Introduction

Nonischemic dilated cardiomyopathy (NIDCM) is defined as left ventricle (LV) enlargement and global systolic function impairment [left ventricular ejection fraction (LVEF) < 45%] in the absence of coronary artery disease or increased loading conditions.1 Patients with NIDCM often suffer from refractory heart failure and even sudden cardiac death (SCD) and need to benefit from cardiac transplantation.2,3 This condition places a heavy financial burden on healthcare systems worldwide, and our team has done a lot of research work on the pathogenesis of DCM.4 It was reported that the therapy with angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers (ACEIs/ARBs) and β-blockers could increase the survival of patients with LV dysfunction caused by NIDCM in clinical trials; however, such patients remain at substantial risk of sudden death from cardiac causes, despite receiving adequate doses of both pharmacologic agents.5 Thus, it is important to accurately identify patients at high risk of death during the early stages of disease.

Heart failure with reduced ejection fraction (HFrEF) has a high incidence and prevalence among patients with NIDCM, which is the most frequent cause of death.6,7 Previous cohort studies presented that nutritional status could provide additional prognostic information in chronic and acute cardiovascular disease (CVD), and the prevalence of malnutrition was higher in patients over 60 years old.8–10 Hypoalbuminemia was extensively used to diagnose malnutrition in older adults.11,12 Hence, in this study, we investigated the association of hypoalbuminemia with clinical outcomes in elderly patients with NIDCM.

Methods Study population

In this study, we retrospectively enrolled 1058 consecutive patients (age ≥60 years) admitted to Guangdong Provincial People's Hospital (Guangzhou, China) from January 2010 to December 2019. Patients who met the diagnostic criteria for NIDCM according to the statement established by the European Society of Cardiology (ESC) were included.1 This study achieved approval from the Ethics Committee of Guangdong Provincial People's Hospital with a waiver of written informed consent because of the retrospective design of the study, but oral informed consent was obtained from conscious patients and all vulnerable patients’ guardian/next of kin by telephone and recorded by trained nurses during the follow-up period.

Data source

Baseline characteristics, medical history, and laboratory results were collected from the electronic medical database. Clinical information was collected from an electronic case report form by one researcher and independently confirmed by another researcher. Basal serum albumin samples were collected on the following morning after admission and then measured by the bromocresol green method using a Beckman Coulter AU5821 or AU5831 (Beckman Coulter Inc., California, USA). Echocardiography was conducted by using the transthoracic cardiac probe (X5-1) with tissue Doppler capability from the Philips iE33 machine and the LVEF was determined using Simpson's biplane method. Linear internal measurements of the LV and its walls were performed in the parasternal view.

Definition and end points

Hypoalbuminemia on admission was defined as a serum albumin level of less than 35 g/l.13 The primary end point of this study was death during hospitalization, and the secondary end point was death during the follow-up period. The end points of all patients were followed up by telephone or reviewing their outpatient clinic records in 2021.

Statistical analysis

Continuous variables were presented as the mean ± SD and compared by Student's t-test. Categorical variables were expressed as the number and percentage and compared using Pearson's chi-square test. Missing values were excluded from the analysis. Kaplan–Meier survival curves were drawn to compare cumulative event rates between groups and survival estimates were analyzed via the log-rank test. Logistic regression analyses and Cox proportional hazard regression models were conducted to evaluate the association of both serum albumin and hypoalbuminemia with prognosis, in which the adjusted odds ratio (OR), hazard ratio, and 95% confidence interval (CI) were calculated. Data were analyzed statistically using SPSS software version 26.0 (IBM Corp., Armonk, New York, USA). A double-sided P-value of less than 0.05 denoted statistical significance.

Results Baseline characteristics

A total of 1058 patients (467 with hypoalbuminemia and 591 with nonhypoalbuminemia) met the inclusion criteria, 14 of whom were admitted for acute decompensated heart failure, 880 were for decompensated heart failure and others were for regularly cardiac function assessment. There were 151 (14.3%) patients with New York Heart Association (NYHA) grade IV disease and 24 patients with tumor history (not active tumor) but none with nephrotic syndrome.

First, detailed baseline data showed that hypertension, diabetes, and tumor history were similar between the two groups, and patients with hypoalbuminemia were older (69.29 vs. 67.61 years old) and had a larger proportion of men. Second, there was no statistical difference in lymphocyte count and hemoglobin; however, more patients in the hypoalbuminemia group combined had an NRS2002 score of at least 3 (a tool to identify patients with high risk of malnutrition). Third, patients with hypoalbuminemia had lower LVEF and high-density lipoprotein cholesterol (HDL-C) and showed higher values of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (Table 1). In the present study, there were 42 individuals who died in hospital and 7 of them were diagnosed with chronic obstructive pulmonary disease (COPD).

Table 1 - Baseline characteristics between patients with or without hypoalbuminemia Patients with NIDCM (N = 1058) HA Non-HA Variables (n = 467) (n = 591) P-value Demographic  Age (years) 69.29 ± 6.67 67.61 ± 5.90 <0.001  Male [n (%)] 336 (71.9) 356 (60.2) <0.001 Medical history  Smoking history [n (%)] 136 (29.1) 144 (24.4) 0.082  Hypertension [n (%)] 145 (31.0) 197 (33.3) 0.430  Diabetes [n (%)] 112 (24.0) 144 (24.4) 0.885  Tumor history [n (%)] 15 (3.2) 9 (1.5) 0.067 Parameters on admission  Serum calcium (mmol/l) 2.18 ± 0.15 2.29 ± 0.12 <0.001  WBC count (109/l) 7.53 ± 2.89 7.46 ± 2.73 0.716  Neutrophil count (109/l) 5.00 ± 2.52 5.01 ± 2.61 0.964  Lymphocyte count (109/l) 1.68 ± 1.51 1.62 ± 0.65 0.400  Hemoglobin) (g/l) 131.74 ± 18.84 131.14 ± 18.61 0.606  Urea (mmol/l) 9.88 ± 7.92 7.89 ± 4.52 <0.001  Glucose (mmol/l) 7.09 ± 3.36 6.68 ± 2.71 0.033  CREA (μmol/l) 128.72 ± 98.34 98.73 ± 44.3 <0.001  Uric (μmol/l) 520.23 ± 200.38 493.14 ± 162.57 0.038  CHOL (mmol/l) 4.15 ± 1.12 4.52 ± 1.05 <0.001  HDL-C (mmol/l) 0.96 ± 0.34 1.09 ± 0.29 <0.001  TG (mmol/l) 1.15 ± 0.64 1.55 ± 1.26 <0.001  AST/ALT ratio 1.38 ± 0.92 1.33 ± 0.70 0.395  NT-proBNP (pg/ml) 8871.68 ± 9996.40 4035.84 ± 5561.39 <0.001 Nutritional score  NRS2002 score ≥3 [n (%)] 161 (34.5) 24 (4.1) <0.001 Echocardiographic features  LAD (mm) 44.46 ± 8.39 43.38 ± 7.85 0.061  LVEDD (mm) 65.27 ± 8.77 65.79 ± 9.46 0.427  PAP (mmHg) 43.98 ± 14.09 40.00 ± 14.57 0.001  LVEF (%) 31.93 ± 10.51 33.98 ± 11.47 0.006 Clinical outcomes  In-hospital mortality [n (%)] 32 (6.9) 10 (1.7) <0.001  Long-term mortality [n (%)] 237 (50.7) 208 (35.2) <0.001

AST/ALT ratio, the ratio of aspartate aminotransferase to alanine aminotransferase; CHOL, total cholesterol; CREA, creatinine; HA, hypoalbuminemia; HDL-C, high-density lipoprotein cholesterol; LAD, left atrial dimension; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricle ejection fraction; NIDCM, nonischemic dilated cardiomyopathy; NRS, nutritional risk screening; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAP, pulmonary artery pressure; TG, triglyceride; WBC, white blood cell.

Relationship between serum albumin and clinical outcomes

During a median follow-up of 67 ± 1.8 months, a total of 987 patients were successfully followed up and 445 all-cause deaths (289 males, 156 females) were recorded, including 237 patients with hypoalbuminemia and 208 patients with nonhypoalbuminemia. Univariate logistic regression analysis showed that there was a significant correlation between serum albumin and in-hospital death OR 0.865, 95% CI 0.815–0.918, P < 0.001). Receiver operator characteristic (ROC) curve analysis showed that serum albumin had good predictive power for in-hospital mortality (AUC = 0.717, 95% CI 0.634–0.800, P < 0.001) (Fig. 1). In addition, a univariate Cox proportional hazard model found that serum albumin as a continuous variable was associated with prognosis during the follow-up period (hazard ratio 1.496, 95% CI 1.241–1.803, P < 0.001).

Fig. 1:

Receiver operator characteristic curve of serum albumin in predicting in-hospital mortality.

Relationship between hypoalbuminemia and clinical outcomes

In this cohort, patients with hypoalbuminemia presented a higher prevalence of in-hospital and long-term mortality than another group (Table 1). Univariate logistic regression analysis showed that hypoalbuminemia was significantly related to increased risk of in-hospital death (OR 4.334, 95% CI 2.185–8.597, P < 0.001). After adjusting for age, serum creatinine, HDL-C, the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT), LVEF and diabetes, hypoalbuminemia remained associated with in-hospital death (OR 2.564, 95% CI 1.039–6.322, P = 0.041).

Kaplan–Meier survival estimates showed that patients with nonhypoalbuminemia had a better prognosis than those with hypoalbuminemia (log-rank χ2 28.96, P < 0.001) (Fig. 2). In addition, univariate and multivariate Cox proportional hazard regression analyses were performed to determine predictive factors for long-term death. The results indicated that hypoalbuminemia was a risk factor for death (hazard ratio 1.496, 95% CI 1.241–1.803, P < 0.001); even after multivariable risk adjustment, it remained an independent predictor for long-term mortality (hazard ratio 1.322, 95% CI 1.046–1.670, P = 0.019) (Table 2).

Fig. 2:

Kaplan–Meier survival curves.

Table 2 - Univariate and multivariate Cox regression analyses for long-term death Univariate Multivariate HR (95% CI) P-value HR (95% CI) P-value HA 1.496 (1.241–1.803) <0.001 1.322 (1.046–1.670) 0.019 Age 1.055 (1.041–1.070) <0.001 1.045 (1.027–1.064) <0.001 Serum creatinine 1.003 (1.002–1.003) <0.001 1.002 (1.001–1.003) <0.001 Triglycerides 0.970 (0.877–1.073) 0.558 LDL-C 0.923 (0.821–1.037) 0.178 HDL-C 0.559 (0.400–0.783) 0.001 0.677 (0.459–0.997) 0.048 Total protein 0.992 (0.979–1.006) 0.273 Lymphocyte count 1.022 (0.942–1.107) 0.603 WBC count 0.982 (0.949–1.017) 0.308 AST/ALT ratio 1.253 (1.088–1.443) 0.002 1.211 (1.022–1.434) 0.027 LVEF 0.967 (0.957–0.977) <0.001 0.968 (0.957–0.979) <0.001 Arrhythmia 1.131 (0.938–1.362) 0.197 Smoking 1.069 (0.868–1.318) 0.529 Hypertension 0.913 (0.746–1.117) 0.377 Diabetes 1.246 (1.007–1.541) 0.043 1.414 (1.103–1.811) 0.006

AST/ALT ratio, the ratio of aspartate aminotransferase to alanine aminotransferase; CI, confidence interval; HA, hypoalbuminemia; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricle ejection fraction; WBC, white blood cell.

Discussion

In the present study, we selected a relatively large Chinese cohort to study the prognostic role of serum albumin in elderly patients with NIDCM. The results showed that serum albumin could serve as a prognostic biomarker, and hypoalbuminemia on admission was independently associated with poor clinical outcomes. This is the first study to report the relationship between serum albumin and prognosis in patients with NIDCM.

NIDCM is a heterogeneous heart muscle disease and one of the most important causes of heart failure.6,14 The molecular basis of the irregular cardiac architecture in DCM involves changes in the structure and composition of cardiomyocytes, which lead to remodeling of the myocardium.15 The outcome of NIDCM is significantly associated with LV remodeling and whether cardiac function is improved by conventional therapy.16 Pathological LV remodeling is closely linked to neurohumoral and local factors, including increased oxidative stress, proinflammatory cytokines, the renin–angiotensin–aldosterone system (RAAS) and the adrenergic nervous system.17–19

In developing countries, the older population refers to aged 60 years and older, in which is more possible to present protein-energy malnutrition related to the poor prognosis in CVD.9,11,20 In most cases, hypoalbuminemia is used to evaluate malnutrition in elderly patients.21 In this study, patients with hypoalbuminemia were older, had a larger proportion of males and presented worse prognosis, which is consistent with a previous study.22 Meanwhile, more patients in this group showed an NRS2002 score of at least 3 that is identified as an effective tool to distinguish patients with high risk of undernutrition.23 In terms of physiological effects, serum albumin could maintain myocardial fluid balance by its osmotic effect and interaction with the endothelial glycocalyx.24 However, hypoalbuminemia may promote myocardial edema and fluid retention, subsequently worsening myocardial dysfunction.25 This disruption of balance may be an underlying mechanism by which hypoalbuminemia is associated with poor prognosis in patients with NIDCM.

On the other hand, serum albumin is the most abundant protein in plasma and contains one of the most important scavengers of reactive oxygen species (ROS) called cysteine residue (CYS34), which means it accounts for most of the antioxidant capacity of human plasma.26,27 When hypoalbuminemia occurs, the antioxidant capacity of human plasma will decrease; this situation suggests that in addition to malnutrition, the potential prognostic value of hypoalbuminemia in CVD may also be related to its declined antioxidant activity.28 HFrEF has a high incidence and prevalence in patients with NIDCM so that the production of ROS within the myocardium and vasculature will substantially increase.6,29,30 ROS contributes to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis, involved in the progression of LV dysfunction.31,32 When abnormal production of ROS exceeds the buffering capacity of the antioxidant defense systems, oxidative stress will occur and cause endothelial dysfunction by reducing the production of nitric oxide (NO).33,34 Cardiac endothelial dysfunction is known to be related to progression and poor prognosis of DCM.35 The oxidative stress of the myocardium caused by an imbalance between the generation and detoxification of ROS may be another potential mechanism to explain the relationship between hypoalbuminemia and clinical outcomes in CVD.

This study provides prognostic implications for better understanding the role of hypoalbuminemia in DCM. Clinicians should consider the effect of hypoalbuminemia when estimating the prognosis of patients with NIDCM. These findings might support the theory that malnutrition and oxidative stress play key roles in the prognosis of NIDCM.

Study limitations

This retrospective study had some limitations. First, it was a single-center study and further validation is needed. Second, potential confounding factors may have affected the results because of the inherent flaws in the study design, even after the adjusted analysis. In the future, we will expand the database and introduce the cross-validation method of machine learning for verification.

Conclusion

A serum albumin level detected at admission can serve as a simple prognostic factor in NIDCM. In elderly patients, hypoalbuminemia is associated with increased risk of in-hospital and long-term mortality.

Conflicts of interest

There are no conflicts of interest.

References 1. Pinto YM, Elliott PM, Arbustini E, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic nondilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J 2016; 37:1850–1858. 2. Merlo M, Cannata A, Gobbo M, Stolfo D, Elliott PM, Sinagra G. Evolving concepts in dilated cardiomyopathy. Eur J Heart Fail 2018; 20:228–239. 3. Reichart D, Magnussen C, Zeller T, Blankenberg S. Dilated cardiomyopathy: from epidemiologic to genetic phenotypes: a translational review of current literature. J Intern Med 2019; 286:362–372. 4. Feng Y, Cai L, Hong W, et al. Rewiring of 3D chromatin topology orchestrates transcriptional reprogramming and the development of human dilated cardiomyopathy. Circulation 2022; 145:1663–1683. 5. Kadish A, Dyer A, Daubert JP, et al. Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004; 350:2151–2158. 6. Seferovic PM, Polovina M, Bauersachs J, et al. Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2019; 21:553–576. 7. Mercurio V, Ambrosio G, Correale M, et al. Innovations in medical therapy of heart failure with reduced ejection fraction. J Cardiovasc Med (Hagerstown) 2023; 24: (Suppl 1): e47–e54. 8. Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997; 349:1050–1053. 9. Kootaka Y, Kamiya K, Hamazaki N, et al. The GLIM criteria for defining malnutrition can predict physical function and prognosis in patients with cardiovascular disease. Clin Nutr 2021; 40:146–152. 10. Ancion A, Allepaerts S, Oury C, et al. Serum albumin level and hospital mortality in acute nonischemic heart failure. ESC Heart Fail 2017; 4:138–145. 11. Zhang Z, Pereira SL, Luo M, Matheson EM. Evaluation of blood biomarkers associated with risk of malnutrition in older adults: a systematic review and meta-analysis. Nutrients 2017; 9:829. 12. Cabrerizo S, Cuadras D, Gomez-Busto F, Artaza-Artabe I, Marín-Ciancas F, Malafarina V. Serum albumin and health in older people: review and meta analysis. Maturitas 2015; 81:17–27. 13. Violi F, Ceccarelli G, Cangemi R, et al. Hypoalbuminemia, coagulopathy, and vascular disease in COVID-19. Circ Res 2020; 127:400–401. 14. Merlo M, Mase M, Cannata A, et al. Management of nonischemic-dilated cardiomyopathies in clinical practice: a position paper of the working group on myocardial and pericardial diseases of Italian Society of Cardiology. J Cardiovasc Med (Hagerstown) 2020; 21:927–943. 15. Dilaveris P, Antoniou CK, Gatzoulis KA. Arrhythmic risk stratification in nonischemic dilated cardiomyopathy: where do we stand after DANISH? Trends Cardiovasc Med 2017; 27:542–555. 16. Yokokawa T, Sugano Y, Nakayama T, et al. Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy. Eur J Heart Fail 2016; 18:375–385. 17. Konstam MA, Kronenberg MW, Rousseau MF, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. SOLVD (Studies of Left Ventricular Dysfunction) Investigators. Circulation 1993; 88 (5 Pt 1):2277–2283. 18. Pouleur HG, Konstam MA, Udelson JE, Rousseau MF. Changes in ventricular volume, wall thickness and wall stress during progression of left ventricular dysfunction. The SOLVD Investigators. J Am Coll Cardiol 1993; 22: (4 Suppl A): 43A–48A. 19. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. On behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000; 35:569–582. 20. World Health Organization. Integrated care for older people: a manual for primary care physicians (Facilitator's Guide) [website]. 2021; Geneva: World Health Organization, 161. 21. Arques S, Ambrosi P, Gelisse R, Luccioni R, Habib G. Hypoalbuminemia in elderly patients with acute diastolic heart failure. J Am Coll Cardiol 2003; 42:712–716. 22. Halliday BP, Gulati A, Ali A, et al. Sex- and age-based differences in the natural history and outcome of dilated cardiomyopathy. Eur J Heart Fail 2018; 20:1392–1400. 23. Kondrup J, Rasmussen HH, Hamberg O, Stanga Z. Ad Hoc ESPEN Working Group. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr 2003; 22:321–336. 24. Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology 2006; 104:1223–1231. 25. Dongaonkar RM, Stewart RH, Geissler HJ, Laine GA. Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function. Cardiovasc Res 2010; 87:331–339. 26. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E. The antioxidant properties of serum albumin. FEBS Lett 2008; 582:1783–1787. 27. Fanali G, di Masi A, Trezza V, et al. Human serum albumin: from bench to bedside. Mol Aspects Med 2012; 33:209–290. 28. Arques S. Human serum albumin in cardiovascular diseases. Eur J Intern Med 2018; 52:8–12. 29. Heymes C, Bendall JK, Ratajczak P, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol 2003; 41:2164–2171. 30. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 2002; 106:3073–3078. 31. Burgoyne JR, Mongue-Din H, Eaton P, Shah AM. Redox signaling in cardiac physiology and pathology. Circ Res 2012; 111:1091–1106. 32. Belch JJ, Bridges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991; 65:245–248. 33. Munzel T, Gori T, Keaney JF, Maack C, Daiber A. Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications. Eur Heart J 2015; 36:2555–2564. 34. Munzel T, Camici GG, Maack C, Bonetti NR, Fuster V, Kovacic JC. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J Am Coll Cardiol 2017; 70:212–229. 35. Roura S, Bayes-Genis A. Vascular dysfunction in idiopathic dilated cardiomyopathy. Nat Rev Cardiol 2009; 6:590–598.