Abstract
BACKGROUND
Blood pressure (BP) responses to dietary sodium and potassium intake vary among individuals. We examined the correlation between BP responses to dietary low-sodium, high-sodium, and potassium supplementation interventions in a feeding study.
METHODS
1,906 Chinese aged ≥16 years participated in the dietary intervention which included a 7-day low-salt intervention (51.3 mmol/day), a 7-day high-salt intervention (307.8 mmol/day), and a 7-day high-salt plus potassium supplementation (60 mmol/day) intervention. BP was measured 9 times during the 3-day baseline observation and during the last 3 days of each intervention phase using a random-zero sphygmomanometer.
RESULTS
The correlation coefficients (95% confidence intervals [CI]) of the BP responses to low-sodium and high-sodium intervention were −0.47 (−0.51 to −0.44), −0.47 (−0.50 to −0.43), and −0.45 (−0.49 to −0.42) for systolic, diastolic, and mean arterial pressure (MAP), respectively (all p<0.0001). The correlation coefficients (95% CI) of the BP responses to high-sodium intervention and potassium supplementation were −0.52 (−0.56 to −0.49), −0.48 (−0.52 to 0.45), and −0.52 (−0.55 to −0.48) for systolic, diastolic, and MAP, respectively (all p <0.0001). The kappa coefficients were moderate, varying from 0.28 to 0.34, between BP responses to low-sodium and high-sodium intervention (all p <0.0001).
CONCLUSIONS
These results indicate there is a moderate correlation between BP responses to low-sodium and to high-sodium interventions, and BP responses to high-sodium intervention and potassium supplementation. Furthermore, our study suggests that individuals who were more sensitive to high-sodium diet might benefit more from a low-sodium and/or high-potassium intervention aimed at lowering BP levels.
Hypertension is an important worldwide public health challenge due to its high prevalence and the concomitant increase in risk of vascular disease.1 Observational epidemiological studies have reported that dietary sodium intake was positively and potassium intake was inversely associated with blood pressure (BP).2–4 Randomized, controlled trials have documented that a moderate sodium reduction or potassium supplementation reduced BP among hypertensives and normotensives.5,6 However, BP responses to dietary sodium and potassium vary considerably among individuals.6–8
Previous studies indicated that BP responses to dietary sodium and potassium changes were normally distributed in populations and there was no evidence for a bimodal distribution.8–10 In addition, BP responses increased among individuals who were older, overweight, with a family history of hypertension, or of African-American descent.9,10 However, there was inconsistent evidence on whether BP responses to dietary sodium and potassium changes were a random phenomenon or a reproducible trait.11 Obarzanek and colleagues reported a modest correlation between systolic BP change with high vs. low sodium and systolic BP change with high vs. medium sodium intake (correlation coefficient=0.27, P=0.002) among 129 DASH-Sodium trial participants and concluded that BP responded to dietary sodium change randomly.11 However, variations in duration between high vs. low sodium and high vs. medium sodium intake among individual study participants added in extra measurement (random) errors in their study, which could dilute the correlation between BP changes.
The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study provides a unique opportunity to study the correlation between individual BP responses to changes in sodium and potassium intake in a large study sample. Investigating the association between BP responses to low and high sodium intake as well as BP responses to potassium supplementation should help to understand the mechanism of BP regulation and develop strategies for the prevention and treatment of hypertension.
METHODS
Study population
The details of the study design and methods for the GenSalt study have been published elsewhere.12 In brief, the GenSalt study was conducted at six study sites located in rural areas of northern China from October 2003 to July 2005. A community-based BP screening was conducted among persons aged 18–60 years in the study villages to identify potential probands and their families for the study. Individuals with mean systolic BP (SBP) of 130–160 mmHg and/or diastolic BP (DBP) of 85–100 mmHg and no use of antihypertensive medications, and their siblings and offspring, were recruited for the dietary intervention study. Individuals who had stage-2 hypertension, secondary hypertension, a history of clinical cardiovascular disease or diabetes, were using antihypertensive medications, pregnant, heavy alcohol users, or currently on a low sodium diet were excluded from the dietary intervention.
The Institutional Review Board at all participating institutes approved the GenSalt study. Written informed consent for the baseline observation and intervention was obtained from each participant prior to data collection or intervention, respectively.
Dietary intervention
Study participants received a low-salt diet (3 g of salt or 51.3 mmol of sodium per day) for 7 days. Then, they received a high-salt diet (18 g of salt or 307.8 mmol of sodium per day) for 7 days. During the first two intervention phases, potassium intake remained unchanged. In the final week, participants maintained a high-salt diet and took a 60 mmol potassium (potassium chloride) supplement daily. Although dietary salt intake was the same for all study participants, dietary total energy intake was varied according to their baseline energy intake. All foods were cooked without salt, and prepackaged salt was added to the individual study participant’s meal, as specified in the protocol, when it was served by the study staff. To ensure compliance with the intervention program, study participants were required to eat their breakfast, lunch, and dinner at the study kitchen under supervision of the study staff during the entire study period. Food consumption of study participants was carefully recorded at each meal by study staff members. Study participants were instructed to avoid consuming any foods that were not provided by the study. In addition, three timed urinary specimens (one 24-h and two overnight) were collected at baseline and in each phase of intervention to monitor participants’ compliance with dietary sodium and potassium intake. The overnight urinary excretions of sodium and potassium were converted to 24-h values on the basis of formulas developed from a random subsample of 238 participants who had collected overnight and 24-h measures on the same days at baseline and in each phase of the intervention.
Data collection
A standard questionnaire was administered by trained staff at the baseline examination to collect information on demographic characteristics, personal and family medical history, and lifestyle risk factors. Body weight and height were measured twice in light indoor clothing without shoes during the baseline examination. Body mass index (BMI) was calculated as kilograms per meters squared (kg/m2). Three BP measurements were obtained each morning of the 3-day baseline observation and on days 5, 6 and 7 of each intervention period by the trained and certified observers using a random-zero sphygmomanometer according to a standard protocol.13 BP was measured with the participant in the sitting position after 5 minutes of rest. In addition, participants were advised to avoid alcohol, cigarette smoking, coffee/tea, and exercise for at least 30 minutes prior to their measurement. All BP observers were blinded to the dietary intervention.
Statistical analysis
The BP levels at baseline and during the intervention were calculated as the mean of nine measurements from three clinical visits during the 3-day baseline observation or on days 5, 6, and 7 of each intervention phase. Mean arterial pressure (MAP) was calculated by adding one third of the pulse pressure to DBP. BP responses were defined as follows: BP response to low-sodium = BP on low-sodium diet − BP at baseline; BP response to high-sodium = BP on high-sodium diet − BP on low-sodium diet; and BP response to potassium supplementation = BP on high-sodium diet with potassium supplementation − BP on high-sodium diet.
Means, 95% confidence intervals (CI), and selected percentiles (25th, 50th, 75th, and 90th) were calculated for BP responses to low-sodium, high-sodium and potassium-supplementation, respectively. The agreements between BP responses to low-sodium and to high-sodium and between BP responses to high-sodium and to potassium supplementation were assessed by calculating Pearson correlation coefficients using BP responses as a continuous variable. Age and gender adjusted partial correlation coefficients were also calculated. The BP responses to dietary sodium changes were also analyzed as categorical variables (quartiles). In addition, three cut-points were used to classify an individual as salt-sensitive: absolute BP level changes were in the top 25th percentile or ≥5 mmHg or ≥10 mmHg. Otherwise, study participants were classified as non-salt-sensitive. The consistency of quartiles of BP responses and salt-sensitivity between low-sodium and high-sodium interventions were assessed by using weighted kappa statistics.
RESULTS
A total of 1,906 GenSalt study participants took part in the dietary sodium and potassium interventions. Of these, 1,871 (98.2%), 1,860 (97.6%), and 1,843 (96.7%) subjects completed the low-sodium, high-sodium and high-sodium plus potassium supplementation interventions, respectively.Table 1 shows baseline characteristics of study participants and the 24-h urinary excretion of sodium and potassium during the baseline and each dietary intervention phase. The results from 24-hour urinary excretion of sodium and potassium during each of the 3 dietary intervention phases indicated excellent compliance to dietary sodium and potassium intervention.
Table 1.
Characteristics of 1,906 study participants at baseline examination and dietary interventions
| Characteristics | Mean (SD) or percentage |
|---|---|
| Age, years | 38.7 (9.6) |
| Male, % | 53.0 |
| Body mass index, kg/m2 | 23.3 (3.2) |
| Cigarette smoking, % | 34.7 |
| Alcohol consumption, % | 29.4 |
| 24-h urinary excretion of sodium, mmol | |
| Baseline | 242.3 (66.7) |
| Low-sodium | 47.5 (15.9) |
| High-sodium | 244.3 (37.7) |
| High-sodium plus potassium supplementation | 254.2 (36.0) |
| 24-h urinary excretion of potassium, mmol | |
| Baseline | 36.8 (9.6) |
| Low-sodium | 31.4 (7.7) |
| High-sodium | 35.7 (7.5) |
| High-sodium plus potassium supplementation | 77.5 (12.8) |
SD = standard deviation
BP levels at the baseline examination and during each dietary intervention phase are presented in Table 2. BPs during low-sodium, high-sodium, and high-sodium plus potassium supplementation interventions were all significantly different from baseline BPs as well as from each other (all p<0.0001).
Table 2.
Blood pressure levels at baseline examination and dietary intervention
| Blood pressure, mm Hg |
Mean (95% CI) | p-values for period difference | ||
|---|---|---|---|---|
| Low-sodium | High-sodium | Potassium- supplementation |
||
| Baseline examination | ||||
| Systolic | 116.9 (116.3, 117.5) |
<0.0001 | <0.0001 | <0.0001 |
| Diastolic | 73.7 (73.3, 74.2) |
<0.0001 | <0.0001 | <0.0001 |
| MAP | 88.1 (87.6, 88.6) |
<0.0001 | <0.0001 | <0.0001 |
| Low-sodium intervention | ||||
| Systolic | 111.4 (110.8, 112.0) |
<0.0001 | <0.0001 | |
| Diastolic | 71.0 (70.6, 71.4) |
<0.0001 | <0.0001 | |
| MAP | 84.5 (84.0, 84.9) |
<0.0001 | <0.0001 | |
| High-sodium intervention | ||||
| Systolic | 116.3 (115.6, 116.9) |
<0.0001 | ||
| Diastolic | 72.9 (72.4, 73.4) |
<0.0001 | ||
| MAP | 87.4 (86.9, 87.8) |
<0.0001 | ||
| High-sodium plus potassium intervention | ||||
| Systolic | 112.7 (112.1, 113.3) |
|||
| Diastolic | 71.5 (71.1, 72.0) |
|||
| MAP | 85.3 (84.8, 85.7) |
|||
BP = blood pressure; MAP = mean arterial pressure; CI = confidence intervals.
Table 3 shows BP changes in response to low-sodium, high-sodium and potassium supplementation interventions. All of the SBP, DBP, and MAP levels decreased from baseline to low-sodium intervention but increased from low-sodium to high-sodium intervention. In addition, BP levels decreased from high-sodium to high-sodium plus potassium supplementation intervention (all p<0.0001).
Table 3.
Blood pressure responses to dietary interventions
| Blood pressure, mmHg | Mean (95% CI) |
p-value | Percentiles | |||
|---|---|---|---|---|---|---|
| 25th | 50th | 75th | 90th | |||
| BP responses to low-sodium intervention (No. = 1,871) | ||||||
| Systolic | −5.5 (−5.8, −5.1) |
<0.0001 | −8.9 | −4.4 | −1.3 | 2.2 |
| Diastolic | −2.8 (−3.0, −2.5) |
<0.0001 | −5.6 | −2.7 | 0.4 | 3.8 |
| MAP | −3.7 (−3.9, −3.4) |
<0.0001 | −6.6 | −3.3 | −0.6 | 2.3 |
| BP responses to high-sodium intervention (No. = 1,860) | ||||||
| Systolic | 4.9 (4.6, 5.1) |
<0.0001 | 0.7 | 4.7 | 8.2 | 12.4 |
| Diastolic | 1.9 (1.7, 2.2) |
<0.0001 | −1.6 | 1.8 | 5.3 | 8.7 |
| MAP | 2.9 (2.7, 3.1) |
<0.0001 | −0.4 | 2.7 | 5.9 | 9.1 |
| BP responses to potassium supplementation (No. = 1,843) | ||||||
| Systolic | −3.5 (−3.8, −3.3) |
<0.0001 | −6.2 | −2.7 | −0.4 | 2.0 |
| Diastolic | −1.4 (−1.6, −1.2) |
<0.0001 | −4.0 | −1.3 | 1.3 | 4.2 |
| MAP | −2.1 (−2.3, −1.9) |
<0.0001 | −4.4 | −1.7 | 0.4 | 2.9 |
BP = blood pressure; MAP = mean arterial pressure; CI = confidence intervals.
Figure 1 shows the scatter plots of SBP, DBP, and MAP responses to low-sodium intervention against BP responses to high-sodium intervention. There was a consistently and significantly inverse correlation between BP responses to low-sodium and to high-sodium intervention. The correlation coefficients (95% confidence intervals [CI]) of the responses to low-sodium intervention and high-sodium intervention were −0.47 (−0.51 to −0.44), −0.47 (−0.50 to −0.43), and −0.45 (−0.49 to −0.42) for SBP, DBP, and MAP, respectively (all p <0.0001). The corresponding age and gender-adjusted partial correlation coefficients (95% CI) were −0.44 (−0.47, −0.40), −0.46 (−0.49, −0.42), and −0.43 (−0.47, −0.40), respectively (all p<0.001).Figure 2 shows the scatter plots of BP responses to high-sodium intervention against BP responses to potassium supplementation. A significant inverse correlation was observed between the BP responses to high-sodium and to potassium supplementation intervention. The correlation coefficients (95% CI) were −0.52 (−0.56, −0.49), −0.48 (−0.52, −0.45), and −0.52 (−0.55, −0.48) for SBP, DBP, and MAP, respectively (all p <0.0001). The corresponding age and gender-adjusted partial correlation coefficients (95% CI) were −0.51 (−0.54, −0.48), −0.48 (−0.51, −0.44), and −0.51 (−0.55, −0.48), respectively (all p<0.001).
Figure1.
Scatter plots of blood pressure responses to low sodium and high sodium interventions (upper panel for systolic pressure, middle panel for diastolic pressure, and lower panel for mean arterial pressure).
Figure2.
Scatter plots of blood pressure responses to high sodium intervention and potassium supplementation (upper panel for systolic pressure, middle panel for diastolic pressure, and lower panel for mean arterial pressure).
Table 4 displays the kappa coefficients of categorized BP responses to low-sodium and high-sodium interventions. The weighted kappa coefficients varied from 0.29 to 0.32 for BP responses to low-sodium and high-sodium interventions by quartiles, which indicated a fair to moderate agreement. The kappa coefficients were consistent and significant (all p <0.0001) while various cut-points were used to define salt-sensitivity, ranging from 0.28 to 0.34
Table 4.
Kappa coefficients of blood pressure responses to low-sodium and high-sodium interventions according to different cut off values
| Quartile | ≥ 75th vs. < 75th percentile |
≥ 5 mm Hg vs. < 5 mm Hg |
≥ 10 mm Hg vs. < 10 mm Hg |
|||||
|---|---|---|---|---|---|---|---|---|
| Kappa (95% CI) |
p-value | Kappa (95% CI) |
p-value | Kappa (95% CI) |
p-value | Kappa (95% CI) |
p-value | |
| Systolic BP | 0.32 ( 0.29, 0.35) |
<0.0001 | 0.31 ( 0.27, 0.36) |
<0.0001 | 0.33 (0.29, 0.37) |
<0.0001 | 0.34 (0.29, 0.39) |
<0.0001 |
| Diastolic BP | 0.31 (0.28, 0.34) |
<0.0001 | 0.32 (0.27, 0.37) |
<0.0001 | 0.30 (0.25, 0.35) |
<0.0001 | 0.31 (0.24, 0.38) |
<0.0001 |
| MAP | 0.29 (0.25, 0.32) |
<0.0001 | 0.28 (0.23, 0.33) |
<0.0001 | 0.29 (0.24, 0.33) |
<0.0001 | 0.28 (0.22, 0.35) |
<0.0001 |
BP = blood pressure; MAP = mean arterial pressure; CI = confidence intervals.
DISCUSSION
This large dietary intervention study identified a moderate correlation between individual BP responses to low-sodium intervention and to high-sodium intervention. Furthermore, BP responses to potassium supplementation were significantly associated with the BP responses to high-sodium intervention. These findings suggest that BP responses to high-sodium intervention and low-sodium intervention might share some common BP regulation mechanisms. In addition, the effect of sodium and potassium on BP might also share some common BP regulation mechanisms. Furthermore, our study suggests that individuals who were more sensitive to a high-sodium diet might benefit more from a low-sodium and/or high-potassium intervention aimed at lowering BP levels.
The GenSalt study is the largest feeding study to examine BP responses to dietary sodium (salt-sensitivity) and potassium (potassium sensitivity) interventions in a free-living population. Our study has been strengthened by the excellent compliance to dietary intervention and careful measurement of study variables. To our knowledge, this study is the first to investigate the correlation between BP responses to low-sodium and to high-sodium interventions and the correlation between BP responses to dietary sodium intervention and potassium supplementation.
Our study was not designed to test the reproducibility of BP responses to dietary sodium interventions, which would require implementing the identical intervention repeatedly. In our study, BP responses to low-sodium intervention were defined as BP differences between low-sodium intervention and baseline observation. Although all study participants were living in a homogeneous environment with high dietary sodium intake, the baseline dietary sodium intake was not controlled in our study. In addition, intra-individual random variations in BP measurements could also dilute the correlation between BP responses to low sodium and high sodium intervention. Therefore, the true correlation coefficients between BP responses to low-sodium and high-sodium intervention could be much greater than those observed in our study. The correlation coefficients observed in our study, however, were much greater than those reported by Obarzanek et al in the DASH-Sodium trial, in which correlation coefficients were not significant due to random variation of BP.11
Our study documented that individuals with a higher BP response to dietary sodium intake (salt-sensitive) had significantly greater BP reductions during potassium supplementation. Skrabal and colleagues conducted a 2-week low-sodium and high-potassium intervention study among 20 normotensive subjects and found that salt-sensitive individuals benefit most from the BP-lowering effect of potassium supplementation.14 Mu and colleagues also reported a greater BP reduction among salt-sensitive children compared to non-salt-sensitive children in a 2-year double-blinded, placebo-controlled trial with potassium supplementation.15 Many studies have also suggested that BP reduction associated with high potassium intake is enhanced in the blacks, hypertensives, and individuals with family histories of hypertension, who are known to be more sensitive to sodium intake.6,16,17 Individuals with salt-sensitive hypertension manifest excessive sodium retention during a period of high sodium intake.18 A number of studies have suggested that changes in dietary potassium alter sodium balance, such that potassium restriction results in sodium retention and potassium supplementation leads to greater natriuresis.9,19 The results from this study and other previous studies indicate that the BP-lowering effect of potassium supplementation is significantly enhanced among individuals who are more sensitive to high dietary sodium intake. Ours study showed that BP levels during high-sodium plus potassium supplementation interventions were significantly lower than baseline and only slightly higher than those observed during the low-sodium intervention. Therefore, dietary potassium supplementation may be an effective way to lower BP among individuals for whom sodium reductions are hard to achieve.
The low-sodium intervention target of this feeding study might not be easy to achieve in a free-living population. However, the correlation between BP responses to low-sodium and high-sodium interventions and between BP responses to high-sodium and potassium-supplementation interventions should be generalizable to other populations. In addition, the baseline dietary sodium intake was not controlled in our study, which could introduce additional variation in BP responses to low-sodium intervention. However, the baseline dietary sodium intake measured by three timed urinary excretions of sodium was not associated with BP responses to sodium or potassium interventions in this study. The random measurement error of BP responses to low-sodium intervention due to the lack of control of baseline sodium intake could dilute the correlation between BP responses to dietary low- and high-sodium interventions.
In summary, the current study indicates that BP responses to low-sodium intake are moderately correlated with BP responses to high-sodium intake. In addition, BP responses to potassium supplementation are significantly associated with BP responses to high-sodium intake. These findings suggest that low sodium intervention and potassium supplementation may be more effective to lower BP among individuals who are salt sensitive.
Acknowledgements
The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Upsher-Smith Laboratories, Inc. has provided Klor-Con M20 potassium tablets for the GenSalt study. Dr. Bazzano was supported by a career development grant (K08HL091108) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Appendix
The GenSalt Study Steering Committee
Dongfeng Gu, Jiang He (Chair), James E Hixson, Cashell E Jaquish, Depei Liu, DC Rao, Paul K Whelton, and Zhijian Yao.
GenSalt Collaborative Research Group
Tulane University Health Sciences Center, New Orleans, USA: Jiang He (PI), Lydia A Bazzano, Chung-Shiuan Chen, Jing Chen, Mei Hao, Lee Hamm, Tanika Kelly, Paul Muntner, Kristi Reynolds, Paul K Whelton, Wenjie Yang, and Qi Zhao.
Washington University School of Medicine, St Louis, USA: DC Rao (PI), Matthew Brown, Charles Gu, Hongyan Huang, Treva Rice, Karen Schwander, and Shiping Wang.
University of Texas Health Sciences Center at Houston: James E Hixson (PI) and Lawrence C Shimmin.
National Heart, Lung, and Blood Institute: Cashell E Jaquish
Chinese Academy of Medical Sciences, Beijing, China: Dongfeng Gu (PI), Jie Cao, Jichun Chen, Jingping Chen, Zhenhan Du, Jianfeng Huang, Hongwen Jiang, Jianxin Li, Xiaohua Liang, Depei Liu, Xiangfeng Lu, Donghua Liu, Qunxia Mao, Dongling Sun, Hongwei Wang, Qianqian Wang, Xigui Wu, Ying Yang, and Dahai Yu.
Shandong Academy of Medical Sciences, Shandong, China: Fanghong Lu (PI), Zhendong Liu, Shikuan Jin, Yingxin Zhao, Shangwen Sun, Shujian Wang, Qengjie Meng, Baojin Liu, Zhaodong Yang, and Chuanrui Wei.
Shandong Center for Diseases Control and Prevention, Shandong, China: Jixiang Ma (PI), Jiyu Zhang, and Junli Tang.
Zhengzhou University: Dongsheng Hu, Hongwei Wen, Chongjian Wang, Minghui Shen, Jingjing Pan, and Liming Yang.
Xinle Traditional Chinese Medicine Hospital, Hebei, China: Xu Ji (PI), Rongyan Li, Haijun Zu, and Junwei Song.
Ganyu Center for Disease Control and Prevention: Delin Wu (PI), Xushan Wang, and Xiaofeng Zhang.
Xi’an Jiaotong University, Shanxi, China: Jianjun Mu (PI), Enrang Chen, Fuqiang Liu, and Guanji Wu.
Chinese National Human Genome Center at Beijing: Zhi-Jian Yao (PI), Shufeng Chen, Dongfeng Gu, Hongfan Li, Laiyuan Wang, and Penghua Zhang.
Footnotes
Conflict of Interest: none.
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