The Analysis of Constitutions of Traditional Chinese Medicine in Relation to Cerebral Infarction in a Chinese Sample

Abstract

Objective:

To investigate the relationships between the constitutions of Traditional Chinese Medicine (TCM) and patients with cerebral infarction (CI) in a Chinese sample.

Methods:

A total of 3748 participants with complete data were available for data analysis. All study subjects underwent complete clinical baseline characteristics' evaluation, including a physical examination and response to a structured, nurse-assisted, self-administrated questionnaire. A population of 2010 neutral participants were used as the control group. Multiple variable regression (MLR) were employed to estimate the relationship between constitutions of TCM and the outcome.

Design:

A cross-sectional study was conducted to evaluate the association of body constitution of TCM and CI.

Settings/Location:

Communications and healthcare centers in Shanghai.

Subjects:

A total of 3748 participants with complete data were available for data analysis.

Outcome measures:

All study subjects underwent complete clinical baseline characteristics' evaluation, including a physical examination and response to a structured, nurse-assisted, self-administrated questionnaire. A population of 2010 neutral participants were used as the control group. MLR were employed to estimate the relationship between constitutions of TCM and the outcome.

Result:

The prevalence of CI was 2.84% and 4.66% in neutral participants and yang-deficient participants (p = 0.012), respectively. Univariate analysis demonstrated a positive correlation between yang deficiency and CI. After adjustment for relevant potential confounding factors, the MLR detected significant associations between yang deficiency and CI (odds ratio = 1.44, p = 0.093).

Conclusion:

A yang-deficient constitution was significantly and independently associated with CI. A higher prevalence of CI was found in yang-deficient participants as compared with neutral participants.

Introduction

It is important to clarify individual differences and general associations in human life and health. Investigators have found that natural endowments and postnatal acquirements in the process of a lifetime form one's constitution; it is the synthesis of morphological structure, physiological function, and psychological state, in which the inherent characteristics of humans are of relative stability. Constitutional medicine is designed to meet the developmental demands of modern Western medicine; however, it has been based on Traditional Chinese Medicine (TCM) theory since the late 1970s. The constitutions of Chinese people are divided into nine patterns: neutral, qi deficient, yang deficient, yin deficient, phlegm–dampness, damp–heat, blood stasis, qi-stagnation, and special constitution.¹ Previous studies have indicated that specific constitutions might have a close correlation with common human diseases.^2

–5 Therefore, constitutions of TCM may aid in the recognition and prevention of chronic diseases through investigation of susceptible bodies and discussion of the relations between constitutions and syndromes.

Stroke, a multifactorial disease, is a principal origin of severe disability and the second leading cause of mortality globally.^6
–8 Among strokes, cerebral infarction (CI) is the most common and is responsible for 50%–80% of all cases^7,9,10; notably, current therapeutic measures are insufficient for reducing deaths caused by this disease. Prevention of CI recurrence is a common problem faced by both TCM and Western medicine. TCM theory considers constitutions as the internal determinants of occurrence, development, and prognoses of diseases; thus, they may provide evidence that promotes prevention of CI recurrence. Constitutions of TCM are associated with hypertension (HTN), which is the main risk factor for CI.⁵ Additionally, yang deficiency is associated with immunotoxicity of hydrocortisone in Th1/Th2-related cytokine production, which may influence the development of CI.⁴ However, little is known regarding the relationships between the constitutions of TCM and CI. Based on previous studies,^4,5 we hypothesize that the constitutions of TCM are associated with CI. This study aimed at evaluating the relationships between constitutions of TCM and CI in a Chinese sample.

Methods

Study population

A risk-factor study for constitutions of TCM and chronic disease was conducted on a random sample of the Chinese population. Participants aged 30–90 years were recruited from both rural and urban communities in Shanghai. More than 4000 participants (both male and female) were invited to a screening visit between 2011 and 2014. Written consent was obtained from all patients before the study, which was performed in accordance with the ethical standards in the Declaration of Helsinki and approved by the Ethics Committee of the Huashan Hospital. Participants with chronic diseases and conditions that might have potentially affected the risk analysis were excluded. Briefly, the exclusion criteria included (1) severe and abnormal renal and liver function and (2) pregnancy. A total of 3748 participants were available for data analysis.

Data collection

All study subjects underwent complete clinical baseline characteristics' evaluation, which included a physical examination and response to a structured, nurse-assisted, self-administrated questionnaire to collect information on age, gender, residential region, visit date, family history, lifestyle, dietary habits, physical activity level during leisure time, smoking, alcohol consumption, and self-reported medical history. Smoking, alcohol consumption, regular exercise, education, and dietary habits were categorized as mentioned in previous studies. In addition, the definitions of HTN, body mass index, diabetes mellitus (DM), and metabolic syndrome (MetS), respectively, were detailed earlier.^11
–13

Self-reported medical and therapy histories were categorized as “no” or “yes.” CI was defined as any damaged area in the brain detected by either magnetic resonance imaging or computed tomography scanning, except for damage caused by a tumor, subdural hematoma, or other brain disorder; or the blockage also appeared on an angiogram; or the patient had a history of CI. The assessment of constitutions of TCM was based on the standard questionnaire (see Supplementary Data available online at www.liebertpub.com/acm).¹

Statistical analysis

Variables that were not normally distributed were log transformed to approximate a normal distribution for analysis. Differences in variables among subjects grouped by constitutions of TCM were determined by one-way analysis of variance. Among the groups, differences in properties were detected by χ ² analysis. Univariate regression analysis was performed to determine constitutions of TCM variables associated with outcomes. Additionally, multiple variable regression (MLR) was performed to both control potential confounding factors and determine the independent contribution of variables to outcomes. Tests were two sided, and a p-value of <0.05 was considered significant. Results were analyzed using the Statistical Package for Social Sciences for Windows, version 16.0 (SPSS, Chicago, IL). Odds ratios (OR) with 95% confidence intervals were calculated for the relative risk of constitution of TCM with the outcome of CI.

Results

Clinical characteristics of subjects

The clinical baseline characteristics of the 3748 Chinese subjects are listed in Table 1. In the total sample, the mean age was 69.33 years, and the mean height and weight were 161.26 cm and 62.37 kg, respectively. The proportions of subjects who had never had smoking and/or alcohol habits were 86.36% and 83.22%, respectively. The prevalence of HTN, coronary artery disease (CAD), DM, and MetS was 42.58%, 13.31%, 16.84%, and 10.81%, respectively. The prevalence of CI was 3.31% in our study sample. There were significant differences in age, HTN, and CAD between the CI and non-CI groups (p-value <0.05 for all).

Table 1.

Baseline Characteristics of Subjects

Variable	Non-CI	CI	Total	p
Demographical information
N	3624	124	3748
Age	69.19 ± 7.5	73.23 ± 7.47	69.33 ± 7.53	<0.001
Gender, n (%)	1973 (54.44)	66 (53.23)	2039 (54.4)	0.789
Height	161.31 ± 15.37	159.77 ± 7.91	161.26 ± 15.19	0.265
Weight	62.42 ± 10.84	60.66 ± 10.23	62.37 ± 10.82	0.074
SBP	134.47 ± 20.06	133.67 ± 21.5	134.44 ± 19.98	0.946
DBP	68.01 ± 22.36	49.6 ± 47.38	67.12 ± 24.07	0.095
HR	74.21 ± 13.67	73.33 ± 15.39	74.19 ± 13.73	0.481
Lifestyle, n (%)
Exercise	2225 (61.4)	76 (61.29)	2301 (61.39)	0.981
Dietary	3144 (87.58)	107 (86.99)	3251 (87.56)	0.979
Smoking	690 (19.04)	20 (16.13)	710 (18.94)	0.416
Alcohol	614 (16.94)	15 (12.1)	629 (16.78)	0.156
Neutral	1953 (53.89)	57 (45.97)	2010 (53.63)	0.082
Medical history, n (%)
HTN	1528 (42.16)	68 (54.84)	1596 (42.58)	0.005
DM	613 (16.92)	18 (14.52)	631 (16.84)	0.483
CAD	398 (10.98)	21 (16.94)	419 (11.18)	0.039
MetS	397 (10.95)	8 (6.45)	405 (10.81)	0.112

CI, cerebral infarction; CAD, coronary artery disease; DBP, diastolic blood pressure; DM, diabetes mellitus; HR, heart resting; HTN, hypertension; MetS, metabolic syndrome; SBP, systolic blood pressure.

Univariate analysis for CI

Univariate linear regression analyses were developed to include constitutions of TCM to estimate their association with CI. The variable of yang deficiency was significantly associated with the outcome (p = 0.012; Table 2). The prevalence of CI was 2.84% and 4.66% in neutral participants and yang-deficient participants (p = 0.012; Fig. 1), respectively. Univariate analysis demonstrated a positive correlation between yang deficiency and CI.

FIG. 1.

Comparison of prevalence of CI between neutral participants and yang-deficient participants. The prevalence of cerebral infract was 2.84% and 4.66% in neutral participants and yang-deficient participants (p = 0.012), respectively. CI, cerebral infraction; TCM, Traditional Chinese Medicine.

Table 2.

Comparison of Prevalence of Cerebral Infarction Among Constitutions of Traditional Chinese Medicine and Neutral

Variable	Non-CI	CI	Total	p
Neutral	1953	57	2010	—
Qi deficient	1106	47	1153	0.060
Yang deficient	860	42	902	0.012
Yin deficient	319	11	330	0.618
Phlegm–dampness	291	11	302	0.439
Damp–heat	122	2	124	0.420
Blood stasis	72	2	74	0.946
Qi stagnation	52	1	53	0.680
Special	83	2	85	0.792

Difference analysis prevalence of CI among constitutions of Traditional Chinese Medicine and neutral by using χ ² test, respectively.

CI, cerebral infarction.

Multiple variable analyses for CI

MLR analyses were employed to evaluate the association between constitutions of TCM and the CI outcome. After adjustment for relevant potential confounding factors, the MLR detected significant associations between yang deficiency and CI (p = 0.043; Table 3). In participants with yang deficiency, the OR for CI was 1.44. No significant associations were found in the other constitutions of TCM (data not shown).

Table 3.

Multiple Variable Analysis to Include Yang Deficient for Cerebral Infarction

Variable	B	S.E.	p	OR	95% CI
Yang deficient	0.364	0.167	0.043	1.44	1.037–1.996

Multiple variable analyses adjusted for age, gender, smoking, alcohol, HTN, DM, MetS.

CI, confidence interval; DM, diabetes mellitus; HTN, hypertension; MetS, metabolic syndrome; OR, odds ratio.

Discussion

In this cross-sectional study, we investigated the relationships between constitutions of TCM and CI in a Chinese sample. To the best of our knowledge, at the large-scale, population-based, cross-sectional study level, this is the first analysis of constitutions of TCM and CI in China. In addition, a standard questionnaire was applied for assessment of constitutions of TCM, which is crucial for obtaining quantitative variables of TCM. This sample was an adequate representation of the Chinese population, and the findings may work similarly well outside of China. Furthermore, it is important for physicians in integrative medicine to understand the relationships between constitutions of TCM and CI. This is partly because constitutions of TCM can help physicians predict and diagnose CI.

One interesting finding was that yang deficiency was significantly and independently associated with CI. The prevalence of CI was more frequent in the yang-deficient group as compared with the neutral group. A positive correlation between yang deficiency and CI was detected through univariate analysis. MLR analyses demonstrated that yang deficiency and CI had significant and independent associations. Researchers found that yin-deficient constitution patients with aspirin resistance had higher recurrences of cerebral infarction,¹⁴ whereas Han et al. found that the damp–heat and qi-stagnation types might lead to greater susceptibility of hypertensive patients to have an intracerebral hemorrhage.¹⁵ Additionally, another study reported that syndromes of phlegm, blood stasis, and qi deficiency are closely correlated with coagulation function, which is a risk factor for acute cerebral infarction. Constitutions of TCM emphasize the effect of constitutional factors on the evolution and tendency of diseases; hence, the theory of constitutions is an important part of the TCM system because disparities in individual constitutions might result in individual susceptibility to certain pathogenic factors or diseases.

A yang-deficient constitution is a basic classification in the constitutional system of TCM, and one study showed that the level of IgG lowered in patients who were inclined to be kidney-yang-deficient.¹⁶ Chronic inflammation strongly influences CI development and is correlated with CI severity and outcome.^17,18 More interestingly, in yang-deficient model mice, a yang-deficient state was associated with Th1/Th2-related cytokine expression, in which the transcriptions of IFN-γ, IL-2, IL-4, and IL-10 were markedly suppressed, and the proliferation of lymphocytes were significantly decreased as well.⁴ Xie et al. revealed that lower serum IL-10 concentrations were significantly associated with ischemic stroke (one type of CI) in the Chinese population.¹⁹ Reduced levels of IL-10 promote proinflammatory pathways, such as NF-κB,²⁰ by increasing circulating levels of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α,²¹ which consequently leads to CI. In addition, one previous study revealed that lymphocytes, especially T cell subtypes, play an important role in the pathogenesis of ischemic stroke.^2,18 Taken together, these results potentially provide one mechanism by which CI patients are involved in the yang-deficient constitution.

Yang deficiency, especially kidney-yang-xu (deficiency), means that there is a yin–yang imbalance and diminishing energy levels in the physiological functioning of the body.^7,22 In microbial cell factories, yang represents carbon metabolism, and yang deficiency represents energy metabolism decreasing as well as ATP generation deficiency²³ and even, to some extent, mitochondrial dysfunction. Evidence indicates a role for mitochondrial dysfunction in CI²⁴ through its link to reactive oxygen species (ROS) production, calcium dysregulation, inflammation, intrinsic apoptotic cell death etc.²⁵ In addition, in TCM theory, yin functions on behalf of antioxidation and yang does so for oxidation.²⁶ A yin–yang imbalance means that there is an imbalance between antioxidation and oxidation that is caused by releasing harmful intermediates called ROS, which is a significant risk factor of CI.²⁷ Yao et al. revealed that some susceptible genes, such as RGS6, mGluR5, GAPDHL19, and IKZF1, are involved in the maintenance of a yang-deficient constitution.²⁸ Thus, these genes are correlated with changes in cAMP and cGMP levels, energy metabolism, and immune function, which exert influences on CI.^29
–31 In summary, yang deficiency might be a potential risk factor for CI, and promotion of yang in CI patients with yang deficiency could likely reduce the recurrence of CI.

In this study, we also investigated the other constitutions of TCM; however, no significant differences were observed. Due to the uneven distribution of samples in each region, there may have been selective bias. Therefore, the results may not fully reflect the overall population or the properties of the survey project. Moreover, this is a cross-sectional study to investigate the associations so as not to confirm a direct causal relationship. A follow-up study should be conducted to detect the cause–effect.

This study suggested that a yang-deficient constitution is both significantly and independently associated with CI. A higher prevalence of CI was found in yang-deficient participants as compared with neutral participants. These findings may provide insights into clinical practice regarding both the prevention and diagnosis of CI.

Footnotes

Acknowledgments

The authors thank the grant from the Institute of Integrative Medicine of Fudan University and the Development Project of Shanghai Peak Disciplines-Integrative Medicine (20150407) to support the study. ClinicalTrials.gov Identifier: NCT02461472; and Shanghai. Support also came from the China Postdoctoral Science Foundation funded project (2017M611461).

Author's Contributions

J.L. and F.X. drafted the article. N.M. and Y.L. participated in the design of the study and performed the statistical analysis. Z.T. and J.D. conceived the study, and participated in its design and coordination and helped to draft the article. All authors read and approved the final article.

Declaration

Author Disclosure Statement

No competing financial interests exist.

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