala University Ethics Committee. Methods The participants were examined in the morning, asked not to smoke or take any medication and to fast from midnight. Blood pressure was measured by a calibrated mercury sphygmomanometer to nearest mmhg after at least 30 min of rest in the supine position. The average of three recordings was used. Brachial artery monitoring The brachial artery was assessed by external B-mode ultrasound (Acuson XP128, 10 MHz linear transducer, Acuson, Mountain View, CA, USA). Imaging was performed 2 3 cm above the elbow for measures of the brachial artery diameter, according to the recommendations of the International Brachial Artery Task Force. 6 To document baseline blood flow velocity, a pulsed Doppler measurement of the brachial artery blood flow velocity was performed. Projection of the sampling volume was in the centre of the vessel. By inflating a blood pressure cuff placed distal to the elbow, the brachial artery was occluded. Application of a pressure of at least 50 mm Hg above systolic blood pressure caused ischaemia of the forearm. After 5 min, blood flow was re-established Table 1 Basic characteristics and major cardiovascular risk factors in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) sample N 1016 Females (%) 50.2 Height (cm) 169 (9.1) Weight (kg) 77 (14) BMI (kg m 2 ) 27.0 (4.3) Fasting blood glucose (mmol 1 1 ) 5.3 (1.6) Current smoking (%) 11 SBP (mm Hg) 150 (23) DBP (mm Hg) 79 (10) Heart rate (beats min 1 ) 62 (8.7) IVRT (ms) 121 (21) E/A ratio 0.92 (0.26) EF (%) 0.67 (0.79) LVMI (g per m 2.7 ) 43 (13.2) Systolic mean velocity during hyperaemia (m s 1 ) 1.17 (0.25) Diastolic mean velocity during hyperaemia (m s 1 ) 0.56 (0.15) SDFV ratio 2.16 (0.45) Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; E/A ratio, ratio of peak velocity of early rapid filling wave (E wave) and peak velocity of atrial filling wave (A wave); EF, ejection fraction; IVRT, left ventricular isovolumetric relaxation time; LVMI, left ventricular mass index determined from left ventricular mass (LVM) determined from the Penn convention and indexed for height to the power of 2.7; SBP, systolic blood pressure; SDFV ratio, systolic to diastolic blood flow velocity ratio during hyperaemia of the brachial artery. Means are given with standard deviations (s.d.) in parenthesis. by rapidly deflating the cuff, inducing a reactive hyperaemia. Following cuff-release, blood flow velocity was measured for 15 s. The ultrasonographic measurements were recorded on videotapes for later analysis. A few seconds following cuff release, in hyperaemia, blood flow velocity during systole and diastole was determined by the average of at least three different cardiac cycles. The velocity-time integral in systole and diastole was thereafter measured. Mean blood flow velocity was further calculated by dividing the velocity-time integral by the time of the respective phase of the cardiac cycle. The SDFV ratio was calculated as the ratio of the systolic to diastolic mean blood flow velocities during hyperaemia. 7 Echocardiography Imaging was performed using 2.5 MHz comprehensive two-dimensional cardiac ultrasound unit equipment, the same as for the brachial artery recordings. LV dimensions were measured with M-mode online from the parasternal projections, using a leading edge convention. Measurements included interventricular septal thickness, posterior wall thickness, LV diameter in end-systole and enddiastole. LV relative wall thickness (RWT) was calculated as (interventricular septal thickness þ posterior wall thickness)/lv diameter in enddiastole. LV mass was determined from the Penn convention and indexed for height to the power of 2.7 to obtain LV mass index (LVMI). The participants were further separated into four different categories of LV geometry, according to Ganau et al. 8,9 Normal LV geometry (n ¼ 391) was considered to be present if LVMI was o51 g per m 2.7 and RWT o0.45. If LVMI was normal, but RWT 40.45 the LV geometry was denoted concentric remodelling (n ¼ 236). Concentric LVH was defined as LVMI above the threshold for LVH, together with RWT 40.45 (n ¼ 140). If RWT was below this cut-off for RWT and LVMI was increased, categorisation into the eccentric group of LVH (n ¼ 75) was made. The ejection fraction was calculated from the M-mode recordings according to the Teichholz formula. The LV diastolic filling pattern of the mitral inflow was obtained by placing the transducer in apical position with the pulsed Doppler sample volume between the tips of the mitral leaflets during diastole. The peak velocity of the early rapid filling wave (E-wave) and the peak velocity of atrial filling (A-wave) were recorded and the E to A ratio (E/A) was calculated. LV isovolumetric relaxation time was measured between aortic valve closure and the start of mitral flow, using the Doppler signal from the area between mitral flow and the LV outflow tract.

Presence of a restrictive filling pattern was evaluated in subjects with an impaired LV systolic function. This pattern was considered to be present if E/A ratio was 41.5 and isovolumetric relaxation time was o96 ms. Statistical analysis The relations between brachial artery blood flow variables and echocardiographic variables were evaluated by multiple regression analyses, adjusting for gender by univariate analysis and for traditional risk factors previously associated with LVH (SBP, DBP, antihypertensive treatment, fasting blood glucose and body mass index). The above risk factors relate to both LV remodelling and to the SDFV ratio, and we believe they are not along the causal pathway. 10 The relations between brachial artery blood flow variables and LV geometry groups were evaluated by ANCOVA, adjusting for gender by univariate analysis and for traditional risk factors previously associated with LVH (SBP, DBP, antihypertensive treatment, fasting blood glucose and body mass index). Two-tailed significance values were given with Po0.05 regarded as significant. StatView (SAS, Cary, NC, USA) was used for calculations. Results Hyperaemic blood flow velocity vs LV systolic function There were significant positive relations between the systolic (P ¼ 0.016) and the diastolic (P ¼ 0.0001) mean blood flow velocities and the ejection fraction. These correlations remained significant when adjusted for multiple CV risk factors: SBP, DBP, antihypertensive treatment, fasting blood glucose and body mass index (P ¼ 0.001 and P ¼ 0.0003, respectively). The SDFV ratio was significantly related to the ejection fraction in an inverse way, only when adjusted for multiple risk factors (P ¼ 0.0027), see Table 2 for details. Hyperaemic blood flow velocity vs LV diastolic function No significant relations were seen between the blood flow parameters and the isovolumetric relaxation time. No relations were seen between the blood flow parameters and the E/A ratio (Table 2). Relations of flow-velocity parameters to LV mass and RWT When adjusted for gender only, the SDFV ratio was related to LVMI (P ¼ 0.0002). This relation was not significant, following adjustment for multiple CV risk factors. Neither of the two compounds of the ratio was significantly related to the LVMI (Table 2). RWT followed the same pattern as LVMI, with a significant relationship with the SDFV ratio following gender adjustment, but not following adjustment for multiple CV risk factors. The R-square value for the relationship between the SDFV ratio and RWT was 0.012. Relations of flow-velocity parameters to LV geometric groups In ANOVA analysis, using the SDFV ratio as the dependant variable and LV geometric groups as a nominal independent variable with four groups, the global P-value for differences between the groups was 0.0048. When we used both the dichotomous variables LVH and high RWT, instead of the LV geometric groups as a nominal independent variable, only high RWT was significant (P ¼ 0.0088 for high RWT, P ¼ 0.10 for LVH and P ¼ 0.45 for the interaction term). In the following post-hoc analysis, the SDFV ratio was significantly increased in subjects with concentric LV remodelling, when compared with subjects with normal LV geometry following adjustment for multiple risk factors (P ¼ 0.007). This relation was also valid when adjusted only for gender (P ¼ 0.01). 3 Table 2 Blood flow velocity parameters during hyperaemia of the brachial artery in relation to parameters of cardiac ultrasound SDFV ratio Systolic V Diastolic V R.C (a) P (a) R.C (b) P (b) R.C (a) P (a) R.C (b) P (b) R.C (a) P (a) R.C (b) P (b) IVRT 0.055 0.117 0.021 0.54 0.004 0.91 0.033 0.30 0.032 0.35 0.006 0.85 E/A ratio 0.023 0.508 0.025 0.50 0.016 0.65 0.004 0.90 0.03 0.38 0.019 0.57 EF 0.066 0.066 0.117 0.0027 0.118 0.001 0.092 0.011 0.130 0.0003 0.132 0.0002 RWT 0.021 0.001 0.002 0.74 0.019 0.11 0.008 0.44.00001 0.57.00002 0.53 LVMI 0.128 0.0002 0.014 0.64 0.046 0.18 0.006 0.84 0.052 0.125 0.009 0.75 Abbreviations: Diastolic V, diastolic blood flow velocity; E/A ratio, ratio of peak velocity of early rapid filling wave (E wave) and peak velocity of atrial filling wave (A wave); EF, ejection fraction; IVRT, isovolumetric relaxation time; LVMI, left ventricular mass index determined from left ventricular mass (LVM) determined from the Penn convention and indexed for height to the power of 2.7; R.C (a), regression coefficient after adjustment for gender only; R.C (b), regression coefficient after adjustment for gender, systolic- and diastolic-blood pressure, antihypertensive treatment, body mass index and fasting blood glucose level; RWT, relative wall thickness; SDFV ratio, systolic to diastolic blood flow velocity ratio during hyperaemia of the brachial artery; Systolic V, systolic blood flow velocity. Mean values are given. P (a), P-value after adjustment for gender only; P (b), P-value after adjustment for gender, systolic and diastolic blood pressure, antihypertensive treatment, body mass index and fasting blood glucose level.

4 Table 3 Blood flow velocity parameters during hyperaemia of the brachial artery in the four different groups of LV geometry n ¼ 842 Normal LV Concentric remodelling Concentric hypertrophy Eccentric remodelling n ¼ 391 n ¼ 236 n ¼ 140 n ¼ 75 Mean s.d. Mean s.d. P (a) P (b) Mean s.d. P (a) P (b) Mean s.d. P (a) P (b) SV 1.16 0.25 1.18 0.24 0.43 0.32 1.19 0.26 0.21 0.20 1.20 0.27 0.20 0.23 DV 0.57 0.16 0.56 0.15 0.25 0.30 0.55 0.15 0.20 0.20 0.56 0.15 0.80 0.69 SDFV ratio 2.10 0.44 2.20 0.46 0.01 0.007 2.23 0.46 0.0027 0.001 2.18 0.42 0.17 0.12 Abbreviations: DV, diastolic blood flow velocity; Normal LV group (LVMI o51 g per m 2.7 and RWT o0.45) was used as a reference; SDFV ratio, systolic to diastolic blood flow velocity ratio; SV, systolic blood flow velocity. Mean values are given. s.d., standard deviation; P (a), adjustment made for gender; P (b), adjustment made for gender, systolic and diastolic blood pressure, antihypertensive treatment, body mass index and fasting blood glucose. However, the systolic and diastolic mean blood velocities individually were not significantly altered in subjects with concentric LV remodelling, when compared with the normal LV group (Table 3). Subjects with concentric LV hypertrophy had an elevated SDFV ratio following adjustment for multiple risk factors (P ¼ 0.001), in comparison with the group with normal LV geometry. The relation persisted also when adjusted only for gender (P ¼ 0.0027). No significant differences between the concentric LV hypertrophy and the normal LV geometry groups were found when assessing the mean blood velocities of systole or diastole separately. No significant differences in SDFV ratio, the systolic or the diastolic blood flow velocities separately, were seen in the group with eccentric LV remodelling, when compared with the subjects with normal LV geometry. Discussion In the present cross-sectional study, the SDFV ratio in the brachial artery was related to concentric remodelling of the left ventricle of the heart, suggesting this new hemodynamic variable as a marker of increased afterload. In a recently published article, 7 the SDFV ratio was shown to contain information on coronary risk, exceeding that of the systolic or diastolic blood flow velocity parameters considered separately. Furthermore, the SDFV ratio in the brachial artery carried information on the atherosclerotic status of the carotid artery. 4 Together, these observations suggest that the SDFV ratio may be a biologically relevant vascular characteristic. It is well known that the arterial tree stiffens with age. Increased systolic blood pressure indicates a stiffening vascular tree with mainly decreased elasticity of the large, central arteries. Their ability to adjust their diameter to permit an even blood flow is impaired. Gradually, the blood flow velocity through these vessels, as well as the pulse wave velocity, increases. This is reflected by an increased blood flow velocity in systole during hyperaemia in the present study. Distribution of the blood to adequately supply the tissues is largely dependant upon the resistance arterioles and the capillary network. In healthy subjects, the peripheral arterioles and the precapillary sphincters alter the lumen of the vessel to allow blood flow in response to the need of the tissues. Because of their large common cross-sectional area, the peripheral resistance has a high impact on the blood flow. This is reflected by the blood flow velocity in diastole during hyperaemia in the present study. Thus, the SDFV ratio combines information regarding large artery stiffness, with information on peripheral resistance. These two properties are the most important features determining the afterload of the LV. If an increased afterload is sustained over time, it will cause myocytes to increase in size to maintain a proper ejection fraction and stroke volume. An increased afterload will also induce collagen deposition in the LV wall. The combination of these adaptations of the LV wall will lead to thickening of the LV wall, in this study represented as concentric remodelling of the LV. As a result of the Frank Starling effect, the LV lumen and contractile forces increase to enhance cardiac output. 11 When this cardiac reserve is exceeded, by volume overload or by the remodelling process following myocardial infarction, eccentric LVH is mainly induced. LVH is a well-known predictor of cardiovascular events and sudden death. 1,12 In a recently published article, 13 a 10% increase in LVMI was associated with a significant increase in cardiovascular risk (arrhythmias, stroke, congestive heart failure, coronary heart disease) and all-cause mortality. 14 An increased SDFV ratio might thus signal an increased risk of concentric remodelling of the LV, eventually leading to overt concentric LVH. It should be pointed out, however, that the SDFV ratio was not elevated in subjects with eccentric LVH. The fact that the SDFV ratio was related to concentric remodelling of the LV, but not to eccentric LVH, further supports its potential as a valuable measure of afterload. Importantly, the relationship between the SDFV ratio and concentric remodelling of the LV was independent of other markers of arterial

stiffness and peripheral resistance, such as SBP and DBP. In the past, the pulsatility index ((Qmax-Qmin)/ Qmean) or the flow pulse amplitude (Qmax-Qmin) measured in a different artery have been used to assess arterial stiffness. Limitations At this point, our findings are only valid for the Prospective Investigation of the Vasculature in Uppsala Seniors cohort, that is, a Caucasian population, 70 years of age, of which 50.2% women, in the region of Uppsala in Sweden. Studies of the SDFV ratio in other populations are needed to further corroborate the value of this new hemodynamic variable. Conclusion The hyperaemic SDFV ratio in the brachial artery was related to concentric remodelling of the left ventricle in an elderly population sample, suggesting this new hemodynamic variable as a valuable marker of increased afterload related to cardiovascular risk. As this is only a cross-sectional evaluation of the usefulness of the SDFV ratio, prospective studies are needed to investigate if this new index of afterload of the LV is a powerful risk factor for future CV events, additive to the prognostic information given by determination of LV geometry. What is known about this topic K Blood flow velocity through the brachial artery during reactive hyperaemia is related to cardiovascular risk factors assessed as the Framingham Risk score. K The systolic and diastolic blood flow velocities of reactive hyperaemia are related to cardiovascular risk factors in divergent ways. K The systolic to diastolic blood flow velocity ratio (SDFV ratio) during hyperaemia of the brachial artery is more closely correlated to cardiovascular risk factors than are the separate components. What this study adds K The systolic to diastolic blood flow velocity ratio (SDFV ratio) is correlated to echocardiographically determined left ventricular (LV) geometry. K Concentric remodelling of the LV, a known marker of increased cardiovascular risk, is more closely related to the SDFV ratio than to the systolic or the diastolic components separately. K The hyperemic systolic to diastolic blood flow velocity (SDFV) ratio was related to concentric remodelling of the LV in an elderly population sample, suggesting this new hemodynamic variable as a valuable marker of increased afterload. Conflict of interest The authors declare no conflict of interest. References 1 Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990; 322(22): 1561 1566. 2 Haider AW, Larson MG, Benjamin EJ, Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk for sudden death. J Am Coll Cardiol 1998; 32(5): 1454 1459. 3 Gnasso A, Carallo C, Irace C, De Franceschi MS, Mattioli PL, Motti C et al. 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