Article, Cardiology

Serum albumin level is associated with the recurrence of acute ischemic stroke

a b s t r a c t

Background: Previous studies have confirmed that low serum albumin levels in acute ischemic stroke patients increased the risk for poor outcome and death, demonstrating the neuroprotective role of albumin. However, there are few studies investigating the relationship between Albumin levels and recurrence of stroke. The aim of this study was to evaluate the effect of Serum albumin level on the risk of recurrence in patients with acute ischemic stroke.

Methods: Seven hundred fifty-three consecutive patients with acute first-ever ischemic stroke were recruited in this study. Recurrent outcome was measured 1 year after stroke through home interviews (n = 692).

Results: Patients with recurrence had significantly lower serum albumin level than those without recurrence (37.07 +- 4.21 vs 38.91 +- 3.25). The multiple logistic regression adjustment for confounding factors showed that the association remained significant for patients in the second albumin quartile, the third quartile, and the fourth quartile compared with patients in the first quartile (adjusted odds ratio [aOR] = 0.543, 95% confidence interval [CI]: 0.307-0.959, P= .036; aOR = 0.449, 95% CI: 0.249-0.812, P= .008; and aOR = 0.290, 95% CI:

0.148-0.570, P b .001).

Conclusion: Lower serum albumin level increases the risk of recurrence in patients with acute ischemic stroke, suggesting that serum albumin level might be used as an indicator for stroke recurrence.

(C) 2016

  1. Introduction

Stroke has been ranked as the leading causes of death and Long-term disability in China and many other countries [1]. With the development of medicine and rehabilitation medicine, the situation of handicap de- gree and mortality has been ameliorated. However, increased recur- rence of stroke has been observed in recent years, leading to doubled rate of disability and death. Surprisingly, traditional vascular risk factors, such as age, hypertension, diabetes, dyslipidemia, and smoking, cannot fully account for the recurrence of stroke.

Serum albumin is a unique multifunctional protein and has been shown to be neuroprotective [2-6]. Several studies have demonstrated the obvious protective influence of serum albumin in many diseases,

* Corresponding author at: Institute of Public Health, School of Nursing, Henan Univer- sity, Kaifeng, China.

E-mail addresses: [email protected] (Q. Zhang), [email protected] (Y.-X. Lei), [email protected] (Q. Wang), [email protected] (Y.-P. Jin), [email protected] (R.-L. Fu), [email protected] (H.-H. Geng),

[email protected] (L.-L. Huang), [email protected] (X.-X. Wang), [email protected] (P.-X. Wang).

such as myocardial infarction and cardiovascular diseases [7-9]. In recent years, some studies have showed a neuroprotective effect of serum albumin in ischemic stroke on animal models.

Some reports have also suggested that relatively low serum albumin levels in acute ischemic stroke patients increased the risk for poor out- come [10] or death [11]. However, there are few studies investigating the relationship between albumin levels and recurrence of stroke. Therefore, the objective of this prospective cohort study with a follow- up period of 12 months was to evaluate the association between albu- min level and stroke recurrence.

  1. Methods
    1. Patients

This prospective cohort study included 753 first-ever ischemic stroke patients during acute phase (the first week following a stroke) with a 1-year follow-up. All patients admitted into the neurological de- partment at Huai-He Hospital in Kaifeng, China, from March 2014 to March 2015 were evaluated for eligibility for the study. Informed

http://dx.doi.org/10.1016/j.ajem.2016.06.049

0735-6757/(C) 2016

Lost follow-up N = 61

Previous stroke N = 290

First-ever stroke N = 851

With Transient ischemic attack N = 68

Without TIA N = 783

With severe dysfunction N = 14

Final study sample N = 769

Date uncompleted N = 16

First study sample N = 753

Acute phase ( 7 day) N = 1141

With follow-up N = 692

Died without recurrent stoke N = 8

Patients followed up with and without recurrent N = 684

All ischemic Stroke respondents N = 1832

Non Acute phase ( 7 day) N = 691

Fig. 1. Flowchart in the selection of study patients.

consent was obtained from all patients before this study. This study complies with the Declaration of Helsinki and was approved by the eth- ical committee of Henan University. All patients were examined for is- chemic stroke, which was confirmed by computed tomographic scan and magnetic resonance imaging according to the fourth Chinese Na- tional Conference’s recommendations on the diagnosis of cerebrovascu- lar diseases [12]. Patients with major cardiac, renal, hepatic, and endocrinological disorders; skeletal disorders; malignant tumor; recent surgery; and recent infections were excluded. A flowchart illustrating the selection of patients is presented in Fig. 1. Six hundred ninety-two cases were included in this study after excluding 61 cases that were lost to follow-up.

Baseline survey

Sociodemographic variables included age, sex, marital status, and living arrangement. Lifestyle factors included smoking, alcohol drinking, family history, Hypertension history, diabetes history, coronary heart disease history, hyperlipidemia, and body mass index (BMI). Hyperten- sion was diagnosed as systolic blood pressure N 140 mm Hg and/or dia- stolic blood pressure N 90 mm Hg based on the average of the 2 blood Pressure measurements, or patient’s self-reported history of hyperten- sion or antihypertensive use, supported by the Joint National Commit- tee VI-VII. Diabetes was diagnosed if the fasting plasma glucose was N 110 mg/dL or if patient was on antidiabetic medications. Smokers were defined as those smoking 1 or more cigarettes per day for 1 year or those with smoking cessation b 5 years [13]. Alcohol drinking was de- fined as consumption of at least 1 alcoholic drink in a week and more years. A positive family history was defined as history of ischemic stroke in a first-degree relatives. Hyperlipidemia was diagnosed as elevated plasma level in at least one of total cholesterol, triglyceride, high- density lipoprotein, and low-density lipoprotein. Weight and height of patients were measured on admission. BMI was categorized according to Chinese weight criteria [14].

Blood sample collection

Blood samples for assessment of albumin were obtained from all patients within 24 hours of admission after stroke onset. Concentrations

of albumin and other laboratory examinations (total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein) were determined using the full automatic biochemical analyzer (Germany, SIEMENS ADVIA2400). Hypoproteinemia was diagnosed if the levels of albumin were b 35 g/L.

Follow-up

Follow-up assessment was conducted in all patients by well-trained home interviewers at 1 year after hospital discharge. The information included recurrence, time of recurrent stroke, type of recurrence, survival status, and cause of death.

Statistical analysis

All statistical analyses were conducted with SPSS 17.0 (SPSS, Inc, Chicago, IL). Categorical variables are reported as frequency and per- centage, and continuous variables are presented as median values or means +- standard deviations (SDs). The associations between albumin level and baseline demographic variables or cerebrovascular risk factors were examined using ?2 test for categorical variables. For the compari- sons between groups, ?2 and Student t test or 1-way analysis of variance were conducted for categorical and continuous variables, re- spectively. In the multivariate analyses, we used the forward selection procedure to adjust for potential clinically relevant confounders, includ- ing age, sex, marital status, residence, smoking, alcohol drinking, family history, hypertension, diabetes, coronary heart disease, hyperlipidemia, and BMI. Statistical significance was defined as a P value b .05.

  1. Results
    1. Patients’ characteristics

A total of 753 ischemic stroke patients were enrolled in the study, and the characteristics of all patients, including follow-up group and lost to follow-up group, are presented in Table 1. There was no signifi- cant difference between follow-up group and lost to follow-up group. Six hundred ninety-two patients (91.9%) completed the first year of follow-up with the mean of age being 64 years (SD = 12.8). The mean

Table 1

Sociodemographic and clinical characteristics of all patients with follow-up vs those lost to follow-up

Table 3

Adjusted odds ratio for the associations between risk factors and hypoalbuminemia of is- chemic stroke

Sociodemographic variables Lost to follow-up Follow-up P value

Variable

aOR

95% CI

P value

n = 61 n = 692

Age (y)

Age (y) .584

b60

Reference

b60 21 (7.3) 266 (92.7)

>= 60

3.231

1.805-5.786

b.001

>= 60 40 (8.6) 426 (91.4)

Sex .789

BMI

Normal weight

Reference

Male

34 (7.9)

398 (92.1)

Underweight

3.970

1.408-11.199

.009

Female

27 (8.4)

294 (91.6)

Overweight

0.599

0.367-0.976

.040

Marital status

Obese

0.359

0.164-0.788

.011

Follow-up investigation

Single

14 (12.3)

100 (87.7)

.092

Married

47 (7.4)

592 (92.6)

Residence

Urban

31 (7.6)

379 (92.4)

.593

Rural

30 (8.7)

313 (91.3)

Hypertension, n (%)

34 (8.4)

372 (91.6)

.790

Diabetes, n (%)

18 (10.6)

152 (89.4)

.201

Coronary heart disease, n (%)

11 (11.3)

86 (88.7)

.230

Hyperlipidemia, n (%)

41 (8.5)

440 (91.5)

.677

Family history, n (%)

10 (8.5)

108 (91.5)

.855

Smoking, n (%)

20 (9.5)

190 (90.5)

.374

Alcohol drinking, n (%)

16 (9.4)

155 (90.6)

.524

BMI

.201

Underweight

3 (17.6)

14 (82.4)

During 1 year after hospital discharge, 22 (3.2%) patients died, with 14 patients dead from the recurrence of ischemic stroke and 8 patients dead from other diseases. Ninety-seven (14.0%) patients had recurrent ischemic stroke. Detailed results for these patients are shown in Table 4. Fig. 2 shows the univariate association between albumin quartiles and outcome events (recurrence and death). The recurrence and mortality rates were significantly higher in patients in the first

Normal weight

24 (8.4)

261 (91.6)

(lowest) albumin quartile than those in patients in the fourth (highest)

Overweight

28 (8.8)

290 (91.2)

quartile (Pb .05).

Obese 6 (4.5) 127 (95.5)

albumin level of all patients was 38.6 (range, 21.16-47.30) g/L. The char- acteristics of patients, stratified according to albumin quartiles, were shown in Table 2. Patients with lower albumin level were more likely to be older; be single; live in rural areas; and have hypertension, coro- nary heart disease, and hyperlipidemia than patients with elevated al- bumin level. The association of risk factors, such as age (60 years as the cutoff value) and BMI, with hypoalbuminemia was observed in pa- tients as assessed by multivariate logistic regression analysis (Table 3).

Table 2

Characteristics of all patients according to quartiles of albumin levels

Variables Quartile of plasma albumin level, g/L P

The characteristics of patients with recurrence of ischemic stroke and those without recurrence of ischemic stroke are shown in Table 5. The prevalence of recurrence was decreased with increased albumin levels, and the first (lowest) albumin quartile patients had the highest prevalence of stroke recurrence. In addition, hypoproteinemia was asso- ciated with increased prevalence of stroke recurrence (Pb .001).

After adjustment for a number of independent predictors, the inde- pendent association between recurrent stroke and albumin level as assessed by multivariate logistic regression analysis is shown in Table 6. After adjustment for confounders, the association remained sig- nificant for patients in the second albumin quartile, the third quartile, and the fourth quartile compared with patients in the first quartile (adjusted odds ratio [aOR] = 0.543, 95% confidence interval [CI]: 0.307-0.959, P= .036; aOR = 0.449, 95% CI: 0.249-0.812, P= .008; and

aOR = 0.290, 95% CI: 0.148-0.570, P b .001). With increased albumin levels, the risk of recurrent stroke was significantly lower. In addition, being single (aOR = 1.785, 95% CI: 1.002-3.119, P= .042) and having di-

abetes (aOR = 2.120, 95% CI: 1.310-3.431, P= .002) were significantly associated with higher risk of recurrent stroke.

Q1 (?36.7) n = 183

Q2

(36.7-38.8) n= 170

Q3

(38.8-40.8) n= 170

Q4 (N 40.8) n= 169

value

The patients with hypoproteinemia had more than 3 times the chance to suffer from recurrence (aOR = 3.261, 95% CI: 1.914- 5.555, P b .001) after adjustment for other indicators. Moreover, being

Age (y) b.001

b60 37 (13.9) 64 (24.1) 74 (27.8) 90 (34.2)

>= 60 146 (34.3) 106 (24.9) 96 (22.5) 78 (18.3)

Sex .228

Male

95 (23.9)

102 (25.6)

96 (24.1)

105 (26.4)

Female

88 (29.9)

68 (23.1)

74 (25.2)

64 (21.8)

Marital status

.022

Single

38 (38.0)

24 (24.0)

22 (22.0)

16 (16.0)

Married

145 (24.5)

146 (24.7)

148 (25.0)

153 (25.8)

Residence

.012

Urban

94 (24.8)

80 (21.1)

97 (25.6)

108 (28.5)

Rural

89 (28.4)

90 (28.8)

73 (23.3)

61 (19.5)

Hypertension, n (%) 88 (23.7) 93 (25.0) 83 (22.3) 108 (29.0) .011

single (aOR = 1.912, 95% CI: 1.093-3.343, P= .023) and having diabetes (aOR = 2.098, 95% CI: 1.295-3.398, P= .003) were significantly associ- ated with higher risk of recurrent stroke.

  1. Discussion

We found that hypoalbuminemia was associated with ischemic stroke recurrence and that patients with hypoalbuminemia had 3.261- fold increased risk of recurrence 1 year after stroke. Besides, patients

Diabetes, n (%)

35 (23.0)

37 (24.3)

42 (27.6)

38 (25.0)

.651

Table 4

Coronary heart disease, n (%)

32 (37.2)

19 (22.1)

24 (27.9)

11 (12.8)

.015

Follow-up outcome of 692 patients

Hyperlipidemia, n (%)

Family history, n (%)

103 (23.4)

27 (24.8)

112 (25.5)

24 (22.0)

102 (23.2)

23 (21.1)

123 (28.0)

35 (32.1)

.008

.236

Classification Number (n = 692) Proportion (%)

Smoking, n (%)

46 (24.2)

42 (22.1)

50 (26.3)

52 (27.4)

.494

Recurrence

Alcohol drinking, n (%)

31 (20.0)

34 (21.9)

42 (27.1)

48 (31.0)

.052

Recurrence

97

15.2

BMI

Underweight

9 (64.3)

0 (0.0)

4 (28.6)

1 (7.1)

b.001

No recurrence

Death

595

84.8

Normal weight

106 (40.6)

66 (25.3)

50 (19.2)

39 (14.9)

Death with recurrence

14

2.0

Overweight

50 (17.2)

72 (24.8)

87 (30.0)

81 (27.9)

Death without recurrence

8

1.2

Obese

18 (14.2)

32 (25.2)

29 (22.8)

48 (37.8)

No death

670

96.8

Fig. 2. Association between albumin and follow-up outcomes. Note: **Pb .001; *Pb .05. Re- currence (a): excluding 8 dead cases without recurrence.

in the first quartile of albumin level were more likely to suffer from re- current stroke and death. The risk of recurrence decreased, respectively, to be 45.7%, 55.1%, and 71.0% for the second quartile, the third quartile, and the fourth quartile of albumin level in patients after adjustment for age, sex, marital status, residence, smoking, alcohol drinking, family his- tory, hypertension, diabetes, coronary heart disease, hyperlipidemia, and BMI. Hypoalbuminemia or low albumin level on admission was an independent predictor for 1-year recurrence rate of acute ischemic stroke. The recurrence rate of stroke increases with decreased albumin level.

Multivariate logistic regression analysis of the relationship between albumin level and mortality was not performed because of small num- bers of death in our study. However, some previous studies had con- firmed that albumin level is closely related to mortality in stroke. Some researchers demonstrated that hypoalbuminemia is an indepen- dent predictor for in-hospital mortality in patients with acute stroke

Table 5

Characteristics between recurrence and no-recurrence groups of ischemic stroke

Variables

Recurrence N = 97

No recurrence N = 587

P value

Age (y)

b60

34 (12.8)

231 (87.2)

.434

>= 60

Sex

63 (15.0)

356 (85.0)

.825

Male

55 (13.9)

340 (86.1)

Female

41 (14.5)

248 (85.5)

Marital status .025

Single 21 (22.1) 74 (77.9)

Married 76 (12.9) 513 (87.1)

Residence .660

Urban 51 (13.6) 325 (86.4)

Rural 46 (14.9) 262 (85.1)

[15,16]. Patients with hypoalbuminemia had increased mortality rate 6 months after the first onset of stroke [11]. However, no long-term follow-up studies have demonstrated the relationship between low al- bumin level and mortality.

In our study, the recurrence of acute first-ever ischemic stroke at 1 year was 14.0%, consistent with the findings as demonstrated in previ- ous studies [17]. Low albumin level has been shown to be capable to predict the severity of ischemic stroke for follow-up at 30 days [18] and 3 months [10]. Several studies in different populations found that serum albumin level had a negative correlation with Stroke severity [8,11]. To the best of our knowledge, few researchers have investigated the correlation of albumin level with stroke recurrence. Our study for the first time found that the serum albumin level on admission was closely related to the recurrence of ischemic stroke during acute phase and that albumin level was negatively correlated with the rate of stroke recurrence in 1 year.

Apart from low level of albumin, our study found that marriage and diabetes were also associated significantly with the recurrence of ische- mic stroke after controlling all other confounding risk factors in a step- wise multiple logistic regression analysis, consistent with the close association of diabetes with the recurrence of ischemic stroke [19]. Dia- betes might increase the risk of recurrent stroke through endogenous cardiovascular. NO system [20] as supported by the fact that hypergly- cemia may destroy the blood-brain barrier and enhance hemorrhagic infarct conversion [21]. However, the exact molecular mechanism of how diabetes affects ischemic stroke recurrence is unclear and requires further investigation.

Serum albumin often has been identified as a nutrition marker relat- ed to nutrition status and inflammation [22]. Previous studies [23,24] had showed that plasma Protein Synthesis was inhibited in malnutrition patients. The acute phase proteins can protect the body from trauma, in- fection, and tissue damage. As demonstrated in this present study, age and BMI were strongly correlated with hypoalbuminemia after adjust- ment of other variables, and a higher prevalence rate of hypoalbumin- emia was associated with lower BMI. The elderly and lower-BMI patients were more vulnerable to malnutrition, which may be partial explanations for the effect of age and BMI on hypoalbuminemia, further supported by a previous study demonstrating that patients with malnu- trition before ischemic stroke had worse neurological function after ill- ness [25].

Albumin serves the transport of hormones, drugs, amino acids, and free fatty acids in the blood as a vehicle and can modulate the colloid os- motic pressure in blood [26]. Serum albumin [3] plays a neuroprotective

Table 6

Adjusted odds ratio for the associations between risk factors and recurrence of ischemic stroke

Variable aOR 95% CI P value

Hypertension, n (%)

54 (14.6)

316 (85.4)

.743

Recurrence

Diabetes, n (%)

32 (21.2)

119 (78.8)

.008

Marital status a, b

Coronary disease, n (%)

15 (18.3)

67 (81.7)

.242

Married

Reference

Hyperlipidemia, n (%)

58 (13.3)

377 (86.7)

.426

Single

1.785 a;

1.002-3.119 a;1.093-3.343 b

.042a;

Family history, n (%)

16 (15.0)

91 (85.0)

.765

1.912 b

.023b

Smoking, n (%)

25 (13.4)

162 (86.6)

.806

Diabetes a, b

Alcohol drinking, n (%)

21 (13.6)

133 (86.4)

.896

No

Reference

BMI

Underweight

4 (28.6)

10 (71.4)

.252

Yes

2.120 a;

2.098 b

1.310-3.431 a;

1.295-3.398 b

.002a;

.003b

Normal weight

41 (16.0)

215 (84.0)

Albumin, quartiles a

Overweight

35 (12.2)

252 (87.8)

Q1 (? 36.7)

Reference

Obese

17 (13.4)

110 (86.6)

Q2 (36.7-38.8)

0.543

0.307-0.959

.036

Albumin, mean (SD)

37.07 +- 4.21

38.91 +- 3.25

b.001

Q3: (38.8-40.8)

0.449

0.249-0.812

.008

Albumin, quartiles, n (%)

b.001

Q4: (> 40.8)

0.290

0.148-0.570

b.001

Q1 (? 36.7)

41 (22.8)

139 (77.2)

Hypoalbuminemia b

3.261

1.914-5.555

b.001

Recurrence: Excluded 8 dead cases without recurrence.

Q2 (36.7-38.8)

23 (13.7)

145 (86.3)

Q3 (38.8-40.8)

21 (12.4)

149 (87.6)

Q4 (N 40.8)

12 (7.2)

154 (92.8)

Hypoalbuminemia, n (%)

26 (30.2)

60 (69.8)

b.001

Model a: Albumin quartiles (Q1, Q2, Q3, Q4) related to other risk factors (age, sex, marital status, residence, smoking, alcohol drinking, family history, hypertension, diabetes, coro- nary heart disease, hyperlipidemia, BMI) from multivariate logistic regression models. Model b: Hypoalbuminemia related to other risk factors from multivariate logistic regres- sion. Recurrence : Excluded 8 dead cases without recurrence.

role in ischemic stroke through a variety of mechanisms, such as im- proving blood flow perfusion of brain [4], enhancing micrangium perfu- sion [27], reducing the various cytokines’ adhesion within postcapillary microcirculation [28], and increasing the transport of free fatty acids postischemia [29]. In addition, albumin also has been reported to reduce the hematocrit value, block the erythrocyte aggregation, and decrease the erythrocyte sedimentation rate [4,30,31]. Serum albumin is conducive to sus- taining neuronal metabolism by increasing the export of pyruvate to neurons after entering the brain under Pathologic conditions [8].

Belayev et al [32] found that delayed high-concentration albumin therapy initiated 2 to 4 hours after stroke onset of transient focal ische- mia in rats had beneficial effects. A previous study showed that moderate-dose human albumin therapy observably improves neuro- logic function and reduces infarction volume and Brain swelling in ani- mals with acute focal ischemic stroke even 4 hours after stroke onset [4]. Another experimental study also demonstrated that moderate- to high- dose human albumin treatment of transient focal cerebral ischemia can improve neurologic function in animals, but the effect was not observed in permanent focal cerebral ischemia [33]. However, Ginsberg et al [2] did not confirm that high-dose albumin treatment can improve neurologic function in patients with acute ischemic stroke. Considering the conflicting results obtained from different groups, more studies are required to validate the relations between albumin therapy and ische- mic stroke.

Few researches have been designed to investigate the effect of albu-

min level on recurrent ischemic stroke. Our study showed that albumin level on admission was negatively correlated with recurrence of acute ischemic stroke. However, some limitations in our study should not be overlooked. Firstly, the period of follow-up is relatively short, and the incidence of death is too low to confirm the correlation between mortal- ity and albumin level. Secondly, the information on location and size of infarction in some patients was lost. Therefore, the data about albumin level at 1 year after stroke were not collected.

  1. Conclusion

Hypoalbuminemia or low albumin level on admission was an inde- pendent predictor of 1-year recurrence of acute ischemic stroke, and the recurrence of stroke increases with the decreased albumin level, suggesting that albumin level might be used as an indicator for evalua- tion of ischemic stroke recurrence.

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