ORIGINAL RESEARCH

published: 25 April 2022

doi: 10.3389/fcvm.2022.860322

Cold Pressor Test in Primary

Hypertension: A Cross-Sectional
Study
Yue Han † , Jun Du † , Jing Wang, Bin Liu, Yu-Ling Yan, Song-Bai Deng, Ya Zou,
Xiao-Dong Jing, Jian-Lin Du, Ya-Jie Liu and Qiang She* on behalf of the CPT Study Group

Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

Objectives: To investigate the characteristics of patients with primary hypertension who

had positive responses to the cold pressor test (CPT).
Methods: This cross-sectional study was conducted between November 2018 to
November 2019, and the CPT was performed in patients with primary hypertension in 48
hospitals. The demographic characteristics and complications were collected through
a questionnaire and physical examinations. A 12-month follow-up was conducted to
identify the occurrence of the following events: a) all-cause mortality; b) myocardial
Edited by: infarction; c) stroke; d) hospitalized for heart failure.
Lin Wei,
Soochow University, China
Results: The CPT was positive in 30.7% of the patients. Compared with the negative
Reviewed by:
CPT group, the positive CPT group was associated with a lower rate of blood pressure
Hongxing Shen, control, and was more likely to have a high salt diet, diabetes, hyperuricemia, left
Jiangsu University, China ventricular wall thickening, carotid plaques, coronary heart disease and heart failure. A
Chen Chen,
Huazhong University of Science and high-salt diet (OR = 1.228, 95%CI: 1.037–1.456) was found to be correlated with the
Technology, China positive result of CPT. Among patients in the positive CPT group, those using diuretics
*Correspondence: had a significantly higher rate of blood pressure control than those not using diuretics
Qiang She
qshe98@cqmu.edu.cn
(54.6 vs.42.6%, x² = 6.756, P = 0.009). After a 12-month follow-up, the incidence of
heart failure in the positive CPT group was significantly higher than that in the negative
† These authors have contributed
equally to this work
CPT group (7.35 vs.5.01%, x² = 3.945, P = 0.047).
Conclusions: Patients with positive responses to the CPT had lower rates of BP control
Specialty section:
and a high risk of heart failure, which may be related to their preference for a high-salt
This article was submitted to
Hypertension, diet. The use of diuretics helps to better control blood pressure in those patients.
a section of the journal
Keywords: cold pressor test, hypertension, diuretic, heart failure, prevalence
Frontiers in Cardiovascular Medicine

Received: 22 January 2022

Accepted: 22 March 2022
Published: 25 April 2022
INTRODUCTION
Citation: Hypertension is an important public health challenge worldwide and it contributes to 51% of stroke
Han Y, Du J, Wang J, Liu B, Yan Y-L, deaths and 45% of ischemic heart disease death worldwide (1–3). Studies have shown that the global
Deng S-B, Zou Y, Jing X-D, Du J-L,
prevalence of hypertension has risen continuously in recent decades, especially in low-income and
Liu Y-J and She Q (2022) Cold
Pressor Test in Primary Hypertension:
middle-income countries (4). It is estimated that 26.4% (972 million) of adults had hypertension
A Cross-Sectional Study. in 2000, and the number in 2025 is predicted to increase by about 60%, to a total of 1.56 billion
Front. Cardiovasc. Med. 9:860322. globally (3). And hypertension is also one of the most important cardiovascular diseases in China.
doi: 10.3389/fcvm.2022.860322 A national study during 2014–2017 showed that 44.7% of Chinese adults aged 35–75 years had

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Han et al. Cold Pressor Test in Hypertension

hypertension (5). And there is a close relationship between blood A 12-month follow-up was conducted to identify the
pressure level and the risk of cardiovascular and cerebrovascular occurrence of the following events: a) all-cause mortality; b)
diseases such as stroke, atrial fibrillation, and especially heart myocardial infarction; c) stroke; d) hospitalized for heart failure
failure. Hypertension leads to heart failure with preserved (The study workflow is shown in Figure 1).
ejection fraction or heart failure with reduced ejection fraction The sample size for this study was estimated based on a
in patients with coronary heart disease or myocardial infarction. previous study which found that the positive rate of CPT in
Previous data of Chinese showed that cardiovascular and normotensive was32.8% (18). PASS 15.0 was used to calculate
cerebrovascular diseases account for more than 40% of all the sample size. A sample size of 1403 produces a two-sided 95%
deaths (6). However, the management of hypertension remains confidence interval with a width equal to 0.050 when the sample
suboptimal in China, with a low treatment rate and control rate. proportion is 33%.
Studies from 1997 to 2017 shows that the ranges of hypertension
prevalence, awareness, treatment, and control rate among Inclusion/Exclusion Criteria
hypertensive patients were 18.0–44.7, 23.6–56.2, 14.2–48.5, and The CPT was performed in patients with primary hypertension
4.2–30.1% respectively (7). Thus, it is important to improve the in 48 hospitals from November 2018 to November 2019.
control rate of hypertension and prevent complications. Patients were included based on the following inclusion
The cold pressor test (CPT), which was developed by a criteria: age above 18 years and a diagnosis of primary
physician in the division of medicine at the Mayo Clinic hypertension (systolic BP ≥ 140 mmHg and/or diastolic BP ≥
Rochester, Edgar A. Hines, Jr. (1906–1978) (8), has been used 90 mmHg on at least three occasions on different days).
as a nonspecific and strong stimulus to sympathetic neural Patients were excluded on the basis of the following criteria:
outflow in humans. It evokes remarkable increases in blood primary aldosteronism or other diseases or causes of secondary
pressure and muscle sympathetic nerve activity (MSNA) with hypertension; systolic BP (SBP) ≥ 180 mmHg and/or diastolic
no significant changes in heart rates (9, 10), and was used BP (DBP) ≥ 110 mmHg; severe heart or lung diseases, acute stage
to assess the vasoconstrictor reserve (11). The reflex pathway stroke (<3 months) or end-tage cancer; inability to undergo the
to activate MSNA may originate from cold nociceptors in the cold pressor test; or pregnancy.
skin that conduct afferent signals by unmyelinated C-fibers,
and the pathway may involve a central vasomotor center that Cold Pressor Test Protocol
serves to regulate MSNA (10, 12). Therefore, CPT was also The participants were seated, and the blood pressure of the right
be used to evaluate the sympathetic reactivity in patients with upper arm was measured three times with a calibrated electronic
orthostatic hypotension (13). For a long time, CPT was also used sphygmomanometer or standard mercury sphygmomanometer
as a tool to study BP variability. Hines and Brown performed after the patients had rested for 20 minutes in a room with
CPT in 40 healthy participants and found that the degree to appropriate temperature. The average blood pressure of the three
which blood pressure responses to cold stimuli can be divided measurements was taken as the basic blood pressure. Then, the
into three categories: a minimal increase of blood pressure in participants immersed their left hands in ice water at 3–5◦ C for 1
healthy participants, a much higher increase of blood pressure minute. The blood pressure of the right upper arm was measured
in hypertension, and a similar reaction to the patients with 0 min, 1 min, 2 min, and 4 min after removal of the left hand from
hypertension in those participants who were recognized at high the ice water. The test was considered positive if the SBP, DBP or
risk for developing hypertension. Thus, CPT was thought to mean arterial pressure (MAP) increased ≥ 15 mmHg after cold
predict a subject’s risk of developing hypertension. Subsequent stimulation. The test was considered negative if the SBP, DBP or
studies have also shown that response to CPT in individuals mean arterial pressure (MAP) increased < 15 mmHg after cold
healthy can predict hypertension (14–17). However, it is not clear stimulation. MAP = (SBP + 2 × DPB)/3 or MAP = DBP +
whether CPT can also predict cardiovascular risk and how is the 1/3 (SBP-DBP).
prevalence of positive CPT in patients with hypertension. Our This study was approved by the ethical committee of
study performed CPT in a large number of patients with primary Chongqing Medical University, and written informed consent
hypertension for the first time, aim to determine the prevalence was obtained from all patients participating in the study.
of the positive CPT in patients with primary hypertension, and
to investigate the characteristics and the risk of cardiovascular Standard for Blood Pressure Under Control
events of those patients. The standard was based on the Guidelines for the prevention
and treatment of hypertension in China (revised in 2018) (6).
MATERIALS AND METHODS The target BP is < 140/90 mmHg for the general population,
< 150/90 mmHg for those older than65 years,< 140/90 mmHg
Study Design and Sample Size Estimation for those with coronary heart disease or kidney disease (without
This was an observational, cross-sectional study. Data from proteinuria), and < 130/80 mmHg for those with diabetes
the enrolled patients were collected during the first interview mellitus, heart failure or kidney disease (with proteinuria).
and then entered into a database, including their medical
and pharmacological histories. The CPT and a physical Statistical Analysis
examination, including measurement of height, weight, and BP All data were input by two independent researchers using
were conducted during the first interview. EpiData V.3.1 (EpiData Association, Odense, Denmark), and

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Han et al. Cold Pressor Test in Hypertension

FIGURE 1 | Study workflow.

the database was established after checking for differences in (2865 patients); in the rest of the patients, it could not be
the two records. SPSS Statistics version 21.0 (IBM, Armonk, performed due to cold intolerance (8.5%).
New York) was used for statistical analysis. Categorical variables A total of 880 patients (30.7%) screened positive with the CPT
were analyzed with χ2 tests. The factors influencing CPT and were placed in the positive group, and the other 1985 were
were screened and determined by multivariable binary logistic placed in the negative group.
regression analysis. Statistical significance was defined as a p-
value < 0.05.
Characteristics of Participants
The baseline data and complications for the included patients
RESULTS are shown in Table 1. The proportion of patients with a high
salt diet, diabetes, hyperuricemia, left ventricular wall thickening,
Cold Pressor Test Results carotid plaques, coronary heart disease and heart failure were
From November 2018 to November 2019, 3132 patients with much greater in the positive group than the negative group (P
primary hypertension in 48 hospitals were invited to participate < 0.05). However, there were no significant differences in the
in our study. The CPT was performed in 91.5% of the population proportion of sex, age, BMI, family history of hypertension,

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Han et al. Cold Pressor Test in Hypertension

TABLE 1 | Clinical characteristics of the participants.

Characteristics Total Positive group Negative group x² P-value

(n/N) N (%) N (%)

Baseline
Sex (male, %) 1303/2865 401 (45.6) 902 (45.4) 0.004 0.950
Age ≥ 65 years 1260/2865 397 (45.1) 863 (43.5) 0.664 0.415
Body mass index (BMI) ≥ 24 kg/m2 1607/2830 508 (58.7) 1099 (56.0) 1.790 0.181
Family history of hypertension 1179/2825 372 (43.2) 807 (41.1) 1.030 0.310
Current smoker 641/2865 203 (23.1) 438 (22.1) 0.353 0.552
Current drinker 579/2865 177 (20.1) 402 (20.3) 0.007 0.932
High salt diet 1496/2865 500 (56.8) 996 (50.2) 10.780 0.001
Hyperlipidemia 1015/2782 328 (38.5) 687 (35.6) 2.148 0.143
Diabetes 512/2818 179 (20.6) 333 (17.1) 4.812 0.028
Hyperuricemia 317/2700 116 (13.9) 201 (10.8) 5.625 0.018
Complications
Left ventricular wall thickening 326/2649 129 (15.8) 197 (10.8) 13.033 0.000
Carotid plaques 404/2574 162 (20.5) 242 (13.6) 19.938 0.000
Higher values of serum creatinine or proteinuria 155/2620 52 (6.4) 103 (5.7) 0.567 0.452
Coronary heart disease 465/2740 168 (19.9) 297 (15.7) 7.454 0.006
Heart failure 92/2722 38 (4.5) 54 (2.9) 4.906 0.027

Body mass index (BMI) referred to weight in kilograms (kg) divided by height in meters squared (m2). Current smoker referred to smoking at least 1 cigarette every day. Current drinker
referred to drinking alcohol at least 1 time/month in the previous 1 year. A high salt diet referred to the intake of at least 6g of salt every day. Hyperlipidemia referred to either TG ≥ 2.26
mmol/L, TC ≥ 5.2 mmol/L, LDL-C ≥ 3.4 mmol/L or self-reported use of lipid-lowering drugs. Diabetes referred to the use of hypoglycemic medication or a measured fasting blood
glucose level ≥ 7.0 mmol/L or non-fasting blood glucose level ≥ 11.1 mmol/L. Hyperuricemia referred to blood uric acid > 420umol/L or 7mg/dL in two tests on different days.

5.335, P = 0.021). In the positive CPT group, most patients took

TABLE 2 | Analysis of factors associated with positive results of CPT.
renin-angiotensin-aldosterone system (RAAS) inhibitors (60.5%)
B S.E. P-value OR (95%CI) to control blood pressure, followed by calcium channel blockers
(CCB, 58.9%), diuretics (16%), and beta-blockers (12.5%). The
Sex 0.031 0.097 0.748 1.032 (0.853–1.249) comparison of the blood pressure control rates among four
Age 0.125 0.088 0.156 1.133 (0.953–1.346) antihypertensive therapies is shown in Figure 2. The blood
BMI 0.086 0.088 0.329 1.089 (0.918–1.293) pressure control rate for patients using diuretics was significantly
Family history of 0.078 0.088 0.374 1.082 (0.910–1.285) higher than that for patients who did not use diuretics (54.6
hypertension
vs.42.6%, x² = 6.756, P = 0.009). However, there was no
High salt diet 0.206 0.087 0.018 1.228 (1.037–1.456) significant difference in whether CCB, beta-blockers, or RAAS
Current drinker 0.077 0.123 0.528 1.080 (0.850–1.374) inhibitors were used.
Hyperlipidemia 0.047 0.273 0.601 1.049 (0.878–1.253) 1,862 patients were followed up for 12-month to determine
Diabetes 0.186 2.952 0.086 1.205 (0.974–1.490) the incidence of adverse events. There was no significant
Hyperuricemia 0.238 3.351 0.067 1.269 (0.983–1.637) difference in all-cause mortality, myocardial infarction, or stroke
between the positive group and the negative group, but the
hospitalization due to heart failure in the positive CPT group
was significantly higher than that in the negative CPT group
smoking, drinking, hyperlipidemia, or higher values of serum (Table 3).
creatinine or proteinuria between the two groups (p > 0.05). A
high-salt diet (OR = 1.228, 95%CI: 1.037–1.456) was found to be
correlated with the positive result of CPT (Table 2).
DISCUSSION
Medication and Adverse Events of CPT, which has long been a standard test for sympathetic
Participants function, has been documented to predict the subsequent risk
Among the 2865 patients included in this study, 2375 patients of hypertension in normotensive persons (14–17). However, the
regularly took antihypertensive drugs, including 766 (87.0%) in physiological basis of the BP responses to the CPT is not yet
the positive CPT group and 1609 (81.1%) in the negative CPT fully understood. Studies have shown that the reason for CPT
group. Among the patients regularly taking antihypertensive increasing BP may be the significant constriction of arterioles
drugs, the blood pressure compliance rate was significantly lower by inducing systemic or local sympathetic nerve activation
in the positive group than the negative group (44.8 vs.49.8%, x² = (9, 19–22), and CPT can increase plasma norepinephrine

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Han et al. Cold Pressor Test in Hypertension

FIGURE 2 | Comparison of blood pressure control rates among different medication. RAAS, renin-angiotensin-aldosterone system; CCB, calcium channel blockers.

(19, 21) and myosympathetic nerve activity (9, 20, 22). TABLE 3 | Incidence of adverse events.
The stimulus itself is also complex and dynamic, and may
Adverse events Positive Negative P-value
cause pain and distress, which, in turn, can contribute to group group
sympathetic activation. (N = 544) (N = 1318)
Keller-Ross et al. conducted a study showing an age-and (n, %) (n, %)
sex-dependent increase in muscle sympathetic nerve activity
incidence and frequency with the CPT (23), which contributed to All-cause mortality 2 (0.37) 2 (0.15) 0.36

greater support of BP during the CPT in the older women. While, Myocardial infarction 0 (0.00) 2 (0.15) 0.363

our study shows that in hypertensive patients, the BP responses Stroke 4 (0.74) 8 (0.61) 0.753

to the CPT were independent of gender and age, and the patients Hospitalized for heart failure 40 (7.35) 66 (5.01) 0.047
with diabetes, carotid artery plaque, and coronary heart disease
in the positive CPT group were significantly higher than those in
the negative group. This may be related to vascular endothelial
dysfunction in these patients. Studies have shown that healthy were more easily observed in the CPT positive group in
endothelial cells maintain low levels of oxidative stress and relax our study.
vascular tension by releasing vascular active mediators such as Previous studies showed that BP responses to CPT vary from
nitric oxide, prostacyclin I2 (PGI2), bradykinin, endothelin-1 individual to individual in healthy people, and our study showed
(ET-1), and angiotensin II (Ang-II) (24–29). Imbalance of these that in the population with primary hypertension, different
factors can lead to endothelial dysfunction, which ultimately individuals still had different responses to CPT, and the high
leads to cardiovascular complications such as arterial plaque and response rate of CPT was 30.7%. We found that patients with
coronary heart disease (30, 31). Nabel et al. (32) showed that CPT responsiveness were characterized by a high-salt diet. Jing
normal arteries dilated and diseased arteries contracted after Chen et al. (33) showed that BP response to the CPT was
CPT. In normal blood vessels, CPT may induce coronary dilation associated with salt sensitivity and potassiumsensitivity. And a
by acting on β 2-adrenergic receptors on coronary vascular low-sodium or high-potassium diet might be more effective to
smooth muscle cells via catecholamines and by stimulating α 2- lower BP among individuals with high responses to the CPT,
adrenergic receptors on coronary endothelial cells to stimulate while a high sodium diet could increase systolic blood pressure
nitric oxide synthesis. Vasoconstriction was observed in patients in patients with positive results of CPT. These results indicate
with cardiovascular disease, such as coronary heart disease. This that high responses to the CPT may be related to salt sensitivity
may also be the reason why coronary heart disease complications of BP.

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Han et al. Cold Pressor Test in Hypertension

Previous studies have also suggested that sympathetic ETHICS STATEMENT

nervous system activity might play an important role in
determining the salt-sensitivity of BP (34), which affects renal The studies involving human participants were reviewed and
hemodynamics, sodium and water processing (35, 36). Salt- approved by the Ethical Committee of Chongqing Medical
sensitive hypertension is characterized by a high blood pressure University. The patients/participants provided their written
response to sodium intake, which is often manifested by informed consent to participate in this study.
abnormal sodium metabolism, renal sodium retention, and
enhanced sympathetic nerve activity. These pathophysiological AUTHOR CONTRIBUTIONS
features further lead to the retention of water and sodium.
Diuretics help the kidneys get rid of excess water and sodium. YH: methodology, performing the experiments, data curation,
Therefore, diuretics have an obvious antihypertensive effect on formal analysis, writing—original draft preparation, and
salt-sensitive hypertension. Our study found that patients with writing—review and editing. JD: methodology, performing the
high responses to CPT and patients with salt sensitivity had experiments, data curation, and formal analysis. JW: performing
similar characteristics, and the use of diuretics improve the the experiments, and data curation. BL: writing—review and
control rate of BP in the positive group of CPT, which also editing. S-BD: validation. Y-LY: writing—review and editing.
suggested that patients with high responses to CPT may also YZ: performing the experiments. X-DJ: data curation. J-LD:
have salt sensitivity of BP. And we also found that the incidence writing—review and editing. Y-JL: data curation. CPT Study
of heart failure was significantly higher in the positive group Group: performing the experiments. QS: supervision, project
than in the negative group of CPT. We thought that may be administration, and writing—review and editing. All authors
related to the higher incidence of water and sodium retention contributed to the article and approved the submitted version.
in the positive group. These findings also support that patients
with high responses to CPT have similar characteristics to FUNDING
patients with salt-sensitive hypertension. Therefore, CPT may
become a new diagnostic method for salt-sensitive hypertension. This work was supported by grants from the foundation
However, there are still few studies on the application of CPT for innovative Research Groups of National Natural Science
in the diagnosis of salt-sensitive hypertension, and we need Foundation of China (81770251) and Chongqing Science and
more studies to compare CPT and acute venous saline load or Technology Foundation (cstc2017shmsA130086).
chronic dietary salt load test to understand the role of CPT in the
diagnosis of salt-sensitive hypertension. ACKNOWLEDGMENTS
CONCLUSIONS The authors thank the other members of the CPT study group
from 48 hospitals in Chongqing: Sha-Sha Zeng, Ping Li, Xian-
Patients with high responses to CPT had lower rates of BP control Hu Luo, Jian-Jun Wu, Hong-Bin Yu, Li-Qun Ran, Ting-Rong
and a high risk of heart failure, which may be related to their Liu, Hong Lu, Yan Lin, Chun Yang, You-Gui Gong, Shi-Quan
preference for a high-salt diet. The use of diuretics helps to better Fu, Heng-Hua Dai, Guo-Fu Li, Qing Zhang, Yuan-You Chen,
control blood pressure in primary hypertensive patients with Qiang Li, Fa-Qiong Liu, Feng Yan, Hao Wang, Shi-Cai Lan, Qing-
positive results of CPT. Bin Liao, Xin-Hua Yang, Zhong-Lin Xu, Ren-Hai Liu, Xun Liu,
Jin-Wu Xu, Yong-Yue Tian, Ze-Hui Ao, Xiao-Ke Wang, Zhen-
DATA AVAILABILITY STATEMENT Yun Wu, Liang-Yi Si, Hong-Jun Liu, Chun-Lin Xiong, Qian-Shu
Zhang, Jie Chen, Ming-Cheng Li, Xiao-Hua Pang, Chang-Qing
The raw data supporting the conclusions of this Yu, Hong-Dong Xia, Lian Zeng, Chuan He, Dong Ma, Mei Yang,
article will be made available by the authors, without Chao-Jiang Zhu, Lu-Xiang Chi, Ya-Li Hong, Hong Huang, Yi
undue reservation. Wang, Hui-Ping Yang, Bing-Quan Xiong, Jing Chen.

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Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 April 2022 | Volume 9 | Article 860322