Aortic Root Dilatation as a Marker of Subclinical Left Ventricular Diastolic Dysfunction in Patients with Cardiovascular Risk Factors

The Journal of International Medical Research 2011; 39: 64 70 Aortic Root Dilatation as a Marker of Subclinical Left Ventricular Diastolic Dysfunction in Patients with Cardiovascular Risk Factors H MASUGATA, 1 S SENDA, 1 K MURAO, 2 H OKUYAMA, 1 M INUKAI, 1 N HOSOMI, 4 Y IWADO, 3 T NOMA, 3 M KOHNO, 3 T HIMOTO 1 AND F GODA 1 1 Department of Integrated Medicine, 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, and 3 Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan; 4 Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan Consensus is lacking about the clinical importance of aortic root dilatation in assessment of the risk of cardiovascular disease. In this study, correlations between aortic root diameter and echocardio - graphic features of left ventricular (LV) diastolic function were investigated in 333 patients with at least one cardiovascular risk factor (hypertension, diabetes or dyslipidaemia) and preserved LV systolic function. Aortic root diameter was measured by M-mode echocardiography, and LV diastolic function was evaluated by measuring the peak velocity of early (E) and late (A) diastolic transmitral blood flow and peak early diastolic mitral annular velocity (E ) by Doppler echocardiography. Linear regression analysis showed that, in men, age was not related to aortic root diameter but hypertension and LV hypertrophy were, whereas the converse was true in women. The parameters E, E/A ratio and E, were related to aortic root diameter in both sexes. Stepwise multiple regression analysis confirmed that E in women and E in men were independently associated with aortic root diameter. It is concluded that aortic root dilatation might be a useful marker of subclinical LV diastolic dysfunction. Patients with preserved systolic function showing aortic root dilatation should, therefore, be given preventative therapy against LV diastolic heart failure. KEY WORDS: AORTIC ROOT DILATATION; LEFT VENTRICULAR DIASTOLIC FUNCTION; AGEING; ECHOCARDIOGRAPHY; CARDIOVASCULAR RISK FACTOR Introduction Some studies have demonstrated that aortic root dilatation probably reflects the effects of hypertension and atherosclerosis. 1,2 By contrast, others have found no differences in aortic root diameter between hypertensive and normotensive individuals after adjustment for age and body size. 3 5 Consensus is lacking on the underlying mechanisms and clinical importance of 64

aortic root dilatation in cardiovascular disease. Several studies have suggested that it could be a useful marker of target organ damage, including left ventricular hypertrophy, carotid atherosclerosis and micro albuminuria in hypertensive patients. 6,7 In addition, aortic root dilatation is frequently associated with raised cardiovascular mortality. 1,8 Clarification of the clinical relevance of aortic root dilatation in patients with cardiovascular risk factors, including hypertension, diabetes and dyslipidaemia is important. The present study was, therefore, carried out to investigate associations between aortic root diameter and various clinical and echocardiographic factors in patients with cardiovascular risk factors. Patients and methods PATIENTS AND PROTOCOL Patients diagnosed at Kagawa University Hospital, Japan, as having at least one of the following three cardiovascular risk factors, hypertension, diabetes mellitus, or dyslipidaemia, classified according to the guidelines of the Japanese Society of Hypertension, the Japan Diabetes Society and the Japan Atherosclerosis Society, 9 11 respectively, were eligible for inclusion in the study. Patients with a history of heart failure or obvious heart disease were excluded. Hypertension was defined as a systolic blood pressure 140 mmhg and/or a diastolic blood pressure 90 mmhg. Blood pressure was measured by the conventional cuff method at the time of echocardiographic examination. The patients age, height and weight were also recorded at that time. The protocol for this study was approved by the Ethics Committee of Kagawa University, Kagawa, Japan, and written informed consent was obtained from all participants. ECHOCARDIOGRAPHIC EXAMINATIONS Examinations were performed by M-mode echocardiography and Doppler imaging with the Vivid 7 system (GE Healthcare, Horten, Norway) to assess cardiac structural changes and cardiac function. M-mode echocardiography The following aortic and left ventricular structural parameters were first measured by M-mode echocardiography: interventricular septal thickness, left ventricular end-diastolic and left ventricular end-systolic dimensions, and left ventricular posterior wall thickness, all at the chordae tendineae level; the endsystolic left atrial dimension; and the aortic root diameter at the level of the sinuses of Valsalva. Left ventricular mass was calculated according to the American Society of Echocardiography convention 12 with the formula, left ventricular mass = 0.80 (1.04 [PW + VS + LVDd] 3 LVDd 3 ) + 0.6, where PW denotes posterior wall thickness, VS denotes interventricular septal thickness and LVDd denotes left ventricular end-diastolic dimension. From this, left ventricular mass index, which reflects left ventricular hypertrophy, was calculated as left ventricular mass divided by body surface area. Left ventricular ejection fraction was estimated by Teichholz s method 13 and a threshold of < 55% was used to indicate left ventricular systolic dysfunction. Doppler imaging Conventional Doppler echocardiography was used to record the velocity of transmitral blood flow in order to assess left ventricular diastolic function. 14,15 This was recorded from the apical transducer position, with the 65

sample volume situated between the mitral leaflet tips. The peak velocity of early transmitral blood flow (E) and the peak velocity of late transmitral blood flow (A) were recorded, and the E/A ratio was calculated. Finally, tissue Doppler echo - cardiography, 16 which measures the velocities created by movement of the regional cardiac wall, was performed by activating the tissue Doppler echocardiographic function in the Vivid 7 system. Mitral annular velocities were recorded from the apical window. Sample volumes were located at the septal site of the mitral annulus. Peak early diastolic mitral annular velocity (E ) was measured over three cardiac cycles and the mean was calculated. 17 19 The parameters obtained from tissue Doppler echocardiography were also analysed as parameters of left ventricular diastolic function. STATISTICAL ANALYSES Data are expressed as the mean ± SD. Statistical analysis was performed using the SPSS software package (SPSS Inc., Chicago, IL, USA). Linear regression analysis was performed to evaluate correlations between aortic root diameter and the various clinical and echocardiographic variables, and stepwise multiple regression analysis was used to assess independent correlations. Values of P < 0.05 were taken to indicate statistical significance. Results In total, 333 patients (190 men, 143 women; mean ±SD age 66 ± 12 years, range 31 96 years) diagnosed at Kagawa University Hospital, Japan, as having at least one of the three cardiovascular risk factors of hypertension, diabetes mellitus or dyslipidaemia, were included in the study. None had a history of atherosclerotic cardiovascular disease or stroke. CLINICAL AND ECHOCARDIOGRAPHIC CHARACTERISTICS Comparisons of clinical and echocardiographic parameters between the male and female patients are summarized in Table 1. Mean age did not differ between men and women, but men had a significantly larger body size (height and weight; P < 0.001). The prevalence of hypertension, diabetes and dyslipidaemia did not differ between the genders. Aortic root diameter was significantly larger in men than in women (P < 0.001). Values for all left ventricular structural parameters were significantly greater in men than women (P 0.032; Table 1). With respect to left ventricular functional features, the absolute values of E and A were significantly higher in women than men (P < 0.001), but E/A ratio and E did not differ between the two groups. LINEAR REGRESSION ANALYSIS Correlations between aortic root diameter and the clinical and echocardiographic characteristics, determined by linear regression analysis, are shown in Table 2. Aortic root diameter was not significantly correlated with age in men, but was in women (P = 0.001). For hypertension, a significant correlation was seen with aortic root diameter in men (P = 0.001) but not in women. With respect to left ventricular structural parameters, aortic root diameter was significantly correlated with left ventricular hypertrophy in men (P = 0.001) but not in women. With respect to parameters of left ventricular diastolic function, significant inverse correlations were seen for men and women for E, E/A ratio and E. 66

TABLE 1: Comparison between men and women of the clinical and echocardiographic characteristics of the studied patients Men Women Statistical Characteristic (n = 190) (n = 143) significance Age, years 66.0 ± 11.7 66.8 ± 12.2 NS Height, cm 165 ± 6 151 ± 6 P < 0.001 Weight, kg 62 ± 12 53 ± 11 P < 0.001 Hypertension, n (%) 122 (64) 98 (69) NS Diabetes mellitus, n (%) 50 (26) 40 (28) NS Dyslipidaemia, n (%) 50 (27) 35 (24) NS Heart rate, beats/min 67 ± 12 69 ± 10 NS Systolic blood pressure, mmhg 131 ± 19 129 ± 18 NS Diastolic blood pressure, mmhg 78 ± 13 74 ± 12 NS Aortic root diameter (mm) 33.1 ± 3.8 28.5 ± 3.5 P < 0.001 LV structural parameters IVS, mm 11.3 ± 2.6 10.5 ± 2.6 P = 0.005 PW, mm 10.7 ± 2.0 9.6 ± 1.9 P < 0.001 ES dimension, mm 28.1 ± 4.4 26.0 ± 4.3 P < 0.001 ED dimension, mm 46.9 ± 5.4 44.9 ± 5.5 P = 0.001 LVMI, g/m 2 116 ± 34 108 ± 33 P = 0.032 LA dimension, mm 36.7 ± 6.1 35.9 ± 6.0 NS LV functional parameters EF, % 70 ± 7 73 ± 7 NS E, cm/s 55 ± 14 63 ± 19 P < 0.001 A, cm/s 71 ± 19 81 ± 21 P < 0.001 E/A ratio 0.82 ± 0.28 0.81 ± 0.26 NS E, cm/s 6.0 ± 1.8 5.7 ± 2.0 NS Data presented as mean ± SD unless stated otherwise. LV, left ventricular; IVS, interventricular septal thickness; PW, posterior wall thickness; ES, end-systolic; ED, end-diastolic; LVMI, left ventricular mass index; LA, left atrial; EF, ejection fraction; E, peak velocity of early diastolic transmitral blood flow; A, peak velocity of late diastolic transmitral blood flow; E, peak early diastolic mitral annular velocity; NS, not statistically significant (P > 0.05). STEPWISE MULTIPLE REGRESSION ANALYSIS Stepwise multiple regression analysis, carried out to identify which clinical and echocardiographic characteristics were independently associated with aortic root diameter, indicated that E was independently associated with aortic root diameter in men (β coefficient = 0.311, F = 19.115, r 2 = 0.096, P < 0.001), and that E (β coefficient = 0.227, P = 0.007) and age (β coefficient = 0.211, P = 0.012) were independently associated with aortic root diameter in women (F = 8.859, r 2 = 0.117, P < 0.001). Discussion The present study has suggested that: (i) in men, age was not related to aortic root diameter but hypertension and left ventricular hypertrophy were; (ii) in women, the converse was true and age was related to aortic root diameter but hypertension and left ventricular hypertrophy were not; (iii) left ventricular diastolic functional parameters, including E, E/A ratio and E, 67

TABLE 2: Comparison between men and women of the correlation coefficients (r) following linear regression analyses between aortic root diameter and various clinical and echocardio - graphic characteristics of the studied patients Men Women Statistical Statistical Characteristic r significance r significance Age 0.029 NS 0.267 P = 0.001 Height 0.153 P = 0.038 0.010 NS Weight 0.158 P = 0.031 0.017 NS Hypertension 0.240 P = 0.001 0.062 NS Diabetes mellitus 0.006 NS 0.089 NS Dyslipidaemia 0.006 NS 0.030 NS Heart rate 0.039 NS 0.182 P = 0.031 Systolic blood pressure 0.080 NS 0.036 NS Diastolic blood pressure 0.034 NS 0.174 P = 0.041 LV structure parameters IVS 0.207 P = 0.005 0.041 NS PW 0.126 NS 0.005 NS ES dimension 0.006 NS 0.073 NS ED dimension 0.185 P = 0.012 0.121 NS LVMI 0.242 P = 0.001 0.104 NS LA dimension 0.025 NS 0.129 NS LV functional parameters EF 0.183 P = 0.013 0.008 NS E 0.207 P = 0.005 0.274 P = 0.001 A 0.030 NS 0.064 NS E/A ratio 0.263 P < 0.001 0.229 P = 0.006 E 0.307 P < 0.001 0.268 P = 0.001 LV, left ventricular; IVS, interventricular septal thickness; PW, posterior wall thickness; ES, end-systolic; ED, end-diastolic; LVMI, left ventricular mass index; LA, left atrial; EF, ejection fraction; E, peak velocity of early diastolic transmitral blood flow; A, peak velocity of late diastolic transmitral blood flow; E, peak early diastolic mitral annular velocity; NS, not statistically significant (P > 0.05). were related to aortic root diameter in both sexes. Previous studies 6,7 have demonstrated that left ventricular hypertrophy is the main independent predictor of aortic root dilatation in hypertensive patients. The data from the present study support this association in men, but also suggest that aortic root dilatation may be a useful marker of left ventricular diastolic dysfunction, as it was seen in both men and women. Left ventricular diastolic dysfunction as measured by the E/A ratio is known to be a marker of increased risk of cardiovascular events in hypertensive patients. 20,21 Just as some previous studies have demonstrated that aortic root dilatation is frequently associated with higher cardiovascular mortality, 1,8 this feature might also predict cardiovascular events in patients with cardiovascular risk factors. The precise mechanisms of the observed differences between men and women in the association between aortic root diameter and various clinical and echocardiographic parameters could not be determined in the 68

present study. Hypertension 22,23 and ageing 24 26 are, however, known to lead to left ventricular diastolic dysfunction by increasing left ventricular wall thickness and interstitial fibrosis, which suggests an association between aortic root dilatation and left ventricular diastolic dysfunction in both sexes. In conclusion, the effects of hypertension and ageing on aortic root dilatation may differ between men and women with cardiovascular risk factors. Aortic root dilatation may, however, be a useful marker of subclinical left ventricular diastolic dysfunction regardless of these differences. Preventative therapy should, therefore, be considered in patients with aortic root dilatation and preserved systolic function to prevent left ventricular diastolic heart failure. Acknowledgements This study was supported in part by a Grantin-Aid for Scientific Research (No. 21500447 to H.M.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and from the Japan Society for the Promotion of Science. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 28 September 2010 Accepted subject to revision 29 September 2010 Revised accepted 17 January 2011 Copyright 2011 Field House Publishing LLP References 1 Gardin JM, Arnold AM, Polak J, et al: Usefulness of aortic root dimension in persons 65 years of age in predicting heart failure, stroke, cardiovascular mortality, all-cause mortality and acute myocardial infarction (from the Cardiovascular Health Study). Am J Cardiol 2006; 97: 270 275. 2 Cipolli JA, Souza FA, Ferreira-Sae MC, et al: Sexspecific hemodynamic and non-hemodynamic determinants of aortic root size in hypertensive subjects with left ventricular hypertrophy. Hypertens Res 2009; 32: 956 961. 3 Kim M, Roman MJ, Cavallini MC, et al: Effect of hypertension on aortic root size and prevalence of aortic regurgitation. Hypertension 1996; 28: 47 52. 4 Palmieri V, Bella JN, Arnett DK, et al: Aortic root dilatation at sinuses of valsalva and aortic regurgitation in hypertensive and normotensive subjects: The Hypertension Genetic Epidemiology Network Study. Hypertension 2001; 37: 1229 1235. 5 Farasat SM, Morrell CH, Scuteri A, et al: Do hypertensive individuals have enlarged aortic root diameters? Insights from studying the various subtypes of hypertension. Am J Hypertens 2008; 21: 558 563. 6 Cuspidi C, Meani S, Fusi V, et al: Prevalence and correlates of aortic root dilatation in patients with essential hypertension: relationship with cardiac and extracardiac target organ damage. J Hypertens 2006; 24: 573 580. 7 Cuspidi C, Meani S, Valerio C, et al: Ambulatory blood pressure, target organ damage and aortic root size in never-treated essential hypertensive patients. J Hum Hypertens 2007; 21: 531 538. 8 Seder JD, Burke JF, Pauletto FJ: Prevalence of aortic regurgitation by color flow Doppler in relation to aortic root size. J Am Soc Echocardiogr 1990; 3: 316 319. 9 Ogihara T, Kikuchi K, Matsuoka H, et al: The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res 2009; 32: 3 107. 10 Japan Diabetes Society: Guidelines for diagnosis of diabetes mellitus. J Jpn Diabetes Soc 1999; 42: 385 404. 11 Teramoto T, Sasaki J, Ueshima H, et al: Diagnostic criteria for dyslipidemia. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb 2007; 14: 155 158. 12 Wallerson DC, Devereux RB: Reproducibility of echocardiographic left ventricular measurements. Hypertension 1987; 9: II6 II18. 13 Teichholz LE, Kreulen T, Herman MV, et al: Problems in echocardiographic volume determinations: echocardiographic angio - graphic correlations in the presence of absence of asynergy. Am J Cardiol 1976; 37: 7 11. 14 Nishimura RA, Appleton CP: Diastology : beyond E and A. J Am Coll Cardiol 1996; 27: 372 374. 69

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