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Cardiac hypertrophy in hypertension: relation to 24-h blood pressure profile and arterial stiffness
International Journal of Cardiology 97 (2004) 29 – 33 www.elsevier.com/locate/ijcard
Cardiac hypertrophy in hypertension: relation to 24-h blood pressure profile and arterial stiffness John P. Lekakis *, Nicos A. Zakopoulos, Athanassios D. Protogerou, Vassilios Th. Kotsis, Theodore G. Papaioannou, Kimon S. Stamatelopoulos, Marios D. Tsitsiricos, Vassiliki Ch. Pitiriga, Christos M. Papamichael, Savvas Th. Toumanides, Myron E. Mavrikakis Department of Clinical Therapeutics, Alexandra University Hospital, 12 Iridanou Street, 11528 Athens, Greece Received 3 January 2003; received in revised form 16 June 2003; accepted 21 June 2003
Abstract Background: In subjects with essential hypertension peripheral blood pressure profile contributes to the pathogenesis of left ventricular hypertrophy. It is not known if central arterial pressure is superior to peripheral blood pressure profile for predicting left ventricular hypertrophy. In the present study 24-h blood pressure profile and central hemodynamics were examined to evaluate mechanical loading factors as determinants of cardiac hypertrophy in mild to moderate untreated essential hypertension. Methods: Forty-eight untreated subjects with mild to moderate essential hypertension were examined by echocardiography for evaluation of left ventricular mass, 24-h ambulatory blood pressure monitoring (ABPM), and applanation tonometry of the radial artery with pulse wave analysis for evaluation of central hemodynamics. Results: Left ventricular mass showed a statistically significant correlation with age, clinic systolic blood pressure, mean heart rate and heart rate variability during 24-h ABPM, augmentation pressure and index and central systolic blood pressure. In a multiple regression analysis including clinic systolic blood pressure, central systolic pressure, mean systolic pressure and pulse pressure during ambulatory monitoring as well as age, independent predictors of left ventricular mass were only age ( P = 0.006) and central systolic blood pressure ( P = 0.04). In conclusion, pulse wave analysis is a valuable method in predicting cardiac hypertrophy in untreated mild to moderate essential hypertension. Central systolic blood pressure should be taken into account for planning therapeutic strategies for prevention of left ventricular hypertrophy in hypertensive patients. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Pulse wave analysis; Left ventricular hypertrophy; Hypertension; Blood pressure
1. Introduction Left ventricular hypertrophy is commonly found in patients with arterial hypertension and significantly magnifies the risk of cardiovascular complications in these patients [1,2]. Although biochemical and genetic factors could be considered as risk factors for the development of left ventricular hypertrophy [3,4], the hemodynamic factors, particularly peripheral systolic blood pressure, are the best characterized stimuli for cardiac hypertrophy [2]. A hemo-
* Corresponding author. Tel.: +30-210-729-9200; fax: +30-210-7299201. E-mail address: [email protected] (J.P. Lekakis). 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.06.011
dynamic parameter that might contribute to the observed vascular hypertrophy is the increased arterial stiffness observed in hypertension [5]. Arterial stiffness has deleterious effects on left ventricular afterload, increases left ventricular mass [6 – 8], decreases coronary perfusion and leads to increased cardiovascular morbidity and mortality in different populations [9 –11]. Ambulatory blood pressure monitoring (ABPM) has been proved to be superior to clinic blood pressure measurement for cardiovascular risk stratification; parameters obtained from the 24-h ABPM have been associated with left ventricular mass in hypertensive patients [12 – 14] and the severity of coronary atherosclerosis in normotensive subjects [10]. Tonometry with pulse wave analysis appears to be a simple and reproducible non-invasive technique for evalu-
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J.P. Lekakis et al. / International Journal of Cardiology 97 (2004) 29–33
ating arterial stiffness [15 – 18], which has been validated by direct recording of the central pressure waveforms. A decrease in arterial distensibility leads to an increase in pulse wave velocity, resulting in early return of reflected waves from peripheral sites and augmentation of the central systolic pressure, which may have detrimental effects in structure and function of the left ventricle [19,20]. In the present study central arterial pressure assessed by applanation tonometry and pulse wave analysis, as well as 24-h blood pressure profile were examined in order to evaluate mechanical loading factors as determinants of increased left ventricular mass in untreated patients with mild to moderate essential hypertension.
2. Methods 2.1. Population Forty-eight consecutive untreated subjects (15 women, 33 men, mean age 55.8 F 12.3 years), referred to the outpatient hypertension clinic for evaluation of arterial hypertension were included in the study. Subjects were defined as having arterial hypertension if they had blood pressure readings above 140/90 mmHg in the hypertension clinic [12,13] and average daytime ambulatory blood pressure above 135/85 mmHg. Secondary hypertension was excluded by physical examination, normal renal function, serum electrolytes and catecholamine excretion. Three patients had diabetes mellitus, 20 were smokers and 13 had hypercholesterolemia. This study has approved by the local scientific committee and all participants gave informed consent before entering the study.
2.2. Echocardiographic measurements Echocardiograms were obtained using a Sigma-1C echocardiograph (Kontron Instruments Inc., Everett, MA) and a 3.5-MHz transducer. Two-dimensional guided M-mode echocardiograms at the level of chordae tendineae were recorded and each echocardiogram was read by two expert echocardiographers; four to six cycles of septal and posterior wall thickness as well as left ventricular internal diastolic and systolic dimensions were measured by each reader, using the guidelines of the American Society of Echocardiography convention of measurement [21]. The average of mean measurements given by the two readers for each echocardiogram was used for calculating the left ventricular mass. The following formula was used for the estimation of left ventricular mass [22]: LV mass = 0.80 (1.04 (IVSd + LVDd + PWTd)3 (LVDd)3) + 0.6 g; LV mass index = LV mass/ BSA, where IVSd is interventicular septal thickness at enddiastole, LVDd is LV internal diameter at end-diastole, PWTd is posterior wall thickness at end-diastole and BSA is body surface area. LV mass >110 g/m2 in women and >134 g/m2 in men was considered as left ventricular hypertrophy [23]. 2.3. Ambulatory blood pressure monitoring All participants underwent 24 h-ABPM on a usual working day using the Spacelabs 90209 ambulatory monitor (Spacelabs Inc., Redmond, WA). Readings were obtained automatically at 15 min intervals throughout the 24-h study period. All subjects included in the study had at least three valid readings per hour; the resulting 80 –96 pairs of systolic and diastolic blood pressure readings per recording, together with the corresponding time of measurement were used to calculate blood pressure derivative. The accuracy of the
Fig. 1. Analysis of aortic pressure waveform. AI is the difference between the second and the first systolic peaks (AP) and is expressed as percentage of the pulse pressure. RTI is the RT between the foot of the pressure wave and the peak provided by the reflected wave and is expressed as percentage of the cardiac period. RTI is an estimate of the aortic pulse wave velocity.
J.P. Lekakis et al. / International Journal of Cardiology 97 (2004) 29–33 Table 1 Characteristics of study population (n = 48)
31
2.5. Statistics
Variable
Mean F S.D.
Age (years) Mean SBP24 (mmHg) Mean DBP24 (mmHg) Mean MBP24 (mmHg) Mean HR24 (bpm) PP24 (mmHg) PW (mm) IVS (mm) EDD (mm) LV mass index (g/m2) Clinic SP (mmHg) Clinic DP (mmHg) AP (mmHg) AI (%) C-SP (mmHg) C-DP (mmHg) RTI (%)
55.8 F 12.3 137.8 F 9.6 83.1 F 9.2 101.7 F 7.2 74.3 F 10.0 54.7 F 11 10.0 F 1.6 10.5 F 1.6 47.1 F 5.5 111.6 F 24.9 148.2 F 23.2 86.1 F 13.8 11.5 F 9.5 22.2 F 10.2 133.9 F 21.5 87.3 F 13.9 13.0 F 2.1
AP, augmentation pressure; AI, augmentation index; C-DP, central diastolic blood pressure; C-SP, central systolic blood pressure; DBP24, diastolic blood pressure during 24-h; EDD, end-diastolic diameter; HR24, heart rate during 24-h; IVS, interventricular septum; LV mass index, left ventricular mass index; MBP24, mean blood pressure during 24-h; Clinic DP, clinic diastolic blood pressure; PP24, pulse pressure during 24-h; Clinic SP, clinic systolic blood pressure; PW, posterior wall; RTI, reflection time index; SBP24, systolic blood pressure during 24-h.
automatic readings was checked against readings taken using a standard mercury sphygmomanometer twice for each ABPM as previously described [10]. 2.4. Pulse wave analysis Each subject was studied the same day with ABPM, in the morning hours and after a 10 min rest period. After blood pressure measurement, an arterial pressure waveform was recorded by applanating the radial artery with a hand held tonometer. Pressure waveforms obtained by this method have been validated by comparing them with waveforms obtained by high fidelity transducer within the artery. Central waveforms were derived from the radial artery waveforms by using a transfer function as previously described [15 – 17]. The following parameters were measured using the PWV Medical blood pressure analysis system (Sydney, Australia): central systolic, diastolic and mean blood pressure, augmentation pressure, augmentation index (AI) and central pulse pressure. The aortic pulse wave velocity was estimated indirectly by calculating the time between the foot of the pressure wave and the inflection point (first peak, Fig. 1), which provides a measure of the timing of the reflected wave [24]. Increased heart rate may influence the arrival time of the reflected wave at central aorta since the cardiac cycle is shortened and, therefore, reflected waves arrive later in systole. Therefore, an adjustment of the timing of reflected waves for cardiac period has been used (reflection time index (RTI)); the lower the RTI, the higher the pulse wave velocity and the higher the arterial stiffness (Fig. 1) [25,26].
Results are expressed as mean F S.D. Unpaired t-test was used to compare variables between patients with and without left-ventricular hypertrophy. v2-test was used to compare proportions between the various groups. Linear regression analysis was performed to describe the correlations between LV mass at one side and the variables obtained from 24-h ABPM and pulse wave analysis at the other. Multiple linear regression analysis was performed to characterize parameters independently associated with LV mass. A P-value < 0.05 was considered statistically significant.
3. Results Characteristics of the hypertensive subjects are shown in Table 1. Fifteen patients had echocardiographic evidence of left ventricular hypertrophy; LV mass index, men >134 g/m2, women >110 g/m2 [23]. Subjects with hypertrophy were older, had higher clinic systolic blood pressure, higher augmentation pressure and index, higher estimated pulse wave velocity (lower RTI), higher central aortic pressure, lower mean heart rate during ABPM and higher pulse pressure during ABPM (Table 2). Twenty three patients were characterized as dippers based on the decrease of the systolic blood pressure by at least 10% during the nigh; LV mass index and also central systolic blood pressure did not differ significantly between dippers and non-dippers (107 F 21 vs. 115 F 27 g/m2, ns and 133.9 F 18 vs. 140 F 23.5 mmHg, ns, respectively). LV mass index correlated significantly in the univariate analysis with age (r = 0.422, P = 0.003), mean heart rate
Table 2 Characteristics of hypertensive subjects with hypertrophy (+) compared to those without hypertrophy ( )
Age (years) Mean SBP24 (mmHg) SD SBP24 (mmHg) Mean DBP24 (mmHg) Mean HR24 (bpm) Mean MBP24 (mmHg) PP24 (mmHg) PW (mm) IVS (mm) EDD (mm) Clinic SP (mmHg) Clinic DP (mmHg) AP (mmHg) AI (%) C-SP (mmHg) C-DP (mmHg) RTI (%)
Hypertrophy (+) (n = 15)
Hypertrophy ( ) (n = 33)
P-value
61.7 F 10.4 140.5 F 9.8 14.7 F 3.1 81.1 F 10.4 69.2 F 10.9 101.6 F 7.1 59.4 F 11.4 10.7 F 1.9 11.3 F 1.5 50.8 F 6.1 163.0 F 28.6 87.0 F 14.3 18.4 F 12.2 27.5 F 9.2 149.3 F 24.8 88.1 F 14.7 12.0 F 2.1
53.2 F 12.3 136.6 F 9.4 15.5 F 3.3 84.5 F 8.6 76.6 F 8.7 101.7 F 7.3 52.5 F 10.6 9.6 F 1.5 10.2 F 1.4 45.4 F 4.4 141.5 F 17.0 85.6 F 13.8 8.4 F 6.0 19.7 F 9.8 126.9 F 15.8 87.0 F 13.8 13.5 F 2.0
P = 0.02 ns ns ns P = 0.01 ns P = 0.06 P = 0.03 P = 0.03 P = 0.001 P = 0.002 ns P < 0.001 P = 0.01 P < 0.001 ns P = 0.01
Abbreviations as in Table 1.
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during ABPM (r = 0.454, P = 0.001), standard deviation of the heart rate (heart rate variability) (r = 0.351, P = 0.01), clinic systolic blood pressure (r = 0.286, P = 0.04), central systolic pressure (r = 0.341, P = 0.01), augmentation pressure (r = 0.407, P = 0.004), AI (r = 0.322, P = 0.02), RTI (r = 0.305, P = 0.03) and marginally to pulse pressure during 24-h monitoring (r = 0.256, P = 0.07). In multiple regression analysis with LV mass index as a dependent variable and predictors age, clinic systolic pressure, central systolic pressure, mean systolic pressure during 24-h ABPM and pulse pressure during ABPM, age ( P = 0.006) and central systolic blood pressure ( P = 0.04) were independently related to LV mass index; the independent association of central systolic pressure and age with LV mass index did not change after including dipping effect to the possible predictors. In the larger group of males multiple regression analysis also showed that central pressure was independently related to LV mass index ( P = 0.029).
4. Discussion Parameters associated with left ventricular hypertrophy, which is often observed in hypertension are still need to be clarified. The salient finding of the present study is that in patients referred for evaluation of untreated mild to moderate essential hypertension, central systolic blood pressure assessed by pulse wave analysis is superior to clinic and ambulatory blood pressure measurements in predicting left ventricular hypertrophy. Pressure overload, humoral and genetic factors contribute to the genesis of cardiac hypertrophy in subjects with arterial hypertension [3,27]. Recent experimental data suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease [27]. Although systolic blood pressure is the bestcharacterized stimulus for left ventricular hypertrophy, relatively little of the variability observed in cardiac hypertrophy could be attributed to blood pressure level as measured clinically [2]. In our study, although clinic systolic blood pressure was related to LV mass in the univariate analysis, it did not enter the group of independent predictors of LV mass index. The 24-h blood pressure profile has been previously shown that affects the left ventricle independently of blood pressure level [12]. In the present study, the following variables obtained during 24-h ABPM proved to be related to LV mass index; heart rate, heart rate variability and marginally pulse pressure. LV mass index did not differ significantly between dippers and non-dippers, a finding not confirming previous studies which showed that a blunted reduction in nocturnal blood pressure plays a pivotal role in some expressions of target organ damage such as left ventricular hypertrophy [28]. The discrepancy could be attributed to the small number of patients in our study.
Patients with increased LV mass index had decreased heart rate during 24-h ABPM. It is an interesting finding and could be explained by the inverse relation existing between heart rate and left ventricular dilatation [12,13], since left ventricular diameter is part of the formula for the estimation of LV mass. Another explanation could be the inverse relation between heart rate and stroke volume; it has been shown that stroke volume is a predictor of LV mass and chamber size, independently of arterial pressure [29]. Pulse pressure during 24-h ABPM is a predictor of cardiac hypertrophy with marginal statistical significance in the univariate analysis; this finding has shown earlier by our group also in normotensives [10]. Pressure parameters from the ambulatory monitoring were not independent predictors of LV mass when central systolic blood pressure was taken into account. Arterial stiffening has been proposed as a factor contributing to cardiac hypertrophy in hypertensive patients [8] and in a rat model of isolated systolic hypertension [7]. Arterial stiffness assessed by the pulse wave velocity [9] or the ratio of stroke volume/pulse pressure [30] is a predictor of cardiovascular morbidity and mortality in patients with arterial hypertension. On the contrary, Chen et al. [31] in Chinese subjects demonstrated that the effects of the derived measures of arterial function were small and provided no better predictive power than blood pressure alone as determinants of LV mass; if genetic factors could explain this discrepancy is not known. Our results clearly indicate that central systolic blood pressure assessed by radial artery applanation tonometry and pulse wave analysis, is a predictor of LV mass index independently of age and blood pressure measurements during 24-h monitoring. It is the first time central blood pressure estimated by this method has been correlated with LV mass independently of clinic or ambulatory blood pressure. It is known that a decrease in arterial distensibility leads to increase in pulse wave velocity, resulting in early return of reflected waves from peripheral sites and augmentation of the central systolic pressure [15]. Recently, Iketani et al. [19] used finger photoplethysmogram and second derivative wave and reported that an increase in the peripheral reflection wave was one of the important factors causing increased LV mass in patients with hypertension. It is interesting that in our study, patients with left ventricular hypertrophy presented also increased estimated aortic pulse wave velocity, indicating increased aortic stiffness; therefore, the increase in AI was not solely due to differences in wave reflection. Our results promote a role for pulse wave analysis in guiding aggressiveness of drug therapy in an attempt to limit the potential negative effect of increased blood pressure on left ventricle. Age was an independent predictor of LV mass suggesting that aging process is an important stimulus accounting for cardiac hypertrophy. In previous reports, age appeared to influence the left ventricular mass. Lindroos et al. [32] observed that cardiac hypertrophy is commonly present in an aged population, while Gardin et al. [33] reported that
J.P. Lekakis et al. / International Journal of Cardiology 97 (2004) 29–33
left ventricular mass increased less than 1 g/year increase in age for both men and women. In conclusion, in addition to the aging process, a factor accounting for the left ventricular hypertrophy in patients with mild to moderate arterial hypertension is increased central arterial pressure. Applanation tonometry and pulse wave analysis appears to be a method valuable for the identification of hypertensive patients at higher risk for developing cardiac hypertrophy and possibly for the evaluation of any therapeutic interventions.
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[15] O’Rourke MF, Kelly R. Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens 1993;11: 327 – 37. [16] Chen CH, Nevo E, Fetics B, Pak PH, Yin FCP, Maughan WL, et al. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Circulation 1997;95: 1827 – 36. [17] Karamanoglu M, O Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 1993;14:160 – 7. [18] Cameron JD, McGrath BP, Dart AM. Use of radial artery applanation tonometry and a generalized transfer factor to determine aortic pressure augmentation in subjects with treated hypertension. J Am Coll Cardiol 1998;32:1214 – 20. [19] Iketani T, Iketani Y, Takazawa K, Yamashina A. The influence of the peripheral reflection wave on left ventricular hypertrophy in patients with essential hypertension. Hypertens Res 2000;23:451 – 8. [20] Chang KC, Tseng YZ, Kuo TS, Chen HI. Impaired left ventricular relaxation and arterial stiffness in patients with essential hypertension. Clin Sci (Colch) 1994;87:641 – 7. [21] Sahn PS, De Maria A, Kisslo J, Weyman A. The committee on the Mmode standardization of the American Society of Echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072 – 83. [22] Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy, comparison to necropsy findings. Am J Cardiol 1986;57:450 – 8. [23] Devereux RB, Lutas EM, Casale RN, et al. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 1984;4:1222 – 30. [24] Murgo JP, Westerhoh N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure wave forms. Circulation 1980;62:105 – 16. [25] London GM, Pannier B, Guerin AP, Marchais S, Safar M, Cuche J. Cardiac hypertrophy, aortic compliance, peripheral resistance and wave reflection in end-stage renal disease: comparative effects of ACE inhibition and calcium channel blockage. Circulation 1994;90: 2786 – 96. [26] Papaioannou TG, Lekakis J, Dagre A, et al. Arterial compliance is an independent factor that predicts acute hemodynamic performance of intra-aortic balloon counterpulsation. Int J Artif Organs 2001;24: 478 – 83. [27] Hart CYT, Meyer DM, Tazelaar HD, Grande JP, Burnett JC, Housmans PR, et al. Load versus humoral activation in the genesis of early hypertensive heart disease. Circulation 2001;104:215 – 20. [28] Cuspidi C, Michev I, Meani S, et al. Reduced nocturnal fall in blood pressure, assessed by two ambulatory blood pressure monitorings and cardiac alterations in early phases of untreated essential hypertension. J Hum Hypertens 2003;17:245 – 51. [29] Jones EC, Devereux RB, O’ Grady MJ, Schwartz JE, Liu JE, Pickering TG, et al. Relation of hemodynamic volume load to arterial and cardiac size. J Am Coll Cardiol 1997;29:1303 – 10. [30] de Simone G, Roman MJ, Koren MJ, Mensah GA, Ganau A, Devereux RB. Stroke volume/pulse pressure ratio and cardiovascular risk in arterial hypertension. Hypertension 1999;33:800 – 5. [31] Chen CH, Ting CT, Lin SJ, Hsu TS, Ho SJ, Chou P, et al. Which arterial and cardiac parameters best predict left ventricular mass? Circulation 1998;98:422 – 8. [32] Lindroos M, Kupari M, Heikkila J, Tilvis R. Echocardiographic evidence of left ventricular hypertrophy in a general aged population. Am J Cardiol 1994;74:385 – 90. [33] Gardin JM, Siscovick D, Anton-Culver H, Lynch JC, Smith VE, Klopfenstein S, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. Circulation 1995;91:1739 – 48.
Cardiac hypertrophy in hypertension: relation to 24-h blood pressure profile and arterial stiffness John P. Lekakis *, Nicos A. Zakopoulos, Athanassios D. Protogerou, Vassilios Th. Kotsis, Theodore G. Papaioannou, Kimon S. Stamatelopoulos, Marios D. Tsitsiricos, Vassiliki Ch. Pitiriga, Christos M. Papamichael, Savvas Th. Toumanides, Myron E. Mavrikakis Department of Clinical Therapeutics, Alexandra University Hospital, 12 Iridanou Street, 11528 Athens, Greece Received 3 January 2003; received in revised form 16 June 2003; accepted 21 June 2003
Abstract Background: In subjects with essential hypertension peripheral blood pressure profile contributes to the pathogenesis of left ventricular hypertrophy. It is not known if central arterial pressure is superior to peripheral blood pressure profile for predicting left ventricular hypertrophy. In the present study 24-h blood pressure profile and central hemodynamics were examined to evaluate mechanical loading factors as determinants of cardiac hypertrophy in mild to moderate untreated essential hypertension. Methods: Forty-eight untreated subjects with mild to moderate essential hypertension were examined by echocardiography for evaluation of left ventricular mass, 24-h ambulatory blood pressure monitoring (ABPM), and applanation tonometry of the radial artery with pulse wave analysis for evaluation of central hemodynamics. Results: Left ventricular mass showed a statistically significant correlation with age, clinic systolic blood pressure, mean heart rate and heart rate variability during 24-h ABPM, augmentation pressure and index and central systolic blood pressure. In a multiple regression analysis including clinic systolic blood pressure, central systolic pressure, mean systolic pressure and pulse pressure during ambulatory monitoring as well as age, independent predictors of left ventricular mass were only age ( P = 0.006) and central systolic blood pressure ( P = 0.04). In conclusion, pulse wave analysis is a valuable method in predicting cardiac hypertrophy in untreated mild to moderate essential hypertension. Central systolic blood pressure should be taken into account for planning therapeutic strategies for prevention of left ventricular hypertrophy in hypertensive patients. D 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Pulse wave analysis; Left ventricular hypertrophy; Hypertension; Blood pressure
1. Introduction Left ventricular hypertrophy is commonly found in patients with arterial hypertension and significantly magnifies the risk of cardiovascular complications in these patients [1,2]. Although biochemical and genetic factors could be considered as risk factors for the development of left ventricular hypertrophy [3,4], the hemodynamic factors, particularly peripheral systolic blood pressure, are the best characterized stimuli for cardiac hypertrophy [2]. A hemo-
* Corresponding author. Tel.: +30-210-729-9200; fax: +30-210-7299201. E-mail address: [email protected] (J.P. Lekakis). 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.06.011
dynamic parameter that might contribute to the observed vascular hypertrophy is the increased arterial stiffness observed in hypertension [5]. Arterial stiffness has deleterious effects on left ventricular afterload, increases left ventricular mass [6 – 8], decreases coronary perfusion and leads to increased cardiovascular morbidity and mortality in different populations [9 –11]. Ambulatory blood pressure monitoring (ABPM) has been proved to be superior to clinic blood pressure measurement for cardiovascular risk stratification; parameters obtained from the 24-h ABPM have been associated with left ventricular mass in hypertensive patients [12 – 14] and the severity of coronary atherosclerosis in normotensive subjects [10]. Tonometry with pulse wave analysis appears to be a simple and reproducible non-invasive technique for evalu-
30
J.P. Lekakis et al. / International Journal of Cardiology 97 (2004) 29–33
ating arterial stiffness [15 – 18], which has been validated by direct recording of the central pressure waveforms. A decrease in arterial distensibility leads to an increase in pulse wave velocity, resulting in early return of reflected waves from peripheral sites and augmentation of the central systolic pressure, which may have detrimental effects in structure and function of the left ventricle [19,20]. In the present study central arterial pressure assessed by applanation tonometry and pulse wave analysis, as well as 24-h blood pressure profile were examined in order to evaluate mechanical loading factors as determinants of increased left ventricular mass in untreated patients with mild to moderate essential hypertension.
2. Methods 2.1. Population Forty-eight consecutive untreated subjects (15 women, 33 men, mean age 55.8 F 12.3 years), referred to the outpatient hypertension clinic for evaluation of arterial hypertension were included in the study. Subjects were defined as having arterial hypertension if they had blood pressure readings above 140/90 mmHg in the hypertension clinic [12,13] and average daytime ambulatory blood pressure above 135/85 mmHg. Secondary hypertension was excluded by physical examination, normal renal function, serum electrolytes and catecholamine excretion. Three patients had diabetes mellitus, 20 were smokers and 13 had hypercholesterolemia. This study has approved by the local scientific committee and all participants gave informed consent before entering the study.
2.2. Echocardiographic measurements Echocardiograms were obtained using a Sigma-1C echocardiograph (Kontron Instruments Inc., Everett, MA) and a 3.5-MHz transducer. Two-dimensional guided M-mode echocardiograms at the level of chordae tendineae were recorded and each echocardiogram was read by two expert echocardiographers; four to six cycles of septal and posterior wall thickness as well as left ventricular internal diastolic and systolic dimensions were measured by each reader, using the guidelines of the American Society of Echocardiography convention of measurement [21]. The average of mean measurements given by the two readers for each echocardiogram was used for calculating the left ventricular mass. The following formula was used for the estimation of left ventricular mass [22]: LV mass = 0.80 (1.04 (IVSd + LVDd + PWTd)3 (LVDd)3) + 0.6 g; LV mass index = LV mass/ BSA, where IVSd is interventicular septal thickness at enddiastole, LVDd is LV internal diameter at end-diastole, PWTd is posterior wall thickness at end-diastole and BSA is body surface area. LV mass >110 g/m2 in women and >134 g/m2 in men was considered as left ventricular hypertrophy [23]. 2.3. Ambulatory blood pressure monitoring All participants underwent 24 h-ABPM on a usual working day using the Spacelabs 90209 ambulatory monitor (Spacelabs Inc., Redmond, WA). Readings were obtained automatically at 15 min intervals throughout the 24-h study period. All subjects included in the study had at least three valid readings per hour; the resulting 80 –96 pairs of systolic and diastolic blood pressure readings per recording, together with the corresponding time of measurement were used to calculate blood pressure derivative. The accuracy of the
Fig. 1. Analysis of aortic pressure waveform. AI is the difference between the second and the first systolic peaks (AP) and is expressed as percentage of the pulse pressure. RTI is the RT between the foot of the pressure wave and the peak provided by the reflected wave and is expressed as percentage of the cardiac period. RTI is an estimate of the aortic pulse wave velocity.
J.P. Lekakis et al. / International Journal of Cardiology 97 (2004) 29–33 Table 1 Characteristics of study population (n = 48)
31
2.5. Statistics
Variable
Mean F S.D.
Age (years) Mean SBP24 (mmHg) Mean DBP24 (mmHg) Mean MBP24 (mmHg) Mean HR24 (bpm) PP24 (mmHg) PW (mm) IVS (mm) EDD (mm) LV mass index (g/m2) Clinic SP (mmHg) Clinic DP (mmHg) AP (mmHg) AI (%) C-SP (mmHg) C-DP (mmHg) RTI (%)
55.8 F 12.3 137.8 F 9.6 83.1 F 9.2 101.7 F 7.2 74.3 F 10.0 54.7 F 11 10.0 F 1.6 10.5 F 1.6 47.1 F 5.5 111.6 F 24.9 148.2 F 23.2 86.1 F 13.8 11.5 F 9.5 22.2 F 10.2 133.9 F 21.5 87.3 F 13.9 13.0 F 2.1
AP, augmentation pressure; AI, augmentation index; C-DP, central diastolic blood pressure; C-SP, central systolic blood pressure; DBP24, diastolic blood pressure during 24-h; EDD, end-diastolic diameter; HR24, heart rate during 24-h; IVS, interventricular septum; LV mass index, left ventricular mass index; MBP24, mean blood pressure during 24-h; Clinic DP, clinic diastolic blood pressure; PP24, pulse pressure during 24-h; Clinic SP, clinic systolic blood pressure; PW, posterior wall; RTI, reflection time index; SBP24, systolic blood pressure during 24-h.
automatic readings was checked against readings taken using a standard mercury sphygmomanometer twice for each ABPM as previously described [10]. 2.4. Pulse wave analysis Each subject was studied the same day with ABPM, in the morning hours and after a 10 min rest period. After blood pressure measurement, an arterial pressure waveform was recorded by applanating the radial artery with a hand held tonometer. Pressure waveforms obtained by this method have been validated by comparing them with waveforms obtained by high fidelity transducer within the artery. Central waveforms were derived from the radial artery waveforms by using a transfer function as previously described [15 – 17]. The following parameters were measured using the PWV Medical blood pressure analysis system (Sydney, Australia): central systolic, diastolic and mean blood pressure, augmentation pressure, augmentation index (AI) and central pulse pressure. The aortic pulse wave velocity was estimated indirectly by calculating the time between the foot of the pressure wave and the inflection point (first peak, Fig. 1), which provides a measure of the timing of the reflected wave [24]. Increased heart rate may influence the arrival time of the reflected wave at central aorta since the cardiac cycle is shortened and, therefore, reflected waves arrive later in systole. Therefore, an adjustment of the timing of reflected waves for cardiac period has been used (reflection time index (RTI)); the lower the RTI, the higher the pulse wave velocity and the higher the arterial stiffness (Fig. 1) [25,26].
Results are expressed as mean F S.D. Unpaired t-test was used to compare variables between patients with and without left-ventricular hypertrophy. v2-test was used to compare proportions between the various groups. Linear regression analysis was performed to describe the correlations between LV mass at one side and the variables obtained from 24-h ABPM and pulse wave analysis at the other. Multiple linear regression analysis was performed to characterize parameters independently associated with LV mass. A P-value < 0.05 was considered statistically significant.
3. Results Characteristics of the hypertensive subjects are shown in Table 1. Fifteen patients had echocardiographic evidence of left ventricular hypertrophy; LV mass index, men >134 g/m2, women >110 g/m2 [23]. Subjects with hypertrophy were older, had higher clinic systolic blood pressure, higher augmentation pressure and index, higher estimated pulse wave velocity (lower RTI), higher central aortic pressure, lower mean heart rate during ABPM and higher pulse pressure during ABPM (Table 2). Twenty three patients were characterized as dippers based on the decrease of the systolic blood pressure by at least 10% during the nigh; LV mass index and also central systolic blood pressure did not differ significantly between dippers and non-dippers (107 F 21 vs. 115 F 27 g/m2, ns and 133.9 F 18 vs. 140 F 23.5 mmHg, ns, respectively). LV mass index correlated significantly in the univariate analysis with age (r = 0.422, P = 0.003), mean heart rate
Table 2 Characteristics of hypertensive subjects with hypertrophy (+) compared to those without hypertrophy ( )
Age (years) Mean SBP24 (mmHg) SD SBP24 (mmHg) Mean DBP24 (mmHg) Mean HR24 (bpm) Mean MBP24 (mmHg) PP24 (mmHg) PW (mm) IVS (mm) EDD (mm) Clinic SP (mmHg) Clinic DP (mmHg) AP (mmHg) AI (%) C-SP (mmHg) C-DP (mmHg) RTI (%)
Hypertrophy (+) (n = 15)
Hypertrophy ( ) (n = 33)
P-value
61.7 F 10.4 140.5 F 9.8 14.7 F 3.1 81.1 F 10.4 69.2 F 10.9 101.6 F 7.1 59.4 F 11.4 10.7 F 1.9 11.3 F 1.5 50.8 F 6.1 163.0 F 28.6 87.0 F 14.3 18.4 F 12.2 27.5 F 9.2 149.3 F 24.8 88.1 F 14.7 12.0 F 2.1
53.2 F 12.3 136.6 F 9.4 15.5 F 3.3 84.5 F 8.6 76.6 F 8.7 101.7 F 7.3 52.5 F 10.6 9.6 F 1.5 10.2 F 1.4 45.4 F 4.4 141.5 F 17.0 85.6 F 13.8 8.4 F 6.0 19.7 F 9.8 126.9 F 15.8 87.0 F 13.8 13.5 F 2.0
P = 0.02 ns ns ns P = 0.01 ns P = 0.06 P = 0.03 P = 0.03 P = 0.001 P = 0.002 ns P < 0.001 P = 0.01 P < 0.001 ns P = 0.01
Abbreviations as in Table 1.
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during ABPM (r = 0.454, P = 0.001), standard deviation of the heart rate (heart rate variability) (r = 0.351, P = 0.01), clinic systolic blood pressure (r = 0.286, P = 0.04), central systolic pressure (r = 0.341, P = 0.01), augmentation pressure (r = 0.407, P = 0.004), AI (r = 0.322, P = 0.02), RTI (r = 0.305, P = 0.03) and marginally to pulse pressure during 24-h monitoring (r = 0.256, P = 0.07). In multiple regression analysis with LV mass index as a dependent variable and predictors age, clinic systolic pressure, central systolic pressure, mean systolic pressure during 24-h ABPM and pulse pressure during ABPM, age ( P = 0.006) and central systolic blood pressure ( P = 0.04) were independently related to LV mass index; the independent association of central systolic pressure and age with LV mass index did not change after including dipping effect to the possible predictors. In the larger group of males multiple regression analysis also showed that central pressure was independently related to LV mass index ( P = 0.029).
4. Discussion Parameters associated with left ventricular hypertrophy, which is often observed in hypertension are still need to be clarified. The salient finding of the present study is that in patients referred for evaluation of untreated mild to moderate essential hypertension, central systolic blood pressure assessed by pulse wave analysis is superior to clinic and ambulatory blood pressure measurements in predicting left ventricular hypertrophy. Pressure overload, humoral and genetic factors contribute to the genesis of cardiac hypertrophy in subjects with arterial hypertension [3,27]. Recent experimental data suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease [27]. Although systolic blood pressure is the bestcharacterized stimulus for left ventricular hypertrophy, relatively little of the variability observed in cardiac hypertrophy could be attributed to blood pressure level as measured clinically [2]. In our study, although clinic systolic blood pressure was related to LV mass in the univariate analysis, it did not enter the group of independent predictors of LV mass index. The 24-h blood pressure profile has been previously shown that affects the left ventricle independently of blood pressure level [12]. In the present study, the following variables obtained during 24-h ABPM proved to be related to LV mass index; heart rate, heart rate variability and marginally pulse pressure. LV mass index did not differ significantly between dippers and non-dippers, a finding not confirming previous studies which showed that a blunted reduction in nocturnal blood pressure plays a pivotal role in some expressions of target organ damage such as left ventricular hypertrophy [28]. The discrepancy could be attributed to the small number of patients in our study.
Patients with increased LV mass index had decreased heart rate during 24-h ABPM. It is an interesting finding and could be explained by the inverse relation existing between heart rate and left ventricular dilatation [12,13], since left ventricular diameter is part of the formula for the estimation of LV mass. Another explanation could be the inverse relation between heart rate and stroke volume; it has been shown that stroke volume is a predictor of LV mass and chamber size, independently of arterial pressure [29]. Pulse pressure during 24-h ABPM is a predictor of cardiac hypertrophy with marginal statistical significance in the univariate analysis; this finding has shown earlier by our group also in normotensives [10]. Pressure parameters from the ambulatory monitoring were not independent predictors of LV mass when central systolic blood pressure was taken into account. Arterial stiffening has been proposed as a factor contributing to cardiac hypertrophy in hypertensive patients [8] and in a rat model of isolated systolic hypertension [7]. Arterial stiffness assessed by the pulse wave velocity [9] or the ratio of stroke volume/pulse pressure [30] is a predictor of cardiovascular morbidity and mortality in patients with arterial hypertension. On the contrary, Chen et al. [31] in Chinese subjects demonstrated that the effects of the derived measures of arterial function were small and provided no better predictive power than blood pressure alone as determinants of LV mass; if genetic factors could explain this discrepancy is not known. Our results clearly indicate that central systolic blood pressure assessed by radial artery applanation tonometry and pulse wave analysis, is a predictor of LV mass index independently of age and blood pressure measurements during 24-h monitoring. It is the first time central blood pressure estimated by this method has been correlated with LV mass independently of clinic or ambulatory blood pressure. It is known that a decrease in arterial distensibility leads to increase in pulse wave velocity, resulting in early return of reflected waves from peripheral sites and augmentation of the central systolic pressure [15]. Recently, Iketani et al. [19] used finger photoplethysmogram and second derivative wave and reported that an increase in the peripheral reflection wave was one of the important factors causing increased LV mass in patients with hypertension. It is interesting that in our study, patients with left ventricular hypertrophy presented also increased estimated aortic pulse wave velocity, indicating increased aortic stiffness; therefore, the increase in AI was not solely due to differences in wave reflection. Our results promote a role for pulse wave analysis in guiding aggressiveness of drug therapy in an attempt to limit the potential negative effect of increased blood pressure on left ventricle. Age was an independent predictor of LV mass suggesting that aging process is an important stimulus accounting for cardiac hypertrophy. In previous reports, age appeared to influence the left ventricular mass. Lindroos et al. [32] observed that cardiac hypertrophy is commonly present in an aged population, while Gardin et al. [33] reported that
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left ventricular mass increased less than 1 g/year increase in age for both men and women. In conclusion, in addition to the aging process, a factor accounting for the left ventricular hypertrophy in patients with mild to moderate arterial hypertension is increased central arterial pressure. Applanation tonometry and pulse wave analysis appears to be a method valuable for the identification of hypertensive patients at higher risk for developing cardiac hypertrophy and possibly for the evaluation of any therapeutic interventions.
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