DOI: 10.1111/eci.12331

ORIGINAL ARTICLE Uricaemia and left ventricular mass in hypertensive patients Cristiana Catena, GianLuca Colussi, Frine Capobianco, Gabriele Brosolo and Leonardo A. Sechi Hypertension Unit, Division of Internal Medicine, Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy

ABSTRACT Background Both hyperuricaemia and left ventricular (LV) hypertrophy are associated with the metabolic syndrome and increased cardiovascular risk. The relationship between uric acid levels and left ventricular mass in hypertension, however, is unclear. In this study, we have investigated this relationship in hypertensive patients without the metabolic syndrome. Materials and methods In a cross-sectional study, 367 nondiabetic, essential hypertensive patients (age 52  14; 194 males and 173 females) free of clinically relevant cardiovascular complications and without the metabolic syndrome were consecutively recruited at a university hypertension clinic. In these patients, we measured plasma levels of uric acid, lipids, glucose and insulin at fast and after an oral glucose load (OGTT), renal function and performed both conventional and tissue Doppler echocardiography. Results Hypertensive patients with LV hypertrophy had higher uric acid levels and greater prevalence of hyperuricemia than patients with normal left ventricular mass. Uric acid levels were directly related with fasting and post-OGTT plasma insulin and with the HOMA index and inversely with 24-h creatinine clearance. Uric acid was also significantly and directly related with the left ventricular mass and multivariate regression analysis showed that this relationship was independent from components of the metabolic syndrome and renal function in women, but not in men. Conclusions Elevated uric acid levels are independently related to the left ventricular mass in hypertensive women without the metabolic syndrome. In these patients with a low cardiovascular risk profile, uric acid might contribute to the development of subclinical cardiac damage. Keywords Hypertension, left ventricular hypertrophy, metabolic syndrome, tissue Doppler echocardiography, uric acid. Eur J Clin Invest 2014; 44 (10): 972–981

Introduction Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in patients with hypertension and is associated with increased incidence of arrhythmia, myocardial infarction and stroke [1]. Increased blood pressure with the related increase in cardiac workload is not the only determinant of cardiac damage in hypertensive patients and the propensity of these patients to develop structural and functional abnormalities of the heart is under the influence of additional hormonal, haemorheologic and metabolic factors [2,3]. The metabolic syndrome with the related insulin resistance and hyperinsulinemia contributes to the cardiovascular risk and is associated with increased LV mass in the general population [3] and in patients with hypertension [4].

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Hyperuricaemia is frequently detected in patients with the metabolic syndrome [5] and prospective studies have reported that elevated uric acid levels are associated with an increased risk of myocardial infarction and stroke [6] and with worse LV function in heart failure patients [7]. Studies conducted in the last decade have evaluated the relationships between uric acid levels and LV mass in hypertension reporting inconsistent findings [8–13], mostly because of interference of components of the metabolic syndrome. Moreover, different findings between men and women were reported in some studies [10,11]. Because of the important link between uric acid levels and the metabolic syndrome and its potential contribution to hypertensive cardiac damage, we sought to investigate the relationship between uric acid and cardiac structural and functional variables in a large group of hypertensive patients without this syndrome.

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Materials and methods Patients Three hundred and sixty-seven patients with mild-to-moderate hypertension, who were consecutively recruited at our university clinic over a period of 8 years, were included in a crosssectional study. Blood pressure was measured by an automated device (Omron M6; OMRON Healthcare Co., Kyoto, Japan) using an appropriately sized cuff after each subject had been supine for 15 min, and the average of three readings was recorded [14]. Diagnosis of hypertension was based on at least 2 blood pressure measurements per visit in at least three visits or use of antihypertensive drugs, according to current guidelines [15]. All patients were white, lived in the north-east of Italy, and were representative of the hypertensive population in this area [16]. Patients younger than 18 years or older than 80 years and pregnant women were excluded, together with patients with history of alcohol abuse or acute illness, diabetes mellitus, metabolic syndrome, ischaemic heart, cardiac valve or other heart diseases, impaired systolic function (ejection fraction of < 50%), glomerular filtration rate (GFR) of < 60 mL/min/ 1
73 m2, use of diuretics, uric acid-lowering drugs or other drugs that could interfere with uric acid levels. Metabolic syndrome was diagnosed according to the American Heart Association criteria [17] when two or more of the following conditions were associated with hypertension: waist circumference of more than 102 cm in men or 88 cm in women; fasting plasma glucose of 100 mg/dL or more or use of hypoglycaemic drugs; triglycerides of 150 mg/dL or more or use of lipidlowering drugs; HDL cholesterol of < 40 mg/dL in men or 50 mg/dL in women. In all patients, secondary forms of hypertension were excluded on the basis of extensive investigations that included analysis of medical records, physical examination, urine analysis, blood biochemistries, 24-h creatinine clearance, plasma renin and aldosterone, urinary cortisol and catecholamines, ECG, echocardiography and renal ultrasound with measurement of renal resistance index. Renal angio-MRI/CT scan, and additional functional tests were performed when appropriate [18]. Two hundred and twenty (60%) of 367 patients had never been treated with antihypertensive drugs. The remaining 147 were treated with drugs (58% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 46% calcium channel blockers, 43% beta-blockers and 7% alpha-blockers) that were withdrawn for at least 2 weeks before the study. No patient was treated with losartan. Patients taking two or more antihypertensive agents were admitted to the hospital for the duration of the washout period and in those with blood pressure higher than 180/110 mm Hg (n = 15) alpha-blockers and/ or calcium channel blockers were given. Before the study,

patients ate a standard diet for 7 days to maintain a sodium intake of 100–150 mmol/day that was checked with measurement of 24-h urinary sodium excretion. Alcohol intake was estimated by a questionnaire [19]. Patients were classified as smokers if they had smoked for at least 5 years, and up to 1 year before the study. The study was approved by the local institutional review board and informed consent was obtained from all patients. Reporting of the study conforms to STROBE statement along with references to STROBE statement and the broader EQUATOR guidelines [20].

Laboratory measurements Venous blood was collected in the morning after an overnight fast, and plasma was frozen at -80°C until assay was performed, usually within 1 month from sampling. Uric acid levels were determined by the uricase–peroxidase system, and hyperuricaemia was defined by levels of more than 7
0 mg/dL in men and 6
0 mg/dL in women, according to the reference values of our laboratory [21]. Triglycerides and total and HDL cholesterol were assayed enzymatically and LDL cholesterol was calculated with the formula of Friedewald. Plasma glucose was measured using the glucose–oxidase method and plasma insulin by RIA. The Homoeostatic Model Assessment (HOMA) index was calculated as an index of insulin sensitivity from fasting glucose (mM) and insulin (lU/mL) using the formula: [(glucose 9 insulin)/22
5]. Glucose tolerance was evaluated by a 180-min oral glucose tolerance test (OGTT) and the area under the curve for glucose (AUC-G) and insulin (AUC-I) concentration during the OGTT was calculated by the trapezoidal rule [22]. GFR was measured by duplicate measurement of 24-h creatinine clearance and normalized for body surface area [23].

Echocardiography Echocardiography was performed as described previously by the same expert investigator who was unaware of the patients’ characteristics [24]. Measurements were obtained with a commercial machine (Aplio CV; Toshiba Medical System, Tokyo, Japan) and a 2
5 MHz transducer under bidimensional crosssectional control. LV mass index was calculated and adjusted for body height, with a cut-off value of 50 g/m2
7 for men and 47 g/m2
7 for women being used to define LV hypertrophy [25]. Concentric geometry was defined as relative wall thickness (RWT) ≥ 0
42 [25] and LV systolic function was estimated by the ejection fraction. Diastolic function was evaluated by pulsed Doppler that was recorded from apical four-chamber view at the level of mitral valve tips. Early- (E) and late-wave (A) diastolic velocities, their ratio (E/A) and the isovolumetric relaxation time (IVRT) were measured [26]. Tissue Doppler imaging (TDI) was also performed in a subset of 97 patients [22]. Early-diastolic and late-diastolic velocities of septal and lateral

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myocardial portions at the level of mitral valve annulus were measured, and the mean values (Em and Am) were calculated on 3 consecutive cycles together with the average Em/Am ratios. Diastolic dysfunction was defined on the basis of velocities lower than the age-specific cut-off value [22].

Statistical analysis Values are reported as mean  SD for normally distributed variables and as median and interquartile ranges for variables with skewed distribution. Normality of distribution was assessed with the Kolmogorov–Smirnov test, and variables with skewed distribution were analysed after logarithmic transformation. Pearson’s chi-square test was used to compare frequency distributions. Student’s t-test was used for comparisons between two groups. Relationships between continuously distributed variables were examined through linear regression analysis, with correlation expressed by Pearson’s correlation coefficient. Multivariate regression analysis was done with inclusion of variables according to the level of correlation found in univariate analysis. A value of P of < 5% was considered to indicate statistical significance. Data analyses were performed using Stata 12.1 (StataCorp LP, College Station, TX, USA).

Results The clinical and biochemical characteristics of the study patients are summarized in Table 1 where patients are divided according to gender. In addition to older age, lower BMI and waist circumference and lower alcohol intake, women had lower uric acid and triglyceride levels, higher HDL cholesterol and lower fasting insulin that was associated with better insulin sensitivity, indicating a better overall metabolic profile than men. As expected, men had greater LV mass index than women, but frequency of LV hypertrophy was comparable between sexes. Among 83 patients with LV hypertrophy, 45 (12%; 24 males, 21 females) had concentric and 38 (11%; 18 males and 20 females) eccentric hypertrophy; concentric remodelling was present in 43 patients (12%; 23 males and 20 females) showing no significant differences in patterns of LV geometry between sexes. Ejection fraction was slightly higher in women who had also lower E/A ratio than men, but difference disappeared after correction by age. Variables of LV diastolic function obtained at TDI and prevalence of diastolic dysfunction did not differ between men and women. Fasting plasma glucose was higher in patients who had antihypertensive treatment washed out before the study than patients who had never received antihypertensive treatment, whereas the remaining glicometabolic and lipid variables, uric acid levels, left ventricular mass index and the other echocardiographic variables were comparable between the groups.

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LV hypertrophy was found in 83 (22
6%; 42 males, 41 females) hypertensive patients and Table 2 shows the characteristics of patients with or without LV hypertrophy. Patients with LV hypertrophy were older had greater BMI and waist circumference, higher blood pressure, higher uric acid levels and more prevalent hyperuricaemia and greater glucose and insulin responses to OGTT than patients without LV hypertrophy. RWT was greater in patients with LV hypertrophy and was associated with worse diastolic function, whereas systolic function did not differ significantly from patients without LV hypertrophy. On univariate analysis, uric acid levels were significantly and directly related to BMI, waist circumference, alcohol consumption, serum triglyceride and creatinine levels, fasting and post-OGTT insulin, HOMA index and inversely to HDL cholesterol and GFR (Table 3). Moreover, uric acid levels were directly related with LV mass index in both men and women and with left atrial diameter, whereas no significant relationship was found with other variables of diastolic function. In addition to uric acid levels, LV mass index was significantly and directly related with age, BMI, waist circumference, systolic blood pressure and plasma creatinine (Table 4). Multivariate regression analysis that included demographic variables, BMI, blood pressure, duration of hypertension, alcohol consumption, plasma creatinine, fasting plasma insulin, HOMA index and components of the metabolic syndrome (waist circumference and fasting glucose, triglyceride and HDL cholesterol levels) showed that uric acid was independently related with waist circumference (b = 0
206, P = 0
003), plasma creatinine (b = 0
435, P < 0
001) and fasting insulin (b = 0
185, P = 0
006) and that LV mass index was independently related with age (b = 0
198, P = 0
001), waist circumference (b = 0
133, P = 0
048) and systolic blood pressure (b = 0
316, P < 0
001). Multivariate regression analysis was also performed separately in men and women (Table 5) including the same variables as above. In hypertensive men, LV mass index was independently related to age and systolic blood pressure and in hypertensive women with systolic blood pressure, AUC-G and uric acid levels.

Discussion Both hyperuricaemia and LV hypertrophy are frequently associated with the metabolic syndrome and contribute to the cardiovascular risk. Past studies that investigated the association between uric acid and LV mass in hypertensive patients reported inconsistent findings, most probably because results were affected by metabolic variables related to this syndrome. For these reasons, we excluded patients with the metabolic syndrome and conducted the study in nondiabetic hypertensive patients free of clinically relevant cardiovascular and renal complications. Findings demonstrate that frequency of hyperuricaemia in hypertensive patients with LV hypertrophy is

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Table 1 Clinical, biochemical and echocardiographic characteristics of the study patients Variable

All patients (n = 367)

Men (n = 194)

Women (n = 173)

P

Clinical characteristics Age, years

52  14

50  14

55  15

0
005

BMI, kg/m2

26
7  4
1

27
2  3
6

26
1  4
6

0
010

91  11

96  9

86  12

< 0
001

Waist circumference, cm

72  11

73  11

72  12

0
405

Systolic blood pressure, mmHg

150  19

151  19

150  18

0
732

Diastolic blood pressure, mmHg

92  12

93  13

91  11

0
053

Heart rate, beats/min

Duration of hypertension, years

5 [1–11]

5 [1–11]

5 [1–10]

0
554

Alcohol consumption, g/day

5 [0–20]

15 [0–39]

0 [0–10]

< 0
001

Biochemical variables Total cholesterol, mg/dL

204  41

200  38

210  44

0
043

HDL cholesterol, mg/dL

61  16

55  13

68  17

< 0
001

LDL cholesterol, mg/dL

124  37

124  35

123  40

Triglycerides, mg/dL Uric acid, mg/dL Hyperuricemia, n (%) Creatinine, mg/dL GFR, mL/min 1
73 m2 Fasting glucose, mg/dL Fasting insulin, lUI/mL

91 [70–115]

98 [76–128]

83 [60–107]

0
790 < 0
001

5
15  1
46

5
84  1
21

4
37  1
32

51 (14)

31 (16)

20 (12)

0
97  0
26

1
08  0
26

0
85  0
18

92  25

93  25

90  24

0
419

89  18

0
271

90  16 7
60 [5
43–10
30]

91  15 8
10 [5
98–10
83]

< 0
001 0
238 < 0
001

6
95 [5
13–10
00]

0
026

HOMA index

1
60 [1
14–2
27]

1
72 [1
17–2
52]

1
46 [1
07–2
10]

0
015

AUC-G, mg/dL min

383  98

376  77

391  120

0
294

AUC-I, lUI/mL min

153 [103–252]

147 [100–255]

161 [104–233]

0
715

Echocardiographic variables LVMI, g/m2
7 LV hypertrophy, n (%)

41
3  13
4

42
9  14
2

39
4  12
2

0
012

83 (23)

42 (21)

41 (24)

0
599

0
38  0
08

0
38  0
08

0
38  0
09

0
894

LV ejection fraction, %

69  7

68  7

71  6

0
001

LAD, mm

38  7

41  7

36  6

< 0
001

E/A ratio

1
13  0
40

1
18  0
41

1
06  0
38

0
007

93  20

89  22

98  21

0
291

RWT, %

IVRT, msec Em, cm/sec

9
7  2
6

9
6  2
4

9
8  3
1

0
676

Em/Am ratio

1
14  0
45

1
08  0
38

1
19  0
50

0
241

E/Em ratio

1
70  2
15

7
57  2
43

7
82  1
87

0
585

48 (49)

23 (49)

25 (50)

0
736

Diastolic dysfunction (TDI), n (%)

Values are expressed as mean  SD. Interquartiles ranges are shown in square brackets [IQR] for variables with skewed distribution. To convert to international units, multiply creatinine by 88
4 (lM), cholesterol by 0
0259 (mM), triglycerides by 0
0113 (mM), uric acid by 59
485 (lM), glucose by 0
05551 (mM) and insulin by 7
175 (pM). Tissue Doppler imaging variables were measured in a subset of 97 patients. BMI, body mass index; GFR, glomerular filtration rate; HOMA, homeostatic model assessment; AUC-G, area under the curve of plasma glucose after oral glucose tolerance test; AUC-I, area under the curve of plasma insulin after oral glucose tolerance test; LVMI, left ventricular mass index; RWT, relative wall thickness; LAD, left atrial diameter; E, early-wave transmitral diastolic velocity; A, late-wave transmitral diastolic velocity; IVRT, isovolumetric relaxation time; Em, early-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging; Am, late-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging; TDI, tissue Doppler imaging.

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Table 2 Clinical, biochemical and echocardiographic variables of patients grouped according to the presence or absence of left ventricular (LV) hypertrophy LV hypertrophy No (n = 284)

Variable

LV hypertrophy Yes (n = 83)

P

Clinical characteristics Age, years

51  14

56  15

0
004

Males, n (%)

152 (53)

42 (51)

0
639

26
4  4
0

27
7  4
4

0
016

Waist circumference, cm

90  11

95  11

< 0
001

Heart rate, beats/min

72  11

71  12

0
616

Systolic blood pressure, mmHg

148  17

158  23

< 0
001

Diastolic blood pressure, mmHg

91  12

95  14

0
054

2

BMI, kg/m

Duration of hypertension, years Previous treatment, n (%) Smokers, n (%) Alcohol consumption, g/day

4 [1–10]

8 [2–12]

0
261

112 (39)

36 (43)

0
520

47 (16)

13 (16)

0
848

6 [0–20]

1 [0–20]

0
363

Biochemical variables Total cholesterol, mg/dL

205  42

201  39

0
470

HDL cholesterol, mg/dL

61  17

60  14

0
541

LDL cholesterol, mg/dL

125  38

120  36

0
297

Triglycerides, mg/dL

91 [68–116]

91 [75–110]

0
760

5
06  1
40

5
46  1
61

0
041

32 (11)

19 (23)

0
007

Creatinine, mg/dL

0
96  0
20

1
02  0
38

0
160

GFR, mL/min/1
73

101  29

95  34

0
216

90  16

91  17

0
566

Uric acid, mg/dL Hyperuricemia, n (%)

Fasting glucose, mg/dL Fasting insulin, lUI/mL

7
45 [5
50–10
71]

7
80 [5
00–9
45]

0
266

HOMA index

1
60 [1
15–2
37]

1
60 [1
06–2
20]

0
976

AUC-G, mg/dL min

371  92

419  110

0
004

AUC-I, lUI/mL min

146 [96–226]

189 [139–308]

0
004

36  7

60  13

< 0
001

0
361  0
070

0
449  0
091

< 0
001

LV ejection fraction, %

70  7

68  8

0
084

LAD, mm

38  6

41  10

0
007

1
16  0
41

1
02  0
35

0
011

IVRT, msec

88  17

100  27

0
021

Em, cm/sec

10
1  2
8

8
6  2
4

0
024

Echocardiographic variables LVMI, g/m2
7 RWT, %

E/A

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Table 2 Continued Variable

LV hypertrophy No (n = 284)

LV hypertrophy Yes (n = 83)

P

Em/Am

1
17  0
44

1
01  0
45

0
148

E/Em

7
22  1
80

9
28  2
47

0
001

34 (45)

14 (64)

0
507

Diastolic dysfunction (TDI), n (%)

Values are expressed as mean  SD. Interquartiles ranges are shown in square brackets [IQR] for variables with skewed distribution. To convert to international units, multiply creatinine by 88
4 (lM), cholesterol by 0
0259 (mM), triglycerides by 0
0113 (mM), uric acid by 59
485 (lM), glucose by 0
05551 (mM) and insulin by 7
175 (pM). Tissue Doppler imaging variables were measured in a subset of 97 patients. BMI, body mass index; GFR, glomerular filtration rate; HOMA, homeostatic model assessment; AUC-G, area under the curve of plasma glucose after oral glucose tolerance test; AUC-I, area under the curve of plasma insulin after oral glucose tolerance test; LVMI, left ventricular mass index; RWT, relative wall thickness; LAD, left atrial diameter; E, early-wave transmitral diastolic velocity; A, late-wave transmitral diastolic velocity; IVRT, isovolumetric relaxation time; Em, early-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging; Am, late-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging; TDI, tissue Doppler imaging.

twofold that of patients without LV hypertrophy and that uric acid levels are significantly and directly related with LV mass. This relationship, however, is independent of possible confounders including renal function and sensitivity to insulin in women, but not in men. The frequent association of increased uric acid levels with insulin resistance has led to indicate hyperuricaemia as a possible additional component to the cluster of conditions that identify the metabolic syndrome. Initial observations reported a strong relationship between decreased insulin-mediated glucose disposal and uric acid levels in healthy subjects [27] and these observations were subsequently replicated in patients with the metabolic syndrome [5]. Also, healthy subjects with asymptomatic hyperuricaemia were reported to be hyperinsulinemic and dyslipidemic and to have higher blood pressure than normouricaemic subjects [28]. The suggested mechanism underlying the relationship between insulin resistance/hyperinsulinemia and uric acid is that elevated plasma insulin decreases renal clearance of uric acid [29]. In this study, we have found a direct relationship of uric acid levels with the HOMA index and fasting and post-OGTT plasma insulin in hypertensive patients without the metabolic syndrome. This finding, obtained in a different set of patients from previous studies, supports the view that elevated uric acid is another of the multiple metabolic abnormalities that comprise the insulin resistance syndrome. Increased LV mass is associated with insulin resistance in the context of the metabolic syndrome [3] and appears to be under the influence of gender, inasmuch as the effects of the metabolic syndrome on LV mass appear to be more pronounced in women [30]. In our hypertensive patients without the metabolic syndrome, the response of both plasma glucose and insulin levels to the OGTT was greater in patients with LV hypertrophy than without LV hypertrophy, but no significant differences were found in the HOMA index. These findings are in agreement with those reported by Sciacqua et al. [31] in 767 never treated

hypertensive subjects and suggest that postprandial glucose levels are a major determinant of LV mass in hypertensive patients without the metabolic syndrome. Because of the relevance that LV hypertrophy has on cardiovascular risk [1], the relationship of uric acid with LV mass of hypertensive patients was examined in previous studies. Viazzi et al. [8] reported an independent association between uricaemia and LV mass in 425 hypertensive patients, 21% of whom had the metabolic syndrome. The same association was observed in a study of 619 hypertensive patients who were followed for 34 months, showing that the combination of hyperuricaemia with LV hypertrophy was an independent predictor of cardiovascular events [9]. Subsequent observations confirmed the association between uric acid and LV mass, although this was found to be gender related [10,11] and a recent study conducted on 534 uncomplicated hypertensive patients has reported an association between circulating uric acid and LV mass index only in women [13]. At opposite, no independent association of uric acid levels with LV mass was reported in a study of 580 newly diagnosed, never treated, hypertensive patients with relatively low prevalence of hyperuricaemia [12] and in other large studies [32,33]. In addition to generic differences in ethnicity, age and gender distribution of patients, duration of hypertension, and prevalence of hyperuricemia or LV hypertrophy, important additional factors could explain the inconsistencies among these studies. These factors include the presence of the metabolic syndrome, impaired renal function and interference of antihypertensive drugs such as diuretics. For these reasons, we excluded patients with the metabolic syndrome, GFR of < 60 mL/min/1
73 m2, and previous use of diuretics. In these patients, we have found a significant correlation between uric acid levels and LV mass, although this correlation was independent of insulin sensitivity and renal function only in women. Relevant to this aspect, previous studies suggested a greater impact on LV structure of women than men of metabolic conditions such as glucose

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Table 3 Univariate correlation analysis with serum uric acid as the dependent variable All patients Variable

r

Men P

r

Women P

r

P

Age

0
046

0
375

0
065

0
369

0
217

0
004

BMI

0
221

< 0
001

0
155

0
031

0
198

0
009

Waist circumference

0
448

< 0
001

0
154

0
087

0
321

< 0
001

Systolic blood pressure

0
048

0
363

0
125

0
082

0
035

0
646

Diastolic blood pressure

0
069

0
188

0
065

0
371

0
022

0
776

Duration of hypertension

0
065

0
213

0
109

0
142

0
159

0
045

Alcohol consumption

0
170

0
002

0
044

0
625

0
155

0
053

Total cholesterol

0
084

0
109

0
013

0
854

0
053

0
488

HDL cholesterol

0
325

< 0
001

0
015

0
840

0
315

< 0
001

LDL cholesterol

0
014

0
790

0
081

0
284

0
048

0
542

Triglycerides

0
305

< 0
001

0
212

0
003

0
224

0
003

Creatinine

0
495

< 0
001

0
246

0
001

0
509

< 0
001

GFR

0
142

0
011

0
209

0
005

0
180

0
027

Fasting glucose

0
072

0
173

0
076

0
300

0
026

0
738

Fasting insulin

0
253

< 0
001

0
217

0
007

0
216

0
015

HOMA index

0
256

< 0
001

0
214

0
008

0
212

0
017

AUC-G

0
061

0
360

0
107

0
028

0
122

0
220

AUC-I

0
140

0
038

0
198

0
028

0
042

0
686

LVMI

0
212

< 0
001

0
147

0
041

0
198

0
009

LAD

0
309

< 0
001

0
312

< 0
001

0
002

0
982

E/A

0
092

0
127

0
081

0
355

0
066

0
459

IVRT

0
042

0
581

0
039

0
707

0
073

0
513

Em

0
092

0
372

0
023

0
878

0
136

0
345

Em/Am

0
067

0
512

0
005

0
972

0
010

0
946

E/Em

0
121

0
245

0
359

0
014

0
078

0
595

BMI, body mass index; GFR, glomerular filtration rate; HOMA, homeostatic model assessment; AUC-G, area under the curve of plasma glucose after oral glucose tolerance test; AUC-I, area under the curve of plasma insulin after oral glucose tolerance test; LVMI, left ventricular mass index; LAD, left atrial diameter; E, early-wave transmitral diastolic velocity; A, late-wave transmitral diastolic velocity; IVRT, isovolumetric relaxation time; Em, early-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging; Am, late-diastolic velocity of septal and lateral myocardial portions at tissue Doppler imaging.

intolerance [34], obesity [35] and the metabolic syndrome [30,36], and therefore, the link between uric acid levels and insulin resistance might contribute to explain our findings. The mechanism(s) underlying the interaction of gender on the association between hyperuricaemia and left ventricular mass, however, remain hypothetical. Greater visceral fat accumulation, increased large artery stiffness and blunting of favourable cardiovascular effects of oestrogen [37] caused in women by insulin resistance [38] are possible explanations that should be tested in future studies.

978

Evidence on the association between hyperuricaemia and cardiovascular outcomes is growing [39], and this association might be of great relevance in patients with high blood pressure because uric acid might contribute to subclinical hypertensive organ damage. Circulating levels of uric acid reflect, among many other factors, the activity of xanthine oxidase, an enzyme crucially involved in purine metabolism. Pharmacologic blockade of xanthine oxidase resulting in decreased uric acid generation has been reported to improve endothelial function and decrease markers of inflammation [39]. Also, the

ª 2014 Stichting European Society for Clinical Investigation Journal Foundation

URIC ACID AND THE HEART

Table 4 Univariate correlation analysis with left ventricular mass index as the dependent variable All patients Variable

r

Men P

Women

r

P

r

P

Age

0
218

< 0
001

0
204

0
004

0
291

< 0
001

BMI

0
219

< 0
001

0
143

0
046

0
276

< 0
001

Waist circumference

0
276

< 0
001

0
041

0
651

0
410

< 0
001

Systolic blood pressure

0
309

< 0
001

0
351

< 0
001

0
250

0
001

Diastolic blood pressure

0
125

0
171

0
178

0
014

0
018

0
815

Duration of hypertension

0
065

0
236

0
066

0
388

0
076

0
347

Alcohol consumption

0
077

0
160

0
065

0
394

0
070

0
384

Total cholesterol

0
002

0
974

0
132

0
067

0
179

0
019

HDL cholesterol

0
074

0
171

0
021

0
782

0
026

0
742

LDL cholesterol

0
034

0
531

0
173

0
021

0
177

0
139

Triglycerides

0
139

0
072

0
030

0
685

0
281

< 0
001

Creatinine

0
169

0
014

0
148

0
041

0
086

0
259

GFR

0
133

0
540

0
157

0
038

0
035

0
669

Fasting glucose

0
020

0
706

0
013

0
862

0
010

0
894

Fasting insulin

0
009

0
881

0
008

0
921

0
016

0
857

HOMA index

0
009

0
881

0
008

0
923

0
022

0
812

AUC-G

0
156

0
145

0
014

0
875

0
356

< 0
001

AUC-I

0
157

0
140

0
198

0
028

0
106

0
300

Uric acid

0
212

< 0
001

0
147

0
041

0
198

0
009

BMI, body mass index; GFR, glomerular filtration rate; HOMA, homeostatic model assessment; AUC-G, area under the curve of plasma glucose after oral glucose tolerance test; AUC-I, area under the curve of plasma insulin after oral glucose tolerance test.

Table 5 Multivariate analysis with left ventricular mass index as the dependent variable in men and women Men Variable

b

P

Women Variable

b

P

Age

0
044

0
707

Systolic blood pressure

0
357

0
001

Age

0
242

0
008

Systolic blood pressure

0
374