Hypertension causes development of organ damage over time and it is associated with an increased risk of cardiovascular and cerebrovascular diseases, and renal failure. It is well known that fluid retention plays a role in the pathogenesis of primary hypertension. Furthermore, fluid retention is known to adversely affect the cardiovascular system, independent of the blood pressure level.1

Blood pressure (BP) fluctuations are a result of the interplay between external environmental stimuli, vascular environment and biological autonomic circulatory regulation.2 Spontaneous variation in blood pressure based on 24-h ambulatory blood pressure monitoring (ABPM) is referred to as blood pressure variability (BPV)3,4 and fluctuation during a 24-h period is referred to as short-term BPV. Average real variability (ARV) is an index that also averages the absolute differences of consecutive measurements.5,6 The ARV index is sensitive to the individual BP measurement order and the relatively low sampling frequency of ABPM and is not affected by the mean BP level.5,7

Increased short-term BPV predicts organ damage8,9 and is associated with an increased risk of cardiovascular events.10–16 The mechanism of this relationship is not clear. Ozkayar et al. found that primary hypertensive patients with high dietary salt intake had high BPV17 and this relationship was independent of the blood pressure level. This conclusion suggests that hypervolemia may also be related to BPV. However, the association between BPV assessed by ABPM and fluid status measured by bioimpedance spectroscopy method in hypertensive patients has not been investigated so far and the relationship between them is not clearly known. For these reasons, in the performed study, we aimed (1) to establish the impact of hydration status on BPV; (2) to investigate potential effect of diuretics on BPV; (3) to examine the potential role of BPV in endothelial and cardiac functions among primary hypertensive patients. It is the first study to evaluate cardiac and endothelial functions along with volume status and BPV among primary hypertensives with no kidney failure. Clarifying the relation of body fluid and BPV in primary hypertensive population could offer specific therapeutic approaches with remarkable impact on this affection.

The study population consisted of 50 patients with a mean age of 54.5±8.8 years. We divided all patients into two groups according to their volume status throughout the one year. The first group consisted of 31 patients with two or more negative OH values (≤0 OH value) in four different bioimpedance spectroscopy measurements. The second group consisted of 19 patients with a positive OH value (0>OH value) in the three or four measurements. Thus, the patients in the first group consisted of patients continuing in negative hydrated status and the patients in the second group consisted of patients who were positive hydrated throughout one-year follow-up. Twentysix patients in negatively hydrated group received diuretic, 12 (44.4%) of them received 12.5mg hydrochlorothiazide, and 14 (54%) of them received 25mg hydrochlorothiazide. Only 1 patient received diuretic (25mg hydrochlorothiazide) in positively hydrated group. The baseline characteristics of the patients in both groups are presented in Table 1. The patients in both groups were similar with regard to age, BUN and BMI but male ratio was more prevalent in positive hydrated group. Diuretic usage in negative hydrated group was significantly higher than other group at enrollment. No patient died during study period. At the end of one-year follow-up, there were no significant changes with regard to weight, height and BMI between basal and twelfth month measurements in patients in both groups.

Systolic and diastolic ARV significantly decreased in both groups (positively and negatively hydrated) along with decrease in blood pressure at the end of the twelfth month. This result can be attributed to antihypertensive treatment (diuretic or vasodilator drugs) in both groups. But, systolic and diastolic ARV (24-h, daytime, nighttime) significantly more decreased in negatively hydrated group than positively hydrated group (Table 2). Similarly, at the end of one-year follow-up, patients in negative hydrated group were found to have significantly lower mean systolic (110.1±14.6 and 128.4±17.1; respectively) and diastolic BP (70.4±7.7 and 80.3±9.8; respectively) compared with baseline (p=0.0011 and p=0.033; respectively). More diuretics (hydrochlorothiazide) were used in the negative hydrated group to control of arterial hypertension (83.9% and 5.3%; respectively. p<0.001). 55.6% of the patients receiving diuretics used 25mg hydrochlorothiazide and the rest used 12.5mg hydrochlorothiazide.

We investigated the effects of parameters on the development high systolic ARV. High systolic ARV was defined as higher systolic ARV levels of the third tertile (15.32) of ARV distribution. The first tertile and median of systolic ARV were 10.72 and 12.8, respectively. Logistic regression analysis was used to determine the relative risks of developing high systolic ARV at the end of the one year follow-up. Only the variables with a statistically significant association in the simple logistic regression model were included in the multiple logistic regression model. In multiple logistic regression analysis, significant risk factors associated with high systolic ARV were as follows: more weight gain during follow-up and higher systolic blood pressure (Table 3).

In our study, target organ damage (TOD) was defined as LVMI values above 115g/m2 among males and 95g/m2 among women and CIMT of 0.9mm or more. Patients who have improvement in both of these two parameters were considered as TOD recovery present. In patients who have TOD recovery, BPV significantly more reduced than patients with no improvement in TOD, like systolic BP and diastolic BP (Table 4). We investigated factors associated with the presence of TOD at follow-up with Generalize Linear Mixed Model for repeated measure with a binary logistic function at Table 5. Significant risk factors associated with the presence of TOD at follow-up were as follows: 24 hour systolic BP and daytime and night time diastolic ARV and night time diastolic BP.

To the best of our knowledge, this is the first study that directly investigates the effect of the volume status on short-term BPV in a group of primary hypertensive patients who do not have kidney failure. It was found that patients with negative hydration status are characterised by lower values of systolic BPV. Although we did not show the relationship between high systolic ARV and OH value in multiple logistic regression analysis, more weight gain which is an indicator of volume increase was associated with high systolic ARV. In our previous study, we showed the significance of negative hydration status with respect to blood pressure control, endothelial, and cardiac functions within same population.20 Increased BPV is clearly associated with higher cardiovascular risk in the general population.13,21,22 Hence, we have shown the importance of negative hydration status to cardiovascular protection with different ways.

Results of Levi-Marpillat et al.’s study indicate that diuretics was associated with a lower short-term BPV compared with the other classes (angiotensin II receptor blockers, angiotensin converting enzyme inhibitors and beta blockers).23 The X-CELLENT trial showed that diuretics, but not angiotensin II receptor blockers, lead to a decrease of 24-h BPV compared with placebo.24 A meta-analysis of randomized trials concluded for a reduction of the visit-to-visit variability in systolic BP, that is, fluctuations of systolic BP over long periods of observation, with the use of non-loop diuretics.25 The results of our study explain how diuretics have BPV lowering effect. We used diuretics to keep the patients negative hydrated during trial and we showed that if the patients were negative hydrated with diuretic usage, they showed better decrease in BPV. The results of our work proved that reduction in BPV due to diuretic use depends on the volume reduction. In terms of explaining mechanism, this research may be considered preliminary as no comparable studies were found in the literature.

Several studies based on 24-h ABPM have shown that antihypertensive drugs decrease ambulatory BPV, a reduction which is proportional to the decrease in mean BP values, suggesting that the effect of antihypertensive treatment on short-term BPV may be largely dependent on the BP lowering, per se.26,27 But, in our study we found a collinearity between the reduction in OH value and BPV, as well as between the reduction in BP and BPV. This situation was independent from blood pressure level. Like ours, a different study showed that antihypertensive drug classes may have different effects on short-term BP variability in a daily life clinical setting, independently from the effects of major confounders such as BP level, age, gender and heart rate.23 This blood pressure independent effect may be related to relationship between the fluid status – BPV found in our study for the first time in the literature.

Trials should be aimed at exploring whether the benefits of BPV lowering by diuretics might translate into a cardiovascular risk reduction in humans. Indeed, the benefits of treatment-induced reduction in BPV have been related to a reduction in TOD in the setting of some experimental animal studies.28,29 Furthermore, BPV has been reported to impact on negative end-organ outcomes.30 The present study is one of the studies that reveal the relationship between BPV and TOD. We found that TOD was less common in patients who had more decrease in BPV. Cross-sectional and longitudinal studies showed a positive association between BPV and cardiovascular risk in pure hypertensive patients. Leoncini et al assessed the independent influence of BPV on multiple target organ damage, including LV mass index, intima media thickness, and renal abnormalities.31 High BPV, measured as SD and ARV, was associated with the simultaneous presence of 2 or more signs of subclinical organ damage, regardless of several confounding variables, including BP. They reported that parameters of BPV and LV mass index gradually increased together, which is line with our findings. The association of systolic BPV with echocardiographic parameters was previously studied by Zakopoulos et al. and they demonstrated that a 0.1mmHg/min increase in the daytime rate of systolic BPV was associated with an increment of 7.087g in the left ventricular mass.32 Unlike these results, Massierer et al. did not show associations between BPV assessed through 24h-ABPM with echocardiographic variables related to diastolic function, left ventricular hypertrophy and cardiac chamber diameters in hypertensive-diabetic patients.33 However, the volume status of patients was not measured in this study. According to our results, we can claim that if hypovolemia was not established in the patients in Massierer et al.’s study, cardiac parameters could not be improved.

Xiong et al found that ARV generally had a strong relationship to intima media thickness as a sign of early atherosclerosis.34 Another study found that ARV had the strongest relationship to arterial stiffness.35 These results were confirmed that the relationship between ARV and arterial stiffness was independent from office BP and average 24-hour BP. In the present study, we analyzed short-term BPV and CIMT in negative and positive hydrated patients. Negative hydrated patients had better results for both BPV and TOD parameters including higher CIMT.

In primary hypertensive patients, we have demonstrated that addition of diuretic to established treatment or intensified diuretic treatment and keeping patients in negative hydration status resulted in more reduction in BPV along with reduced blood pressure at twelfth month of follow-up. More weight gain and higher systolic blood pressure are major risk factors of high systolic ARV, but not hypervolemia. In patients who have TOD recovery, BPV significantly more reduced than patients with no improvement in TOD, like systolic BP and diastolic BP. Potential effect of diuretics on BPV could be the guide to an optimal antihypertensive treatment in higher risk patients. Further investigation is required to define potential beneficial effects of negative hydration status, to identify treatments that reduce BPV and to clarify whether those therapeutic interventions provide additional prognostic benefit, independent of a reduction in mean BP.

The authors report no specific funding in relation to this research.

The authors declare no conflicts of interests.