Abstract

Background:

Left ventricular (LV) hypertrophy and LV diastolic dysfunction, which are common cardiac changes in hypertensive patients, are modified by several nonhemodynamic (eg, genetic, neurohumoral, and metabolic) factors. However, the influence of serum lipids on these LV changes has not been sufficiently studied. Although low high-density lipoprotein (HDL) cholesterol is well known to be a major risk factor for coronary heart disease, it is unclear whether HDL cholesterol plays a role in hypertensive heart disease.

Methods:

In 274 patients with treated essential hypertension, two-dimensional and Doppler echocardiography were performed, and LV mass, ratio of peak velocity of atrial filling to early diastolic filling (A to E ratio [A/E]), and deceleration time of the E-wave were evaluated. The relationship of dyslipidemia, especially low HDL cholesterol, to LV hypertrophy and diastolic function was investigated in these patients.

Results:

In a univariate regression analysis, HDL cholesterol was inversely associated with LV mass, A/E, and deceleration time. The association of HDL cholesterol with LV diastolic function was observed in both men and women. Its association with LV mass was gender-dependent, being significant only in women. Triglycerides were weakly correlated with LV mass and A/E, but total and low-density lipoprotein cholesterol had no correlations with these indices. In a multiple regression analysis, only low HDL cholesterol among several lipid levels was an independent predictor of both LV mass and LV diastolic dysfunction.

Conclusions:

Our findings suggest that low HDL cholesterol may unfavorably modify LV structure and diastolic function in patients with treated essential hypertension.

Left ventricular (LV) hypertrophy and LV diastolic dysfunction, which are common cardiac consequences of hypertension, are both independent risk factors for cardiovascular morbidity and mortality.1,2,3,4 Although LV hypertrophy is primarily considered as an adaptation to the increased afterload, this structural adaptation of LV in hypertension is modified by several nonhemodynamic factors such as genetic, neurohumoral, and metabolic factors.5,6,7 The LV diastolic dysfunction (abnormal relaxation) in hypertensive patients results from an increase in afterload (systemic arterial pressure) and LV hypertrophy, especially concentric hypertrophy.8 However, diastolic dysfunction also may be affected by some factor other than blood pressure (BP) or cardiac hypertrophy in treated hypertension, as it was shown that diastolic impairments of LV function persisted despite effective control of BP in treated hypertensive patients and that these impairments were independent of LV hypertrophy.9 In fact, abnormalities in glucose and insulin metabolism have been shown to accelerate the deterioration of LV diastolic function in essential hypertension.10,11,12

Dyslipidemia is another of the metabolic abnormalities observed most frequently in hypertensive patients. However, the influence of serum lipids on ischemia-independent cardiac structural and functional changes has not been fully elucidated.13,14,15 A positive association between total and low-density lipoprotein (LDL) cholesterol and coronary heart disease is well established, and low high-density lipoprotein (HDL) cholesterol and elevated triglycerides are also known to be risk factors for coronary events.16,17 Despite the growing evidence concerning the impact of these lipid disorders on coronary heart disease, little is known about whether dyslipidemia plays a part in hypertensive heart disease. Thus, the major aim of the present study was to clarify the relationship of dyslipidemia, especially of low HDL cholesterol, to LV hypertrophy and diastolic function in patients with essential hypertension.

Methods

Patients

A total of 274 patients with essential hypertension (144 men and 130 women; mean age (± SD), 61 ± 13 years) were enrolled in our study. Patients with secondary hypertension, coronary heart disease, valvular heart disease, atrial fibrillation, congestive heart failure, renal failure (serum creatinine ≥ 133 μmol/L (1.5 mg/dL)), overt diabetes mellitus, or unsatisfactory B-mode and Doppler echocardiograms were excluded from this study. Individuals treated with lipid-lowering drugs or participants whose serum triglycerides were ≥4.52 mmol/L (≥400 mg/dL) were also excluded from the study. Hypertension was defined as a systolic BP of ≥140 mm Hg and/or a diastolic BP of ≥90 mm Hg by repeated measurements or when medication was taken for treatment of hypertension. Among the 274 patients, 235 (86%) were receiving antihypertensive drugs, including combination therapy in some cases. A total of 175 patients (64%) were treated with calcium channel blockers, 107 (39%) with renin angiotensin system inhibitors, 80 (29%) with β-blockers, 37 (14%) with diuretics, and 31 (11%) with other classes of agents. In all, 39 patients (14%) were treated with diet or exercise therapy, or both, without antihypertensive medication. All subjects gave their informed consent to participate in the present study.

Glucose and lipid measurement

Blood samples were obtained in the morning after an overnight (≥12 h) fast. Fasting plasma glucose and serum concentrations of total cholesterol, HDL cholesterol, and triglycerides were determined by standard laboratory measurements; LDL cholesterol was calculated using the Friedewald formula.18

Echocardiographic examination

On the same day or within 1 week of the blood sampling, comprehensive two-dimensional echocardiography was performed using a cardiac ultrasound unit (Sonos 5500; Hewlett Packard, Andover, MA) as previously described.19 Echocardiographic parameters were measured by the consensus of two experienced investigators who were blinded to the metabolic data of the subjects. Measurements included interventricular septal thickness at end-diastole (IVSTd), posterior wall thickness at end-diastole (PWTd), and LV diameter at end-diastole (LVDd). The LV relative wall thickness was calculated as (IVSTd+PWTd)/LVDd. LV mass was estimated using the formula validated by Devereux and Reichek20: LV mass (g) = 1.04 × {(IVSTd+PWTd+LVDd)3 − LVDd3}− 13.6. The LV mass index was obtained traditionally by dividing the LV mass by body surface area (LVMI(a), g/m2). The LV mass was also indexed by height to the 2.7 power (LVMI(h), g/m2.7), to take into account the influence of obesity that is partly overlooked when indexing for body surface area.21

To assess LV diastolic function, the diastolic filling of LV (LV inflow) was examined using Doppler echocardiography. The LV diastolic filling pattern was obtained with the sample volume at the tips of the mitral valve in the apical four-chamber view and recorded at the end-expiratory phase during quiet breathing.22 The peak velocity of the early diastolic filling wave (E wave) and the peak velocity of atrial filling (A wave) were recorded and the A to E ratio (A/E) was calculated. The deceleration time was measured as the time between the top of the E wave and the point where the descending part of the E wave or its asymptote crossed the zero line.

Statistical analysis

Values are expressed as mean ± SD. Unpaired t test was used for comparison between the two groups. The significance of differences among more than two groups was evaluated by an unpaired analysis of variance with subsequent use of Fisher's multiple comparison test. Relationships between variables were assessed using univariate linear regression analyses and Pearson's correlation coefficient. Stepwise multiple regression analyses were performed to identify independent predictors of LV mass and LV diastolic function. Age, gender, body mass index, systolic and diastolic BP, fasting plasma glucose, and total LDL, and HDL cholesterol, triglycerides, as well as use of each type of antihypertensive drug (calcium channel blocker, renin angiotensin system inhibitor, β-blocker, or diuretic) were included as potential independent variables. LVMI(a), LVMI(h), relative wall thickness, and heart rate were added as independent variables in the analysis for diastolic function. A value of P < .05 was accepted as statistically significant.

Results

Clinical and echocardiographic characteristics of the study subjects are shown in Table 1. There were no significant differences in age, body mass index, systolic BP, diastolic BP, or fasting plasma glucose between men and women. Heart rate was somewhat increased in women. However, no gender differences were found in the percentage of patients treated with any type of antihypertensive drug (data not shown). Serum levels of total cholesterol and HDL cholesterol were higher, and that of triglycerides was lower, in women than in men. LVMI(a), LV mass normalized for body surface area, in addition to IVSTd, PWTd, and LVDd were significantly increased in men compared with women, but LVMI(h), LV mass normalized for height2.7, did not differ between genders. The A/E ratio and deceleration time, indices of LV diastolic function, also did not differ by gender.

Table 1

Clinical and echocardiographic characteristics of the study subjects

 All (n = 274) Men (n = 144) Women (n = 130) 
Age, y 61 ± 13 60 ± 13 62 ± 11 
Body mass index, kg/m2 24.3 ± 3.3 24.5 ± 2.8 24.0 ± 3.8 
Systolic blood pressure, mm Hg 143 ± 14 143 ± 13 142 ± 15 
Diastolic blood pressure, mm Hg 83 ± 9 84 ± 9 82 ± 10 
Heart rate, beats/min 66 ± 10 64 ± 10 68 ± 10* 
Fasting plasma glucose, mmol/L 5.50 ± 0.81 5.55 ± 0.82 5.46 ± 0.80 
Total cholesterol, mmol/L 5.23 ± 0.73 5.11 ± 0.73 5.37 ± 0.70 
LDL cholesterol, mmol/L 3.25 ± 0.66 3.19 ± 0.64 3.31 ± 0.68 
HDL cholesterol, mmol/L 1.37 ± 0.41 1.24 ± 0.29 1.52 ± 0.46 
Triglycerides, mmol/L 1.33 ± 0.67 1.47 ± 0.74 1.17 ± 0.53 
IVSTd, mm 10.7 ± 1.7 11.1 ± 1.7 10.3 ± 1.7 
PWTd, mm 10.7 ± 1.6 11.1 ± 1.5 10.2 ± 1.5 
LVDd, mm 45.5 ± 4.5 47.1 ± 3.8 43.8 ± 4.7 
LVMI(a), g/m2 124 ± 30 130 ± 29 116 ± 30 
LVMI(h), g/m2.7 57.6 ± 15.0 58.5 ± 14.3 56.5 ± 15.7 
Relative wall thickness 0.48 ± 0.09 0.48 ± 0.08 0.47 ± 0.10 
E wave velocity, m/sec 0.70 ± 0.16 0.69 ± 0.17 0.71 ± 0.16 
A wave velocity, m/sec 0.79 ± 0.17 0.77 ± 0.18 0.82 ± 0.16* 
A/E ratio 1.19 ± 0.34 1.18 ± 0.34 1.20 ± 0.34 
Deceleration time, msec 226 ± 45 227 ± 43 226 ± 48 
 All (n = 274) Men (n = 144) Women (n = 130) 
Age, y 61 ± 13 60 ± 13 62 ± 11 
Body mass index, kg/m2 24.3 ± 3.3 24.5 ± 2.8 24.0 ± 3.8 
Systolic blood pressure, mm Hg 143 ± 14 143 ± 13 142 ± 15 
Diastolic blood pressure, mm Hg 83 ± 9 84 ± 9 82 ± 10 
Heart rate, beats/min 66 ± 10 64 ± 10 68 ± 10* 
Fasting plasma glucose, mmol/L 5.50 ± 0.81 5.55 ± 0.82 5.46 ± 0.80 
Total cholesterol, mmol/L 5.23 ± 0.73 5.11 ± 0.73 5.37 ± 0.70 
LDL cholesterol, mmol/L 3.25 ± 0.66 3.19 ± 0.64 3.31 ± 0.68 
HDL cholesterol, mmol/L 1.37 ± 0.41 1.24 ± 0.29 1.52 ± 0.46 
Triglycerides, mmol/L 1.33 ± 0.67 1.47 ± 0.74 1.17 ± 0.53 
IVSTd, mm 10.7 ± 1.7 11.1 ± 1.7 10.3 ± 1.7 
PWTd, mm 10.7 ± 1.6 11.1 ± 1.5 10.2 ± 1.5 
LVDd, mm 45.5 ± 4.5 47.1 ± 3.8 43.8 ± 4.7 
LVMI(a), g/m2 124 ± 30 130 ± 29 116 ± 30 
LVMI(h), g/m2.7 57.6 ± 15.0 58.5 ± 14.3 56.5 ± 15.7 
Relative wall thickness 0.48 ± 0.09 0.48 ± 0.08 0.47 ± 0.10 
E wave velocity, m/sec 0.70 ± 0.16 0.69 ± 0.17 0.71 ± 0.16 
A wave velocity, m/sec 0.79 ± 0.17 0.77 ± 0.18 0.82 ± 0.16* 
A/E ratio 1.19 ± 0.34 1.18 ± 0.34 1.20 ± 0.34 
Deceleration time, msec 226 ± 45 227 ± 43 226 ± 48 

IVSTd = interventricular septal thickness at end-diastole; LVDd = left ventricular diameter at end-diastole; LVMI(a) = left ventricular mass indexed by body surface area; LVMI(h) = left ventricular mass indexed by height2.7; PWTd = posterior wall thickness at end-diastole. Values are mean ± SD.

*

P < .05 and

P < .01 v men.

We examined the association of lipid levels with echocardiographic parameters of LV hypertrophy and diastolic function, in all subjects or separately in men and women. No significant correlation was found between total or LDL cholesterol and LV mass or diastolic function without regard to gender (Table 2). In contrast, HDL cholesterol showed significant negative correlations with all parameters of LV hypertrophy, ie, LVMI(a) and LVMI(h), and diastolic dysfunction (A/E and deceleration time) in the overall subject group. The association of HDL cholesterol with LV diastolic function was observed in both men and women. However, its association with LV mass was gender-dependent; ie, HDL cholesterol was inversely associated with LVMI(a) and LVMI(h) in women only. Triglycerides showed a positive correlation with LV mass in all subjects and in women and a weak correlation with the A/E ratio only in men.

Table 2

Correlation between lipid levels and indices of LV hypertrophy and diastolic function

 LVMI(a) LVMI(h) A/E DcT 
Total Cholesterol     
All −0.07 −0.02 0.03 0.05 
Men −0.06 −0.04 0.06 0.06 
Women 0.00 0.02 −0.01 0.04 
LDL Cholesterol     
All 0.00 0.05 0.07 0.12 
Men −0.06 −0.03 0.06 0.10 
Women 0.10 0.14 0.08 0.14 
HDL Cholesterol     
All −0.21 −0.22 −0.15* −0.18 
Men −0.02 −0.05 −0.19* −0.17* 
Women −0.24 −0.31 −0.17* −0.20* 
Triglycerides     
All 0.13* 0.14* 0.12 0.09 
Men −0.01 0.03 0.17* 0.08 
Women 0.21* 0.21 0.06 0.10 
 LVMI(a) LVMI(h) A/E DcT 
Total Cholesterol     
All −0.07 −0.02 0.03 0.05 
Men −0.06 −0.04 0.06 0.06 
Women 0.00 0.02 −0.01 0.04 
LDL Cholesterol     
All 0.00 0.05 0.07 0.12 
Men −0.06 −0.03 0.06 0.10 
Women 0.10 0.14 0.08 0.14 
HDL Cholesterol     
All −0.21 −0.22 −0.15* −0.18 
Men −0.02 −0.05 −0.19* −0.17* 
Women −0.24 −0.31 −0.17* −0.20* 
Triglycerides     
All 0.13* 0.14* 0.12 0.09 
Men −0.01 0.03 0.17* 0.08 
Women 0.21* 0.21 0.06 0.10 

DcT = deceleration time of the E wave. Values are correlation coefficients.

*

P < .05;

P < .01.

We found that HDL cholesterol and triglycerides were also correlated with body mass index (HDL cholesterol, r = −0.31, P < .001; triglycerides, r = 0.26, P < .001) and with fasting plasma glucose (HDL cholesterol, r = −0.20, P = .001; triglycerides, r = 0.25, P < .001) in all subjects. These two lipid levels showed no association with age, BP, or heart rate (data not shown).

Next, we subdivided each study group (men and women) by gender-specific tertiles of HDL cholesterol and triglycerides. We then examined the influence of the lowest HDL cholesterol tertile (men, <1.14 mmol/L [44 mg/dL]; women, <1.27 mmol/L [49 mg/dL]) or the highest triglyceride tertile (men, ≥ 1.56 mmol/L [138 mg/dL]; women, ≥ 1.32 mmol/L [117 mg/dL]) on LV mass and diastolic function. All subjects were divided by these lipid levels into four groups; subjects without the lowest HDL cholesterol or the highest triglyceride tertile (group 1, n = 133), with the highest triglyceride tertile alone (group 2, n = 47), with the lowest HDL cholesterol tertile alone (group 3, n = 49), and with both the lowest HDL cholesterol and the highest triglyceride tertiles (group 4, n = 45). There were no significant differences in age, gender (percentage of men), BP, or heart rate among the four study groups (Table 3). Body mass index was higher in groups 2, 3, and 4 than in group 1. The fasting plasma glucose level in group 4 was higher than that in groups 1 and 3. All lipid parameters had group-specific differences as shown in Table 3. LVMI(h), but not LVMI(a), was slightly but significantly increased in group 4 compared with group 1 (Figs. 1A, 1B). The A/E ratio in groups 3 and 4 (ie, those subjects who were in the lowest tertile of HDL cholesterol) was significantly higher than in the other groups, and group 4 had the highest A/E ratio (1.31 ± 0.29) among the four study groups (Fig. 1C). The deceleration time in group 4 (245 ± 48 msec) was also prolonged significantly in comparison with the other three groups (Fig. 1D).

Table 3

Comparison of clinical findings among the four groups divided by HDL cholesterol and triglyceride levels

 Group 1 (n = 133) Group 2 (n = 47) Group 3 (n = 49) Group 4 (n = 45) 
Age, y 60 ± 12 59 ± 11 62 ± 15 63 ± 11 
Gender (men), % 50.4 59.6 59.2 44.4 
Body mass index, kg/m2 23.3 ± 3.3 25.0 ± 2.6* 25.0 ± 3.4* 25.5 ± 3.1* 
Systolic blood pressure, mm Hg 142 ± 14 142 ± 17 144 ± 13 143 ± 13 
Diastolic blood pressure, mm Hg 84 ± 9 84 ± 11 83 ± 8 83 ± 9 
Heart rate, beats/min 66 ± 10 66 ± 10 65 ± 10 68 ± 9 
Fasting plasma glucose, mmol/L 5.38 ± 0.75 5.59 ± 0.68 5.43 ± 0.92 5.85 ± 0.92*, 
Total cholesterol, mmol/L 5.22 ± 0.70 5.59 ± 0.58* 4.92 ± 0.68*, 5.22 ± 0.82 
LDL cholesterol, mmol/L 3.18 ± 0.64 3.22 ± 0.56 3.42 ± 0.61* 3.28 ± 0.83 
HDL cholesterol, mmol/L 1.62 ± 0.38 1.45 ± 0.27* 1.00 ± 0.14*, 1.00 ± 0.14*, 
Triglycerides, mmol/L 0.92 ± 0.27 2.02 ± 0.71* 1.10 ± 0.24*, 2.08 ± 0.55*, 
 Group 1 (n = 133) Group 2 (n = 47) Group 3 (n = 49) Group 4 (n = 45) 
Age, y 60 ± 12 59 ± 11 62 ± 15 63 ± 11 
Gender (men), % 50.4 59.6 59.2 44.4 
Body mass index, kg/m2 23.3 ± 3.3 25.0 ± 2.6* 25.0 ± 3.4* 25.5 ± 3.1* 
Systolic blood pressure, mm Hg 142 ± 14 142 ± 17 144 ± 13 143 ± 13 
Diastolic blood pressure, mm Hg 84 ± 9 84 ± 11 83 ± 8 83 ± 9 
Heart rate, beats/min 66 ± 10 66 ± 10 65 ± 10 68 ± 9 
Fasting plasma glucose, mmol/L 5.38 ± 0.75 5.59 ± 0.68 5.43 ± 0.92 5.85 ± 0.92*, 
Total cholesterol, mmol/L 5.22 ± 0.70 5.59 ± 0.58* 4.92 ± 0.68*, 5.22 ± 0.82 
LDL cholesterol, mmol/L 3.18 ± 0.64 3.22 ± 0.56 3.42 ± 0.61* 3.28 ± 0.83 
HDL cholesterol, mmol/L 1.62 ± 0.38 1.45 ± 0.27* 1.00 ± 0.14*, 1.00 ± 0.14*, 
Triglycerides, mmol/L 0.92 ± 0.27 2.02 ± 0.71* 1.10 ± 0.24*, 2.08 ± 0.55*, 

Values are mean ± SD or percentage.

*

P < .05 v group 1.

P < .05 v group 2.

P < .05 v group 3.

Comparison of LVMI(a) (A), LVMI(h) (B), A to E ratio (C), and deceleration time of the E wave (D) among the four groups divided by HDL cholesterol and triglyceride levels. Values are given as mean ± SD. *P < .05 compared with group 1; †P < .05 compared with group 2; ‡P < .05 compared with group 3.

To confirm whether the effect of low HDL cholesterol on LV hypertrophy was independent of other factors (especially high triglycerides, glucose levels, obesity, gender, and use of specific types of antihypertensive drugs) and whether its effect on LV diastolic function was independent of LV hypertrophy, we investigated possible predictive factors for LVMI(a), LVMI(h), A/E ratio, and deceleration time using a stepwise regression analysis in all subjects. As a result, low HDL cholesterol as well as age, male gender, body mass index, systolic BP, and use of β-blockers was an independent determinant of LV mass, both LVMI(a) and LVMI(h) (Table 4). When the analysis was performed separately in men and women, the independent relation of low HDL cholesterol to LV mass was observed in women only (data not shown). As for the association with LV diastolic function, low HDL cholesterol was a significant predictor of both A/E ratio and deceleration time, independent of other predictive factors such as age, relative wall thickness, heart rate, and use of diuretics. A high level of triglycerides in addition to total and LDL cholesterol could not be adopted as an independent determinant of LV mass or diastolic dysfunction.

Table 4

Independent predictors for LV mass and diastolic dysfunction by stepwise regression analysis

 Standardized Regression Coefficient F Value P Value 
LVMI(a)    
Systolic blood pressure 0.236 18.65  
Use of β-blockers 0.220 16.12  
Gender (male) 0.213 13.36  
Age 0.182 10.37  
HDL cholesterol −0.180 9.30 < .0001 
LVMI(h)    
Body mass index 0.291 26.52  
Systolic blood pressure 0.233 19.17  
Age 0.234 18.03  
Use of β-blockers 0.215 16.40  
HDL cholesterol −0.160 7.92 < .0001 
A/E ratio    
Age 0.484 89.88  
Relative wall thickness 0.166 10.54  
HDL cholesterol −0.139 7.53  
Heart rate 0.130 6.64 < .0001 
Deceleration time    
Age 0.273 23.26  
Use of diuretics 0.169 9.04  
HDL cholesterol −0.164 8.66  
Relative wall thickness 0.138 5.94 < .0001 
 Standardized Regression Coefficient F Value P Value 
LVMI(a)    
Systolic blood pressure 0.236 18.65  
Use of β-blockers 0.220 16.12  
Gender (male) 0.213 13.36  
Age 0.182 10.37  
HDL cholesterol −0.180 9.30 < .0001 
LVMI(h)    
Body mass index 0.291 26.52  
Systolic blood pressure 0.233 19.17  
Age 0.234 18.03  
Use of β-blockers 0.215 16.40  
HDL cholesterol −0.160 7.92 < .0001 
A/E ratio    
Age 0.484 89.88  
Relative wall thickness 0.166 10.54  
HDL cholesterol −0.139 7.53  
Heart rate 0.130 6.64 < .0001 
Deceleration time    
Age 0.273 23.26  
Use of diuretics 0.169 9.04  
HDL cholesterol −0.164 8.66  
Relative wall thickness 0.138 5.94 < .0001 

Discussion

The relationship between LV hypertrophy and HDL cholesterol levels in hypertensive patients or population-based samples has been reported in previous studies, with conflicting results.14,15,23,24,25,26,27 Among these studies, only one report by Schillaci et al14 has revealed an independent relationship of low HDL cholesterol to LV mass in male and female hypertensive patients. The present observations concerning the associations between several lipid levels and LV mass are broadly consistent with their findings. In our study, however, the significant association of HDL cholesterol with LV mass by univariate and multivariate regression analyses was observed only in women. Although the exact reason for the inconsistent findings in men among these studies is unclear, the gender (women)–specific influence of HDL cholesterol on LV mass was also reported from the Framingham Heart Study.23 Furthermore, LV hypertrophy has a greater impact on total and cardiac mortality in women than in men.28 These findings suggest that the contribution of low HDL cholesterol to hypertensive heart disease is possibly stronger in women than in men, as low HDL cholesterol appears to raise the risk for coronary heart disease more potently in women compared with men.29

Impaired LV diastolic relaxation is another common cardiac change observed in hypertensive patients; this diastolic dysfunction has a prognostic significance, independent of BP and LV mass.4 Nonetheless, the relationship of serum lipids to LV diastolic function in essential hypertension has never been investigated until now. Only one recent study showed in a limited population of postmenopausal women that total, LDL, and HDL cholesterol were correlated with an abnormal LV diastolic filling pattern. In the present study, we first demonstrated that HDL cholesterol, but not total or LDL cholesterol, had a significant association with impairments of LV diastolic relaxation in both men and women with essential hypertension, and that the association between the two was independent of traditional determinants of impaired LV relaxation such as age and LV concentric hypertrophy. Therefore, our findings suggest that low HDL cholesterol may exert an adverse effect on LV diastolic function in hypertensive subjects regardless of gender, BP level, or LV structure.

In the present study, triglyceride levels showed a small correlation with LV mass and diastolic function, although total or LDL cholesterol was not associated with these echocardiographic indices at all. In addition, LV hypertrophy and LV diastolic dysfunction were most advanced in a subgroup with both low HDL cholesterol and high triglycerides. Individuals in this group were also accompanied with increased body mass index and elevated plasma glucose level, and so they appeared to belong to a cluster of multiple interrelated abnormalities in lipid and glucose metabolism along with hypertension and obesity, called the metabolic syndrome.30,31 Insulin resistance with compensatory hyperinsulinemia is considered to be a primary pathophysiologic basis of the syndrome in hypertensive subjects.30,31 As a possible explanation for the effects of low HDL cholesterol on cardiac structural and functional alterations, therefore, the involvement of insulin resistance and hyperinsulinemia could be included. In fact, serum levels of HDL cholesterol are inversely correlated with serum insulin levels,32 and some studies have reported that hyperinsulinemia or insulin resistance is related to LV hypertrophy and diastolic dysfunction in hypertensive patients.12,33 However, other studies have shown that such abnormalities in insulin metabolism per se are not associated with either increased LV mass or impaired LV diastolic function.10,27,34,35 Our multiple regression study also showed that the associations of low HDL cholesterol with these cardiac changes were independent of the other components of the metabolic syndrome such as BP, body mass index, plasma glucose, and serum triglyceride levels. However, the independent relationship of HDL cholesterol to LV structure and function may have reflected a relationship to other, unmeasurable variables that were more directly implicated in the pathogenesis of the association, as we did not determine the plasma insulin concentration or insulin resistance index in the present cohort. Further investigations are needed to clarify whether insulin resistance is really involved in the relationship between low HDL cholesterol and LV hypertrophy and diastolic dysfunction.

A limitation of the present study may be that the majority of patients in this study were administered antihypertensive drugs. Therefore, we must consider the possibility that some types of antihypertensive agents may have affected cardiac structure and function and lipid levels.12,36 In particular, β-blockers and diuretics unfavorably affect serum lipid profiles36 and also may influence LV dimension and diastolic filling patterns. However, our multivariate analysis proved that the associations of low HDL cholesterol with LV mass and LV diastolic function were independent of the use of these types of antihypertensive drugs.

In conclusion, the present study has demonstrated that low serum level of HDL cholesterol is one of the independent determinants of LV mass in patients with essential hypertension and that low HDL cholesterol is also related to the deterioration of LV diastolic function, independent of that exerted by LV hypertrophy. These findings observed in patients with chronically treated hypertension suggest that such a metabolic factor as low HDL cholesterol modifies the growth and diastolic properties of LV in these patients, even if antihypertensive treatments suppress the elevation of BP. Low HDL cholesterol may be a risk factor not only for coronary heart disease but also for hypertensive heart disease.

References

1.
Levy
D
,
Garrison
RJ
,
Savage
DD
,
Kannel
WB
,
Castelli
WP
:
Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study
.
N Engl J Med
 
1990
;
322
:
1561
1566
.
2.
Koren
MJ
,
Devereux
RB
,
Casale
PN
,
Savage
DD
,
Laragh
JH
:
Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension
.
Ann Intern Med
 
1991
;
114
:
345
352
.
3.
Bella
JN
,
Palmieri
V
,
Roman
MJ
,
Liu
JE
,
Welty
TK
,
Lee
ET
,
Fabsitz
RR
,
Howard
BV
,
Devereux
RB
:
Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study
.
Circulation
 
2002
;
105
:
1928
1933
.
4.
Schillaci
G
,
Pasqualini
L
,
Verdecchia
P
,
Vaudo
G
,
Marchesi
S
,
Porcellati
C
,
de Simone
G
,
Mannarino
E
:
Prognostic significance of left ventricular diastolic dysfunction in essential hypertension
.
J Am Coll Cardiol
 
2002
;
39
:
2005
2011
.
5.
Schunkert
H
,
Hense
HW
,
Holmer
SR
,
Stender
M
,
Perz
S
,
Keil
U
,
Lorell
BH
,
Riegger
GAJ
:
Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy
.
N Engl J Med
 
1994
;
330
:
1634
1638
.
6.
Morgan
HE
,
Baker
KM
:
Cardiac hypertrophy: mechanical, neural, and endocrine dependence
.
Circulation
 
1991
;
83
:
13
25
.
7.
de Simone
G
,
Palmieri
V
,
Bella
JN
,
Celentano
A
,
Hong
Y
,
Oberman
A
,
Kitzman
DW
,
Hopkins
PN
,
Arnett
DK
,
Devereux
RB
:
Association of left ventricular hypertrophy with metabolic risk factors: the HyperGEN study
.
J Hypertens
 
2002
;
20
:
323
331
.
8.
Andrén
B
,
Lind
L
,
Hedenstierna
G
,
Lithell
H
:
Left ventricular hypertrophy and geometry in a population sample of elderly males
.
Eur Heart J
 
1996
;
17
:
1800
1807
.
9.
Phillips
RA
,
Coplan
NL
,
Krakoff
LR
,
Yeager
K
,
Ross
RS
,
Gorlin
R
,
Goldman
ME
:
Doppler echocardiographic analysis of left ventricular filling in treated hypertensive patients
.
J Am Coll Cardiol
 
1987
;
9
:
317
322
.
10.
Nagano
N
,
Nagano
M
,
Yo
Y
,
Iiyama
K
,
Higaki
J
,
Mikami
H
,
Ogihara
T
:
Role of glucose intolerance in cardiac diastolic function in essential hypertension
.
Hypertension
 
1994
;
23
:
1002
1005
.
11.
Miyazato
J
,
Horio
T
,
Takishita
S
,
Kawano
Y
:
Fasting plasma glucose is an independent determinant of left ventricular diastolic dysfunction in nondiabetic patients with treated essential hypertension
.
Hypertens Res
 
2002
;
25
:
403
409
.
12.
Watanabe
K
,
Sekiya
M
,
Tsuruoka
T
,
Funada
J
,
Kameoka
H
:
Effect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension
.
J Hypertens
 
1999
;
17
:
1153
1160
.
13.
Sundström
J
,
Lind
L
,
Vessby
B
,
Andrén
B
,
Aro
A
,
Lithell
H
:
Dyslipidemia and an unfavorable fatty acid profile predict left ventricular hypertrophy 20 years later
.
Circulation
 
2001
;
103
:
836
841
.
14.
Schillaci
G
,
Vaudo
G
,
Reboldi
G
,
Verdecchia
P
,
Lupattelli
G
,
Pasqualini
L
,
Porcellati
C
,
Mannarino
E
:
High-density lipoprotein cholesterol and left ventricular hypertrophy in essential hypertension
.
J Hypertens
 
2001
;
19
:
2265
2270
.
15.
Palmiero
P
,
Maiello
M
,
Passantino
A
,
Antoncecchi
E
,
Deveredicis
C
,
DeFinis
A
,
Ostuni
V
,
Romano
E
,
Mengoli
P
,
Caira
D
:
Correlation between diastolic impairment and lipid metabolism in mild-to-moderate hypertensive postmenopausal women
.
Am J Hypertens
 
2002
;
15
:
615
620
.
16.
Gordon
DJ
,
Rifkind
BM
:
High-density lipoprotein—the clinical implications of recent studies
.
N Engl J Med
 
1989
;
321
:
1311
1316
.
17.
Manninen
V
,
Tenkanen
L
,
Koskinen
P
,
Huttunen
JK
,
Mänttäri
M
,
Heinonen
OP
,
Frick
MH
:
Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment
.
Circulation
 
1992
;
85
:
37
45
.
18.
Friedewald
WT
,
Levy
RI
,
Fredrickson
DS
:
Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge
.
Clin Chem
 
1972
;
18
:
499
502
.
19.
Iwashima
Y
,
Horio
T
,
Kuroda
S
,
Takishita
S
,
Kawano
Y
:
Influence of plasma aldosterone on left ventricular geometry and diastolic function in treated essential hypertension
.
Hypertens Res
 
2002
;
25
:
49
56
.
20.
Devereux
RB
,
Reichek
N
:
Echocardiographic determination of left ventricular mass in man: anatomic validation of the method
.
Circulation
 
1977
;
55
:
613
618
.
21.
de Simone
G
,
Daniels
SR
,
Devereux
RB
,
Meyer
RA
,
Roman
MJ
,
de Divitiis
O
,
Alderman
MH
:
Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight
.
J Am Coll Cardiol
 
1992
;
20
:
1251
1260
.
22.
Rakowski
H
,
Appleton
C
,
Chan
KL
,
Dumesnil
JG
,
Honos
G
,
Jue
J
,
Koilpillai
C
,
Lepage
S
,
Martin
RP
,
Mercier
LA
,
O'Kelly
B
,
Prieur
T
,
Sanfilippo
A
,
Sasson
Z
,
Alvarez
N
,
Pruitt
R
,
Thompson
C
,
Tomlinson
C
:
Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography
.
J Am Soc Echocardiogr
 
1996
;
9
:
736
760
.
23.
Levy
D
,
Garrison
RJ
,
Savage
DD
,
Kannel
WB
,
Castelli
WP
:
Left ventricular mass and incidence of coronary heart disease in an elderly cohort: the Framingham Heart Study
.
Ann Intern Med
 
1989
;
110
:
101
107
.
24.
Gardin
JM
,
Arnold
A
,
Gottdiener
JS
,
Wong
ND
,
Fried
LP
,
Klopfenstein
HS
,
O'Leary
DH
,
Tracy
R
,
Kronmal
R
:
Left ventricular mass in the elderly: the Cardiovascular Health Study
.
Hypertension
 
1997
;
29
:
1095
1103
.
25.
Palmieri
V
,
de Simone
G
,
Roman
MJ
,
Schwartz
JE
,
Pickering
TG
,
Devereux
RB
:
Ambulatory blood pressure and metabolic abnormalities in hypertensive subjects with inappropriately high left ventricular mass
.
Hypertension
 
1999
;
34
:
1032
1040
.
26.
Armario
P
,
Hernández del Rey
R
,
Sánchez
P
,
Martín-Baranera
M
,
Torres
G
,
Juliá
J
,
Pardell
H
:
Determinants of left ventricular mass in untreated mildly hypertensive subjects: hospitalet study in mild hypertension
.
Am J Hypertens
 
1999
;
12
:
1084
1090
.
27.
Sundström
J
,
Lind
L
,
Nyström
N
,
Zethelius
B
,
Andrén
B
,
Hales
CN
,
Lithell
HO
:
Left ventricular concentric remodeling rather than left ventricular hypertrophy is related to the insulin resistance syndrome in elderly men
.
Circulation
 
2000
;
101
:
2595
2600
.
28.
Liao
Y
,
Cooper
RS
,
Mensah
GA
,
McGee
DL
:
Left ventricular hypertrophy has a greater impact on survival in women than in men
.
Circulation
 
1995
;
92
:
805
810
.
29.
Wilson
PWF
:
High-density lipoprotein, low-density lipoprotein and coronary artery disease
.
Am J Cardiol
 
1990
;
66
:
7A
10A
.
30.
Ferrannini
E
,
Haffner
SM
,
Mitchell
BD
,
Stern
MP
:
Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome
.
Diabetologia
 
1991
;
34
:
416
422
.
31.
Grundy
SM
:
Hypertriglyceridemia, insulin resistance, and the metabolic syndrome
.
Am J Cardiol
 
1999
;
83
:
25F
29F
.
32.
Goodfriend
TL
,
Egan
B
,
Stepniakowski
K
,
Ball
DL
:
Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans
.
Hypertension
 
1995
;
25
:
30
36
.
33.
Lind
L
,
Andersson
PE
,
Andrén
B
,
Hänni
A
,
Lithell
HO
:
Left ventricular hypertrophy in hypertension is associated with the insulin resistance metabolic syndrome
.
J Hypertens
 
1995
;
13
:
433
438
.
34.
Hara-Nakamura
N
,
Kohara
K
,
Sumimoto
T
,
Lin
M
,
Hiwada
K
:
Glucose intolerance exaggerates left ventricular hypertrophy and dysfunction in essential hypertension
.
Am J Hypertens
 
1994
;
7
:
1110
1114
.
35.
Galvan
AQ
,
Galetta
F
,
Natali
A
,
Muscelli
E
,
Sironi
AM
,
Cini
G
,
Camastra
S
,
Ferrannini
E
:
Insulin resistance and hyperinsulinemia: no independent relation to left ventricular mass in humans
.
Circulation
 
2000
;
102
:
2233
2238
.
36.
Kasiske
BL
,
Ma
JZ
,
Kalil
RSN
,
Louis
TA
:
Effects of antihypertensive therapy on serum lipids
.
Ann Intern Med
 
1995
;
122
:
133
141
.