Abstract
BACKGROUND
The association between impaired renal function and increase left ventricular mass was shown to be related to increase in arterial stiffness, which indicates that vascular homeostasis and remodeling may impact the left ventricular hypertrophy (LVH) in patients with renal dysfunction.
METHODS
We measured the peripheral arterial reactive hyperemia index (RHI) and estimated glomerular filtration rate (eGFR) in 317 hypertensive patients comprising 115 normal RHI (RHI > 1.67) and normal eGFR (eGFR ≥ 90ml/min per 1.73 m2), 136 low RHI (RHI ≤ 1.67), 27 low eGFR (60 ≤ eGFR < 90ml/min per 1.73 m2) and 39 low RHI combined with low eGFR.
RESULTS
Multivariate logistic regression analysis identified lg RHI (odds ratio (OR): 0.001, 95% confidence interval (CI): 10–6 to 0.426, P = 0.024) and lg eGFR (OR: 0.009, 95% CI: 10–4 to 0.414, P = 0.016) as independent factors correlated with LVH respectively in hypertensive patients. Compared with normal RHI and eGFR patients, the extent of LVH in patients with either low RHI (OR: 1.224 95% CI: 0.451 to 3.327, P = 0.691) or low eGFR (OR: 0.593 95% CI: 0.070 to 5.037, P = 0.632) did not significantly increase, while it increased significantly in patients with low RHI combined with low eGFR (OR: 4.629 95% CI: 1.592 to 13.458, P = 0.005).
CONCLUSIONS
The concurrence of endothelial and mild renal dysfunction was significantly associated with the severity of LVH in hypertensive patients.
Keywords: blood pressure, endothelial dysfunction, hypertension, left ventricular hypertrophy, renal dysfunction.
It is widely accepted that endothelial dysfunction is the basis for the development of cardiovascular diseases, including cardiac remodeling, and that it predicts future cardiovascular morbidity.1 There have been a few reports showing a significant association between endothelial dysfunction and increased left ventricular mass (LVM),2–5 whereas 1 report could not find the association.6 In a recent prospective study, endothelial dysfunction (investigated by intra-arterial infusions of acetylcholine) was associated with the progression of LVM.5
Similarly, renal impairment is recognized as a powerful and independent risk factor for left ventricular hypertrophy (LVH).7 LVH is a very common structural abnormality among patients with end-stage renal disease, with a prevalence of more than 70%.8 More recently, a high prevalence of LVH has also been described in patients with less severe renal impairment. Data from the Framingham study,9 the Hoorn study,7 as well as from recent investigations,10–15 showed that the relationship between renal dysfunction (renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) < 60 to 90ml/min per 1.73 m2 or serum creatinine 1.5 to 3.0mg/dl in men and 1.4 to 3.0mg/dl in women and/or the presence of microalbuminuria) and increased LVM is continuous. Importantly, chronic kidney disease (CKD) with mild renal dysfunction accounted for most of the individuals with CKD,16,17 which rationalizes the clinical significance of LVH in patients with earlier stages of renal dysfunction.
Notably, the association between impaired renal function and increase LVM was shown to be related to increase in arterial stiffness,7 which indicates that vascular homeostasis and remodeling may additively aggravate the abnormality of left ventricular geometry. However, to the best of our knowledge, there is no study reporting the impact of vascular homeostasis and remodeling on LVH in hypertensive patients with earlier renal dysfunction (defined as an eGFR between 60 and 89ml/min per 1.73 m2). Therefore, in this study, we measured endothelial function using a fingertip pulse amplitude tonometry (PAT) device and eGFR in a group of patients to clarify the impact of endothelial dysfunction on LVH in patients with earlier stage of renal dysfunction and hypertension.
METHODS
We describe the methods below with additional technical details available in the Supplementary Methods.
Study patients and design
We evaluated 387 consecutive hypertensive patients who were subjected to peripheral endothelial function measurement at Second Affiliated Hospital of Nanchang University, from December 2013 to January 2015. Primary hypertension was defined as being received antihypertensive drugs or systolic blood pressure ≥140mm Hg and/or diastolic blood pressure ≥90mm Hg. Exclusion criteria were secondary hypertension, cardiomyopathy (hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy), previously diagnosed diabetes mellitus, moderate or severe reduction in eGFR (eGFR < 60ml/min per 1.73 m2), Parkinson’s disease, severe systemic diseases including systemic lupus erythematosus, severe liver disease, patients with significant aortic or mitral valve disease, and inadequate image visualization were also excluded. Of those eligible for participation, we excluded 70 subjects because of patients without hypertension (n = 11), moderate or severe reduction in eGFR (eGFR < 60ml/min per 1.73 m2) (n = 23), poor PAT signal quality (n = 3), missing covariate data (n = 32) and duplicate record (n = 1) (Supplementary Figure S1).
All patients underwent routine medical history, physical examination, echocardiography, digital pulse amplitude, and laboratory assessment. The study was approved by the Medical Research Ethics Committee of Second Affiliated Hospital of Nanchang University and a signed informed consent was obtained from each patient before participation.
Creatinine clearance
eGFR was calculated according to the modified glomerular filtration rate estimating equation for Chinese patients with CKD: eGFR modification of diet in renal disease (MDRD) = 186 × (serum creatinine in mg/dl)−1.154 × (age in years)−0.203×0.742 (if female) × 1.233.18 Definition and classification of stages of CKD were made using standard criteria.19
Echocardiography
All echocardiographic studies were performed with a Siemens-Acuson Sequoia 512 ultrasound machine (Siemens, Erlangen, Germany). Two-dimensional and 2-dimensionally guided M-mode images were recorded from standardized views according to the recommendations of the American Society of Echocardiography.20 LVH was defined as left ventricular mass index (LVMI) ≥ 125g/m2 in men, and ≥ 120g/m2 in women, respectively.21
Determination of digital pulse amplitude
Digital pulse amplitude was measured with a PAT device placed on the tip of each index finger (Endo-PAT 2000 device, Itamar Medical, Caesarea, Israel), as described previously.22 All tests were performed in the morning in a quiet, air-conditioned room with a temperature of 22–24 °C. Reactive hyperemia index (RHI) ≤ 1.67 were considered abnormal.23,24
Statistical analysis
The detailed statistical analysis is available in the Supplementary Methods.
RESULTS
Clinical characteristics of study groups
Table 1 details the clinical characteristics of all study groups. A total of 317 hypertensive patients were finally included in the study comprising 115 normal RHI (RHI > 1.67) and normal eGFR (eGFR ≥ 90ml/min per 1.73 m2), 136 low RHI (RHI ≤ 1.67), 27 low eGFR (60 ≤ eGFR < 90ml/min per 1.73 m2) and 39 low RHI combined with low eGFR (Supplementary Figure S1). The mean age of the patients was 63.00 (55.00, 70.00) years and there were 152 males and 165 females. Mean LVMI was 90.26 (78.96, 101.97) g/m2 and the prevalence of LVH was 8.5%. Patients with both earlier renal dysfunction (60 ≤ eGFR < 90ml/min per 1.73 m2) and endothelial dysfunction (RHI ≤ 1.67) were older and had higher LVMI and lower relative wall thickness when compared with patients with normal renal function and normal endothelial function.
Table 1.
Clinical characteristics of hypertensive patients among groups
| Variable | All patients (n = 317) |
Patients with normal eGFR and RHI (n = 115) |
Patients with low RHI (n = 136) |
Patients with low eGFR (n = 27) |
Patients with low eGFR and RHI (n = 39) |
|---|---|---|---|---|---|
| Gender, male, n (%) | 152 (47.9%) | 48 (41.7%) | 67 (49.3%) | 15 (55.6%) | 22 (56.4%) |
| Age, years | 63.00 (55.00, 70.00) | 59.00 (51.50, 67.00) | 63.00 (55.50, 69.00)‡ | 69.00 (60.50, 73.50)† | 70.00 (63.50, 76.00)* |
| Body mass index, kg/m2 | 24.52 (21.97, 26.89) | 24.34 (21.97, 27.10) | 24.89 (22.67, 27.34) | 24.49 (21.94, 26.10) | 24.22 (21.09, 26.75) |
| Current smoking, n (%) | 79 (24.9%) | 29 (25.2%) | 33 (24.3%) | 4 (14.8%) | 13 (33.3%) |
| Current alcohol consumption, n (%) | 58 (18.3%) | 17 (14.8%) | 29 (21.3%) | 2 (7.4%) | 10 (25.6%) |
| Systolic blood pressure, mm Hg | 138.00 (127.00, 150.00) | 142.00 (130.50, 156.00) | 133.83 (124.00, 143.00)† | 142.00 (132.00, 148.50) | 136.00 (126.34, 153.83) |
| Diastolic blood pressure, mm Hg | 79.00 (70.00, 86.00) | 80.00 (72.00, 89.50) | 78.00 (70.00, 82.00) | 80.00 (69.00, 88.00) | 76.67 (68.50, 83.84) |
| Pulse pressure, mm Hg | 59.33 (50.00, 70.00) | 60.00 (51.00, 72.67) | 57.84 (47.17, 67.34) | 60.00 (52.00, 71.67) | 57.67 (49.50, 73.00) |
| Homocysteine, µmol/l | 12.28 (9.73, 16.50) | 10.96 (9.54, 13.81) | 12.50 (9.62, 17.55)† | 15.32 (12.53, 18.89) | 16.76 (12.14, 19.15)† |
| RHI | 1.64 (1.40, 2.00) | 2.08 (1.87, 2.45) | 1.43 (1.25, 1.55)* | 1.93 (1.79, 2.20)§ | 1.46 (1.27, 1.55)* |
| Fasting blood glucose, mg/dl | 92.08 (85.78, 102.35) | 91.72 (85.69, 100.64) | 92.62 (86.59, 103.89) | 90.82 (84.60, 101.45) | 90.10 (85.23, 99.02) |
| Estimated GFR, ml/min per 1.73 m2 | 111.37 (91.79, 132.89) | 122.16 (104.53, 139.16) | 117.14 (103.80, 136.54)§ | 75.95 (67.77, 82.71)* | 79.90 (72.38, 85.76)* |
| Uric acid, µmol/l | 5.47 (4.36, 6.58) | 5.07 (4.13, 6.01) | 5.34 (4.18, 6.25)§ | 6.68 (6.02, 7.86)* | 6.53 (5.84, 7.59)* |
| Total cholesterol, mg/dl | 175.95 (152.75, 203.79) | 174.79 (154.10, 202.63) | 171.31 (148.11, 201.47) | 178.66 (150.43, 208.24) | 184.84 (155.07, 220.23) |
| LDL cholesterol, mg/dl | 107.50 (88.55, 129.54) | 106.73 (88.75, 129.35) | 104.02 (87.39, 127.42) | 107.89 (93.19, 130.51) | 125.29 (95.52, 145.01) |
| HDL cholesterol, mg/dl | 38.28 (32.48, 44.47) | 39.44 (34.42, 45.63) | 37.51 (31.90, 43.89) | 34.80 (31.32, 41.76) | 39.06 (31.32, 46.21) |
| Triglycerides, mg/dl | 121.31 (88.55, 174.43) | 120.42 (85.45, 189.49) | 120.86 (88.99, 168.68) | 119.54 (89.87, 159.38) | 123.96 (92.97, 166.46) |
| Heart rate, beat/min | 71.00 (63.00, 79.00) | 70.00 (64.00, 78.00) | 72.00 (63.50, 79.00) | 72.00 (61.50, 85.50) | 71.00 (63.50, 80.00) |
| Medications | |||||
| Beta-blockers, n (%) | 88 (27.8%) | 21 (18.3%) | 41 (30.1%)† | 11 (40.7%)† | 15 (38.5%)† |
| ACE-Is or ARBs, n (%) | 245 (77.3%) | 86 (74.8%) | 110 (80.9%) | 21 (77.8%) | 28 (71.8%) |
| Calcium-channel blockers, n (%) | 259 (81.7%) | 101 (87.8%) | 105 (77.2%)† | 25 (92.6%) | 28 (71.8%)† |
| Statins, n (%) | 197 (62.1%) | 70 (60.9%) | 87 (64.0%) | 19 (70.4%) | 21 (53.8%) |
| Aspirin, n (%) | 137 (43.2%) | 47 (40.9%) | 63 (46.3%) | 12 (44.4%) | 15 (38.5%) |
| Diuretics, n (%) | 66 (20.8%) | 21 (18.3%) | 24 (17.6%)‡ | 6 (22.2%) | 15 (38.5%)† |
| Echocardiographic data | |||||
| LVIDd, mm | 47.00 (44.00, 50.00) | 46.00 (43.00, 49.00) | 47.00 (45.00, 49.00)§ | 48.00 (45.00, 51.00) | 49.00 (46.50, 54.50)* |
| LVIDs, mm | 30.00 (27.00, 33.00) | 29.00 (26.00, 31.50) | 30.00 (27.00, 32.50)§ | 30.00 (27.00, 33.00)‡ | 32.00 (30.00, 39.00)* |
| RWT, cm | 0.40 (0.37, 0.44) | 0.40 (0.36, 0.44) | 0.40 (0.38, 0.46)‡ | 0.39 (0.37, 0.43) | 0.38 (0.33, 0.43)† |
| LVMI, g/m2 | 90.26 (78.96, 101.97) | 85.46 (75.42, 99.21) | 89.95 (79.33, 101.77)§ | 93.51 (80.55, 105.34)‡ | 96.98 (84.55, 122.41)* |
| LVH, n (%) | 27 (8.5%) | 7 (6.1%) | 10 (7.4%)‡ | 1 (3.7%)‡ | 9 (23.1%)† |
Normal eGFR: eGFR ≥ 90ml/min per 1.73 m2; low eGFR: eGFR < 90ml/min per 1.73 m2; normal RHI: RHI > 1.67; Low RHI: RHI ≤ 1.67.
Abbreviations: RHI, reactive hyperemia index; eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LVIDd, left ventricular internal diameter in diastole; LVIDs, left ventricular internal diameter in systole; RWT, relative wall thickness; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy.
* P < 0.001, † P < 0.05 compared with patients having normal RHI and eGFR; § P < 0.001, ‡ P < 0.05 compared with patients having low RHI and eGFR.
Simple linear analysis revealed a significantly negative correlation between the lg LVMI and lg eGFR (r = −0.212, P < 0.001) (Figure 1A) or lg RHI (r = −0.197, P < 0.001) (Figure 1B) respectively in all patients. There was no significant correlation between lg eGFR and lg RHI (r = −0.074, P = 0.191) (Supplementary Figure S2).
Figure 1.
Correlation of lg LVMI with lg eGFR (A) or lg RHI (B) in patients with hypertension. Abbreviations: RHI, reactive hyperemia index; eGFR, estimated glomerular filtration; LVMI, left ventricular mass index.
Correlation of the clinical factors with LVMI or the presence of LVH in hypertensive patients
Table 2 details the univariate and multivariate linear regression analyses to identify the correlation between lg LVMI and clinical factors in all patients. Gender (male), current smoking, current alcohol consumption, lg homocysteine level, lg RHI, lg heart rate, lg uric acid level, lg eGFR level, and lg high-density lipoprotein level were significantly correlated with lg LVMI by the univariate linear regression analyses. Multivariate linear regression analysis revealed that lg RHI (β = −0.258, 95% confidence interval (CI): −0.398 to −0.117, P < 0001), lg eGFR (β = −0.153, 95% CI: −0.244 to −0.062, P = 0.001), gender (male) (β = 0.055, 95% CI: 0.035 to 0.076, P < 0.001), and lg heart rate (β = −0.200, 95% CI: −0.345 to −0.055, P = 0.007) were independently correlated with lg LVMI in hypertensive patients (model R 2 = 0.170).
Table 2.
Univariate and stepwise multivariate of linear regression analyses for log LVMI in hypertensive patients
| Variable | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| β (95% CI) | P value | β (95% CI) | P value | |
| Gender, male | 0.058 (0.036, 0.080) | <0.001 | 0.055 (0.035, 0.076) | <0.001 |
| Current smoking | 0.046 (0.020, 0.072) | 0.001 | — | |
| Current alcohol consumption | 0.040 (0.011, 0.069) | 0.007 | — | |
| Lg age | 0.068 (−0.056, 0.192) | NS (0.279) | Not selected | |
| Lg body mass index | 0.085 (−0.076, 0.246) | NS (0.298) | Not selected | |
| Lg homocysteine | 0.073 (0.023, 0.124) | 0.005 | — | |
| Lg reactive hyperemia index | −0.271 (−0.421, −0.121) | <0.001 | −0.258 (−0.398, −0.117) | <0.001 |
| Lg heart rate | −0.207 (−0.362, −0.051) | 0.009 | −0.200 (−0.345, −0.055) | 0.007 |
| Lg DBP | 0.039 (−0.122, 0.200) | NS (0.634) | Not selected | |
| Lg SBP | 0.065 (−0.127, 0.257) | NS (0.508) | Not selected | |
| Lg PP | 0.022 (−0.078, 0.123) | NS (0.664) | Not selected | |
| Lg uric acid | 0.160 (0.075, 0.245) | <0.001 | — | |
| Lg eGFR | −0.189 (−0.285, −0.092) | <0.001 | −0.153 (−0.244, −0.062) | 0.001 |
| Lg fasting blood glucose | 0.055 (−0.083, 0.193) | NS (0.432) | Not selected | |
| Lg TG | −0.002 (−0.052, 0.047) | NS (0.923) | Not selected | |
| Lg HDL | −0.107 (−0.207, −0.006) | 0.038 | — | |
| Lg LDL | 0.031 (−0.052, 0.114) | NS (0.462) | Not selected | |
| Lg TC | −0.015 (−0.133, 0.104) | NS (0.810) | Not selected | |
Dashes indicate that the variable did not enter the multivariate stepwise linear regression model.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure; PP, pulse pressure; eGFR, estimated glomerular filtration rate; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; LVMI, left ventricular mass index; CI, confidence interval; NS, not significant.
Table 3 details the univariate and multivariate logistic regression analyses to identify the correlation of clinical factors for the presence of LVH in hypertensive patients. Gender (male), lg RHI, lg uric acid, and lg eGFR were significantly correlated with the presence of LVH by the univariate logistic regression analyses. Multivariate logistic regression analysis revealed that lg RHI (odds ratio (OR): 0.001, 95% CI: 10–6 to 0.426, P = 0.024), lg eGFR (OR: 0.009, 95% CI: 10–4 to 0.414, P = 0.016) and gender (male) (OR: 2.731, 95% CI: 1.139 to 6.545, P = 0.024) were independently correlated with the presence of LVH in hypertensive patients, respectively. This model was reliable (P = 0.786 by the Hosmer-Lemeshow test). The interaction between lower RHI and eGFR for the presence of LVH was statistically significant (OR: 0.021, 95% CI: 0.001 to 0.294, P = 0.004).
Table 3.
Logistic regression analysis of clinical factors for the presence of LVH among hypertensive patients
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | |
| Gender, male | 2.804 (1.189, 6.610) | 0.018 | 2.731 (1.139, 6.545) | 0.024 |
| Current smoking | 1.571 (0.676, 3.655) | NS (0.294) | Not selected | |
| Current alcohol consumption | 1.640 (0.659, 4.084) | NS (0.288) | Not selected | |
| Lg age | 0.853 (0.012, 60.064) | NS (0.942) | Not selected | |
| Lg body mass index | 0.184 (0.001, 49.346) | NS (0.553) | Not selected | |
| Lg homocysteine | 0.941 (0.161, 5.494) | NS (0.947) | Not selected | |
| Lg reactive hyperemia index | 0.001 (10–6, 0.286) | 0.016 | 0.001 (10–6, 0.426) | 0.024 |
| Lg heart rate | 0.034 (10–4, 7.472) | NS (0.220) | Not selected | |
| Lg DBP | 6.894 (0.026, 1833) | NS (0.498) | Not selected | |
| Lg SBP | 1.329 (0.002, 1051) | NS (0.933) | Not selected | |
| Lg PP | 0.582 (0.018, 18.711) | NS (0.760) | Not selected | |
| Lg uric acid | 64.288 (2.114, 1955) | 0.017 | — | |
| Lg eGFR | 0.008 (10–4, 0.300) | 0.009 | 0.009 (10–4, 0.414) | 0.016 |
| Lg Fasting blood glucose | 3.159 (0.036, 280.343) | NS (0.615) | Not selected | |
| Lg TG | 0.205 (0.030, 1.378) | NS (0.103) | Not selected | |
| Lg HDL | 0.094 (0.003, 3.125) | NS (0.186) | Not selected | |
| Lg LDL | 2.630 (0.145, 47.700) | NS (0.513) | Not selected | |
| Lg TC | 0.373 (0.006, 22.929) | NS (0.639) | Not selected | |
Dashes indicate that the variable did not enter the multivariate forward Wald logistic regression model.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure; PP, pulse pressure; eGFR, estimated glomerular filtration rate; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; LVMI, left ventricular mass index; CI, confidence interval; NS, not significant.
The concurrence of endothelial and mild renal dysfunction was significantly associated with the severity of LVH in hypertensive patients
Compared with patients with normal endothelial and renal function, LVMI was significantly increased in hypertensive patients with both endothelial dysfunction and mild reduction in eGFR (60 ≤ eGFR < 90ml/min per 1.73 m2; Figure 2). Meanwhile, no difference for LVMI was found for the patients with either low RHI or low eGFR when compared with the patients with both normal endothelial and renal function (Figure 2).
Figure 2.
Comparison of LVMI in hypertensive patients with normal eGFR and RHI, decreased eGFR, decreased RHI, or decreased eGFR combined with decreased RHI, respectively. Abbreviations: RHI, reactive hyperemia index; eGFR, estimated glomerular filtration; LVMI, left ventricular mass index.
Table 4 further details the relations of study groups to the presence of LVH in hypertensive patients. The extent of LVH increased significantly in patients with low RHI combined with low eGFR (OR: 4.629, 95% CI: 1.592 to 13.458, P = 0.005) when compared with normal RHI and eGFR patients. Meanwhile, there were no differences for the extent of LVH between low RHI (OR: 1.224, 95% CI: 0.451 to 3.327, P = 0.691) or low eGFR (OR: 0.593, 95% CI: 0.070 to 5.037, P = 0.632) patients with normal RHI and eGFR patients, respectively. The relation was confirmed after adjustment for confounder factors (models 1–4).
Table 4.
Relation of study groups to the presence of left ventricular hypertrophy in hypertensive patients
| Models | Normal RHI and eGFR | Low RHI | Low eGFR | Low RHI and eGFR | ||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | P trend | OR (95% CI) | P trend | OR (95% CI) | P trend | OR (95% CI) | P trend | |
| Crude | 1.000 | — | 1.224 (0.451, 3.327) | 0.691 | 0.593 (0.070, 5.037) | 0.632 | 4.629 (1.592, 13.458) | 0.005 |
| Model 1 | 1.000 | — | 1.141 (0.416, 3.128) | 0.797 | 0.518 (0.060, 4.447) | 0.549 | 4.171 (1.413, 12.314) | 0.010 |
| Model 2 | 1.000 | — | 1.142 (0.416, 3.135) | 0.797 | 0.409 (0.046, 3.672) | 0.425 | 3.398 (1.084, 10.653) | 0.036 |
| Model 3 | 1.000 | — | 1.270 (0.444, 3.634) | 0.656 | 0.424 (0.045, 4.015) | 0.455 | 3.863 (1.180, 12.650) | 0.026 |
| Model 4 | 1.000 | — | 1.286 (0.432, 3.827) | 0.653 | 0.419 (0.044, 4.027) | 0.451 | 4.645 (1.269, 17.000) | 0.020 |
Normal eGFR: eGFR ≥ 90ml/min per 1.73 m2; low eGFR: eGFR < 90ml/min per 1.73 m2; normal RHI: RHI > 1.67; low RHI: RHI ≤ 1.67.
Model 1: adjusted for gender; Model 2: further adjusted for log uric acid; Model 3: further adjusted for current smoking, current alcohol consumption, log homocysteine, log heart rate and log HDL cholesterol; Model 4: further adjusted for log age, log body mass index, log diastolic blood pressure, log systolic blood pressure, log pulse pressure, log fasting blood glucose, log total cholesterol, log LDL cholesterol, and log triglycerides.
Abbreviations: RHI, reactive hyperemia index; eGFR, estimated glomerular filtration rate; OR, odds ratio; CI, confidence interval.
Impact of renal or endothelial dysfunction on left ventricular geometry in hypertensive patients
Compared with the patients having normal renal function, LVMI was significantly increased in patients with mild reduction in eGFR (P < 0.001) (Supplementary Figure S3A). Meanwhile, relative wall thickness was significantly decreased (P = 0.004) and left ventricular internal diameter in diastole (LVIDd) (P = 0.001) and LVID in systole (LVIDs) (P < 0.001) were significantly increased in patients with mild reduction in eGFR (Supplementary Figure S3B–D).
Although LVMI and LVIDs were also significantly increased in patients with endothelial dysfunction (P = 0.018; Supplementary Figure S4A,D), relative wall thickness and LVIDd were not different between patients with or without endothelial dysfunction (Supplementary Figure S4B,C).
The impact of gender on left ventricular geometry in hypertensive patients
Supplementary Table S1 details the impact of gender on clinical indexes in hypertensive patients. Male patients had a higher LVMI (95.70 vs. 84.58g/m2, P < 0.001), higher prevalence of LVH (12.5% vs. 4.8%, P = 0.016), and more increased LVIDd (48 vs. 45mm, P < 0.001) and LVIDs (32 vs. 29mm, P < 0.001) than female patients. However, no differences of RHI and eGFR were found between male and female patients.
DISCUSSION
In the present study, we identified that LVMI was already significantly increased in hypertensive patients with mild reduction in eGFR (60 ≤ eGFR < 90ml/min per 1.73 m2). Most importantly, we demonstrated for the first time that the concurrence of endothelial dysfunction and mild reduction in eGFR was significantly associated with the severity of LVH in patients with hypertension. These results supported a clinically significant hypothesis that estimation of endothelial function might improve the risk stratification for LVH in hypertensive patients with renal impairment.
LVH has been demonstrated as a determinant of renal outcome and an independent prognosticator for the composite end point of all-cause death and cardiovascular morbidity in hypertensive patients.25,26 In those with LVH and moderate renal dysfunction at baseline (GFR < 60ml/min per 1.73 m2) compared with those without such entities, serum creatinine, eGFR, and hemodialysis-guided outcomes were increased by the severity of CKD, which was associated with a 2.5-fold increase in coronary artery disease, 4-fold in stroke, and 3.2-fold in the composite.26 The correlation of LVH with the renal and cardiovascular outcomes highlights the clinical significance of LVH in hypertensive patients with impaired renal function. In the present study, we identified a significantly negative correlation of LVMI with eGFR (Figure 1A) and found a significant increase of LVMI in patients with mild reduction in eGFR and hypertension (Supplementary Figure S3A). The above results extended the clinical significance of the relation between LVH and impaired renal function from population with moderate renal dysfunction (eGFR < 60ml/min per 1.73 m2) to earlier stage of renal dysfunction (60≤ eGFR < 90ml/min per 1.73 m2).9–15 In view of the individuals with early stages of renal dysfunction have a higher risk of cardiovascular disease morbidity and mortality than that from kidney failure, cardiovascular risk factor management in those patients is critical.16,17
Endothelial dysfunction, one of the most important cardiovascular risk factors, is prevalent in essential hypertension,27 and it is recognized as an independent risk factor for LVH.2–5 More importantly, along with the amelioration of endothelial dysfunction in hypertensive patients, LVMI was also reduced significantly.28 In the present study, RHI was identified to be negatively correlated with LVMI in hypertensive patients with renal impairment (Figure 1B). Furthermore, a significant increase of LVMI was found in hypertensive patients with decreased RHI (Supplementary Figure S4A). However, compared with the patients having both normal RHI and normal eGFR, there was no significant difference for LVMI in patients with either low RHI or low eGFR (Figure 2). By contrast, LVMI was significantly increased in patients with both low RHI and low eGFR (Figure 2). This result was not consistent with the previous studies.2–5 A small cohort of patients and a short-term period of patients should be taken into consideration. However, this result should be notable because it indicated that the concurrence of endothelial dysfunction correlated with the increased extent of LVH in patients with mild reduction in eGFR and hypertension. Moreover, we identified that the concurrence of endothelial dysfunction significantly correlated with the increased extent of LVH in hypertensive patients with mild reduction in eGFR with or without adjustments of the confounding factors (Table 4). Therefore, our results supported a hypothesis that the estimation of endothelial function might improve the risk stratification for LVH in hypertensive patients who progressed to only mild reduction in eGFR.
The association between impaired renal function and increased LVM was previously shown to be related to increase in arterial stiffness because the association was not statistically significant after adjustment for arterial stiffness estimates.7 The authors thus hypothesized that the association between renal insufficiency and increased LVM could be mediated through increased arterial stiffness. However, such an association was not found in the present study. The lg RHI did not correlate with lg eGFR (Supplementary Figure S2) in all patients. Either lg RHI or lg eGFR was independently correlated with lg LVMI or the presence of LVH respectively in hypertensive patients (Tables 2 and 3). This result did not support the notion that the association between mild reduction in eGFR and LVH could be somewhat mediated through endothelial dysfunction in the present study. One of the possible reasons for the discrepancy between the previous study and the present study might be the different estimation method for vascular function. Peripheral arterial endothelial function assessed using an Endo-PAT 2000 device mainly reflects the micrangium function while arterial stiffness estimates reflects the small and medium-sized artery function.24,29 Nevertheless, the results from the present and previous studies highlighted the importance of vascular and renal association in hypertensive patients with LVH. Though recent studies have shown that elevated levels of fibroblast growth factor 23 was linked to greater risk of LVH and endothelial dysfunction in CKD patients,30,31 more detailed studies are still required to investigate the mechanisms underlying the effect of the interaction of endothelial and renal dysfunction on LVH in hypertensive patients.
We further identified the impact of renal dysfunction on left ventricular geometry in hypertensive patients. Although relative wall thickness, an index which was used to identify the concentric or eccentric LVH in patients,32 was normal in patients with or without decreased eGFR, it was significantly decreased in patients with mild reduction in eGFR (Supplementary Figure S3B). Moreover, the LVIDd and LVIDs were both significantly increased in patients with mild reduction in eGFR when compared with the patients having normal eGFR (Supplementary Figure S3C,D). These results indicated that hypertensive patients tended to present an eccentric LVH with mild reduction in eGFR. By contrast, the impact of endothelial dysfunction on left ventricular geometry in hypertensive patients was not consistent (Supplementary Figure S4).
The impact of gender on the LVH in hypertensive patients should be notable in the present study because LVMI and the presence of LVH were significantly correlated with male (Tables 2 and 3) and male patients had a higher prevalence of LVH than female patients (Supplementary Table S1). However, no differences of RHI and eGFR were found between male and female patients (Supplementary Table S1). Different studies from all over the world have shown that the gender effect on prevalence of LVH varies from population to population.33–37 Whether these differences are due to criteria used or cutoff points used needs to be addressed in future studies.
The present study has certain limitations. Firstly, our study is a cross-sectional design, future prospective study is warranted to demonstrate the causality for the association of endothelial dysfunction and mild renal dysfunction with the severity of LVH in hypertensive patients. Secondly, we did not record the duration of drug use and the values of certain parameters such as RHI, eGFR, and LVMI probably influenced to an extent by medications. In addition, the study investigated only a relatively small number of patients in a single center. The duration of hypertension and/or renal dysfunction should also be taken into the consideration because the ages of the patients with both low eGFR and RHI were relatively older than the other groups. The mechanism underlying the effect of the interaction of endothelial dysfunction and mild renal dysfunction on LVH in hypertensive patients is still unknown. Despite these limitations, however, this study provided the evidence for the significant increase of LVMI in hypertensive patients with only mild reduction in eGFR and more importantly it provided the first evidence that the concurrence of endothelial dysfunction and mild renal dysfunction was significantly associated with the severity of LVH in hypertensive patients.
In conclusion, our results supported a hypothesis that the estimation of endothelial function and eGFR in hypertensive patients might be clinically significant. Further in vivo and in vitro experiments will be needed to determine the mechanisms of vascular and renal association in LVH and a multicenter trial with a large-scale study population and prospective design is warranted to further examine the role and clinical significance of such an association in hypertensive patients.
SUPPLEMENTARY MATERIAL
Supplementary materials are available at American Journal of Hypertension (http://ajh.oxfordjournals.org).
DISCLOSURE
The authors declared no conflict of interest.
Supplementary Material
ACKNOWLEDGMENTS
This work was supported by a grant from the National Natural Science Foundation of China (grant no. 81200187) and a grant from the Natural Science Foundation in Jiangxi Province (grant no. 20122BAB215014).
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