Article, Cardiology

Hypoalbuminemia predicts clinical outcome in patients with type B acute aortic dissection after endovascular therapy

a b s t r a c t

Background: Few studies have reported that serum albumin (SA) levels on admission were associated with in- creased risk of long-term outcomes in patients with type B Acute aortic dissection . The aim of this study was to investigate the effect of admission levels of SA on survival among patients with type B AAD undergoing Endovascular therapy (EVT).

Methods: A total of 131 patients with type B AAD undergoing EVT were retrospectively enrolled and followed up for 2.1 years. They were divided into hypoalbuminemia and nonhypoalbuminemia groups. We analyzed the in- cidence of inhospital complications and long-term mortality. Kaplan-Meier curves and multivariable Cox regres- sion analyses were used to investigate the associations between SA levels and survival.

Results: Among 131 type B AAD patients, hypoalbuminemia was detected in 61 (46.6%) at admission. Compared to those without hypoalbuminemia, patients with hypoalbuminemia did not have higher inhospital complica- tions; however, Kaplan-Meier analysis showed that they did have a significantly lower survival rate (73.8% vs 92.5%; log-rank ?2 = 9.8; P = .002). Multivariable Cox regression analysis further revealed that hypoalbumin- emia was an independent predictor of long-term mortality among patients with type B AAD (hazard ratio, 4.28; 95% confidence interval, 1.36-13.47; P = .013), over 2.1 years.

Conclusions: Hypoalbuminemia is common in type B AAD patients and is independently associated with in- creased risk of long-term death. Renal dysfunction may be the main pathophysiological mechanism underlying hypoalbuminemia in patients with type B AAD.

(C) 2016

  1. Introduction

Acute aortic dissection is a type of vascular emergency that is associated with high morbidity and mortality [1]. Dissections confined to the descending aorta (type B) are associated with a better inhospital survival rate than those involving the Ascending aorta (type A) [2]. However, long-term outcomes associated with type B AAD are not nec- essarily better than those of type A AAD [3-5]. Therefore, given the var- iable prognosis of type B AAD with current management strategies, predictors of poor outcomes have been sought. Indeed, several predic- tors associated with long-term adverse events of AAD have been stud- ied. Some markers, such as false lumen status and maximum aortic diameter, must be evaluated by computed tomography (CT)

* Corresponding authors at: Department of Emergency Medicine, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, 610041, Sichuan, China. Tel./fax: +86 28

83584358.

E-mail addresses: [email protected] (X. Du), [email protected] (Y. Cao).

1 These authors contributed equally to this work.

angiography or Digital subtraction angiography [6,7]. However, the anatomy of aortic dissection is often complex and is not necessarily con- sistent, even during the initial hospital stay. Thus, it may be challenging to estimate the complete nature of the AAD by these simple imaging pa- rameters alone.

Acute aortic dissection is associated with an inflammatory reaction and thrombosis, evidenced by a significant elevation in inflammatory markers, including D-dimer and C-reactive protein (CRP) [8,9]. D- Dimer and CRP levels during hospital admission show significant tem- poral variations, and some studies indicated that these biomarkers were not associated with Inhospital mortality among patients with AAD [10-12]. Serum albumin (SA), a stable protein in the human serum that is associated with inflammation and platelet activation, is re- portedly a strong independent predictor for long-term mortality in car- diovascular diseases, such as acute coronary syndrome and heart failure [13-15]. However, SA has not been studied as a potential predictor of long-term outcomes among patients with type B AAD undergoing endovascular therapy (EVT). The primary goal of this study was to ex- amine the hypothesis that low SA is an independent predictor of surviv- al in type B AAD.

http://dx.doi.org/10.1016/j.ajem.2016.03.067

0735-6757/(C) 2016

1370 R. Zeng et al. / American Journal of Emergency Medicine 34 (2016) 13691372

  1. Methods
    1. Ethical considerations

This study was performed in accordance with the Helsinki Declara- tion and was approved by the Human Ethical Committee of West China Hospital.

Patient population and follow-up

From hospital records, we identified type B AAD patients who were admitted between January and December 2012. All hospitalized pa- tients were screened for type B AAD based on discharge diagnoses. The inclusion criteria were as follows: (1) type B AAD presenting within 14 days of symptom onset and CT with contrast confirming a dissected descending aorta containing both a true and false lumen and (2) receiv- ing endovascular stent graft placement. One hundred forty-one patients were enrolled in the present study. The exclusion criteria were patients with malignant tumor, infectious diseases, chronic heart failure (2 pa- tients), chronic hepatopathy history (2 patients), and chronic renal dis- ease history (3 patients) and loss to follow-up (3 patients). Finally, 131 patients were included in this study. On average, patients were followed up for 2.1 years after admission. Clinical characteristics, inhospital out- comes, and long-term mortality were collected from hospital admission records and by telephone interviews. Inhospital outcomes included acute renal failure, acute Limb ischemia, hypotension, hypoxemia, myo- cardial ischemia/infraction, coma, and Pericardial tamponade. Patients were followed up until meeting a study primary end point (death).

Diagnosis of AAD

univariate Cox models were then simultaneously entered into a multi- variable Cox model. From the multivariable model, we identified vari- ables were significant (P b .05) predictors of mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each of them by Cox proportional hazards analysis; all other P values were con- sidered statistically significant when less than .05.

  1. Results
    1. Baseline patient characteristics

We studied 131 patients (97 males; mean age, 51 +- 13 years; range, 28-91 years) with type B AAD who were undergoing EVT. The medium follow-up duration was 2.1 (1.3-3.7) years, 13 patients (9.9%) died in hospital, and 8 patients (6.1%) died after discharge from hospital. Base- line characteristics of the study cohort are shown in Table 1. The mean Albumin level was 35 +- 6 g/L (range, 21-70 g/L). Sixty-one patients (46.6%) were hypoalbuminemic, according to the definition of serum al- bumin less than or equal to 34 g/L. Hypoalbuminemia was more com- mon in patients with old age, high hemoglobin (Hb), lower levels of systolic blood pressure at admission, and higher levels of creatinine. There were no differences in other parameters between those with and without hypoalbuminemia (Table 1).

Hypoalbuminemia and cardiac events

In hospital, there were no significant differences in acute renal fail- ure, acute limb ischemia, hypotension, hypoxemia, myocardial ische- mia/infraction, coma, and pericardial tamponade between those with and without hypoalbuminemia (Table 2.).

The diagnosis of Stanford type B AAD was confirmed by typical clinical symptoms combined with CT scanning performed at the time of admission. Acute phase AAD was defined as admission to our hospital within 2 weeks after the onset of AAD symptoms, whereas chronic AAD was defined as AAD that occurred more than 2 weeks before admission.

Data collection

Clinical information from each patient was gathered through review of Clinical Notes and charts. Demographic data, including Cardiovascular risk factors and comorbidities, were collected. The investigation results, including blood tests and electrocardiographic and CT findings, were also recorded. The type of endovascular stent graft placement therapy was documented. Drug treatments before admission, during the hospi- tal stay, and at discharge were recorded. Inhospital complications were also gathered through medical records and information provided by telephone interviews.

Table 1

Baseline characteristics of patients with type B AAD

Patient characteristics SA <=34 g/L

(n = 61)

(n = 70)

Age (y)

54 +- 14

48 +- 12

.008

Males, n (%)

42 (68.9)

55 (78.6)

.206

Hypertension, n (%)

50 (82.0)

56 (80.0)

.775

Arteriosclerosis, n (%)

16 (26.2)

18 (25.7)

.947

Smoking, n (%)

24 (39.3)

32 (45.7)

.462

SBP (mm Hg)

143 +- 28

157 +- 30

.007

DBP (mm Hg)

88 +- 25

93 +- 20

.184

Heart rate (beats/min)

85 +- 17

87 +- 16

.346

LVEF (%)

59 +- 12

62 +- 9

.250

BUN (mmol/L)

6.4 +- 3.0

5.5 +- 2.1

.066

Creatinine (umol/L)

102 +- 58

83 +- 30

.022

eGFR (mL/min/1.73 m2)

61 +- 45

72 +- 36

.123

ALT, IU/L

34 +- 49

38 +- 44

.623

AST, IU/L

75 +- 252

35 +- 49

.198

Hb, g/dL

122 +- 21

140 +- 18

b.001

Negative urine protein, n (%)

58 (95.1)

69 (98.6)

.247

Imaging findings

Periaortic hematoma, n (%)

2 (3.3)

4 (5.7)

.506

False lumen status

.197

Patent false lumen, n (%) 9 (14.8)

4 (5.7)

Partially TFL, n (%)

14 (23.0)

15 (21.4)

Completely TFL, n (%)

38 (62.3)

51 (72.9)

Coronary arteries involved, n (%)

1 (1.6)

0 (0.0)

.282

Renal artery involved, n (%)

23 (37.7)

33 (47.1)

.276

Common iliac artery involved, n (%)

5 (8.2)

9 (12.9)

.389

Internal iliac artery involved, n (%)

2 (3.3)

3 (4.3)

.764

External iliac artery involved, n (%)

1 (1.6)

5 (7.1)

.133

Antihypertensive medication in hospital

ARB/ACEI, n (%)

23 (37.7)

21 (30.0)

.352

CCB, n (%)

58 (95.1)

68 (97.1)

.539

?-Blockers, n (%)

54 (88.5)

60 (85.7)

.633

Diuretics, n (%)

11 (15.9)

16 (22.9)

.303

SA N 34 g/L P

Statistical analysis

Data analyses were performed using SPSS for Windows 17.0 (SPSS, Inc, Chicago, IL). Continuous variables are presented as the mean +- SD, and categorical variables are presented as frequency or percentage. Type B AAD patients were divided into hypoalbuminemia and normal albumin groups. Normally distributed data of continuous variables were compared by the Student t tests between the groups, and the non- parametric Mann-Whitney U test was used for abnormally distributed data. Categorical variables were analyzed by using ?2 test or Fisher exact test. Kaplan-Meier curves were performed by log-rank test to demonstrate the association between long-term survival and SA. Cox proportional hazards models were run to investigate whether hypoal- buminemia (SA <= 34 g/L) was associated with time to mortality during the study period. To construct the Cox model, univariate models for each of the all predictor variables were run, with all-cause mortality as the outcome variable. Those variables that were significant (P b .05) in

Abbreviations: SBP, systolic blood pressure at admission; DBP, diastolic blood pressure at admission; LVEF, left ventricular ejection fraction; BUN, blood urea nitrogen; TFL, thrombosed false lumen; ARB, Angiotensin II receptor; ACEI, angiotensin-converting en- zyme inhibitor; CCB, Calcium-channel blocker.

R. Zeng et al. / American Journal of Emergency Medicine 34 (2016) 13691372 1371

Table 2 Relationships between inhospital complications and serum albumin in patients with type B AAD

SA > 34 g/L

SA ? 34 g/L

P = .002

Cumulative Survival

Inhospital complications

SA <= 34 g/L (n = 61)

SA N 34 g/L (n = 70)

P

Acute renal failure, n (%)

7 (11.5)

6 (8.6)

.579

Acute limb ischemia, n (%)

5 (7.1)

5 (8.2)

.821

Hypotension, n (%)

6 (9.8)

6 (8.6)

.802

Hypoxemia, n (%)

12 (19.7)

15 (21.4)

.804

Myocardial ischemia/infraction, n (%)

4 (6.6)

1 (1.4)

.126

Coma, n (%)

5 (8.2)

3 (4.3)

.351

Pericardial tamponade, n (%)

0 (0.0)

2 (2.9)

.183

At 2.1-year follow-up, survival was significantly lower in patients with hypoalbuminemia compared with those without (73.8% vs 92.5%; log-rank ?2 = 9.8; P = .002; Figure), the unadjusted HR was

4.35 (95% CI, 1.59-11.90; P = .001). Univariate Cox regression analysis showed that hypoalbuminemia, age, acute limb ischemia, hypotension, hypoxemia, arteriosclerosis, coma, and myocardial infarction or ische- mia were associated with long-term mortality (Table 3). After adjusting for these potential confounders in the multivariable analysis, hypoalbu- minemia (HR, 4.28; 95% CI, 1.36-13.47; P = .013), age (HR, 1.06; 95% CI, 1.02-1.11; P = .006), and coma (HR, 23.33; 95% CI, 4.66-116.86;

P b .001) were found to be the most powerful predictors of all-cause mortality in type B AAD patients, over 2.1 years (Table 3).

Causes of hypoalbuminemia in patients with type B AAD

The mean levels of alanine aminotransferase (ALT), aspartate ami- notransferase (AST), and urea nitrogen were normal in our study co- hort, and there was no difference between the patients with hypoalbuminemia and those without. The serum higher levels of creat- inine (Cr) and lower of Hb were observed in patients with hypoalbu- minemia than in those without. However, estimated glomerular filtrate rate (eGFR) and urine protein did not significantly differ be- tween the 2 groups (Table 1).

  1. Discussion

The present study indicated that hypoalbuminemia was present in 47% of patients with type B AAD undergoing EVT. At baseline, patients with hypoalbuminemia had lower levels of Hb, but higher levels of Cr, which supports the hypothesis that type B AAD patients with hypo- albuminemia may have more severity of AAD with some degree of renal failure. Importantly, the presence of hypoalbuminemia was indepen- dently associated with significantly increased risk of long-term death, after adjustments for potential confounders. Thus, our results suggest that after endovascular stent graft placement, we might be able to strat- ify the risk of long-term mortality among patients with type B AAD hypoalbuminemia.

Table 3

Cox regression of all-cause mortality for patients with type B AAD

Variables Univariate analysis Multivariate analysis

HR

95% CI

P

HR

95% CI

P

Hypoalbuminemia

4.35

1.59-11.90

.004

4.28

1.36-13.47

.013

Age, per year increase

1.04

1.01-1.07

.006

1.06

1.02-1.11

.006

Acute limb ischemia

3.31

1.11-9.88

.032

0.32

0.08-1.32

.116

Hypotension

8.58

3.40-21.62

b.001

3.22

0.78-13.26

.106

Hypoxemia

3.03

1.27-7.23

.012

0.43

0.15-1.22

.111

Arteriosclerosis

3.39

1.44-8.01

.005

0.90

0.32-2.53

.842

Coma

29.58

10.36-84.43

b.001

23.33

4.66-116.86

b.001

MI

1.35

1.18-3.11

.039

0.08

0.01-1.03

.053

Abbreviation: MI, myocardial infarction or ischemia.

Follow-up Time (days)

Figure. Kaplan-Meier survival analysis showing patients with type B AAD with hypoalbu- minemia (SA, <= 34 g/L) had significantly worse survival than patients without hypoalbuminemia.

There may be several explanations as to why a decreased SA level was associated with long-term adverse events. In general, hypoalbu- minemia is an excellent marker for the severity of a variety of acute ill- nesses. For instance, a low SA level during hospitalization for an acute myocardial infarction has been reported to be an independent predictor of no-reflow, in-stent restenosis, heart failure, 40-month cardiac death, Left ventricular remodeling, and the severity of coronary artery stenosis [13,16-18]. Thus, hypoalbuminemia in acute myocardial infarction might reflect myocardial damage and the severity of myocardial infarc- tion during the acute phase. Hypoalbuminemia was also associated with noncardiac mortality. In agreement with previous studies, stroke and reinfarction were significantly higher among patients with hypoalbu- minemia after following up for a long duration [19,20]. A high SA level is protective against stroke and is neuroprotective during stroke by de- creasing the incidences of Brain edema and mortality [19]. Hypoalbu- minemia most frequently results from decreasing nutritional intake, inflammatory responses, oxidative stress, Liver dysfunction, Nephrotic syndrome, and cachexia [21]. Serum albumin has some physiological properties associated with vascular function [22], including mainte- nance of plasma colloid osmotic pressure, anti-inflammatory properties, antioxidant functions, and platelet activation in initiation [23,22,24], which are involved in pathophysiological mechanisms of AAD. In our study, SA levels are presumably reflective of the severity of type B AAD in the acute phase, and it may be that the severity expressed by hy- poalbuminemia has a lasting impact on long-term mortality.

Thromboinflammatory status is associated with prognosis of AAD [12]. Hypoalbuminemia is associated with the activation of inflammato- ry mediators, such as CRP and matrix metalloproteinases, which are known to predict worse AAD outcomes [21,9,12,8]. Serum albumin also has Platelet function inhibition and antithrombotic effects. Partial thrombosis of the false lumen is an independent predictor of mortality in AAD patients [6]. As a consequence of arterial injury and rupture, AAD causes the release of tissue factor, which signals activation of the extrinsic pathway of the coagulation cascade reaction. Collectively, platelets are a pivotal factor in thrombosis. Increasing platelet activation and platelet dysfunction have been observed to occur in AAD patients during the acute phase [25,26]. Serum albumin is an important inhibitor of platelet activation and aggregation, which can further exert its inhibition effect by inhibiting arachidonic acid lipid oxidase and neutralizing factor Xa [23]. Therefore, SA level is reflective of the thromboinflammatory status in AAD.

Serum albumin plays an antioxidant role by inhibiting the endoge-

nous peroxidase and blocking the exogenous oxidant [19]. Albumin can combine with a large amount of free fatty acids in the blood to pro- tect them from lipid peroxidation damage [27]. Albumin also can reduce or eliminate the toxicity of internal or external Toxic substances by

1372 R. Zeng et al. / American Journal of Emergency Medicine 34 (2016) 13691372

binding with them, which effectively stabilizes the environment, resists endothelial damage, and further reduces the risk of complications and mortality [28]. Oxidative stress has been suggested to play an important role in AAD, and low albumin levels and hypertension are significantly associated with aortic dissection [29,30]. Thus, one of the possible ex- planations for why hypoalbuminemia is associated with inhospital complications and long-term mortality of AAD are the properties of the antioxidant, albumin.

Loss of nutrients due to increased hepatic venous congestion de- creases hepatic synthesis of albumin. In our study, we used ALT and AST to evaluate the liver function of patients with type B AAD and found no difference in admission levels of ALT between patients with hypoalbuminemia and those without. Indeed, we did not find sufficient evidence to support the concept that liver dysfunction may be the cause of hypoalbuminemia in AAD patients. Renal dysfunction, such as ne- phrotic syndrome, can lead to hypoalbuminemia. In our study, we used Cr and eGFR to evaluate the renal function of patients with type B AAD and showed that the presence of hypoalbuminemia had no effect on eGFR. This result suggests that renal dysfunction may be one of the causes of hypoalbuminemia in AAD patients.

  1. Limitations

Our analysis has several limitations that should be considered when interpreting our findings. First, this is a single-center, respective cohort study, and our results may not be extended to patients in other regions. Second, some inflammatory and thrombotic biomarkers, such as inter- leukin 6, CRP, and D-dimer, were not detected in the present study; thus, we could not investigate the association between inflammatory or thrombotic biomarkers and SA. Third, we recorded SA levels only on admission, and a series of measurements during hospitalization at different time points may be more valuable for evaluation of the relation between SA and prognosis. Finally, the sample size in our study was rel- atively small; therefore, prospective, large-scale multicenter studies are required to confirm our results.

  1. Conclusions

We showed that hypoalbuminemia was a powerful predictor for the prognosis of type B AAD patients undergoing endovascular stent graft placement. Because hypoalbuminemia is also a marker of malnutrition, it provides further impetus for prospectively examining a potential preven- tative or therapeutic role for nutritional intervention in patients with AAD.

Declaration of interest“>Declaration of interest

The authors declare that they have no competing interests.

Acknowledgment

This work was supported financially by grants from the Science Foundation of Science and Technology Department in Sichuan (nos. 2015SZ0180 and 2014JY0204).

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