The relationship between the levels of plasma total homocysteine and insulin resistance in uncomplicated mild-to-moderate primary hypertension

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Primary hypertension (HT) is the most frequent independent risk factor for cardiovascular disease. It was demonstrated that plasma total homocysteine (tHcy) is an important and modifiable cardiovascular risk factor, which correlates with the severity of atherosclerotic disease,1 despite some discordant results.2 Although data supporting the cause–effect relationship between HT and tHcy are limited, tHcy may play a role in the pathogenesis of HT. The mechanism of this relationship has not been elucidated yet. Plausible pathophysiological mechanisms such as impairment of vascular endothelial function, diminished nitric oxide bioavailability, increased oxidative stress, smooth muscle cell dysfunction and increased arterial stiffness are considered to link tHcy with HT.3 On the other hand, it could be postulated that hyperhomocysteinemia and HT may be coincidentally integral components of insulin resistance syndrome (IRS).4 Moreover, the long-term effects of HT on the renal vascular structures may lead to hyperhomocysteinemia due to decreasing homocysteine clearance.

One hundred and fourteen untreated and uncomplicated patients with mild to moderate HT, defined by multiple blood pressure (BP) readings of 140/90 mm Hg (65 males, mean age 43±8 years), and age- and sex-matched 85 healthy subjects (47 males, mean age 41±8 years) were enrolled. This study was approved by the Ethics Committee of Trakya University, Medical Faculty. All subjects gave a written informed consent prior to enrollment.

Subjects with GFR<85 ml/min/1.73 m2, overt proteinuria, myocardial infarction or stroke and angina pectoris were excluded. Pregnancy, diabetes mellitus, liver and renal diseases, malignancy, infection and multivitamin use were considered as exclusion criteria as well. Patients who had hypertensive retinopathy grade III and IV were excluded from the study.

Blood pressure measurement and definition of HT were consistent with WHO/ISH hypertension guidelines.5

Plasma tHcy, insulin and C-peptide were measured by the chemiluminometric assay (Immulite, DPC, and Los Angeles, USA). Insulin resistance was determined by Homeostasis Model Assessment [HOMA-IR, (fasting glucose (mmol/l) × fasting insulin (μIU/l)/22.5].

Plasma tHcy concentrations that showed a positive skewness were log-transformed to improve normality for statistical testing. Unpaired Student's t-test was used to evaluate differences in continuous variables between patients and controls, subjects with and without insulin resistance, smoker and non-smoker. χ2-Test was performed to determine the differences in dichotomized variables between patients and controls. Pearson correlation test was performed to evaluate the relationship between parameters. We evaluated the independent relationship between tHcy and HT using stepwise linear regression analysis. Data were given as mean±s.d., all P-values were two sided; P<0.05 was considered statistically significant.

The main physical and biochemical findings of patients and control subjects were shown in Table 1. Mean tHcy level was significantly higher in patients compared to the controls. According to previous evidence, hyperhomocysteinemia was defined as a tHcy concentration corresponding to the 75th percentile of fasting tHcy from the control group. The upper quartile of tHcy concentrations corresponded to 10.9 μmol/l in our study. Total homocysteine levels greater than 10.9 μmol/l were detected in 55 of 114 patients (48.2%) compared to 21 of 85 healthy subjects (24.7%) (P<0.001). Moreover, hyperhomocysteinemic patients had significantly higher systolic blood pressure (SBP) (157.96±14.93 vs 153.17±10.02 mm Hg, P<0.05) and diastolic blood pressure (DBP) (101.49±10.92 vs 96.63±7.21 mm Hg, P<0.01) compared with normohomocysteinemic patients.

Table 1 Clinical characteristics and laboratory findings of the study groups

Pearson correlation test showed some relationship between parameters in hypertensive patients. Log-tHcy was positively correlated with SBP (r: 0.325, P: 0.0001), DBP (r: 0.332, P: 0.0001), body mass index (BMI, r: 0.116, P: 0.021), waist circumference (WC, r: 0.215, P: 0.004), Waist-to-hip circumference ratio (WHR, r: 0.116, P: 0.0251), insulin (r: 0.157, P: 0.03), C-peptide (r: 0.269, P: 0.0001), HOMA-IR (r: 0.173, P: 0.015), uric acid (r: 0.269, P: 0.001), and serum creatinine (r: 0.284, P: 0.001). In linear stepwise analysis, log-tHcy, age, lipids (total cholesterol, LDL-C, HDL-C and triglyceride), WC, WHR, BMI, HOMA-IR, insulin, glucose were taken into consideration as independent variables. Log of tHcy concentration was the strongest predictor of both SBP (β=0.248, P=0.013, 95% CI=2.750–22.945) and DBP (β=0.259, P=0.011, 95% CI=2.297–17.042).

All cases were separated according to insulin resistance (with or without insulin resistance, HOMA-IR4 or HOMA-IR<4, respectively) and variables of two groups were compared. Regarding tHcy level, subjects with insulin resistance had significantly higher Log-tHcy levels than subjects without insulin resistance (1.11±0.27 vs 0.98±0.21 μmol/l, P=0.025). In terms of smoking, tHcy levels did not differ between smoking and non-smoking subjects.

Descriptive findings in our study indicated that hypertensive patients were associated with IRS and hyperhomocysteinemia. In the hypertensive group, hyperhomocysteinemic patients had higher SBP and DBP compared with normohomocysteinemic patients. Since our patients had normal renal function, folic acid and vitamin B12 concentrations and were free from overt atherosclerotic diseases, tHcy might be a causal factor for HT rather than a secondary result of HT and/or atherosclerosis. Recent studies indicating that tHcy lowering therapies reduce the BP support the possibility that the link between homocysteine and BP is causal.6 To eliminate the possible overlapping effects of different factors on HT, we performed multiple linear regression analysis using either SBP or DBP as a dependent variable. This analysis suggested that tHcy levels were the most prominent factor for HT. Our results were in accordance with most reports that suggested HT is associated with elevated plasma tHcy levels,7, 8 but not all.9 Inaccurate BP measurement, ethnic differences, gene–environment interaction, diet and age of participants may be responsible for this discrepancy.

The mechanism through which hypertension is related to plasma tHcy levels is unclear. Recent evidence suggests that tHcy might lead to HT through endothelial dysfunction. In addition to endothelial dysfunction, insulin resistance could be considered a pivotal mechanism to explain the relationship between tHcy and HT; however, there are some conflicting data about the relationship between insulin resistance and tHcy concentrations.4 To the best of our knowledge, there is limited data concerning the relationship between tHcy and insulin resistance components in the uncomplicated mild to moderate HT. One study conducted on nondiabetic hypertensive Chinese population documented that tHcy concentration was higher in hypertensives than normotensive individuals; however, plasma tHcy values showed no correlation with steady-state plasma glucose concentration, a measurement of insulin sensitivity, during an insulin suppression test in groups of hypertensive and normotensive subjects.10 Moreover, no correlation between tHcy and other metabolic components of IRS was observed in this study. Second study was conducted on young hypertensive patients with insulin resistance and patients with HT were found to have significantly higher BMI, insulin levels and plasma tHcy concentration than controls.11 Our results are consistent with the above mentioned study since we show a relationship among HT, tHcy concentration and the components of IRS. Nonetheless, it should be noted that due to its cross-sectional design, our study does not allow a definitive description of causal relationships.

In conclusion, our findings suggest that uncomplicated mild to moderate hypertensive patients have elevated plasma tHcy levels. Plasma tHcy level is associated with some components of IRS, and hypertension.


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Correspondence to S Ustundag.

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