A Study on the Correlation Between Cerebral Small Vascular Disease and Constitution Types of Traditional Chinese Medicine

WANG Lian (王 莲), ZENG Rong (曾 嵘), FENG Hao-li (冯浩丽), LI Lin (李 琳), ZHAO Liang (赵 粮)

1. Shanxi University of Chinese Medicine, Taiyuan 030024, China

2. Department of Neurology, Shanxi Provincial People's Hospital, Taiyuan 030012, China

3. Department of Traditional Chinese Medicine, Shanxi Provincial People's Hospital, Taiyuan 030012, China

ABSTRACT Objective:To study the correlation between cerebral small vascular disease and constitution types of Traditional Chinese Medicine (TCM). Methods:The severity of lacunar infarction and leukoaraiosis were graded in 230 patients with cerebral small vascular disease, and they were divided into TCM constitution types. The survey of TCM constitution types was carried out by using standardized TCM constitution scale, and order multivariate Logistic regression was used to analyze the correlation between TCM constitution types with severity of lacunar infarction and leukoaraiosis. Results:Yang-deficiency (阳虚) constitution, blood-stasis constitution and phlegm-dampness constitution were the most common TCM constitution types in patients with lacunar infarction, accounting for 33.7%, 12.5%, 11.5% respectively.Yang-deficiency constitution, blood-stasis constitution and Yin-deficiency (阴虚) constitution were the most common TCM constitution types in patients with leukoaraiosis, accounting for 28.8%,18.5%,13.7%respectively. There were significant differences in lacunar infarction of Yang-deficiency constitution and blood stasis constitution (P＜0.05), and there were significant differences in leukoaraiosis of phlegmdampness constitution and blood-stasis constitution (P＜0.05). Single factor analysis showed that the main risk factors of lacunar infarction were age, smoking, alcohol consumption, Yang-deficiency constitution and blood-stasis constitution, and the main risk factors of leukoaraiosis were age, smoking, hypertensive disease, phlegm-dampness constitution and blood-stasis constitution. The ordered multivariate Logistic regression analysis found that the severity of lacunar infarction was closely related to age, and the severity of leukoplosis was closely related to age, smoking and hypertension disease. Conclusion:TCM constitution types of lacunar infarction in patients with small cerebral vascular disease is mainly Yang-deficiency constitution and blood-stasis constitution, and the risk factors include age, smoking, alcohol consumption,Yang-deficiency constitution and blood-stasis constitution. Age is closely related with lacunar infarction.TCM constitution types with leukoaraiosis are mainly phlegm-dampness constitution and blood-stasis constitution, and the risk factors are age, smoking, hypertension disease, phlegm-dampness constitution and blood-stasis constitution. Age, smoking and hypertension disease are closely related with leukoaraiosis.

KEYWORDS Cerebral small vascular diseas; Lacunar infarction; Leukoaraiosis; Constitutional types of traditional Chinese medicine; Risk factors

TCM constitution refers to the comprehensive and relatively stable inherent characteristics of the human body in the process of life, formed on the basis of innate endowments and acquired in terms of form, structure, physiological function and psychological state. It is the human personality characteristics adapted to the natural and social environment formed in the process of human growth and development[1]. The constitution of TCM believes that the constitution of TCM is related to disease, and the condition of constitution determines the incidence and tendency of the disease[2,3]. Therefore, in the process of disease health management, special attention should be paid to the differences of people with different constitution characteristics.

Cerebral small vessel disease (CSVD) is a common type of age-related cerebrovascular disease in the clinic. It is a series of imaging,pathological syndromes caused by various causes affecting small arteries, arterioles, capillaries,venules and venules in the brain[4]. With the acceleration of population aging, the high incidence of cerebrovascular disease risk factors, and the popularization and wide application of neuroimaging technology, the incidence and detection rate of CSVD is increasing year by year. CSVD accounts for about 25% of global ischemic stroke causes and 60% of hemorrhagic stroke causes[5]. Domestic studies have shown that CSVD accounts for about 46% of all ischemic strokes, and 45% of all dementias[5]. CVD has been included in the theme of World Stroke Day in 2008-"little strokes, big trouble"[6], and has become one of the hot spots of neuroscience research. CSVD can have an acute onset, manifested as cerebral parenchymal microhemorrhage or ischemic stroke. Most of them have an insidious onset, slow development,and usually lack specific clinical manifestations,so they are often ignored by patients and even medical staff. Symptoms such as decreased cognitive function (vascular dementia), abnormal balanced gait, mental and emotional changes,urinary incontinence, and decreased living ability[7]have severely affected the patient's psychology,quality of life and social function, and the current expert consensus on the preventive treatment of CSVD only targets the controllable cerebrovascular disease risk factors, clinically manifested cerebrovascular disease and secondary preventive treatment drugs. Therefore, from November 2018 to October 2020, we carried out TCM constitution identification and related investigations of patients with CSVD to understand the constitution status of patients with CSVD. On the basis of integrating the concept of TCM treatment for disease prevention and the method of body differentiation and adjustment, this paper is to explore suitable and feasible management methods for the prevention and treatment of CSVD with integrated Chinese and Western medicine.

MATERIALS AND METHODS

Clinical Data

General information

The observed cases were patients with CSVD admitted to the Department of Neurology in our hospital from November 2018 to October 2020. A total of 230 cases, 90 males and 140 females, were 41 to 87 years old, with an average of 60.81±9.43 years old. 230 patients with CSVD included 100 cases of lacunar infarction combined with leukoaraiosis, 84 cases of simple lacunar infarction,and 46 cases of simple leukoaraiosis. Determination of TCM constitution type of 230 patients: 35 cases of blood-stasis constitution, 23 cases of phlegmdampness constitution, 11 cases of Qi-deficiency constitution, 29 cases of Yin-deficiency constitution,8 cases of Qi-stagnation constitution, 71 cases of Yang-deficiency constitution, 8 cases of damp-heat constitution, 44 cases of neutral constitution, 1 case of special constitution.

Diagnostic criteria

Western medicine diagnostic criteria

The diagnostic criteria of CSVD refers to the 2015 edition of China Consensus on the Diagnosis and Treatment of CSVD (《中国脑小血管病诊治共识》)[8]. Criteria for determining cerebrovascular risk factors: ①Definition of hypertension[9]: Three-time blood pressure values measured on different days of the patient in a quiet state, systolic blood pressure 140 mm Hg and (or) diastolic blood pressure 90 mm Hg, or a clear diagnosis of hypertension in the past: The current oral antihypertensive drug blood pressure control is also included in the normal range of hypertension cases. ②Definition of diabetes[10]:Typical symptoms of diabetes (polydipsia, polyphagia,polyuria, unexplained weight loss), and the patient's fasting blood-glucose (no calories eaten for at least 8 hours) 7.0 mmol/L, or random blood glucose 11.1 mmol/L, or blood glucose value after 2 hours glucose load 11.1 mmol/L; or a clear diagnosis of diabetes in the past, currently oral hypoglycemic drugs or insulin injections and blood sugar control within the normal range are also included in diabetes cases. ③Smoking history: smoking 10 cigarettes/d for 1 year. ④Alcohol consumption history: alcohol consumption 100 g/d, for more than 5 consecutive years.

Determination criteria of TCM constitution type

The determination of TCM constitution type refers to theClassification and Determination of TCM Constitution(《中医体质分类与判定》)promulgated by the China Association of Chinese Medicine in 2009[11], which divides the constitution into 9 types of neutral constitution, Yang-deficiency constitution, Yin-deficiency constitution, phlegmdampness constitution, damp-heat constitution, and blood-stasis constitution, Qi-stagnation constitution,Qi-deficiency constitution, and special constitution.

Inclusion criteria

① Head MR imaging meets the imaging diagnostic criteria for CSVD. ② The patient has a clear mind, normal language function, and cooperation in physical examination. ③ Those who are willing to accept clinical investigations and can complete the questionnaire. ④ Aged over 18 years old.

Exclusion criteria

① Magnetic resonance angiography (MRA)showed 50% stenosis of large intracranial vessels.② Cervical vascular ultrasound confirmed carotid artery 50% stenosis. ③ Unable to cooperate with the examination, such as speech impairment,hearing impairment, etc.. ④ The patient is involved in central nervous system diseases,such as multiple sclerosis, Binswanger's disease,carbon monoxide poisoning and other patients who cause brain white matter abnormalities[12].⑤ With infarction under the cortex or watershed infarction, there are infarct lesions＞ 20 mm under the cortex. ⑥ A history of cerebral hemorrhage or large-area cerebral infarction. ⑦ Complicated with other serious diseases such as shock, intracranial tumors, severe liver and kidney dysfunction, etc.. ⑧Contraindications with MRI scans or unable to scan.⑨ Pregnant or breastfeeding women. ⑩ Patients or family members who are not willing to participate.

Elimination criteria

The questionnaire is not filled in as required.The data collection is incomplete, and incomplete items exceeds 20%.

Methods

① All patients signed an informed consent form and approved by the Ethics Committee of Shanxi Provincial People's Hospital. ② Routine head MRI,MRA, cervical vascular color Doppler ultrasound,and TCD were routinely checked on admission for all patients, and cases that met the criteria were included. ③ Grading of the severity of lacunar infarction[13]: Grade 0 refers to lesions without lacunar infarction; Grade 1 refers to 1-3 lesions;Grade 2 refers to 4-10 lesions; Grade 3 refers to more than 10 lesions. ④ The grading of the severity of leukoaraiosis refers to Wohlun's grading criteria[14]:Grade 0 refers to no lesions; Grade 1 refers to focal white matter lesions; Grade 2 refers to diseases that begin to merge; Grade 3 refers to diffuse signal of the entire area containing or not containing U fibers has been fused changes. ⑤ Recognition of TCM constitution: a questionnaire survey is used to evaluate and diagnose patients by professionals,and review by senior qualified physicians. The primary constitution type of the patient is determined based on the result as "yes" with the highest score.In the identification of neutral constitution, the "tend to be" constitution is classified into the physique type of "yes". In the identification of biased physique, the most prominent constitution type is mainly used.

Statistical Methods

The acquired patient data was organized to establish a database, and statistical software SPSS22.0 was used for data analysis. For twosided testing, set α=0.05 as the testing standard.Measurement data are expressed as mean ±standard deviation (x–±s), and measurement data comparison uses analysis of variance. Enumeration data comparison usesχ2test. The ordered multivariate logistic regression was used for analysis.P＜0.05 as the difference is statistically significant

RESULTS

Distribution of TCM Constitution in Lacunar Infarction of Different Severity

The difference between Yang-deficiency constitution and blood-stasis constitution at the different levels of lacunar cerebral infarction was statistically significant (P＜0.05). Among them, bloodstasis constitution was the main type of lacunar infarction in grade 1 (5.4%), and Yang-deficiency constitution was the main type of lacunar infarction of grade 2 and 3, which were 13.6% and 16.3%respectively. Due to the fact that the number of cases did not meet the statistical requirements,statistical analysis was not performed, and the rest of the constitution type had no statistical significance. The results were shown in Table 1.

Comparison of Risk Factors of Cerebrovascular Disease in Different Severity of Lacunar Infarction

The severity of lacunar cerebral infarction was significantly different from age, smoking, and alcohol consumption (P＜0.05), but there was no significant difference from gender, hypertension, and diabetes.Taking TCM constitution type and various risk factors as independent variables, lacunar cerebral infarction as dependent variable, single factor analysis found that age, smoking, alcohol consumption, Yangdeficiency constitution, blood-stasis constitution are the main risk factors of lacunar infarction. The above risk factors were included in the orderly multivariate logistic regression analysis, showing that age is closely related to lacunar infarction (age: OR=1.044,95% CI 0.010-0.075,P＜0.05). The results were shown in Table 2.

Distribution of TCM Constitution with Different Severity of Leukoaraiosis

The difference between phlegm-dampness constitution and blood-stasis constitution was statistically significant (P＜0.05). Among them, bloodstasis constitution was dominant in leukoaraiosis of grade 1 and 2, respectively 8.9%, 5.5%. Phlegmdampness constitution was the main type in leukoaraiosis of grade 3, which was 5.5%. The number of cases of Qi-deficiency constitution, Qistagnation constitution, and special constitution did not meet the statistical requirements, therefore statistical analysis was not performed. The remaining constitution types had no statistically significant difference. The results were shown in Table 3.

Comparison of Risk Factors for Leukoaraiosis with Different Severity for Cerebrovascular Disease

There was a statistically significant difference inthe severity of leukoaraiosis with age, hypertension and smoking (P＜0.05), but there was no statistically significant difference in gender, diabetes, and alcohol consumption. Taking TCM constitution type and various risk factors as independent variables, leukoaraiosis as dependent variable,single factor analysis found that age, hypertension,smoking, phlegm-dampness constitution, bloodstasis constitution were the main risk factors of leukoaraiosis. The above risk factors were included in the orderly multivariate logistic regression analysis, showing that age, smoking,hypertension were closely related to leukoaraiosis(age: OR=1.052, 95%CI 0.002-0.101,P＜0.05;smoking: OR =5.280, 95%CI 0.572-2.756,P＜0.05;hypertension: OR=3.158, 95%CI 0.277-2.022,P＜0.05). The results were shown in Table 4.

Table 1. TCM Constitution Distribution of Lacunar Infarction with Different Severity [Cases (%)]

Table 2. Comparison of Risk Factors of Cerebrovascular Disease in Different Severity of Lacunar Infarction

Table 3. Distribution of TCM Constitution with Different Severity of Leukoaraiosis [Cases (%)]

Table 4. Comparison of Risk Factors of Leukoaraiosis with Different Severity for Cerebrovascular Disease

DISCUSSION

The 2015 edition ofConsensus on the Diagnosis and Treatment of Cerebral Small Vascular Diseases[8]pointed out that the most common risk factors for CSVD are age, diabetes and hypertension. The research results of YANG Nan from Guangdong[15]found that blood stasis syndrome is the main pathogenic factor and pathological product of ischemic stroke combined with cerebral microhemorrhage. The research results of ZHONG Jing-xin from Guangdong[16]also showed that the TCM constitution of patients with CSVD with leukoarais is mainly phlegm-dampness constitution and blood-stasis constitution. The risk factors for leukoaraiosis are age, hypertension and blood-stasis constitution. WU Ying[17]from Shanghai believes that the TCM constitution of patients with cerebral microhemorrhage is mainly phlegmdampness constitution and blood-stasis constitution,and advanced age, hypertension and blood-stasis constitution are the main risk factors. PEI Pei[18]from Beijing showed that the TCM constitution of patients with CSVD is mainly phlegm-dampness constitution and blood-stasis constitution, and age is positively correlated with the severity of lacunar infarction and leukoaraiosis. YANG Xue-ping[19]from Sichuan believes that the TCM constitution of patients with CSVD is mainly composed of Qideficiency constitution, Yang-deficiency constitution,and Qi-stagnation constitution. This study found that age, smoking, alcohol consumption, Yang-deficiency constitution, blood-stasis constitution are the main risk factors for lacunar cerebral infarction.Age, hypertension, smoking, phlegm-dampness constitution, blood-stasis constitution are the main risk factors for leukopenia. After grading the severity of lacunar cerebral infarction and leukoaraiosis,we studied their correlation with TCM constitution in more detail, and found that the two are also related, showing that blood-stasis constitution accounts most in grade 1 lacunar infarction. Yangdeficiency constitution accounts for the largest proportion in both grades 2 and 3 of lacunar infarction. Blood-stasis constitution accounts for the largest proportion in grade 1 and 2 leukoaraiosis,and phlegm-dampness constitution accounts for the largest proportion in the grade 3 leukopenia,which indicates that Yang-deficiency, blood stasis,and phlegm-dampness are the most important pathogenic factors in CSVD lacunar infarction and cerebral leukoaraiosis. The results of this study are not completely consistent with the results of previous studies. The reason may be the cases included in the study are all from various regions of Shanxi Province. Shanxi has diverse topography and great elevation differences. It belongs to a temperate continental monsoon climate, with large differences in temperature between winter and summer, and large temperature differences between day and night. Shanxi residents like cooked wheaten food,mainly grains, with lot intake of salt and vinegar,and greatly insufficient intake of vegetables and fruits. Therefore, local residents are mainly Yangdeficiency constitution, followed by blood-stasis constitution and phlegm-dampness constitution.Inner Canon of Huangdi(《黄帝内经》) records:"The north is a place of closure and storage in nature. The north is topographically high and very cold. People there live outside and drink milk. So they tend to suffer from abdominal flatulence and fullness due to invasion of cold into the viscera...The sages make use of various therapeutic methods and select the most suitable one." This also shows that different geographical environments, climatic conditions and living habits have an impact on human constitution, which may lead to differences in the distribution of constitution types.

Patients with Yang-deficiency constitution mainly show symptoms of aversion to cold, lack of warmth in the hands and feet, and prefer hot drinks and food. Due to "Yang Qi is weak, and it cannot penetrate into the meridian", the warmth is not enough, and the Qi transformation is weakened.Therefore, the deficiency cold is internally generated.The stagnation of Qi and blood leads to disease.Spiritual Pivot Questions and Answers(《灵枢•口问》) records "If there is not enough Qi in the upper region, it will lead to insufficiency of brains,ringing in the ears, hanging the head and dizziness."indicating that insufficient Qi in the upper region(Yang Qi) is the internal basis of encephalopathy.Deficiency of Yang Qi in the brain cannot transport essence, blood and body fluid up, leading to the collaterals of the brain not nourishing (CSVD),emptiness of the brain marrow, insufficiency of the brain, manifested by memory loss, slow response,etc. dementia in the long-term. Patients with phlegm-dampness constitution mainly present with phlegm-dampness symptoms such as body obesity,abdomen fullness, sticky mouth and greasy moss.Phlegm-dampness constitution refers to a variety of causes that act on the body, causing visceral dysfunction, imbalance of Qi and Qi transformation,and water and fluid metabolism disorder, water and dampness aggregation[20]. Patients with blood-stasis constitution mainly show symptoms of blood stasis such as dull skin color and dark purple tongue.The cause of blood stasis refers to the exception of injury, which is formed by various causes acting on the human body to cause Qi and blood dysfunction and unfavorable Qi and blood flow[20]. Under pathological conditions, the formation of blood stasis is often accompanied by water-liquid metabolism disorders, which leads to the accumulation of phlegm. At the same time as the water-liquid metabolism is impaired, Qi and blood disorders can also occur, and the movement of Qi and blood is unsmooth, resulting in blood stasis[20]. ZHU Danxi believed that "phlegm and blood stasis are both Yin pathogen, and it can produce blood stasis due to phlegm, but also cause phlegm and blood stasis to form the same disease." Turbid phlegm and blood stasis are both pathological products, which can be cause and effect each other, and they can also be mixed together to cause the occurrence of CSVD. The cause of turbid phlegm and blood stasis is more complicated, or it is caused by insufficient kidney Yang, dysfunction of opening and closing,causing water and dampness to stop gathering, and gathering into phlegm. Or the failure of life-gate fire cannot warm the spleen Yang, and the water and grain cannot be transformed into essence, which can also be transformed into phlegm and dampness.Or it may be injured by emotions, liver-Qi stagnation for a long time, dysfunction of spleen and stomach transportation, leading to Qi, blood and body fluid transfusion disorder. Body fluid is coagulated into phlegm. Blood stagnation is stasis. Phlegm and blood stasis are mutually condensed. Or long-term intake of fat, sweet and greasy food, obstructing the stomach. Body fluid is not moving, and then phlegm and dampness is generated. Although the causes of the above-mentioned pathological factors are different, their common pathogenesis is the stasis of the brain's collaterals, which leads to the orifice unnourished, lack of mental function, and onset of stroke, dizziness, amnesia, dementia, etc.,which is also consistent with the characteristics of CSVD with various risk factors and different clinical manifestations.

The TCM constitution theory regards constitution as the research object instead of disease. TCM constitution is related to disease. The constitution state determines the disease and the tendency of the disease[2,3], and the constitution is also adjustable[21]. As the most common insidious cerebrovascular syndrome in the elderly, CSVD is a chronic and complex disease, which has the harmfulness of aggravated disease mutation. The current expert consensus on the prevention and treatment of CSVD is only for the controllable cerebrovascular disease risk factors, clinical manifestations of CSVD and secondary preventive treatment drugs. Clinical treatment of CSVD has paid more attention to the "symptomatic" treatment,while neglecting the adjustment of the "syndrome"and "root causes", often treating the symptoms but not the root causes. Therefore, based on the results of TCM constitution identification, targeted interventions in diet, exercise regimen, emotional conditioning, daily life, and the application of TCM appropriate technology are adopted to correct and improve the biased constitution, reduce the incidence of diseases, take precautions before getting sick. However, whether or not the occurrence of CSVD can be prevented and reversed by correcting the TCM constitution requires further prospective multi-center clinical research with large samples.