Prognostic Factors for Patients with Sinus Rhythm and Patients with Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction; The Importance of Albumin for Prognosis

Authors

G. Kozdag Gold1*, K. Karauzum2, D. Ural2, O. Argan3, I. Karauzum2, A. Agacdiken Agir2, T. Sahin2
1Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, United States of America.
2Kocaeli University, Faculty of Medicine, Cardiology, Kocaeli Turkey.
3Balikesir University, Faculty of Medicine, Cardiology, Balikesir, Turkey.

Article Information

*Corresponding author: Guliz Kozdag Gold, Albert Einstein College of Medicine - Montefiore Medical Center, Bronx, United States of America.
Received Date: January 08, 2024
Accepted Date: January 16, 2024
Published Date: January 19, 2024

Citation: G. Kozdag Gold, K. Karauzum, D. Ural, O. Argan, I. Karauzum, A. Agacdiken Agir, T. Sahin. (2024) “Prognostic Factors for Patients with Sinus Rhythm and Patients with Atrial Fibrillation in Heart Failure with Reduced Ejection Fraction; The Importance of Albumin for Prognosis.” J Clinical Cardiology Interventions, 4(1); DOI: http;//doi.org/10.2024/07.1043.
Copyright:  © 2024 Guliz Kozdag Gold. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Atrial fibrillation (AF) and heart failure have become cardiovascular epidemic in recent years. AF is the most common arrythmia in patients with heart failure and its prevalence is increased in parallel to the severity of heart failure, ranging from 10 to 50%. There are prognostic parameters like reduced left ventricular systolic function and right ventricular function that are among independent predictors of poor outcomes in patients with advanced systolic heart failure. Prognostic parameters could be different in patients with AF and in patients with sinus rhythm in heart failure. The aim of this study was to examine and compared to prognostic risk factors in patients with sinus rhythm and in patients with AF in heart failure with reduced ejection fraction (HFrEF) (left ventricular ejection fraction [LVEF] ≤40%)

Methods: 603 consecutive patients (399 men and 204women) with HFrEF of both ischemic and non-ischemic etiology were followed up for a mean period of 77 months. The mean age was 65 ± 12 years, the mean LVEF was 25.8±8.5% and the mean right ventricular fractional area change was 47.5±11.9 %, the mean brain natriuretic peptide level was 1955.3±3423.7 pg/mL. There were 424 patients with sinus rhythm and 179 patients with AF in this heart failure cohort. The primary endpoint was cardiovascular mortality.

Results: During the follow-up period, 251 (42%) patients died due to cardiovascular causes. 188 (44%) of patients with sinus rhythm and 63 (35 %) patients with AF died during follow up period p=0.037. Age, LVEF, right ventricular fractional area change, respiratory rate, albumin level, walking distance were among statistically significant parameters in univariate analysis in both groups.

After adjusting for multiple confounders in multivariate Cox regression analysis showed that the Age  (HR-1.042, 95% CI 1.023-1.061, p<0.001), hospitalization (HR- 0.798, 95% CI 0.697-0.913, p=0.001), the walking distance (HR-0.582, 95% CI 0.414- 0.817, p=0.002) , E/e’ (HR- 1.035, 95% CI 1.010-1.055, p=0.005), urea level (HR- 1.004, 95% CI 1.001-1.007, p=0.012) and serum albumin level  (HR- 0.685, 95% CI 0.515-0.909, p=0.009) were the  independent parameters that predict prognosis in  patients with sinus rhythm  in HFrEF, however, the age (HR-1.091, 95% CI 1.060- 1.124, p<0.001) and albumin level (HR-0.545, 95% CI 0.336- 0.885, p=0.014) were independent parameters that predict prognosis in  patients with AF in HFrEF in this cohort.

Conclusion:  Age, hospitalization, walking distance in one minute, E/e’, urea level and serum albumin level were independent parameters that predict prognosis in patients with sinus rhythm in HFrEF however, age and serum albumin level were independent predictors for prognosis in patients with AF in HFrEF.

Keywords

Sinus rhythm, atrial fibrillation, heart failure with reduced ejection fraction, albumin, prognosis

Introduction

Atrial fibrillation (AF) and heart failure (HF) have become a cardiovascular epidemic in recent years1,2. AF is the most common arrhythmia in patients with HF, and its prevalence is increased in parallel to the severity of heart failure, ranging from 10 to 50%1,3-7. It is widely acknowledged that HF promotes AF and that AF worsens HF prognosis7-14 AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF. AF precedes and follows HF with both preserved and reduced ejection fraction15Individuals with AF or HF who subsequently develop the other condition have a poor prognosis12. AF can precipitate acute HF and may facilitate the progression of HF in several ways. Due to rapid heart rates an irregular ventricular rhythm loss of atrioventricular synchrony, and an increase mitral and tricuspid regurgitation, the presence or onset of AF may further decrease cardiac output and aggravate HF7,16,17.

Patients with heart failure with reduced ejection fraction (HFrEF) and AF are generally older, have a greater symptom burden, lower quality of life, and more comorbidity than those without AF18-21. Patients with AF may also be at higher risk of adverse outcomes, including HF hospitalization and death20.

Aims of this study were to examine and compared to prognostic risk factors in patients with sinus rhythm and in patients with atrial fibrillation (AF) in HFrEF (left ventricular ejection fraction [LVEF] ≤40%).

Method

Patients who were hospitalized with acute decompensated HFrEF between March 2004 and May 2014 in cardiology department of Kocaeli University Hospital which is a high-volume specialized HF clinic. After the index hospitalizations patients were followed in a dedicated HF clinic. The study group consisted of 603 patients who were discharged alive from the hospital. HFrEF was defined as a left ventricular ejection fraction (LVEF) ≤ 40%, as determined by transthoracic echocardiography in patients with clinical signs and symptoms of HF. Baseline demographic characteristics; risk factors; clinical findings; biochemical laboratory results B-type natriuretic peptide (BNP), C-reactive protein, and tri-iodothyronine levels; and echocardiography reports were recorded. AF was diagnosed on a standard 12-lead electrocardiogram (ECG) during the hospitalization. Exclusion criteria were acute coronary syndromes in last six months, an indication for cardiac surgical procedure, primary chronic liver disease, malignant diseases and end-stages with diseases where life expectancy was less than one year and patients with pacemaker rhythm were excluded from the analysis.

Outcome data were obtained from patients or caregiver reports (communicated by outpatient clinical visits of phone contact) or hospital databases. Data collection for each patient was censored at the time point of their most recent contact with the study team or date of death.

Data collection

The cardiology clinic of Kocaeli University Hospital has a detailed clinical database of HF patients. The collected data included demographic information and medical history such as age, gender, prior cerebrovascular events, peripheral arterial disease, chronic obstructive pulmonary disease (COPD), chronic renal dysfunction, hypertension, and diabetes mellitus. Clinical findings and symptoms at admission were evaluated for the study. Demographic information, medical history and clinical signs and symptoms were used as clinical variables. Patient’s rhythm and QRS duration were obtained from 12-lead electrocardiography (ECG). The method of ejection fraction assessment used was modified Simpson method and chamber’s diameters had been measured according to recent echocardiography guidelines in all patients. Baseline biochemical analysis including blood urea nitrogen, creatinine, hepatic enzymes, serum sodium and potassium, cholesterols, serum albumin, thyroid stimulating hormone, free T3, free T4, BNP, hemoglobin and hematocrit levels were recorded in all patients. Medical therapy including beta-blockers, ACE-inhibitors, ARBs, aspirin, nitrates, digoxin and diuretics were computed as positive if the patients had these medications at discharge. All these data were obtained from the hospital database. Survival status of the patients in the study was obtained from the hospital records or from telephone contact with the patient or family members.

The study protocol was approved by local institutional ethic committees.

Statistical analysis

The statistical analysis of the study was performed using SPSS 21.0 software (SPSS Inc., Chicago, IL). Continuous variables are presented as mean ± standard deviation and categorical variables as numbers, percentages, or proportions. The normality of continuous variable’s distribution was determined using the Kolmogorov-Smirnov test. Between-group comparisons were performed using the chi-square test for categorical variables, independent-samples t test for continuous variables with normal distributions and the Mann-Whitney U test for continuous variables with abnormal distributions. Cox proportional hazard analysis was used to arrive at the independent predictors of survival. The Kaplan-Meier method was used to analyze the timing of events during follow-up. All analyses were two-sided and considered significant at a value p value of 0.05.

Results

Six hundred and three patients were enrolled into the study, the mean age was 65±12 years old, 399 (66%) was male and 204 (34%) was female. While 424 (70%) patients were on sinus rhythm, 179 (30%) patients had atrial fibrillation during the index hospitalization (Table 1).

Table 1: General Characteristics of the study cohort.

 

n=603

Age (years)

65.0±12.0

Gender (Male/female)

399/204 (66%/34%)

Sinus rhythm/atrial fibrillation

424/179 (70%/30%)

NYHA

3.1±0.2

SBP  (mmHg)

123.5±18.0

DBP (mmHg)

75.0±11.5

Hemoglobin (g/dL)

12.5±1.9

BNP (pg/mL)

1955.3±3423.7

Creatinine (mg/dL)

1.4±0.8

Urea (mg/dL)

69.5±41.7

LVEF (%)

25.8±8.5

RVFAC (%)

47.5±11.9

E/e’

15.0±6.2

Coronary artery disease

377 (63%)

Diabetes mellitus

243 (40%)

Hypertension

441 (73%)

Aspirin Use

500 (83%)

ACE-I Use

436 (72%)

ARB Use

127 (21%)

Betablocker Use

434 (72%)

Thiazides

342 (57%)

Loop diuretics

501 (83%)

Spironolactone Use

292(48%)

Digoxin

129 (21%)

Statin

335 (56%)

SBP: Systolic blood pressure, DBP: Diastolic blood pressure. BNP: Brain natriuretic peptide, LVEF: Left ventricular ejection fraction. RVFAC: Right ventricular fractional area change, ACE-I: Angiotensin-converting enzyme inhibitor, Angiotensin II Receptor Blockers

The patients with AF were older than the patients with sinus rhythm, p=0.045. Heart rate was higher and left atrial dimension was larger in the AF group (p<0.001 and <0.001). There were more patients with coronary artery disease in patients with sinus rhythm p<0.001, (Table 2).

Table 2: Clinical differences between patients who were in sinus rhythm and patients with atrial fibrillation in the study group.

 

Patients with sinus rhythm (n=424)

Patients with atrial fibrillation (n=179)

          p

Age (years)

64.3±11.9

66.4±11.0

0.045

Gender (Men/women)

287/137(68%/32%)

112/67 (63%/ 37%)

0.225

Hospitalization

2.6±1.3

2.6±1.3

0.907

Death

188 (44%)

63 (35 %)

0.037

NYHA functional class

3.1±0.3

3.1±0.2

0.503

SBP  (mmHg)

122.9.1±18.1

124.78.1±17.6

0.236

DBP (mmHg)

74.5±11.4

75.8.1±11.8

0.202

Heart rate (in a minute)

79.8±13.5

90.9±23.0

<0.001

Hemoglobin (g/dL)

12.5±1.9

12.5±1.9

0.907

BNP (pg/mL)

1867.4±2665.7

1992.4±3699.6

0.682

Creatinine (mg/dL)

1.5±0.9

1.3±0.6

0.01

Urea (mg/dL)

70.2±43.8

67.9±36.3

0.492

eGFR (mL/min/1.73m2)

57.3±24.4

59.6±26.9

0.304

CRP (mg/L)

2.6 ±4.3

2.5±3.8

0.628

AST (U/L)

83.1±270.8

51.9±108.3

0.044

ALT (U/L)

78.9±246.0

53.9±131.8

0.107

FT3/FT4

1.9±0.8

1.8±0.6

0.260

LA dimension (mm)

46.1±5.9

50.5±6.8

<0.001

LVEF (%)

25.5±8.3

26.5±9.1

0.193

RVFAC (%)

47.8±11.7

46.9±12.3

0.379

E/e’

14.8±6.5

15.5±6.0

0.228

Coronary artery disease

290 (68%)

87(49%)

<0.001

Diabetes mellitus

186 (44%)

57(32%)

0.006

Hypertension

305 (72%)

136 (76%)

0.306

Aspirin Use

365 (86%)

135(75%)

0.001

ACE-I Use

323 (76%)

113(63%)

0.001

ARB Use

85 (20%)

42(23%)

0.330

Betablocker Use

308(73%)

126(70%)

0.574

Thiazides

245(58%)

97(54%)

0.416

Loop diuretics

349 (82%)

152(85%)

0.436

Spironolactone Use

201(47%)

91(51%)

0.441

Digoxin

64(15%)

65(36%)

<0.001

Statin

262(62%)

73(41%)

<0.001

NYHA: New York heart association, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, BNP: Brain natriuretic peptide, eGFR: Estimated glomerular filtration rate, CRP: C-reactive protein, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, FT3: Free triiodothyronine, FT4: Free thyroxine, LA: Left atrium, LVEF: Left ventricular ejection fraction, RVFAC: Right ventricular fractional area change, E: Early diastolic velocity, e’: E prime, ACE-I: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin receptor blocker. p<0.05 was considered statistically significant.

More patients with sinus rhythm died compared to patients with AF during follow up period 44% vs 35 %, p=0.037 (Table 2).

Patients who did not survive during the follow up period in sinus rhythm were older, hospitalized more, had shorter walking distance, higher respiratory rate, worse renal function, and liver function. Non survivors in sinus rhythm also had worse left and right heart systolic functions (Table 3).

Table 3: Statistically different parameters between patients who were survival and patients who were non survival in sinus rhythm.

 

Patients with sinus rhythm in heart failure reduced ejection fraction

 

 

 

p

Survivals (n=236)

Non survival

(n=188)

Age (years)

60.9±11.7

68.6±10.7

<0.001

Hospitalization

2.4±1.2

2.9±1.3

0.024

NYHA

3.0±0.1

3.1±0.4

<0.001

Walking distance in one minute >300 feet

181 (77%)

92(49%)

<0.001

Respiratory rate

24.2±3.9

27.3±4.7

<0.001

Hematocrit (%)

38.0±5.8

36.7±5.7

0.026

Creatinine (mg/dL)

1.3±0.7

1.7±1.1

<0.001

Urea (mg/dL)

59.4±34.4

83.8±50.1

<0.001

eGFR (mL/min/1.73m2)

62.0±24.0

51.5±23.7

<0.001

Homocysteine

16.3±7.7

18.0±8.7

0.056

Albumin (g/dL)

3.7±0.5

3.3±0.6

<0.001

AST (U/L)

33.9±53.4

144.9±394.2

<0.001

ALT (U/L)

31.0±40.3

139.0±358.2

<0.001

Estimated PASP (mmHg)

39.7±13.9

43.3±15.3

0.011

LVEF (%)

27.5±7.6

23.0±8.4

<0.001

RVFAC (%)

51.1±8.9

43.6±13.4

   <0.001

E/e’

         13.2±5.4

            16.9±7.1

   <0.001

NYHA: New York heart association, eGFR: Estimated glomerular filtration rate, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, PASP: Pulmonary artery systolic pressure, LVEF: Left ventricular ejection fraction, RVFAC: Right ventricular fractional area change, E: Early diastolic velocity, e’: E prime. p<0.05 was considered statistically significant.

Patients who did not survive during the follow up period in atrial fibrillation were older, hospitalized more, had shorter walking distance, higher respiratory rate, worse renal functions, and liver functions. Non survivors in atrial fibrillation also had worse left and right heart systolic functions (Table 4).

Table 4: Statistically different parameters between patients who were survival and patients   who were non survival in atrial fibrillation.

 

Patients with atrial fibrillation in heart failure reduced ejection fraction

 

     

           p

Survivals (n=116)

Non survival (n=63)

Age (years)

64.1±10.4

70.6±10.9

<0.001

Hospitalization

2.3±1.0

3.3±1.5

<0.001

NYHA

3.0±0.2

3.1±0.3

0.142

Walking distance in one minute >300 feet

76 (66%)

28 (44%)

0.006

Respiratory rate

24.9±4.3

26.6±4.6

0.015

Hematocrit (%)

38.3±5.5

36.6±5.8

0.050

Creatinine (mg/dL)

1.2±0.5

1.5±0.7

0.005

Urea (mg/dL)

63.2±31.3

76.4±42.1

0.034

eGFR (mL/min/1.73m2)

64.0±30.1

51.6±16.9

0.001

Homocysteine

13.8±8.3

16.6±6.5

0.022

Albumin (g/dL)

3.7±0.5

3.3±0.6

<0.001

AST (U/L)

30.1±23.3

92.0±173.7

0.006

ALT (U/L)

29.4±29.7

99.0±212.3

0.012

Estimated PASP (mmHg)

43.8±15.1

51.3±13.4

0.001

LVEF (%)

28.2±9.0

23.5±8.4

0.001

RVFAC (%)

48.9±11.0

43.1±13.7

0.004

E/e’

14.4±5.0

17.4±6.1

0.001

NYHA: New York heart association, eGFR: Estimated glomerular filtration rate, AST: Aspartate aminotransferase, ALT: Alanine aminotransferase, PASP: Pulmonary artery systolic pressure, LVEF: Left ventricular ejection fraction, RVFAC: Right ventricular fractional area change, E: Early diastolic velocity, e’: E prime. p<0.05 was considered statistically significant.

In Cox regression analysis age, hospitalization numbers, walking distance in one minute, e/e’, albumin level and urea level were independent predictors for cardiovascular death in patients with sinus rhythm. Age and albumin level were independent predictors in patients with AF.

Table 5: Cox Regression Analysis for cardiovascular death in patients with sinus rhythm and in patients with atrial fibrillation in heart failure reduced ejection fraction.

Variable

Hazard Ratio

95% CI

P value

Patients with sinus rhythm

 

 

 

Age

1.042

1.023-1.061

<0.001

Hospitalization

0.798

0.697-0.913

0.001

Walking distance in one minute

0.582

0.414-0.817

0.002

e/e’

1.035

1.010-1.055

0.005

Albumin

0.685

0.515-0.909

0.009

Urea

1.004

1.001-1.007

0.012

Patients with atrial fibrillation

 

 

 

Age

1.091

1.060-1.124

<0.001

Albumin

0.545

0.336-0.885

0.014

CI: Confidence interval, NYHA: New York Heart association, LVEF: Left ventricular ejection fraction, p<0.05 was considered statistically significant.

To define the predictor level in the study population, we used ROC curve analysis to detect the predictive cutoff values of albumin level for the occurrence of cardiovascular death in sinus rhythm (area under the curve [AUC]=0.294; 95% confidence interval [CI], 0.244–0.344; P < 0.001). The ROC curves showed that the best cutoff value for predicting cardiovascular death in sinus rhythm group was an albumin level of 2.95 mg/dL (76% sensitivity and 94% specificity) (Figure 1).

A graph of survival function

Description automatically generated

Figure 1: Survival differences between albumin level ≤2.95 g/dL and > 2.95 g/dL in patients with sinus rhythm.

The predictive cutoff values of albumin level for the occurrence of cardiovascular death in AF (area under the curve [AUC]=0.290; 95% confidence interval [CI], 0.208–0.372; P < 0.001). The ROC curves showed that the best cutoff value for predicting cardiovascular death in sinus rhythm group was an albumin level of 2.95 mg/dL (73% sensitivity and 97% specificity) (Figure 2). 

A graph of survival function

Description automatically generated

Figure 2. 1: Survival differences between albumin level ≤2.95 g/dL and > 2.95 g/dL in patients with atrial fibrillation.

Discussion

Patients who died during follow up period were older, had worse left heart and right heart systolic functions and their kidney and liver functions were more impaired compared to patients who survived in sinus rhythm group and AF group. Their walking distances were less, and respiratory rate were higher in patients who died in both groups. In both groups’ albumin levels were one of the independent predictors.

The normal reference range for serum albumin in adults is 3.5 and 5 g/dl.  Serum albumin concentration is physiologically slightly lower in women than in men and decreases slightly with age. Serum albumin carries many endogenous and exogenous substances, such as inorganic ions, fatty acids, bilirubin, vitamins, hormones and steroids, and drugs22.

Albumin represents a very abundant and important circulating antioxidant. Serum albumin may be the most important antioxidant in the whole blood22-24. The antioxidant properties of human serum albumin are largely dependent on Cys34 and its contribution to the maintenance of intravascular homeostasis, including protecting the vascular endothelium under disease conditions related to oxidative stress24.

Serum albumin contributes to maintaining capillary membrane stability and fluid balance across the capillary wall through its colloid osmotic effect and interaction with the endothelial glycocalyx. According to Starling’s law hydrostatic capillary pressure is the main force responsible for the fluid transfer from the intravascular to the interstitial space. The plasma colloid osmotic pressure, of which approximately 80% of the effect results from serum albumin, is the main force opposing fluid extravasation outside the intravascular compartment. The imbalance of Starling's forces because of hypoalbuminemia induces a net extravasation of fluid to the interstitial space, leading to formation of interstitial edema, hypovolemia, and fluid retention. Pulmonary fluid homeostasis has specific characteristics that protect against an isolated decrease in serum colloid osmotic pressure, and increase in pulmonary capillary hydrostatic pressure, even moderate, is necessary for the development of pulmonary edema22,25.

Prevalence of hypoalbuminemia varies from 20 to 25% in chronic heart failure to 90% in frail elderly patients with acute heart Failure. Hypoalbuminemia is due to decreased liver synthesis, increased catabolism, increased vascular permeability and renal and enteral loss22,25. Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic diseases such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis26. The occurrence of new onset heart failure was significantly related to low serum albumin concentration27.

In a study, 8870 individuals without cardiovascular disease were followed for a mean of 7.5 years. The albumin levels were inversely associated with the risk of AF among women but not among men. Additional adjustment for cases of coronary heart disease, congestive heart failure, and stroke that occurred during follow-up did not attenuate these associations28. Zhao et all demonstrated that in Chinese population low albumin level was independently associated with AF in a retrospective study29. 12.833 individuals participated in the study. During a median follow-up of 25.1 years, 2259 (17.6%) participants developed incident AF.  The serum albumin level was independently inverse associated with incident AF in a linear pattern. However, Mendelian randomization analyses did not support a causal role of serum albumin in the etiology of AF in this study30. In a prospective study low levels of serum albumin were associated with the occurrence of new onset AF during the first 48 h of intensive care unit admission. The incidence of new onset AF during the first 48 h of intensive care unit admission was 18%. Serum albumin levels were also significantly associated with the number of episodes of new onset AF in multivariate analysis31

In an observational study that included 385 patients with systolic heart failure followed for 25 months, serum albumin was a significant prognosis indicator for heart failure, and it added important information to NT-proBNP32. Hypoalbuminemia was also a strong predictor of death and delisting for adverse outcome in patients with heart failure listed for heart transplantation33. Low baseline serum albumin levels were independently associated with reduced 4-year survival in patients with HF and severe secondary mitral regurgitation enrolled in the COAPT trial34.

A total of 48 studies examining 44.048 patients with HF were analyzed. The results suggested that hypoalbuminemia was associated with significantly higher in-hospital mortality as well as long-term mortality with a predictive accuracy comparable to that reported for serum BNP. These findings suggested that serum albumin may be useful in determining high-risk patients35.

In this study low serum albumin levels were independent predictors both in patients with sinus rhythm and in patients with AF. It seems that serum albumin may represent the total systemic effects of heart failure. Serum albumin levels could be used as a guide for efficiently management of HFrEF. Serum albumin level may also be a guidance for advanced heart failure therapies.

Limitations
The limitation of this study is that it is a single-center and retrospective analysis study.
Disclosure Statement

No potential conflict of interest was reported by the authors.
Conclusion
In advanced HFrEF decreased albumin level predicts poor prognosis either in patients in sinus rhythm or inpatients with atrial fibrillation.  It may be used as a represent parameter of systemic respond to HF. Monitoring of albumin levels after HF diagnosis may be used as a guide to see the results of HF treatments.

References

  1. Anter E, Jessup M, Callans D J. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation. 2009; 119:2516-2525.
  2. Braunwald E. Shattuck Lecture: cardiovascular medicine at the tern ofthe millennium: triumphs, concerns, and opportunities.N Engl J Med.1997;337:1360–1369.
  3. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy Am J Cardiol 2003 91 2D–8D.
  4. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946 –952.
  5. Swedberg K, Olsson LG, Charlesworth A, Cleland J, Hanrath P, Komajda M, Metra M, Torp-Pedersen C, Poole-Wilson P. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with betablockers: results from COMET. Eur Heart J 2005; 26:1303 –1308.
  6. van Veldhuisen DJ, Aass H, El Allaf D, Dunselman PH, Gullestad L, Halinen M, Kjekshus J, Ohlsson L, Wedel H, Wikstrand J; MERIT-HF Study Group. Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study. Eur J Heart Fail 2006; 8:539 –546.
  7. Linssen GCM, Rienstra M, Jaarsma Tiny, Voors AA, van Gelder IC, Hillege HL, van Veldhuisen DJ. Clinical and prognostic effects of atrial fibrillation in heart failure patients with reduced and preserved left ventricular ejection fraction. European Journal of Heart Failure 2011;13: 1111–1120.
  8. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. A study of 390 patients. Circulation 1991; 84:40–48.
  9. Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 1998; 32:695 –703.
  10. Crijns HJ, Tjeerdsma G, de Kam PJ, Boomsma F, van Gelder IC, van den Berg MP, van Veldhuisen DJ. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J 2000;21: 1238 –1245.
  11. van den Berg MP, van Gelder IC, van Veldhuisen DJ. Impact of atrial fibrillation on mortality in patients with chronic heart failure. Eur J Heart Fail 2002; 4:571 –575.
  12. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 2003; 107:2920 – 2925.
  13. Roy D, Talajic M, Nattel S, Wyse DG, Dorian P, Lee KL, Bourassa MG, Arnold JM, Buxton AE, Camm AJ, Connolly SJ, Dubuc M, Ducharme A, Guerra PG,mHohnloser SH, Lambert J, Le Heuzey JY, O’Hara G, Pedersen OD, Rouleau JL, Singh BN, Stevenson LW, Stevenson WG, Thibault B, Waldo AL; Atrial Fibrillation and Congestive Heart Failure Investigators. Rhythm control versus rate control for atrial fibrillation and heart failure. New Engl J Med 2008; 358:2667 –2677.
  14. Tuinenburg AE, van Veldhuisen DJ, Boomsma F, van den Berg MP, de Kam PJ, Crijns HJ. Comparison of plasma neurohormones in congestive heart failure patients with atrial fibrillation versus patients with sinus rhythm. Am J Cardiol 1998; 81:1207 – 1210.
  15. Santhanakrishnan R, Wang N, Larson MG,  Magnani JW,  McManus DD  Lubitz  SA,  Ellinor PT,  SCheng  Vasan RS,  Lee DS,  Wang  TJ,  Levy D, Benjamin EJ,  Ho JE. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved vs. reduced ejection fraction. Circulation 2016; 133:484–492.
  16. Hagens VE, Crijns HJ, Van Veldhuisen DJ, Van Den Berg MP, Rienstra M, Ranchor AV, Bosker HA, Kamp O, Tijssen JG, Veeger NJ, Van Gelder IC; Rate Control versus Electrical cardioversion for persistent atrial fibrillation study group. Rate control versus rhythm control for patients with persistent atrial fibrillation with mild to moderate heart failure: results from the Rate Control versus Electrical cardioversion (RACE) study. Am Heart J 2005;149:1106–1111.
  17. Neuberger HR, Mewis C, van Veldhuisen DJ, Schotten U, van Gelder IC, Allessie MA, Bo¨ hm M. Management of atrial fibrillation in patients with heart failure. Eur Heart J 2007;28:2568 – 2577.
  18. Mogensen UM, Jhund PS, Abraham WT, Desai AS, Dickstein K, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, Køber L, McMurray JJV. Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol. 2017;70:2490–2500.
  19. Ponikowski P, Alemayehu W, Oto A, Bahit MC, Noori E, Patel MJ, Butler J, Ezekowitz JA, Hernandez AF, Lam CSP, O'Connor CM, Pieske B, Roessig L, Voors AA, Westerhout C, Armstrong PW; VICTORIA Study Group. Vericiguat in patients with atrial fibrillation and heart failure with reduced ejection fraction: insights from the VICTORIA trial. Eur J Heart Fail. 2021;23:1300–1312.
  20. Olsson LG, Swedberg K, Ducharme A, Granger CB, Michelson EL, McMurray JJV,  Puu M, Yusuf S,  Pfeffer MA; CHARM Investigators. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction. Results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol. 2006;47:1997–2004.
  21. Jawad H. Butt,  Kieran F. Docherty, Pardeep S. Jhund, Rudolf A. de Boer, Michael Böhm, Akshay S. Desai,  Howlett JG,  Inzucchi SE,  Kosiborod MN,  Martinez FA,  Nicolau JC,  Petrie MC, Ponikowski P, Bengtsson O,  Langkilde AM,  Schou M, Sjöstrand M,  Solomon SD,  Sabatine MS,  McMurray JJ V,  Køber L. Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: insights from DAPA‐HF. Eur J Heart Fail. 2022; 24: 513–525.
  22. Arques S. Human serum albumin in cardiovascular diseases. European Journal of Internal Medicine  2018;52:8–12.
  23. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Lett 2008 Jun 11;582:1783–1787.
  24. Anraku M, Chuang VT, Maruyama T, Otagiri M. Redox properties of serum albumin. Biochim Biophys Acta 2013;1830:5465–5472.
  25. Arques S, Ambrosi P. Human serum albumin in the clinical syndrome of heart failure. J Card Fail 2011;17:451–458.
  26. Don BR, Kaysen G. Serum albumin: relationship to inflammation and nutrition. Semin Dial 2004;17:432–437.
  27. Filippatos GS, Desai RV, Ahmed MI, Fonarow GC,  Love TE,  Aban IB,  Iskandrian AE,  Konstam MA, Ahmed A. Hypoalbuminaemia and incident heart failure in older adults. Eur J Heart Fail 2011;13:1078–1086.
  28. Mukamal KJ, Tolstrup JS, Friberg J, Grønbaek M, Jensen G. Fibrinogen and albumin levels and risk of atrial fibrillation in men and women (the Copenhagen City Heart Study). Am J Cardiol 2006;98:75–81.
  29. Zhao D, Jiao H, Zhong X, Wang W, Li L. The association between serum albumin levels and related metabolic factors and atrial fibrillation: A retrospective study. Medicine (Baltimore). 2022;101:e31581.
  30. Liao LZ, Zhang SZ, Li WD, Liu Y, Li JP, Zhuang XD, Liao XX. Serum albumin and atrial fibrillation: insights from epidemiological and mendelian randomization studies. Eur J Epidemiol. 2020;35:113-122. 
  31. van Beek DEC, Kuijpers YAM, Königs MHH, van der Horst ICC, Scheeren TWL. Low serum albumin levels and new-onset atrial fibrillation in the ICU: a prospective cohort study. J Crit Care. 2020; 56:26-30.
  32. Su W, An T, Zhou Q, Huang Y, Zhang J, Zhang Yuhui, Wei B, Sun X, Zou C, Lou Kejia. Serum albumin is a useful prognostic indicator and adds important information to NT-proBNP in a Chinese cohort of heart failure. Clin Biochem 2012;45:561–565.
  33. Alshawabkeh LI, Hu N, Carter KD,  Opotowsky AR, Light-McGroary K,  Cavanaugh JE,  Bartlett HL. Wait-list outcomes for adults with congenital heart disease listed for heart transplantation in the U.S. J Am Coll Cardiol 2016;68:908–917.
  34. Kent Y Feng, Andrew P Ambrosy, Zhipeng Zhou, Ditian Li, Jeremy Kong, Jonathan G Zaroff, Jacob M Mishell, Ivy A Ku, Andrea Scotti, Augustin Coisne, Björn Redfors, Michael J Mack, William T Abraham, JoAnn Lindenfeld, Gregg W Stone; COAPT Trial Investigators. Association between serum albumin and outcomes in heart failure and secondary mitral regurgitation: the COAPT trial. Eur J Heart Fail. 2023;25:553-561.
  35. Iskandarani ME,  Kurdi BE, Murtaza G,  Paul  TK,  Refaat MM. Prognostic role of albumin level in heart failure: A systematic review and meta-analysis. Medicine (Baltimore). 2021;100:e24785.