Cold pressor test at baseline examination and dietary sodium and potassium interventions of the GenSalt (Genetic Epidemiology Network of Salt Sensitivity) study.
Age- and sex-adjusted mean systolic blood pressure (BP) responses to low-sodium, high-sodium, and high-sodium plus potassium supplementation interventions by quartiles of area under the curve of systolic BP response to the cold pressor test (A) and diastolic BP response to dietary interventions by quartiles of area under the curve of diastolic BP response to the cold pressor test (B).
Age- and sex-adjusted prevalence of high salt sensitivity or high-potassium sensitivity defined as a systolic blood pressure change in the top 30th percentile during the dietary sodium and potassium interventions among all study participants according to quartiles of area under the curve of blood pressure responses to the cold pressor test.
Chen J, Gu D, Jaquish CE, Chen C, Rao DC, Liu D, Hixson JE, Hamm LL, Gu CC, Whelton PK, He J, GenSalt Collaborative Research Group. Association Between Blood Pressure Responses to the Cold Pressor Test and Dietary Sodium Intervention in a Chinese Population. Arch Intern Med. 2008;168(16):1740–1746. doi:10.1001/archinte.168.16.1740
Blood pressure (BP) responses to the cold pressor test (CPT) and to dietary sodium intake might be related to the risk of hypertension. We examined the association between BP responses to the CPT and to dietary sodium and potassium interventions.
The CPT and dietary intervention were conducted among 1906 study participants in rural China. The dietary intervention included three 7-day periods of low sodium intake (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]), high sodium intake (18 g/d of salt [307.8 mmol/d of sodium]), and high sodium intake plus potassium chloride supplementation (60 mmol/d). A total of 9 BP measurements were obtained during the 3-day baseline observation and the last 3 days of each intervention using a random-zero sphygmomanometer.
Blood pressure response to the CPT was significantly associated with BP changes during the sodium and potassium interventions (all P < .001). Compared with the lowest quartile of BP response to the CPT (quartile 1), systolic BP changes (95% confidence intervals) for the quartiles 2, 3, and 4 were −2.02 (−2.87 to −1.16) mm Hg, −3.17 (−4.05 to −2.28) mm Hg, and −5.98 (−6.89 to −5.08) mm Hg, respectively, during the low-sodium intervention. Corresponding systolic BP changes during the high-sodium intervention were 0.40 (−0.36 to 1.16) mm Hg, 0.44 (−0.35 to 1.22) mm Hg, and 2.30 (1.50 to 3.10) mm Hg, respectively, and during the high-sodium plus potassium supplementation intervention were −0.26 (−0.99 to 0.46) mm Hg, −0.95 (−1.70 to −0.20) mm Hg, and −1.59 (−2.36 to −0.83) mm Hg, respectively.
These results indicate that BP response to the CPT was associated with salt sensitivity and potassium sensitivity. Furthermore, a low-sodium or high-potassium diet might be more effective to lower BP among individuals with high responses to the CPT.
Hypertension is an important public health challenge in the United States and worldwide because of its high prevalence and the concomitant increase in risk of cardiovascular and kidney disease.1- 3 High dietary sodium and low potassium intake have been associated with an increased blood pressure (BP) in animal experiments, observational epidemiologic studies, and randomized controlled clinical trials.4- 6 However, there is substantial scientific evidence suggesting that BP responses to dietary sodium or potassium intake vary considerably among individuals.5,7- 9 Previous studies have indicated that salt sensitivity or potassium sensitivity is more common among individuals who are older, overweight, hypertensive, or of African American descent.5,10 In addition, dietary potassium intake also affects salt sensitivity.11 However, other predictors for salt sensitivity or potassium sensitivity of BP have not been well studied.
The cold pressor test (CPT), which measures the response of BP to the stimulus of external cold, has long been a standard test to characterize sympathetic nervous system activity and has been documented to predict the subsequent risk of hypertension in normotensive persons.12- 15 Previous studies have also suggested that sympathetic nervous system activity might play an important role in determining the salt sensitivity of BP.16 The association between BP responses to the CPT and salt sensitivity, however, has not been well studied. The only published study that examined this association reported that the mean increase in BP and its recovery time from peak to baseline during the CPT was significantly higher in salt-sensitive children compared with their counterparts who were not salt sensitive among 268 school children.17 In that study, salt sensitivity was tested using a short-term protocol in which children were salt loaded with an oral saline drink and salt depleted by administering furosemide.
A positive association of BP with dietary sodium intake and an inverse association with dietary potassium intake have been reported in rural Chinese populations.18,19 In the INTERSALT study (the International Cooperative Study on Electrolytes and Blood Pressure), mean dietary intake of sodium was much higher and the intake of potassium was lower in the Chinese population compared with other populations in the world.20 Dietary sodium intake was particularly high and potassium intake was low in Chinese living in north China.21 We examined the association between BP responses to the CPT and BP responses to dietary sodium and potassium interventions among 1906 Chinese men and women aged 18 to 60 years, who participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study.
The GenSalt study was conducted in rural areas in north China from October 2003 to July 2005. A community-based BP screening was conducted among persons aged 18 to 60 years in the study villages to identify potential probands and their families for the study. Those with a mean systolic BP between 130 and 160 mm Hg and/or a mean diastolic BP between 85 and 100 mm Hg and no use of antihypertensive medications and their siblings and offspring were recruited for the dietary intervention study. The detailed eligibility criteria for the probands and their siblings and/or offspring are presented elsewhere.22 In general, individuals who had stage 2 hypertension, secondary hypertension, use of antihypertensive medications, history of clinical cardiovascular disease or diabetes, or heavy alcohol use or were pregnant or currently on a low-sodium diet were excluded from the dietary intervention. Among the 1906 eligible individuals, 1858 (97.5%) completed the entire dietary sodium and potassium interventions. Of them, a total of 1813 participants also completed the CPT and were included in the current analysis.
Institutional review boards at all participating institutes approved the GenSalt study. Written informed consent forms for the baseline observation and for the intervention program were obtained from each participant.
A standard questionnaire was administered by a trained staff member at the baseline examination to collect information on demographic characteristics, personal and family medical history, and lifestyle risk factors (including cigarette smoking, alcohol drinking, and physical activity).
Three BP measurements were obtained at each clinical visit by trained and certified observers according to a common protocol adapted from procedures recommended by the American Heart Association.23 Blood pressure was measured with the participant in a sitting position after 5 minutes of rest. In addition, participants were advised to avoid alcohol, cigarette smoking, coffee and/or tea, and exercise for at least 30 minutes before their BP measurement. A random-zero sphygmomanometer was used, and 1 of 4 cuff sizes (pediatric, regular adult, large, or thigh) was chosen on the basis of the circumference of the participant's arm.23 Blood pressure was measured each morning of the 3-day baseline observation and on days 2, 5, 6, and 7 of each intervention period by the same BP technician using the same sphygmomanometer to avoid interobservation variation.
All BP observers participated in a special training session on the use of a standardized protocol for measurement of BP. To be certified as a GenSalt BP observer, satisfactory performance on a written test of how to prepare study participants for BP measurement, select the correct cuff size, and use standard techniques for BP measurement—during a standardized videotape examination and concordant measurements of BP with an instructor—were required. All BP observers were blinded to the dietary intervention and the CPT results.
The CPT was conducted during the baseline examination (Figure 1). After the participant had remained sitting for 20 minutes, 3 BP measurements were obtained using a standard mercury sphygmomanometer before the ice water immersion. Then, the participant immersed his or her left hand in the ice water bath (3°C to 5°C) to just above the wrist for 1 minute. Blood pressure measurements at 0, 60, 120, and 240 seconds were obtained using a standard mercury sphygmomanometer after the left hand had been removed from the ice water bath. The CPT was well tolerated in all subjects, and no adverse effect was reported.
The study participants received a low-sodium diet (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]) for 7 days. Then, they received a high-sodium diet (18 g/d of salt [307.8 mmol/d of sodium]) for 7 days. During the first 2 intervention phases, potassium intake remained unchanged. In the final week, the participants maintained a high-sodium diet and took a 60-mmol/d potassium chloride supplement (Figure 1). There was no washout period between the 3 intervention phases in order to observe BP changes from the low-sodium to the high-sodium intervention and from the high-sodium to the high-sodium plus potassium supplementation intervention. 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. Although dietary salt intake was the same for all study participants, dietary total energy intake was varied into 5 levels according to their baseline energy intake. To ensure study participants' compliance to the intervention program, they were required to have 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. The study participants were instructed to avoid consuming any foods that were not provided by the study. In addition, 3 timed urinary specimens were collected at baseline and in each phase of intervention to monitor participants' compliance to dietary sodium and potassium intake. The results from 24-hour urinary excretion of sodium and potassium at the baseline examination and during each of the 3 dietary intervention phases showed excellent compliance. For example, the mean (SD) 24-hour urinary excretions of sodium and potassium were 241.8 (68.2) mmol and 36.8 (10.0) mmol, respectively, at baseline, 46.7 (15.7) mmol and 31.0 (8.0) mmol, respectively, during the low-sodium intervention, 244.5 (40.4) mmol and 36.2 (8.1) mmol, respectively, during the high-sodium intervention, and 251.9 (36.9) mmol and 77.3 (12.6) mmol, respectively, during the high-sodium plus potassium supplementation intervention.
Blood pressure levels at baseline and during intervention were calculated as the mean of 9 measurements from 3 clinical visits during the 3-day baseline observation or on days 5, 6, and 7 of each intervention period. Responses were defined as follows: BP response to low sodium intake = BP during the low-sodium intervention − BP at baseline; BP response to high sodium intake = BP during the high-sodium intervention − BP during the low-sodium intervention; and BP response to potassium supplementation = BP during the high-sodium plus potassium supplementation intervention − BP during the high-sodium intervention. Blood pressure responses to dietary sodium and potassium interventions were analyzed as both continuous and categorical variables. High salt sensitivity was defined as a BP decrease in the top 30th percentile of all responses during the low-sodium intervention or a BP increase in the top 30th percentile during the high-sodium intervention. High potassium sensitivity was defined as a BP decrease in the top 30th percentile during the high-sodium plus potassium supplementation intervention among all study participants. The area under the curve (AUC) of BP responses to the CPT was calculated. Area under the curve summarizes the magnitude of BP increase and its recovery time from peak to baseline during the CPT and is more informative than BP change at any single time point.
Age- and sex-adjusted mean values of continuous variables and percentages of categorical variables for exposures, covariates, and outcomes were calculated by quartiles of AUC of systolic BP responses to the CPT. The statistical significance of differences in these characteristics across quartiles was examined by means of the Z test (continuous variables) or the Wald χ2 test (categorical variables) in multivariate regression models after adjustment for age and sex. Multivariate linear and logistic regression analyses were used to explore the association between BP responses to the CPT and BP responses to low-sodium, high-sodium, and high-sodium plus potassium supplementation interventions. The AUC of BP responses to the CPT were categorized into quartiles and the quartile with the lowest value was used as the reference group. To test for a linear trend, the medians of AUC in each quartile were treated as a continuous variable in regression models. Age, sex, education, cigarette smoking, alcohol consumption, physical activity, body mass index, baseline BP, and 24-hour urinary excretion of sodium were adjusted in the multivariate models.
The characteristics of study participants by quartile of AUC of systolic BP responses to the CPT are presented in Table 1. On average, participants with higher systolic BP responses to the CPT were older, more likely to be male, cigarette smokers, and alcohol drinkers and more physically active. In addition, those with higher systolic BP responses to the CPT were heavier, had higher baseline BP, and higher dietary salt intake as measured by 24-hour urinary excretion of sodium. As expected, the mean maximum changes in both systolic and diastolic BP increased with higher AUC of systolic BP responses to the CPT. The pattern of study participants' characteristics by quartile of AUC of diastolic BP responses to the CPT was similar to that for the systolic BP responses and therefore is not shown.
Figure 2 displays the age- and sex-adjusted mean systolic BP responses to the low-sodium, high-sodium, and high-sodium plus potassium supplementation interventions by quartile of AUC of systolic BP responses to the CPT (Figure 2A) and diastolic BP responses to dietary interventions by quartiles of AUC of diastolic BP responses to the CPT (Figure 2B). There were dose-response relationships between systolic BP responses to the CPT and systolic BP responses to the low-sodium, high-sodium, and high-sodium plus potassium supplementation interventions (all P < .001 for linear trend). A similar pattern was observed for diastolic BP, although the association was only statistically significant for BP responses to the low-sodium intervention (P < .001 for linear trend).
After adjustment for important covariates, there were statistically significant associations between the quartiles of BP response to the CPT and BP response to the dietary interventions (Table 2). Similar results were found when BP response to the CPT was used as a continuous variable. After adjustment for important covariates, 1 standard deviation difference in the AUC of systolic BP responses to the CPT was associated with a −2.59–mm Hg (95% confidence interval [CI], −2.91 to −2.27 mm Hg) (P < .001) reduction in systolic BP during the low-sodium intervention, a 0.98–mm Hg (95% CI, 0.70 to 1.27 mm Hg) (P < .001) increase in systolic BP during the high-sodium intervention, and a −0.72–mm Hg (95% CI, −0.99 to −0.44 mm Hg) (P < .001) reduction in systolic BP during the high-sodium plus potassium supplementation intervention. One standard deviation difference in the AUC of diastolic BP responses to the CPT was associated with a −1.35–mm Hg (95% CI, −1.63 to −1.07 mm Hg) (P < .001) reduction in diastolic BP during the low-sodium intervention, a 0.33–mm Hg (95% CI, 0.05 to 0.61 mm Hg) (P = .02) increase in diastolic BP during the high-sodium intervention, and a −0.40–mm Hg (95% CI, −0.64 to −0.16 mm Hg) (P = .001) reduction in diastolic BP during the high-sodium plus potassium supplementation intervention.
The age- and sex-adjusted prevalence of high salt sensitivity or high potassium sensitivity for systolic BP was greater among persons with a higher BP response to the CPT (Figure 3). For instance, according to the quartiles of BP response to the CPT (for systolic BP: <558.9, 558.9-607.0, 607.1-667.3, ≥667.4; and for diastolic BP: <346.0, 346.0-382.3, 382.4-419.0, ≥419.1), the prevalence of high salt sensitivity during the low-sodium intervention was 12.8%, 24.7%, 33.0%, and 48.2%, respectively, for systolic BP and 20.9%, 25.3%, 31.6%, and 42.8%, respectively, for diastolic BP. The prevalence of high salt sensitivity during high-sodium intervention was 23.5%, 26.6%, 31.3%, and 43.1%, respectively, for systolic BP and 27.0%, 30.4%, 36.3%, and 33.7%, respectively, for diastolic BP. Finally, the prevalence of high potassium sensitivity during the high-sodium plus potassium supplementation intervention was 23.1%, 25.7%, 34.1%, and 35.9%, respectively, for systolic BP and 28.6%, 31.0%, 30.4%, and 30.1%, respectively, for diastolic BP. After adjustment for important covariates, odds ratios of high salt or potassium sensitivity significantly increased by quartiles of AUC of BP response to the CPT for systolic BP (Table 3). The association was not as strong for diastolic BP.
This large population-based diet intervention study identified a dose-response relationship between BP responses to the CPT and to dietary sodium and potassium interventions. This relationship was statistically significant and independent of other covariates. To our knowledge, our study is the first investigation to report a relationship between BP responses to the CPT and salt sensitivity and potassium sensitivity. These findings have important clinical and public health implications.
Dietary sodium reduction and potassium supplementation have been recommended as an effective approach for the treatment and prevention of hypertension in populations.24,25 Identifying individuals who are more sensitive to dietary sodium and potassium interventions will enable targeted lifestyle modification among individuals who may particularly benefit from a low-sodium and high-potassium diet. In addition, salt sensitivity has been associated with increased risk of cardiovascular disease and premature death.26,27 From a public health perspective, salt-sensitive individuals at high risk for hypertension and cardiovascular disease could be identified before disease development, and effective and appropriate lifestyle modifications could be implemented for primary prevention. Our study indicates that BP responses to the CPT are significantly related to salt sensitivity and potassium sensitivity. The CPT might help to identify individuals who are more salt sensitive or potassium sensitive. Further studies should examine the reproducibility of BP responses to the CPT and dietary sodium and potassium interventions.
Being highly responsive to the CPT has been associated with an increased risk of hypertension in previous studies.12- 15 Menkes et al14 reported a significant association between BP response to the CPT and subsequent risk of hypertension among 910 young white men. Among those in the lowest, middle 2, and upper quartiles of maximum systolic BP response to the CPT, the cumulative incidence of hypertension was 2.4%, 3.0%, and 6.7%, respectively, over 20 to 36 years of follow-up. Kasagi et al15 reported that systolic hyperreactors (defined as maximal systolic BP response to the CPT >15 mm Hg) had a 37% higher risk of hypertension compared with systolic normal reactors over 28 years of follow-up among 824 normotensive participants. Our study indicated that individuals who were highly responsive to the CPT might be more sensitive to dietary sodium and potassium interventions. Therefore, a diet low in sodium or high in potassium should be recommended to this group for the purpose of prevention and treatment of hypertension.
The CPT is known to cause a global sympathetic activation and result in significant arteriolar vasoconstriction, with a subsequent increase in BP.12,28- 31 Several studies have shown that the CPT increases plasma norepinephrine concentration28,29 and muscle sympathetic nerve activity.12,30,31 The increase in muscle sympathetic nerve activity correlates highly with increases in both mean arterial BP and peripheral venous norepinephrine concentration.12 Salt sensitivity has also been related to heightened sympathetic nervous system activity, which affects renal hemodynamics, tubular sodium, and water handling.20,32 Furthermore, an interaction between dietary sodium intake, sympathetic nervous system activity and BP has been suggested.33 Blood pressure responses to the CPT and to dietary sodium and potassium interventions might share the same underlying physiological pathway. Further studies are warranted to examine this important question.
In our study, systolic BP response to the CPT is a stronger predictor of salt sensitivity or potassium sensitivity than diastolic BP response. Systolic BP is affected directly by arteriolar vasoconstriction due to sympathetic activation induced by the CPT. Indeed, previous studies have indicated that systolic but not diastolic BP response to the CPT predicts the subsequent risk of hypertension.14,15
Our findings are noteworthy because they are based on a large, well-controlled dietary intervention study. Compliance to dietary intervention and to the CPT was excellent. In addition, careful measures of study and outcome variables allowed for precise estimation of the association. To our knowledge, this study is the first to report a strong relationship between the CPT and salt sensitivity and potassium sensitivity in adults. Our study also has limitations. Although exposure to a 1-week low-sodium and 1-week high-sodium intervention has become the standard method for testing salt sensitivity in clinical research, the relationship between the effects of this relatively short intervention and an individuals' long-term response to dietary sodium intake is unknown. Several clinical studies, however, have indicated that salt sensitivity estimated by this method is a reproducible phenomenon.34,35
In conclusion, our study indicates that BP response to the CPT is associated with salt sensitivity and potassium sensitivity. The CPT might aid in identifying individuals who are more sensitive to dietary sodium or potassium interventions. In addition, a low-sodium or high-potassium diet might be more effective to lower BP among individuals who are highly responsive to the CPT. Future studies to confirm our findings will have important clinical and public health implications.
Correspondence: Jing Chen, MD, MSc, Department of Medicine, Tulane University School of Medicine, 1443 Tulane Ave SL45, New Orleans, LA 70112 (email@example.com).
Accepted for Publication: December 3, 2007.
Author Contributions:Study concept and design: J. Chen, D. Gu, Jaquish, Rao, Liu, Hixson, Whelton, and He. Acquisition of data: J. Chen, D. Gu, C.-S. Chen, Rao, Liu, and He. Analysis and interpretation of data: J. Chen, C.-S. Chen, Hamm, C. C. Gu, and He. Drafting of the manuscript: Chen and He. Critical revision of the manuscript for important intellectual content: D. Gu, Jaquish, C.-S. Chen, Rao, Liu, Hixson, Hamm, C. C. Gu, Whelton, and He. Statistical analysis: C.-S. Chen, C. C. Gu, and He. Obtained funding: Rao, Hixson, and He. Administrative, technical, and material support: Jaquish, Hixson, and He. Study supervision: J. Chen, Hamm, and He.
Financial Disclosure: None reported.
Funding/Support: The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by a cooperative agreement project grant (U01HL072507) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Tulane University Health Sciences Center, New Orleans, Louisiana: Jiang He (principal investigator [PI]), Lydia A. Bazzano, Chung-Shiuan Chen, Jing Chen, Tanika N. Kelly, L. Lee Hamm, Paul Muntner, Kristi Reynolds, Paul K. Whelton, and Wenjie Yang; Washington University School of Medicine, St Louis, Missouri: D. C. Rao (PI), Matthew Brown, Charles Gu, Treva Rice, Karen Schwander, and Shiping Wang; Chinese Academy of Medical Sciences, Beijing, China: Dongfeng Gu (PI), Jie Cao, Jichun Chen, Xiufang Duan, Jianfeng Huang, Jinghan Huang, Jianxin Li, Depei Liu, Donghua Liu, Enchun Pan, Yang Wei, and Xiqui Wu; Shandong Academy of Medical Sciences, Shandong, China: Fanghong Lu (PI), Shikuan Jin, Qingjie Meng, Fan Wu, and Yingxin Zhao; Shandong Center for Disease Control and Prevention, Shandong, China: Jixiang Ma (PI), Weika Li, and Jiyu Zhang; Zhengzhou University, Henan, China: Dongsheng Hu (PI), Yaxin Ding, Hongwei Wen, Meixi Zhang, and Weidong Zhang; Xinle Traditional Chinese Medicine Hospital, Hebei, China: Xu Ji (PI), Rongyan Li, and Haijun Zu; Nanjing University of Medical Sciences, Jiangsu, China: Cailiang Yao (PI), Yongchao Li, Chong Shen, and Jiayi Zhou; Xi’an Jiaotong University, Shanxi, China: Jianjun Mu (PI), Enrang Chen, Qinzhou Huang, and Man Wang; Chinese National Human Genome Center at Beijing, Beijing, China: Zhi-Jian Yao (PI), Shufeng Chen, Dongfeng Gu, Hongfan Li, Laiyuan Wang, Penghua Zhang, and Qi Zhao; University of Texas Health Sciences Center at Houston: James E. Hixson (PI) and Lawrence C. Shimmin; National Heart, Lung, and Blood Institute, Bethesda, Maryland: Cashell E. Jaquish