Red cell distribution width to albumin ratio is a risk factor for atrial fibrillation in general population

doi:10.21203/rs.3.rs-2887915/v1

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Red cell distribution width to albumin ratio is a risk factor for atrial fibrillation in general population

https://doi.org/10.21203/rs.3.rs-2887915/v1

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Background: Red cell distribution width to albumin ratio (RAR) has been demonstrated to be associated with the risk of cardiovascular diseases. However, it is still unknown whether the RAR affects atrial fibrillation (AF) . Therefore, this study aimed to investigate the association between RAR and AF in general population.

Methods: A total of 2436 participants were retrospectively enrolled. Red cell distribution width, albumin and other data were collected. AF was confirmed using 12-lead electrocardiogram (ECG) or 24-hour Holter. All participants were divided into four groups according to the RAR values by quartile (Q1, Q2, Q3, Q4). Univariate and multivariate logistic regression were performed to examine the correlation between RAR and AF.

Results: Among the 2436 participants, 227 (9.3%) AF cases were observed. The RDW and RAR were significantly higher in AF group than in non-AF group (all P<0.001). Univariate logistic regression showed an positive association between RAR and AF (P<0.001). In multivariate logistic regression, RAR was found to be an independent risk factor of AF after adjusting for confounding factors (OR:2.015, 95%CI:1.315-3.089, P=0.001) .

Conclusions: The present study indicated that elevated RAR level was independently correlated with increased risk of AF in general population.

Red cell distribution width

Albumin

Atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice for decades, the prevalence of AF ranges from 2–12% in the general population [1–2]. Epidemiology studies have shown that AF is associated with acute myocardial infarction, heart failure, stroke, death, peripheral embolism, and other adverse outcomes [2–3]. Up to now, fibrosis, inflammation and oxidative stress are reported to influence many cardiovascular diseases. However, the mechanisms of developing and maintaining AF remain unclear [4]. Although clinical treatments of AF have been developed to reduce the burden of disease, the estimated number of patients in the world is up to 33.5 million [5]. Therefore, it is important to identify the modifiable risk factors for AF.

Previous studies have demonstrated that the red cell distribution width (RDW), an index of variation of erythrocyte volume, is associated with cardiovascular death, heart failure, fatal coronary disease and sub-clinical inflammation [6–8]. Low serum albumin levels are also linked to ischemic heart disease, heart failure, atrial fibrillation, stroke and inflammation [9]. The RAR, a combination of red cell distribution width and albumin, is a novel index of inflammation. Prior researches have suggested that RAR may be helpful in assessing the outcomes in of acute biliary pancreatitis attacks [10], 60-day mortality in patients with acute respiratory distress syndrome [11], and carotid plaques in patients with CHD [12]. However, the association of RAR and AF has not been clarified in prior studies. The current study was therefore carried out to investigate the association among general population who undergoing coronary angiography in our center.

Study Participants

For the cross-sectional study, a total of 2436 consecutive participants who had been admitted to our center due to chest pain or tightness and underwent coronary artery angiography (CAG) for the first time between 2016 and 2020 were retrospectively enrolled. Those individuals were not enrolled in this study for the reasons: lacking electrocardiograms, and missing essential data. The AF (including paroxysmal AF, persistent AF and permanent AF) was confirmed using 12-lead electrocardiogram (ECG) or 24-hour Holter. AF rhythm was defined as (I) irregular R-R intervals (II) absence of distinct repeating P waves (III) irregular atrial activity show on ECG. The final diagnosis of AF were reviewed and conformed by the two researchers.

This study was carried out in accordance with the ethical guidelines of the Declaration of Helsinki. The written informed consents for participation were not presented owing to the retrospective nature of this study. Additionally, this study was approved by the Ethics Committee of Wujin Hospital Affiliated with Jiangsu University, which waived the need for informed consent.

Data Collection

The data were collected from the electronic medical records. Demographic and clinical data, including age, sex, body mass index (BMI), smoking, drinking, hypertension, diabetes mellitus (DM), and coronary artery disease (CAD) were collected by cardiologists. Fasting venous blood samples were taken from the subjects after admission. The biochemical parameters including fasting serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), red cell distribution width (RDW) and albumin for all included patients were gathered. RAR was calculated as follows: red cell distribution width / albumin. Level of RAR was divided into four groups by quartile.

Statistical Analysis

Statistical analysis was performed using SPSS version 25.0. The normally distributed continuous variables were expressed as mean ± standard deviations. And the non-normally distributed continuous variables were expressed as median (first and third quartile). The comparisons in continuous variables were analyzed by the Student t test, One-Way ANOVA or non-parametric Mann-Whitney test, as approprite. Categorical variables were described as frequencies and percentages. Differences between groups were tested with the Chi-square for categorical variables. Univariate logistic regression analysis was used to identify the risk factors for AF. Meanwhile, multivariate logistic regression analysis was carried out to evaluate the association between RAR and AF after adjusting for potential confounding variables. Odds ratio (OR) and 95% confidence interval (95% CI) were presented for the logistic regression analyses. All P values were two sided. A P value less than 0.05 was considered as statistically significant.

Baseline Characteristics of the Study Population

The baseline characteristics for the study participants were summarized in Table 1. The median age of the study participants was 65 years, and 1550 (63.6%) were males. A total of 227 (9.3%) AF patients were identified. Patients with AF were older, had higher proportion of male gender and smoking status (P < 0.05). The presence of AF was strongly inversely associated with CAD diagnosed on CAG (P < 0.001). Compared to those without AF, patients with AF had significantly lower levels of TC, TG, LDL-C and albumin (all P < 0.001). The RDW and RAR levels were significantly higher in patients with AF than in subjects without AF (all P < 0.001).

There was no significant difference in the proportion of HBP, DM, drinking history between AF and non-AF group in over population. The statistically significant difference was also not observed in levels of BMI and HDL-C between the two groups.

Table 1

Characteristics of included participants at baseline
Variables	AF (n = 227)	Non-AF (n = 2209)	P value
Age(y)	70(63,76)	65(56,71)	< 0.001
Male (n,%)	130(57.3)	1420(64.3)	0.036
Hypertension (n,%)	160(70.5)	1464(66.3)	0.200
DM (n,%)	45(19.8)	518(23.4)	0.217
CAD (n,%)	107(47.6)	1623(73.5)	< 0.001
Smoking (n,%)	66(29.1)	850(38.5)	0.005
Drinking (n,%)	36(15.2)	317(14.4)	0.539
BMI(kg/m²)	24.77(22.49,27.22)	24.53(22.43,26.75)	0.111
TC (mmol/L)	4.15(3.41,4.75)	4.43(3.74,5.13)	< 0.001
TG (mmol/L)	1.37(0.95,1.93)	1.55(1.10,2.26)	< 0.001
HDL-C (mmol/L)	1.07(0.92,1.24)	1.07(0.93,1.26)	0.688
LDL-C (mmol/L)	2.57(2.07,3.17)	2.85(2.28,3.43)	< 0.001
RDW(%)	12.70(12.20,13.20)	12.50(12.20,13.30)	< 0.001
Albumin (g/dL)	38.30(35.60,40.70)	39.10(36.90,41.50)	< 0.001
RAR (%/g/dL)	3.35(3.13,3.63)	3.19(2.98,3.44)	< 0.001

DM, diabetes mellitus; CAD, coronary artery disease, BMI, body mass index; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; RDW, red cell distribution width; RAR, red cell distribution width / albumin ratio.

Comparison of RAR quartile

Then, the participants were assigned into four groups (Q1: < 2.99, Q2:2.99–3.20, Q3: 3.20–3.45, Q4: ≥3.45) according to the RAR quartile. As shown in Table 2, patients with the highest RAR level tended to be older ( 69 versus 62 years), had a higher proportion of AF (14.6% versus 6.3%), lower levels of TC, TG, LDL-C and albumin compared to those with lowest RAC level (all P < 0.001). Furthermore, participants in Q4 group were likely to have a higher RDW level than those in Q1 group ( P < 0.001).

Table 2

Baseline characteristics of study participants by RAR quartile
Variables	Q1 (n = 608)	Q2 (n = 610)	Q3 (n = 609)	Q4(n = 609)	P value
Age(y)	62 (54, 68)	65(55,71)	67(59,73)	69(61,74)	< 0.001
Male (n,%)	377 (62.0)	382 (62.6)	391 (64.2)	400 (65.7)	0.541
Hypertension (n,%)	406 (66.8)	414 (67.9)	419 (68.8)	385 (63.2)	0.179
DM (n,%)	152 (25.0)	146 (23.9)	134 (22.0)	131 (21.5)	0.431
CAD (n,%)	403 (66.3)	435 (71.4)	431 (71.0)	461 (75.8)	0.004
AF (n,%)	38 (6.3)	34 (5.6)	66 (10.8)	89 (14.6)	< 0.001
Smoking (n,%)	211 (34.7)	235 (38.5)	225 (36.9)	245 (40.2)	0.231
Drinking (n,%)	89 (14.6)	86 (14.1)	84 (13.8)	94 (15.4)	0.858
BMI(kg/m²)	24.80 (22.84,27.04)	24.90(22.86,26.74)	24.39(22.45,26.78)	24.03(21.64,26.56)	< 0.001
TC (mmol/L)	4.58(3.88,5.33)	4.48(3.79,5.14)	4.39(3.70,5.10)	4.11(3.49,4.82)	< 0.001
TG (mmol/L)	1.68(1.22,2.54)	1.63(1.17,2.27)	1.52(1.11,2.21)	1.29(0.92,1.88)	< 0.001
HDL-C (mmol/L)	1.11(0.96,1.29)	1.08(0.93,1.27)	1.06(0.94,1.26)	1.04(0.90,1.20)	0.769
LDL-C (mmol/L)	2.93(2.33,3.49)	2.90(2.33,3.42)	2.84(2.24,3.47)	2.60(2.16,3.22)	< 0.001
RDW(%)	12.05(11.80,12.40)	12.3(12.0,12.7)	12.6(12.3,13.1)	13.2(12.65,13.70)	< 0.001
Albumin (g/dL)	43.0(41.4,44.7)	39.9(38.6,41.0)	38.0(36.9,39.25)	35.3(33.6,36.8)	< 0.001

Association of RAR and AF

The results of logistic regression analyses were presented in Table 3. Univariate logistic regression showed that age (OR:1.056, 95% CI:1.040–1.071, P < 0.001) and RDW (OR:1.414, 95% CI:1.218–1.642, P < 0.001) were significantly associated with increase risk of AF. Male gender (OR:0.745, 95%CI:0.564–0.982, P = 0.037), CAD (OR:0.322, 95% CI:0.244–0.425, P < 0.001), smoking (OR:0.655, 95% CI:0.0.486–0.884, P = 0.006), TC (OR: 0.728, 95% CI:0.636–0.834, P < 0.001), TG (OR:0.812, 95% CI:0.709–0.931, P = 0.003), LDL-C (OR:0.724 95% CI:0.615–0.852, P < 0.001), and albumin (OR:0.936, 95% CI:0.902–0.971, P < 0.001) were all statistically associated with a low risk of AF. And a positive relationship was observed between the RAR and AF risk (OR:2.567, 95% CI:1.724–3.822, P < 0.001).

After adjusting for these confounding factors, the highest quartile (Q4) of RAR was independently associated with an increased risk of AF compared with the lowest quartile (Q1) of RAR (OR:2.015, 95% CI:1.315–3.089, P = 0.001). Furthermore, the positive association between older age and older age remained significant (OR:1.057, 95% CI: 1.040–1.074, P < 0.001). In particular, the analysis revealed that CAD and LDL-C (OR:0.270, 95% CI:0.201–0.363, P < 0.001 and OR:0.813, 95% CI:0.704–0.939, P = 0.005, respectively) were markedly inversely associated with AF.

Table 3

Univariate and multivariate logistic regression for the relationship between variables and AF
Variables		Univariate			Multivariate
	OR	95%CI	P	OR	95%CI	P
Age	1.056	1.040–1.071	< 0.001	1.057	1.040–1.074	< 0.001
Male	0.745	0.564–0.982	0.037			0.672
Hypertension	1.215	0.902–1.638	0.201
DM	0.807	0.574–1.135	0.218
CAD	0.322	0.244–0.425	< 0.001	0.270	0.201–0.363	< 0.001
Smoking	0.655	0.486–0.884	0.006			0.617
Drinking	1.125	0.733–1.638	0.539
BMI	0.102	0.994–1.074	0.102
TC	0.728	0.636–0.834	< 0.001	0.813	0.704–0.939	0.005
TG	0.812	0.709–0.931	0.003			0.994
HDL-C	0.870	0.522–1.448	0.591
LDL-C	0.724	0.615–0.852	< 0.001			0.211
RDW	1.414	1.218–1.642	< 0.001			0.286
Albumin	0.936	0.902–0.971	< 0.001			0.176
RAR,Q1	Reference			Reference
Q2	0.885	0.550–1.427	0.617	0.811	0.497–1.324	0.402
Q3	1.823	1.203–3.764	0.005	1.490	0.965–2.302	0.072
Q4	2.567	1.724–3.822	< 0.001	2.015	1.315–3.089	0.001

To our knowledge, this is the first study focus on the relationship between the red cell distribution width to albumin ratio (RAR) and atrial fibrillation (AF) in general population hospitalized with coronary angiography for the first time. The results suggested that elevated RAR was independently associated with AF. RAR might be a potential parameter to estimate presence of AF.

Inflammation in cardiac tissue and circulatory processes can modulates calcium homeostasis and connexins, which are related with triggers and maintain of AF in the general population [13]. Moreover, studies on atrial fibrillation pathophysiology provided an update knowledge regarding inflammation and atrial fibrosis, potential as therapeutic targets [14]. Red blood cell distribution width (RDW), an index of variation of erythrocyte volume, reflects the degree of anemia traditionally. The conventional reference range of RDW is roughly comprised between 12% and 15%. Previous studies have reported that RDW could be used beyond anemia in clinics. Several pathophysiological mechanisms underling cardiovascular diseases including inflammation, oxidative stress, adrenergic stimulation and reduced iron mobilization have been reported, in which RDW play an important role [15]. A report of 2140 patients with symptomatic heart failure revealed that RDW was significantly associated with cardiovascular death or hospitalization for heart failure (HR1.17; 95%CI 1.10–1.25) [6]. Besides, it was important to note that RDW was demonstrated to be an independently indicator for sub-clinical inflammation [8, 16]. Subsequently, increasingly evidence have suggested that the RDW is a prognostic marker of AF in various clinical settings [17]. Moreover, admission levels of RDW was correlated with new-onset AF in patients after a primary percutaneous coronary intervention [18]. Similarly, in our study, the RDW levels were found to be significantly higher in patients with AF than those without AF.

Albumin, an essential protein for important physiologic effects in human plasma, was proven to be associated with chronic inflammation [19]. Albumin concentrations tend to decline in the inflammatory conditions. And linear regression analysis discovered little effect of CRP on albumin levels, although the mechanisms underlying this remain unclear [20]. A previous study comprised of 285930 patients demonstrated that albumin level is strongly negatively correlated with the risk of cardiovascular death, as well as with the reduction of anti-inflammatory activity and oxidative stress, especially in males [21]. Based on the mechanisms, recent study conducted in 909 patients with AF in China showed that AF patients had lower levels of albumin. Lower serum albumin levels was significantly associated with AF [22]. As reported, the patients with AF recurrence after ablation had a significantly higher level of red blood cell distribution width (RDW) at baseline than those with sinus rhythm [23]. In consistent with these reports, the results in our study revealed that albumin was inversely associated with AF. Additionally, albumin was not an independent risk factor for AF after adjustment for confounding variables.

The RAR has been considered as a new and reliable parameter related with a variety of disease in clinical practice. Recent research has suggested that RAR is a better prognostic factor of aortic aneurysms rather than RDW [24]. Huang M, et al found that RAR is significantly related with carotid plaques in patients with coronary heart disease [12]. A study of 3042 patients with sepsis and AF indicated that RAR was strongly independently associated with the risk of all-cause mortality. A linear relationship between the RAR and in-hospital mortality in patients with sepsis and AF was obtained [25].

Our results suggested that the RAR played an important role in the presence of AF. When we divided individuals according to the RAR levels, we found participants in the highest RAR quartile (Q4) were inclined to have higher prevalence of AF than those in the lowest quartile (Q1). Although RAR was calculated using RDW and albumin, regression analysis showed RAR was an independent risk factor for AF after adjustment of age, TC, CAD and other confounding factors. Additionally, the RAR may be a simply measured and therapeutic target for preventing AF in clinical practice. The findings might provide valuable new insight into AF research. The exact mechanism underling the close association of RAR and AF need to explore in future studies.

There were several limitations in the present study. Firstly, this was a single-center retrospective and observational study. Therefore, there was unavoidably case selection bias. The findings should be further confirmed by multicenter studies. Secondly, 12-lead electrocardiogram (ECG) or 24-hour Holter might be less able to detect AF than 72-hour Holter. And it could not evaluate whether RAR has a different relationship with different types of AF. Finally, nutrition, CRP, BNP and other clinical parameters were not available in the analysis for missing too many values. So it is necessary to certify the results by large sample data in prospective study.

In conclusion, results in the current study revealed that RAR was independently associated with the risk for AF. The RAR may be a simple and reliable clinical marker to identify patients with high risk of AF from the general population. Further studies are required to confirm the association.

DM: diabetes mellitus; CAD: coronary artery disease; BMI: body mass index; TC: total cholesterol; TG: triglyceride; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; RDW: red cell distribution width; RAR: red cell distribution width / albumin ratio.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Wujin Hospital Affiliated with Jiangsu University (2023-SR-055). And the study was carried out in accordance with relevant national laws and the principles outlined in the Declaration of Helsinki. The data were collected from the electronic medical records. Hence the written informed consents for participation were not presented. In addition, the ethics committee of Wujin Hospital Affiliated with Jiangsu University permitted the use of patient data without informed consent.

Consent for publication

Not applicable.

Availability of data and materials

The data used to support the findings of this study are available from the corresponding author ([email protected]) on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors’ contributions

SYB designed and carried out the study. SYB and LWH contributed to data collection, analysis. SYB drafted the manuscript. SYB and LWH revised the manuscript. Both authors read and approved this final manuscript.

Acknowledgements

We sincerely thank the colleagues at the department of Cardiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China.

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No competing interests reported.

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Version 1

posted

You are reading this latest preprint version

Red cell distribution width to albumin ratio is a risk factor for atrial fibrillation in general population

Status:

Version 1

Abstract

Background

Methods

Study Participants

Data Collection

Statistical Analysis

Results

Baseline Characteristics of the Study Population

Comparison of RAR quartile

Association of RAR and AF

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1