Ischemic stroke has become the leading cause of disability and mortality in China [
Homocysteine (Hcy) is a sulfur-containing amino acid mainly derived from methionine. Recently, mounting evidences have shown that hyperhomocysteinemia (HHcy) might be an independent risk factor of early neurological deterioration [
H-type hypertension, which refers to concurrence of primary hypertension and HHcy, is a special hypertension type. Approximately 75% of the hypertensive patients simultaneously have HHcy in China [
The present study was conducted in Stroke Center of First Hospital Affiliated to Soochow University and included 372 patients who had been diagnosed with acute ischemic stroke according to the World Health Organization (WHO) criteria [
Sociodemographic information on age (calculated according to the ID birth date), gender, education level, marital status were collected. Education level included “under junior”, “senior/vocational high school”, “college degree or above”. Marital status was divided into “unmarried”, “married”, “divorced”, and “spouse”. Lifestyle factors include smoking and alcohol consumption; past medical history, family history, disease history of hypertension history, diabetes history, stroke history, hyperlipidemia history, and coronary heart disease history were obtained. “Smoking consumption” was defined as having 10 or more cigarettes per day for more than one year [
Venous blood samples from patients were collected on an empty stomach the second day of hospitalization for further determination including hemoglobin contents, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglyceride (TG), uric acid, glucose, and so on. The serum Hcy levels were measured within 24 h of hospitalization using enzymatic cycling method. HHcy was defined as Hcy concentration >=12.0 umol/L.
National Institutes of Health Stroke Scale (NIHSS) was measured both at admission and after two weeks to evaluate the severity of stroke outcome. NIHSS ranged from 0 to 42, and higher score on NIHSS represented more severe stroke. The modified Rankin Scale (mRS) was measured to assess the patients’ functional prognosis, with a span from 0 to 6. We set 0-2 as favorable prognosis and 3-6 as poor outcome. We followed up the enrolled patients 3 month and 1 year after discharge. The primary endpoint event of the present study was stroke recurrence and the secondary endpoint events were cardiovascular event including coronary heart disease, myocardial infarction, heart failure, coronary artery reconstruction, cardiopulmonary resuscitation, or all-cause mortality (death for any cause). Stroke recurrence referred to the following: (1) original neurologic impairment improved or disappeared, then new ipsilateral or contralateral symptoms emerged for at least 24 hours; (2) original neurologic impairment aggravated with exclusion of progressive stroke; (3) the above situation was confirmed by head CT or MRI. The follow-up was conducted by 2 trained neurological doctors who were blinded to the baseline information and grouping situation.
Statistical analysis was performed with SPSS13.0 (SPSS, Inc., Chicago, IL, USA). Normally distributed continuous variables were reported as mean ± Standard Deviation (SD), while deviation and categorical variables were presented as frequency and percentage. Kolmogorov–Smirnov was used for the test of normal distribution of quantitative data and Levene’s test was used to test homogeneity of variance. T test or one-way ANOVA was performed to compare the distribution of quantitative data.
A total of 372 (240 males and 132 females) patients with acute ischemic stroke were finally included and the baseline information of the cases were listed in Table
The most common risk factors of stroke in our study.
Variables | |
---|---|
Age (year), n (%) | |
129 (34.7%) | |
≥60 | 243 (65.3%) |
Gender, n (%) | |
Male | 240 (64.5%) |
Female | 132 (35.5%) |
Hypertension, n (%) | 254 (68.3%) |
Diabetes melitus, n (%) | 74 (19.9%) |
Cardiac diseases, n (%) | 80 (21.5%) |
Hyperlipidemia, n (%) | 75 (20.2%) |
HHcy, n (%) | 181 (48.7%) |
High level of urid acid, n (%) | 48 (12.9%) |
High level of Hs-CRP, n (%) | 158 (42.5%) |
Table
The clinical features of patients with H-type hypertension or without H-type hypertension.
Variables | Control group | HBP group | HHcy group | H-type HBP group | P | |
---|---|---|---|---|---|---|
Age | 57.23 ± 13.87 | 63.97 ± 12.05 | 64.85 ± 12.20 | 67.37 ± 13.02 | 12.115 | 0.000 |
Male | 40 (62.5%) | 69 (54.3%) | 35 (64.8%) | 96 (75.6%) | 12.675 | 0.005 |
Diabetes melitus | 7 (10.9%) | 37 (29.1%) | 3 (5.6%) | 27 (21.3%) | 17.141 | 0.001 |
Cardiac diseases | 10 (15.6%) | 17 (13.4%) | 13 (24.1%) | 34 (26.8%) | 8.470 | 0.037 |
Systolic pressure | 131.83 ± 9.63 | 149.28 ± 18.82 | 138.85 ± 16.54 | 147.98 ± 17.29 | 19.634 | 0.000 |
Diastolic pressure | 79.02 ± 9.54 | 85.69 ± 14.22 | 78.61 ± 10.67 | 83.15 ± 13.13 | 6.087 | 0.000 |
Tempeture (°C) | 36.54 ± 0.33 | 36.54 ± 0.32 | 36.61 ± 0.37 | 36.64 ± 0.50 | 1.567 | 0.197 |
TC (mmol/l) | 4.07 ± 0.90 | 4.28 ± 1.03 | 3.89 ± 0.80 | 4.25 ± 1.19 | 2.265 | 0.081 |
TG (mmol/l) | 1.21 ± 0.43 | 1.73 ± 1.30 | 1.16 ± 0.58 | 1.52 ± 1.07 | 5.927 | 0.001 |
HDL-C (mmol/l) | 1.23 ± 0.27 | 1.25 ± 0.38 | 1.25 ± 0.29 | 1.22 ± 0.32 | 0.156 | 0.926 |
LDL-C (mmol/l) | 2.41 ± 0.70 | 2.54 ± 0.89 | 2.27 ± 0.72 | 2.54 ± 0.86 | 1.767 | 0.153 |
Glucose (mmol/l) | 5.74 ± 1.89 | 6.82 ± 2.81 | 5.42 ± 1.16 | 6.22 ± 2.30 | 6.209 | 0.000 |
Urid acid (U/L) | 282.88 ± 79.00 | 285.40 ± 77.28 | 295.5 ± 88.55 | 345.72 ± 113.72 | 11.306 | 0.000 |
Hs-CRP (mg/L) | 4.14 ± 4.82 | 4.21 ± 4.62 | 5.06 ± 5.04 | 5.91 ± 5.21 | 3.139 | 0.025 |
Hcy (umol/l) | 7.99 ± 2.51 | 8.35 ± 2.39 | 23.33 ± 21.83 | 21.84 ± 25.20 | 21.273 | 0.000 |
Note:
The severity of stroke was assessed by using the NIHSS score, which was obtained both on admission and 2 weeks after treatment. Our results showed that the score on admission in the H-type hypertension group (6.32 ± 5.91) was significantly higher compared with that in the normal group (3.97 ± 3.59) (P < 0.05), while we did not observe the difference of baseline NIHSS between the H-type hypertension group and simple hypertension group or simple HHcy group. In addition, there is no obvious association between H-type hypertension and NIHSS score after 2 weeks treatment (P = 0.106). These findings were presented in Table
Comparison of NIHSS score on admission and 2 weeks after treatment among groups.
Variables | n | NIHSS score | NIHSS score |
---|---|---|---|
Control group | 64 | 3.97 ± 3.59 | 2.80 ± 3.18 |
HBP group | 127 | 5.39 ± 5.44 | 4.37 ± 6.45 |
HHcy group | 54 | 6.15 ± 6.14 | 5.22 ± 7.79 |
H-type HBP group | 127 | 6.32 ± 5.91 | 5.20 ± 7.72 |
F value | 2.898 | 2.052 | |
P value | 0.031 | 0.106 |
Note:
mRS score was used to present the long-term neurological functional recovery of the stroke patients. Our results showed that mRS scores were 2.39 ± 1.52 and 1.77 ± 1.21 at 90-day follow- up, 1.98 ± 1.43 and 1.34 ± 1.20 at one-year follow-up in H-type hypertension group and control group, respectively. The mRS score was significantly different between the H-type hypertension group and the control group (P < 0.05). These results were shown in Table
Comparison of mRS score at 90-day and 1-year follow-up among groups.
Variables | n | mRS score | mRS score |
---|---|---|---|
Control group | 64 | 1.77 ± 1.21 | 1.34 ± 1.20 |
HBP group | 127 | 2.05 ± 1.43 | 1.59 ± 1.20 |
HHcy group | 54 | 2.20 ± 1.47 | 1.76 ± 1.58 |
H-type HBP group | 127 | 2.39 ± 1.52 | 1.98 ± 1.43 |
F value | 2.994 | 3.743 | |
P value | 0.031 | 0.011 |
Note:
In the present study, stroke endpoint events were defined as stroke recurrence, all cardiovascular diseases and all-cause death. During 1 year of follow-up, a total of 33 (8.87%) recurrent stroke, 8 (2.15%) cardiovascular events, and 12 (3.22%) all-cause deaths were recorded in all the enrolled patients. 16 patients (12.6%) with H-type hypertension reached the combined endpoint events compared with 3 (4.69%) patients in the control group, 8 (6.30%) patients in the simple hypertension, and 5 (9.26%) patients with simple HHcy during the 90-day follow-up period. During the 1-year follow-up period, patients reached to the combined endpoint events were 29 (22.83%), 4 (6.25%), 13 (10.24%), and 7 (12.96%) in the H-type hypertension group, control group, simple hypertension group, and simple HHcy group, respectively. (Figure
Incurrence of endpoint events at 90-day and 1-year follow-up among groups.
Kaplan–Meier survival analysis showed that when we compared all acute ischemic stroke patients at 1-year period, patients with H-type hypertension had the lowest cumulative survival, as shown in Figure
Cox regression analysis of risk factors related to endpoint events of ischemic stroke.
Single factor analysis | Multiple analysis | |||
---|---|---|---|---|
Risk factors | HR | 95% CI | HR | 95% CI |
Age | 3.137 | 1.497-6.654 | 2.740 | 1.236-6.073 |
Gender | 0.797 | 0.443-1.432 | 0.793 | 0.422-1.492 |
Diabetes melitus | 0.548 | 0.248-1.212 | 0.641 | 0.374-1.296 |
Cardiac diseases | 2.438 | 1.390-4.275 | 2.041 | 1.082-3.849 |
Systolic pressure | 1.807 | 1.037-3.149 | 1.494 | 0.820-2.722 |
Diastolic pressure | 1.297 | 0.682-2.468 | 1.322 | 0.656-2.665 |
Total cholesterol | 1.763 | 0.429-7.244 | 1.057 | 0.233-4.807 |
Triglycerides | 0.975 | 0.502-1.893 | 1.121 | 0.531-2.366 |
LDL | 1.122 | 0.650-1.938 | 1.046 | 0.583-1.877 |
Glucose | 2.075 | 1.211-3.556 | 2.047 | 1.146-3.655 |
Uric acid | 1.063 | 0.480-2.354 | 0.793 | 0.350-1.795 |
Hs-CRP | 2.174 | 1.254-3.771 | 1.531 | 0.855-2.740 |
Note: stroke endpoint events were defined as stroke recurrence, all cardiovascular diseases, and all-cause death.
Cox regression analysis of H-type hypertension related to endpoint events of ischemic stroke.
Single factor analysis | Multiple factor analysis | |||
---|---|---|---|---|
Variables | HR | 95% CI | HR | 95% CI |
control | 1.000 | 1.000 | ||
simple hypertension | 1.009 | 0.252-4.035 | 0.819 | 0.202-2.316 |
Simple HHcy | 1.876 | 0.298-7.070 | 1.669 | 0.441-6.312 |
H-type hypertension | 3.890 | 1.198-12.634 | 2.694 | 0.817-8.883 |
Note: stroke endpoint events were defined as stroke recurrence, all cardiovascular diseases, and all-cause death.
Cumulative survival curve of the stroke patients among groups.
Stroke is one of the major causes of increased morbidity and mortality all over the world. In China, the prevalence of hypertension is high and HHcy is one of the common risk factors for hypertension in Chinese populations. Recently, H-type hypertension has become a research hotspot in the area of cerebral-cardiovascular diseases.
In the present study, higher NIHSS score and mRS score were noted in H-type hypertension group, compared with that in the non-H-type hypertension group, which implied poor short-term and long-term outcomes in H-type hypertension patients. Moreover, incidence of endpoint events, especially stroke recurrence was higher in H-type hypertension patients compared with other groups, together with the lowest cumulative survival in this group. Several researches had come to the similar results. Chongke Zhong et al. found that enrolled patients with H-type hypertension were at the highest risk of poor outcome among all participants [
Some recent studies suggested that hypertension and HHcy might have a certain synergistic effect [
The primary mechanisms of H-type hypertension acting on stroke remained unclear. Guo G found that the risk of plaques occurrence in patients with H-type hypertension was 1.63 times of patients with simple (or isolated) systolic hypertension. They further discovered that high homocysteine concentration might aggravate the oxidative stress in hypertension to produce contributory effects on vascular impairment [
This study is to investigate the correlation between H-type Hypertension and acute ischemic stroke. However, this study has several limitations. The Hcy concentration was measured only at one time-point within 24 hours after stroke onset, and we have no data on possible changes in Hcy plasma level or blood pressure during long-term clinical follow-up period. Therefore, these relationships were not examined on the 90-day and 1-year clinical outcome. Subsequently, several studies indicated that medicines such as aspirin, clopidogrel, statins, and hypotensive drugs may decrease inflammatory mediator levels and affect the results, and some medicines may affect Hcy metabolism. However, we did not record patients’ medications at baseline. Additionally, the relatively small sample size was used in this study, and the follow-up period was relatively short, which remained as a limitation on overall assessment of the results.
In conclusion, our study indicated that H-type hypertension may cause increased susceptibility to poor outcome and prognosis among acute ischemic stroke patients, which deserved further prevention measures.
Data supporting the results in the article can be found, including, where applicable, hyperlinks to public datasets analyzed or generated during the study.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.
Tan Li and Jiajia Zhu contributed equally to this work.
This research was supported by grants from Science and Technology Project of Suzhou Municipal Health Planning Commission (lczx201503) and Suzhou people’s Livelihood Science and Technology Program (SS201532).