Internal and Emergency Medicine

https://doi.org/10.1007/s11739-024-03612-9

IM - ORIGINAL

Prognostic role of serum albumin levels in patients with chronic heart

failure
Giuseppe Armentaro1 · Valentino Condoleo1 · Carlo Alberto Pastura1 · Maria Grasso2 · Angelo Frasca1 ·
Domenico Martire1 · Velia Cassano1 · Raffaele Maio1 · Leonilde Bonfrate3 · Daniele Pastori4 · Tiziana Montalcini5,6 ·
Francesco Andreozzi1,6 · Giorgio Sesti7 · Francesco Violi4 · Angela Sciacqua1,6

Received: 8 January 2024 / Accepted: 9 April 2024

© The Author(s) 2024

Abstract
Background Hypoalbuminemia is common in heart failure (HF) patients; however, there are no data regarding the possible
long-term prognostic role of serum albumin (SA) in the younger population with chronic HF without malnutrition. The aim
of this study was to examine the long-term prognostic role of SA levels in predicting major adverse cardiac events (MACE)
in middle-aged outpatients with chronic HF.
Methods In the present retrospective analysis, 378 subjects with HF were enrolled. MACE (non-fatal ischemic stroke, non-
fatal myocardial infarction, cardiac revascularization or coronary bypass surgery, and cardiovascular death), total mortality,
and HF hospitalizations (hHF) occurrence were evaluated during a median follow-up of 6.1 years.
Results In all population, 152 patients had a SA value < 3.5 g/dL and 226 had a SA value ≥ 3.5 g/dL. In patients with
SA ≥ 3.5 g/dL, the observed MACE were 2.1 events/100 patient-year; while in the group with a worse SA levels, there were
7.0 events/100 patient-year (p < 0.001). The multivariate analysis model confirmed that low levels of SA increase the risk
of MACE by a factor of 3.1. In addition, the presence of ischemic heart disease, serum uric acid levels > 6.0 mg/dL, chronic
kidney disease, and a 10-year age rise, increased the risk of MACE in study participants. Finally, patients with SA < 3.5 g/
dl had a higher incidence of hHF (p < 0.001) and total mortality (p < 0.001) than patients with SA ≥ 3.5 g/dl.
Conclusions Patients with chronic HF that exhibits low SA levels show a higher risk of MACE, hHF and total mortality.

Keywords Chronic heart failure · Albumin · MACE · Comorbidities

Introduction mortality rate of about 50% during the five-year follow-up

Heart failure (HF) is a growing health problem, prevalence
ranges from about 1.5 to 4% in developed countries [1].
Despite important pharmacological innovations in recent
years, the prognosis of HF patients remains poor with a
[1]. Another critical issue in HF is represented by comor-
bidities that show a crucial role on diagnosis, treatment,
and prognosis. Among non-cardiovascular (CV) comor-
bidities malnutrition and frailty, often under-diagnosed and

4
* Angela Sciacqua Department of Clinical Internal, Anesthesiological
sciacqua@unicz.it and Cardiovascular Sciences, Sapienza University of Rome,
Viale del Policlinico 155, 00161 Rome, Italy
1
Department of Medical and Surgical Sciences, University 5
Department of Clinical and Experimental Medicine,
Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
University Magna Grecia, 88100 Catanzaro, Italy
2
Section of Gastroenterology and Hepatology, Department 6
Research Center for the Prevention and Treatment
of Health Promotion, Mother and Child Care, Internal
of Metabolic Diseases (CR‑METDIS), University Magna
Medicine and Medical Specialties (PROMISE), University
Græcia, 88100 Catanzaro, Italy
of Palermo, Piazza Delle Cliniche N.2, 90127 Palermo, Italy
7
3 Department of Clinical and Molecular Medicine, University
Clinica Medica “A. Murri”, Department of Biomedical
Rome-Sapienza, Viale Regina Elena N. 324, 00161 Rome,
Sciences and Human Oncology, University of Bari Aldo
Italy
Moro, Bari, Italy

Vol.:(0123456789)

undertreated, have particular relevance affecting clinical
prognosis especially in elderly [2–4].
In this setting, hypoalbuminemia represents a marker
of malnutrition and frailty, but also of comorbidities and
inflammatory state burden [5, 6]. Hypoalbuminemia is a
common condition in HF, with a prevalence up to 89% and
is associated with an increased risk of HF onset and progres-
sion, as well as CV morbidity and mortality [6–15]. These
findings are most evident in acute HF also in nonagenarian
patients, in which severe hypoalbuminemia is a potential
predictor of poor in-hospital outcome [16–18]. In addition,
hypoalbuminemia was found to be a significant independent
predictor of mortality in both acute and chronic HF; how-
ever, the follow-up in these studies rarely exceeded one year
and study populations are mainly represented by elderly with
acute HF [17–27].
The prognostic role of albumin is also confirmed in
chronic HF patients with secondary mitral insufficiency
[28]. Furthermore, recent studies suggest that changes in
SA levels over time are associated with different prognosis
in patients with chronic HF. In fact, while a decrease in SA
levels over time is associated with a worse prognosis, an
increase is associated with a better prognosis; this is proba-
bly because SA levels reflect the general condition of chronic
HF patients [29]. Data are also confirmed by a recent meta-
analysis, where hypoalbuminemia worsens the prognosis in
both inpatients and outpatients [30].
In addition, the prognostic value of SA is particularly evi-
dent in high-intensity care populations such as HF patients
in cardiogenic shock or patients in intensive care; indeed, in
this category of patients, in addition to reduced SA levels,
a reduction in SA levels during hospitalization worsens the
prognosis [31, 32]. To our knowledge, the prognostic signifi-
cance of hypoalbuminemia has not yet been fully evaluated
in the HF clinical setting. According with this, there are
no data regarding the possible long-term prognostic role of
albumin in the younger population with chronic HF, espe-
cially in patients without malnutrition. The purpose of the
present study was to examine the long-term prognostic role
of serum albumin (SA) levels in predicting major adverse
cardiac events (MACE) in middle-aged outpatients with
chronic HF, after adjustment for known confounding fac-
tors and especially for inflammation, nutritional status, liver
and kidney function. Total mortality and HF hospitalizations
(hHF) during follow-up were also evaluated.
Materials and methods
Study population
In this retrospective analysis, 378 subjects with HF were
enrolled, between October 2012 and June 2022, at the
Internal and Emergency Medicine
Geriatric Department of “Magna Graecia” University-
Hospital of Catanzaro, Italy. The study included outpatients
suffering from chronic HF from the CATAnzaro Metabolic
Risk factors (CATAMERI) Study, an ongoing longitudi-
nal observational study assessing cardio-metabolic risk in
individuals, recruited at the University Hospital of Catan-
zaro. They were recruited according to the indications of
the European Society of Cardiology (ESC) guidelines for
the diagnosis and treatment of acute and chronic HF [1].
The eligibility criteria included: written informed consent;
age > 18 years; NYHA classes II–III. The exclusion crite-
ria included: acute HF in the previous 6 months, chronic
HF with NYHA class IV, respiratory failure, severe renal
dysfunction (estimated glomerular filtrate (eGFR) < 30 mL/
min/1.73m2); nephrotic syndrome, macroalbuminuria,
severe hepatic impairment (Child–Pugh Class C); pregnancy
or breastfeeding, malnutrition evaluated as Mini Nutritional
Assessment (MNA) < 17 pts and cachexia [33]. A careful
medical history was obtained in all subjects. A complete CV
physical examination was performed, and both body weight
and body mass index (BMI) were also measured. Blood sam-
ples were collected for the determination of several labora-
tory parameters.
The study was approved by the local Institutional Eth-
ics Committees of University “Magna Graecia” of Catan-
zaro (code protocol number 2012.63). All patients signed
informed consent and the study procedures were carried
out in accordance with the principles of the Declaration of
Helsinki.
Laboratory parameters
All laboratory measurements were performed on peripheral
blood samples after at least 12 h of fasting. SA was meas-
ured with a colorimetric spectrophotometric method (Bro-
mocresol green). Glycaemia was determined by the glucose
oxidase method (glucose analyzer, BeckmanCoulter, Milan)
and the homeostasis model assessment (HOMA) index was
used for the determination of Insulin resistance [34]. Enzy-
matic methods (Roche Diagnostics GmbH, Mannheim, Ger-
many) were used for determination of blood levels of total
cholesterol, low-density lipoprotein (LDL) cholesterol, high-
density lipoprotein (HDL) cholesterol, and triglycerides.
Alanine aminotransferase (ALT), aspartate aminotransferase
(AST) by pyridoxal phosphate activated (liquid reagent),
and gamma-glutamyltransferase (γ-GT) were evaluated by
standardized method (COBAS Integra 800-Roche Diagnos-
tics GmbH, Mannheim, Germany). Creatinine was measured
using the Jaffé method. The CKD-EPI (Chronic Kidney Dis-
ease Epidemiology Collaboration) equation was used for the
estimation of glomerular filtration rate (eGFR) [35]. Serum
uric acid (UA) levels were assessed using URICASE/POD
method (Boehringer Mannheim, Mannheim, Germany). The
Internal and Emergency Medicine
immuno-turbidimetric method automated system (Cardio
Phase hs-CRP, Milan, Italy) was used to assess the high-
sensitivity C-reactive protein (hs-CRP).
Cardiovascular endpoints
MACE were identified as study endpoints (non-fatal
ischemic stroke, non-fatal coronary events, and CV death).
Total mortality and HF hospitalizations (hHF) during fol-
low-up were also evaluated. The diagnosis of myocardial
infarction was made according to the universal definition
[36]. CV death included progressive HF and death related to
surgical or percutaneous revascularization procedures, and
sudden death. The diagnosis of ischemic stroke was deter-
mined by clinical manifestations and radiological findings
[37]. Data on MACE were collected during the follow-up.
A standardized form was filled out by the examiners when
an event occurred. Details of each event were recorded, as
well as death certificates, hospital discharge letter or copy of
hospitalization medical record, and other clinical documen-
tation obtained from patients or their relatives.
Statistical analysis
Data were expressed as mean ± standard deviation (SD),
median and interquartile range (IQR), and number and per-
centage for categorical variables, when appropriate. Stu-
dent’s t-test was performed for unpaired data for continuous
variables, Mann–Whitney’s test for unpaired data for non-
continuous variables and χ2 tests for categorical variables.
According to the clinical cut-off of SA (3.5 g/dL), the over-
all population was divided into two groups; of interest, this
value has been already associated with increased thrombotic
risk [38, 39]. Simple linear regression and multivariate step-
wise linear regression models were constructed to evaluate
independent predictors of hypoalbuminemia, both as a con-
tinuous and dichotomous variable. Variables that correlated
significantly with MACE were entered into a multivariate
stepwise linear regression model to evaluate independent
predictors of SA levels. The accuracy of the SA value as a
predictor of MACE, both as a categorical and continuous
variable, was evaluated by processing a receiver operating
characteristic (ROC) curve. The area under the curve (AUC)
described the magnitude to which the SA value was associ-
ated with the onset of events. The number of events per 100
patient-year was used to calculate the incidence of events.
The onset of MACE was not assessed at the same time,
because the follow-up was not uniform for all patients, so a
regression analysis based on the Cox proportional model was
used, correcting the analysis for possible covariates asso-
ciated with the finding of MACE. In particular, a univari-
ate Cox regression model was performed on the incidence
of MACE; subsequently, the variables that significantly
correlated with the appearance of MACE were included in
a multivariate Cox regression model to calculate the hazard
ratio (HR) for the independent predictors associated with
the incidence of MACE. Analysis was corrected for phar-
macological treatments. The differences were considered
statistically significant for p value < 0.05. All analyses were
performed using the SPSS 20.0 statistical program for Win-
dows (SPSS Inc., Chicago, IL, USA).
Results
Study population
378 patients were enrolled with average age of
67.1 ± 11.2 years, 107 were females and 271 males, 220
had HF with mildly reduced (HFmrEF) and preserved ejec-
tion fraction (HFpEF) and 158 were affected by HF with
reduced ejection fraction (HFrEF). In all study population,
152 patients had a SA value < 3.5 g/dL, and none of these
received albumin supplementation during follow-up, while
the remaining 226 had a SA value ≥ 3.5 g/dL (Supplemen-
tary Fig. 1). The median follow-up was 6.1 (3.1–9.9) years.
Table 1 shows the epidemiological and clinical character-
istics of the entire study population, stratified by the clinical
cut-off of SA (3.5 g/dL). Statistically significant differences
between the two groups were observed for prevalence of
Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia
significantly higher in patients with lower SA levels. There
was no difference between the two groups for intake of anti-
hypertensive drugs, oral antidiabetics, insulin, oral anticoag-
ulants, anti-aggregants, statins, beta-blockers, loop diuretics,
SGLT2-inhibitors, sacubitril–valsartan, and mineralocorti-
coid receptor antagonists. Regarding clinical, hemodynamic,
and laboratory parameters, there were no statistically signifi-
cant differences between the two groups, except, obviously,
for SA levels, but also for hs-CRP and microalbuminuria,
significantly higher in patients with SA < 3.5 g/dL (Table 1).
In addition, the two groups differed in MNA with worse
results in lower albumin levels group.
Variables associated with hypoalbuminemia
in the study population
From the first simple linear regression model, considering
albumin as a continuous variable, the following variables
correlated significantly: hs-CRP (r = −0.398; p < 0.001),
MNA score < 23 pts (r = 0.189; p < 0.001), NAFLD
(r = −0.206; p < 0.001) and microalbuminuria (r = −0.109;
p = 0.015). At multivariate stepwise linear regression, the
variable that was most associated with serum albumin levels
were hs-CRP serum levels and the whole model correlated
for 35.3% of albumin levels. Data were also confirmed by the
 Internal and Emergency Medicine

Table 1  Clinical, All population (n 378) Albumin < 3.5 g/ Albumin ≥ 3.5 g/ p*
epidemiological, laboratory, dl (n. 152) dl (n. 226)
echocardiographic parameters,
and pharmacotherapy of study Age, years 67.0 ± 11.2 67 ± 10.9 66.9 ± 11.4 0.551ǂ
population at baseline according
Female gender, n (%) 107 (28.3) 46 (30.2) 61 (26.9) 0.488*
to clinical cut-off of serum
albumin BMI, Kg/m2 31.0 ± 4.8 30.8 ± 4.6 31.1 ± 5.0 0.450ǂ
IHD, n (%) 233 (61.6) 95 (62.5) 138 (61.0) 0.778*
Arterial hypertension, n (%) 196 (51.9) 72 (47.4) 124 (54.9) 0.152*
AF, n (%) 76 (20.1) 26 (17.1) 50 (22.1) 0.232*
Dyslipidemia, n (%) 145 (38.9) 69 (45.4) 76 (33.6) 0.021*
SAS, n (%) 119 (31.4) 55 (36.1) 64 (28.3) 0.106*
CKD, n (%) 95 (21.1) 41 (26.9) 54 (23.9) 0.498*
COPD, n (%) 81 (21.4) 35 (23.0) 46 (20.3) 0.534*
NAFLD, n (%) 42 (11.1) 29 (19.0) 13 (5.7) < 0.001*
Obesity, n (%) 92 (24.3) 41(26.9) 51(22.6) 0.327*
T2DM, n (%) 193 (51.0) 78 (51.3) 115 (50.1) 0.934*
Alcohol, n (%) 63 (16.6) 22 (14.4) 41 (18.1) 0.348*
Smokers, n (%) 134 (35.4) 59 (38.8) 75 (33.1) 0.261*
MLHFQ, pt 95.3 ± 11.2 95.23 ± 3.0 226 ± 3.1 0.619ǂ
MNA, pts 22.9 ± 3.3 21.7 ± 2.9 23.8 ± 3.2 < 0.001ǂ
SBP, mmHg 123.0 ± 15.6 122.0 ± 15.9 124.0 ± 15.4 0.166ǂ
DBP, mmHg 74.09 ± 9.7 73.9 ± 10.1 74.3 ± 9.4 0.704ǂ
HR, bfm 68.9 ± 14.5 69.7 ± 15.5 68.42 ± 13.9 0.387ǂ
RR, afm 18.9 ± 1.8 18.8 ± 1.9 18.9 ± 1.7 0.745ǂ
Hb, g/dl 12.2 ± 1.6 12.1 ± 1.7 12.2 ± 1.5 0.546ǂ
Hct, % 38.3 ± 5.4 37.9 ± 5.5 38.53 ± 5.3 0.304ǂ
Na, mmol/l 140.7 ± 33.1 140.61 ± 3.0 140.7 ± 2.5 0.685ǂ
Mg, mg/dl 1.9 ± 0.2 1.95 ± 0.2 1.93 ± 0.2 0.742ǂ
K, mmol/l 4.4 ± 0.41 4.4 ± 0.3 4.4 ± 0.4 0.503ǂ
HOMA, pts 6.0 ± 2.0 6.1 ± 2.9 5.9 ± 2.9 0.502ǂ
HbA1c, % 6.7 ± 0.7 6.7 ± 0.6 6.7 ± 0.7 0.827ǂ
eGFR, ml/min/1.73m2 70.7 ± 18.9 68.6 ± 18.5 72.2 ± 19.0 0.071ǂ
Microalbuminuria, mg/l 34.2 ± 14.2 41.4 ± 17.4 29.3 ± 8.6 < 0.001ǂ
LDL, mg/dl 63.36 ± 28.9 62.32 ± 27.2 64.06 ± 30.1 0.566ǂ
Triglycerides, mg/dl 128.0 ± 46.1 124.5 ± 34.8 131.6 ± 52.3 0.147ǂ
AST, U/L 21.4 ± 9.2 20.7 ± 7.9 21.9 ± 9.9 0.205ǂ
ALT, U/L 20.8 ± 9.7 19.6 ± 6.9 21.5 ± 11.2 0.063ǂ
γ-GT, U/L 36.0 ± 20.2 36.1 ± 18.4 35.9 ± 21.4 0.941ǂ
Albumin, mg/dl 3.8 ± 0.46 3.3 ± 0.2 4.1 ± 0.3 < 0.001ǂ
NT-pro-BNP, pg/ml 2283.3 ± 582.4 2320.8 ± 556.0 2258.1 ± 19.0 0.305ǂ
Uricemia, mg/dl 5.9 ± 1.2 4.5 ± 1.1 5.8 ± 1.3 0.173ǂ
hs-CRP, mg/l 3.9 ± 0.9 4.5 ± 1.1 3.4 ± 0.4 < 0.001ǂ
LAVi, ml/m2 44.5 ± 11.5 44.5 ± 12.4 44.5 ± 10.9 0.990ǂ
LVEF, % 43.0 ± 9.1 42.9 ± 9.3 43.1 ± 8.9 0.816ǂ
CI, ml/min/1.73 m2 1909.1 ± 197.6 1897.6 ± 196.1 1916.7 ± 198.6 0.358ǂ
E/A 0.80 ± 0.46 0.79 ± 0.47 0.81 ± 0.45 0.817ǂ
E/e’ 15.4 ± 4.6 15.5 ± 4.6 15.3 ± 4.5 0.681ǂ
TAPSE, mm 17.6 ± 3.8 17.4 ± 3.5 17.7 ± 4.0 0.369ǂ
s-PAP, mmHg 42.3 ± 11.1 43.1 ± 10.1 41.7 ± 11.3 0.237ǂ
TAPSE/s-PAP, mm/mmHg 0.45 ± 0.19 0.44 ± 0.18 0.46 ± 0.19 0.199ǂ
β-blockers, n (%) 337 (89.1) 134 (77.9) 203 (89.8) 0.609*
ACEi/ARBs, n (%) 189 (50.0) 73 (48.0) 116 (51.3) 0.529*
MRAs, n (%) 156 (41.3) 60 (39.4) 96 (42.4) 0.560*
Internal and Emergency Medicine

Table 1  (continued) All population (n 378) Albumin < 3.5 g/ Albumin ≥ 3.5 g/ p*
dl (n. 152) dl (n. 226)

ARNI, n (%) 171 (45.2) 72 (47.4) 99 (43.8) 0.494*

SGLT2i, n (%) 158 (41.8) 66 (43.4) 92 (40.7) 0.600*
Loop diuretics, n (%) 297 (78.6) 127 (83.5) 170 (75.2) 0.053*
OADs, n (%) 193 (50.9) 78 (51.3) 115 (50.9) 0.934*

*performed by chi-square test

ǂ
performed by t-test for unpaired data
BMI body mass index, IHD ischemic heart disease, AF atrial fibrillation, SAS sleep apnea syndrome, CKD
chronic kidney disease, COPD chronic obstructive pulmonary disease, NAFLD non-alcoholic fatty liver
disease, T2DM type 2 diabetes mellitus, MLHFQ minnesota living with heart failure questionnaire, MNA
mini-nutritional assessment, SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate, RR
respiratory rate, Hb hemoglobin, Hct hematocrit, Na Sodium, Mg Magnesium, K Potassium, HOMA home-
ostatic HbA1c: glycated hemoglobin, e-GFR estimate glomerular filtration rate, LDL low-density lipopro-
teins, AST aspartate aminotransferase, ALT alanine aminotransferase, γ-GT gamma-glutamyltransferase,
NT-pro-BNP N-terminal pro-brain natriuretic peptide, hs-CRP high-sensitivity C-reactive protein, LAVi left
atrial volume index, LVEF left ventricular ejection fraction, CI cardiac index, RVOTp right ventricular out-
flow tract proximal, E/A ratio between wave E (the wave of rapid filling in early diastole) and wave A (the
wave of atrial contraction), E/e’ between wave E and wave e′ (reliable estimate of changes in end-diastolic
blood pressure), TAPSE tricuspid annular plane systolic excursion, s-PAP systolic pulmonary arterial pres-
sure, ACEi angiotensin-converting enzyme inhibitors, ARBs Angiotensin II receptor blockers, MRAs miner-
alocorticoid receptor antagonists, ARNI angiotensin receptor/neprilysin inhibitor, SGLT2i sodium–glucose
cotransporter 2 inhibitors, OADs oral antidiabetic drugs

second simple linear regression model; in fact, considering
albumin as a dichotomous variable, the following variables
correlated significantly: hs-CRP (r-0.513; p < 0.001), MNA
score < 23 pts (r = 0.213; p < 0.001), NAFLD (r = −0.114;
p = 0.004) and microalbuminuria (r = −0.039; p = 0.004).
At multivariate stepwise linear regression analysis, hs-CRP
levels were the main variable that was most associated, and
the whole model correlated for 43.6% of SA levels (supple-
Major adverse cardiovascular events
and hospitalization for Heart Failure
In the whole population a total of 94 (24.9%) MACE were
observed (3.8 events/100 patient-year) (Fig. 1). In par-
ticular, 45 (11.9%) were non-fatal coronary events (1.8
events/100 patient-year), 25 (6.6%) non-fatal stroke events
(1.0 events/100 patient-year) and 24 (6.3%) CV death (0.9

Fig. 1  Adjusted Kaplan–Meier

on MACE, according to cut-off
value of SA, Adjusted for: SA
as dichotomous value, IHD, UA
as dichotomous value, CKD,
and Age as 10 years. MACE
major adverse cardiovascular
events, SA Serum albumin,
IHD ischemic heart disease, UA
uric acid, CKD chronic kidney
disease

mentary Tables 1–2). events/100 patient-year). In patients with SA < 3.5 g/dL,
 Internal and Emergency Medicine

MACE observed were 60 (6.8 events/100 patient-year); while
in the group with SA ≥ 3.5 g/dL were 34 (2.1 events/100
patient-year) (p < 0.001) (Log-Rank test p < 0.001, Fig. 1).
Non-fatal coronary events were 27 (17.8%) in the first
group (3.1 events/100 patient-year) and 18 (7.9%) in the
second group (1.1 events/100 patient-year) (p = 0.003); fur-
thermore, non-fatal stroke events were 17 (11.2%) in the
first group (1.9 events/100 patient-year) and 8 (3.5%) in
the second group (0.5 events/100 patient-year) (p = 0.003).
CV death events were 16 (10.5%) in the first group (1.8
events/100 patient-year) and 8 (3.5%) in the second group
(0.5 events/100 patient-year) (p = 0.006) (Table 2). In addi-
tion to CV death, during the follow-up, 46 (12.2%) deaths
due to non-CV causes occurred (1.9 events/100 patient-
year), of which 30 (19.7%) in patients with SA < 3.5 g/dL
(3.4 events/100 patient-year) and 16 (7.0%) in patients with
SA ≥ 3.5 (1.0 events/100 patient-year) (p < 0.001). To fur-
ther evaluate the relationship between SA and MACE, we
divided the population into increasing tertiles of SA, each
tertile consisted of 126 patients. Specifically, we observed
more MACE in the tertile with lower SA levels followed by
the second and third tertiles, in detail: 52 MACE in the first
tertile, 28 in the second tertile and 14 in the third tertile,
confirming the association between reduced SA levels and
MACE (p < 0.001). Regarding hHF during follow-up, there
were 112 (29.6%) hospitalizations in the whole study popu-
lation (4.6 events/100 patient-year), of which 68 (44.7%)
in the group with SA < 3.5 g/dL (7.7 events/100 patient-
year) and 44 (19.5%) in the group with SA ≥ 3.5 g/dL (2.8
events/100 patient-year) (p < 0.001).
The accuracy of SA as a predictive value of the onset of
MACE both as a continuous (Fig. 2A) and as dichotomous

Table 2  Cardiovascular events All population Albumin < 3.5 g/dl Albumin ≥ 3.5 g/dl p
and hHF in the study population (n. 378) (n. 152) (n. 226)
according to clinical cut-off of
serum albumin MACE, n (%) 94 (3.8) 60 (6.8) 34 (2.1) < 0.001*
Nonfatal Stroke, n (%) 25 (1.0) 17 (1.9) 8 (0.5) 0.003*
NF Coronary events, n (%) 45 (1.8) 27 (3.1) 18 (1.1) 0.003*
CV mortality, n (%) 24 (0.9) 16 (1.8) 8 (0.5) 0.006*
Non CV Mortality, n (%) 46 (1.9) 30 (3.4) 16 (1.0) < 0.001*
Total mortality, n (%) 70 (2.8) 46 (5.2) 24 (1.5) < 0.001*
hHF, n (%) 112 (4.6) 68 (7.7) 44 (2.8) < 0.001*

*performed by chi square test

Data described as number of patients (number of events per 100 patient-year)
hHF Heart failure hospitalizations, MACE major adverse cardiovascular events, NF Non-fatal, CV cardio-
vascular

Fig. 2  A ROC curves on MACE, according to SA as continuous vari- B ROC curves on MACE, according to SA as dichotomous vari-
able. AUC​ area under the curve, MACE major cardiovascular adverse able. AUC​ area under the curve, MACE major cardiovascular adverse
events, ROC receiver operating characteristic, SA serum albumin. events, ROC receiver operating characteristic, SA serum albumin
Internal and Emergency Medicine

value (Fig. 2B) was evaluated by AUC. Figure 2A shows the Table 3  Univariate Cox regression analysis on MACE
ROC curve of SA as a continuous variable; notably, SA as HR 95% CI p
a continuous variable has a greater discriminating power in
predicting the development of MACE (AUC 0.708; stand- Female gender, yes/no 1.471 0.183–11.820 0.717
ard error 0.030; 95% CI 0.650–0.766; p < 0.001), compared Age, 10 years 1.296 1.021–1.824 0.013
with SA as a dichotomous value (AUC 0.663; standard error IHD, yes/no 2.241 1.940–5.343 0.046
0.032; 95% CI 0.600–0.725; p < 0.001) (Fig. 2B). AF, yes/no 2.164 0.753–6.218 0.152
SAS, yes/no 1.015 0.522–1.972 0.965
Cox regression analysis CKD, yes/no 3.449 1.559–7.629 0.002
COPD, yes/no 2.449 0.923–6.499 0.072
Cox linear regression analysis shows a statistically sig- NAFLD, yes/no 1.619 0.693–3.783 0.265
nificant association between MACE and age (considering Obesity, yes/no 1.346 0.653–2.777 0.421
10 years’ variation), CKD, Ischaemic heart disease (IHD), T2DM, yes/no 1.019 0.474–2.193 0.961
systolic blood pressure (SBP) and UA > 6 mg/dL (Table 3). Alcohol, yes/no 1.400 0.518–3.781 0.507
The variables significantly associated with the onset of Smokers, yes/no 1.397 0.659–2.962 0.383
MACE in the Cox univariate analysis were included in a SBP, mmHg 1.030 1.003–1.058 0.032
multivariate analysis model to define the independent pre- DBP, mmHg 0.981 0.938–1.025 0.387
dictors of clinical outcome (Table 4). Of interest, albumin HR, bfm 1.014 0.991–1.037 0.239
levels < 3.5 g/dL were associated with 3.1-fold increase in RR, afm 1.162 0.951–1.419 0.143
the risk of MACE, the presence of IHD and circulating UA Hb, g/dl 1.156 0.865–1.544 0.327
levels > 6.0 mg/dL explained an increased risk of MACE by Hct, % 1.048 0.960–1.145 0.293
2.3- and 2.2-fold, respectively. The presence of CKD also K, mmol/l 1.345 0.596–3.038 0.476
doubles the risk of MACE. Finally, a 10-year increase in age HbA1c > 6.8%, yes/no 1.871 0.956–3.662 0.068
results in a 33% higher risk of MACE.The text continues LDL, mg/dl 1.002 0.990–1.015 0.723
here. AST, 1 U/L 1.006 0.983–1.029 0.622
ALT, 1 U/L 1.024 1.000–1.048 0.055
γ-GT, 1 U/L 0.990 0.978–1.002 0.109
Discussion MNA, 1 pt 0.955 0.897–1.016 0.141
Albumin < 3.5 g/dl, yes/no 6.177 2.895–13.182 < 0.001
This study, conducted in a population of middle-age outpa- NT-pro-BNP, pg/ml 1.000 1.000–1.001 0.286
tients with HF (both HFrEF and HFmrEF/HFpEF, NYHA UA > 6.0 mg/dl, yes/no 3.706 1.900–7.227 < 0.001
class II and III) with several comorbidities, showed that Iron deficiency, yes/no 2.875 1.081–7.649 0.034
there is an association between low SA levels and incidence hs-CRP, mg/l 0.797 0.642–0.990 0.040
of MACE during a median follow-up of 6.1 years. Specifi- NYHA class I, yes/no 2.035 0.061–68.111 0.692
cally, SA values < 3.5 g/dl increased the risk of MACE by NYHA class II, yes/no 6.435 0.644–64.263 0.113
3.1-fold. This association also persisted after adjustment of NYHA class III, yes/no 1.706 0.171–16.982 0.649
other demographic and clinical variables, including age, sex, MACE major adverse cardiovascular events, IHD ischemic heart dis-
concomitant cardiovascular disease, nutritional status, liver ease, AF atrial fibrillation, SAS sleep apnea syndrome, CKD chronic
and kidney function. The analysis of the processed ROC kidney disease, COPD chronic obstructive pulmonary disease,
curve and measurement of relative AUC also demonstrated NAFLD non-alcoholic fatty liver disease, T2DM type 2 diabetes mel-
litus, SBP systolic blood pressure, DBP diastolic blood pressure, HR
the accuracy of SA levels as predictor of MACE occurrence. heart rate, RR respiratory rate, Hb hemoglobin, Hct hematocrit, K
These results are clinically relevant because albumin repre- Potassium, HbA1c glycated hemoglobin, LDL low-density lipopro-
sents a routinely dosed analyte in daily clinical practice for teins, AST aspartate aminotransferase, ALT alanine aminotransferase,
HF patients with several comorbidities. γ-GT gamma-glutamyltransferase, MNA mini nutritional assessment,
NT-pro-BNP N-terminal pro-brain natriuretic peptide, UA uric acid,
SA value < 3.5 g/dL has already been described as a risk hs-CRP high-sensitivity C-reactive protein
factor for the development of MACE in both inpatients
and outpatients [40, 41]. In fact, in the general population,
hypoalbuminemia is a powerful and independent predictor [38, 39]. In recent years, the prognostic role of low SA value
of all-cause mortality and CV mortality [42, 43]. In addition, in patients with HF has been established, but with different
several studies have shown that hypoalbuminemia predicts study population and methodology. Indeed, several studies
the occurrence of HF in particular patients’ settings, such have demonstrated a close association between reduced SA
as CKD, elderly and diabetic patients independently of tra- levels and poor prognosis in both acute and chronic HF [40,
ditional CV risk factors and CV and non-CV comorbidities 42]. However, these studies considered mainly hospitalized

Table 4  Multivariate stepwise Cox regression analysis on MACE
HR CI 95% p
Albumin < 3.5 g/dl, yes/no 3.114 1.899–5.106 < 0.001
IHD, yes/no 2.264 1.311–3.909 0.003
UA > 6.0 mg/dl, yes/no 2.183 1.275–3.737 0.004
CKD, yes/no 2.050 1.263–3.327 0.004
Age, 10 years increase 1.336 1.055–1.692 0.016
MACE major adverse cardiovascular events, IHD ischemic heart dis-
ease, UA uric acid, CKD chronic kidney disease
or elderly subjects during a short follow-up, in addition
patients showed frequently malnutrition, with a reduction in
the functional reserve for a greater burden of comorbidities.
According with this, in a retrospective cohort study
including 8,246 patients hospitalized for acute HF, hypoal-
buminemia was an important predictor of 30-day and 1-year
mortality in this setting, regardless of the HF phenotype,
both HFrEF and HFpEF. Moreover, SA levels < 3.4 g/dl
were associated with a two-fold increase in mortality risk
at 1 year, in elderly patients hospitalized for acute HF. In
this study more than 50% of the population showed SA lev-
els < 3.4 g/dL, this could be explained by the higher number
of comorbidities, especially liver and kidney disease, and by
hospitalization that results in a major inflammatory burden,
all conditions that may negatively affect circulating albu-
min levels [21]. Considering this, it is not surprising that
in the sub-analysis of the CHARM study, after adjustment
for confounding factors, albumin has lost its prognostic role
during a median follow-up of 3.2 years, in fact in the mul-
tivariate model also parameters of liver dysfunction were
included [7]. Furthermore, in the COAPT study, in patients
with chronic HF and functional mitral insufficiency, having
serum albumin levels < 4 g/dl was associated with reduced
survival over a 4-year follow-up, but was not associated with
an increased incidence of hospitalization [28].
In addition, an observational study of 5779 chronic HF
patients with a mean age of 75 years confirmed the prog-
nostic role of SA. Indeed, SA levels < 3.8 g/dl were associ-
ated with an increased risk of mortality (HR: 5.74, 95% CI:
4.08–8.07, p < 0.001) during a mean follow-up of 576 days.
Moreover, in the study, SA levels at follow-up were avail-
able in 77% of enrolled patients, and it was seen that a
decrease in albumin on follow-up was an independent pre-
dictor of increased mortality (HR: 2.58, 95% CI: 2.12–3.14,
p < 0.001); confirming the prognostic role of SA in patients
with chronic HF [29].
Our study has been conducted in middle-aged outpatients,
with a median follow-up of 6.1 years excluding patients with
liver dysfunction and malnutrition, well-known confound-
ers that may affect SA levels and MACE occurrence. Of
interest, in our study SA levels did not lose their predictive
Internal and Emergency Medicine
power even after correction for liver and kidney function,
inflammation, and nutritional status. In addition, ROC
curves analysis showed a predictive accuracy of SA levels
both as continuous (AUC 0.708) and dichotomous (AUC
0.663) value for MACE occurrence. This result is consistent
with previous data from our group reporting a high preva-
lence of SA < 3.5 g/dL in type 2 diabetes mellitus (T2DM)
patients with a significant association with poor survival and
enhanced occurrence of venous and arterial thrombosis [40].
In fact, hypoalbuminemia as a marker of underlying comor-
bidities, malnutrition, cachexia, and inflammatory state, may
justify a poor clinical prognosis [6]. However, in the present
study circulating albumin levels were mainly justified by hs-
CRP, indicating that chronic low grade inflammation could
represent the main predictor of SA levels.
Of interest, in our analysis IHD, UA and CKD dou-
bled the risk of MACE in the study population and age as
10 years increase augmented the risk of 33%, thus confirm-
ing the prognostic value of these factors in particular in
HF patients [44–46]. Thus, it is appropriate to ask whether
hypoalbuminemia is only an epiphenomenon, a marker of
comorbidities burden and inflammation, or it represents a
causal factor for MACE. Of interest, besides to be the most
represented protein in blood, albumin performs several
physiological functions; in fact, it is primarily responsible
for oncotic blood pressure and it can inhibit coagulation
activation through modulation of hepatic biosynthesis of
coagulation factors or heparin-like activity [47]. In addition,
albumin exerts antiplatelet activity by blocking thromboxane
A2 activity or via an oxidative stress-mediated mechanism
[48]. In fact, hypoalbuminemia confirms its prognostic role
in different clinic al settings, it increases the risk of MACE
in acute and chronic HF, but also in hospitalized patients
regardless of the cause of hospitalization and in T2DM.
Furthermore, in our work, the prognostic role of circulating
albumin levels is confirmed for long-term follow-up, even
after correction for known confounding factors, in particular
for clinical conditions that may result in hypoalbuminemia
such as nutritional status, inflammation, liver and kidney
disease [40, 41]. Finally, we observed that patients with SA
values < 3.5 g/dl showed an increased risk for hHF compared
to patients with higher SA values.
These results are in agreement with previous evidence
demonstrating that reduced SA levels increase the risk of HF
onset and progression. In fact, hypoalbuminemia, by reduc-
ing the colloid-osmotic pressure of the bloodstream, can pro-
mote pulmonary and systemic congestion with a consequent
worsening of heart failure [11, 12]. According with this, as
a future perspective, the potential prognostic role of serum
albumin on risk on a combined endpoint of non-fatal events,
and additionally on hHF and all-cause mortality, could be
evaluated.
Internal and Emergency Medicine
The present study has also several limitations; at first,
it is a retrospective observational study. Another important
limitation is represented by the imbalance of patients’ num-
ber according to two groups, the low percentage of women
and the relatively small sample size with a long duration
of enrollment. In addition, our study measured SA levels
only at baseline and did not assess whether increasing SA
levels could result in an improved prognosis and eventually
a reduction in MACE; this issue deserves further investiga-
tions. This suggests a potential role of SA as a biomarker
able to identify patients with chronic HF at high risk of
developing MACE even in the absence of malnutrition and
inflammation, in this context it is not possible to exclude a
direct role of albumin in CV risk. According with this, it’s
important to remark the potential negative impact of hypoal-
buminemia on efficacy of antithrombotic and antiplatelet
drugs, further increasing the risk of MACE [40, 41].
Considering the results of our study, it seems important
to include SA levels among the variables considered in the
scores used to stratify the risk of patients with HF such as
the MECKI score for HFrEF, and to the variables consid-
ered in the MAGGIC meta-analysis for HF in the various
phenotypes [49, 50].
Conclusion
This study, conducted on outpatients with HF and several
comorbidities, showed that there is an association between
lower SA levels and MACE occurrence during a long-term
follow-up. In particular, a value < 3.5 g/dL of SA levels
was associated with a 3.1-fold increased risk. Notably, this
association persists even after adjustment for confounding
factors such as age, inflammation, nutritional status, liver
and kidney function. Present data suggest the potential use-
fulness of SA as prognostic factor for incident MACE and
hHF in outpatients with HF during a long-term follow-up,
in particular for a value < 3.5 g/dL and it may be helpful to
identify patients with a lower response to antithrombotic
drugs. Of interest, in the study population, the group with
SA < 3.5 g/dl had a higher total mortality than the group
with SA ≥ 3.5 g/dl. In conclusion, a considerable proportion
of patients with chronic HF exhibits low SA levels and show
a higher risk of MACE, hHF and total mortality.
Supplementary Information The online version contains supplemen-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 11739-0​ 24-0​ 3612-9.
Authors contribution GA, VaC (Valentino Condoleo), CAP, MG, AF,
DM, VeC (Velia Cassano), LB, DP, RM, TM, FA, GS, FV and AS
participated in study conceptualization and design. GA, FV and AS
participated in the methodology acquisition, analysis, and interpreta-
tion of data. GA, VaC, CAP, MG, AF, DM, VeC, LB, DP, RM, TM,
FA, GS, FV and AS participated in writing–original draft preparation.
GA, VaC, CAP, MG, AF, DM, VeC, LB, DP, RM, TM, FA, GS, FV
and AS participated in writing–review and editing. GA, FV and AS
participated in study supervision. GA, VaC, CAP, MG, AF, DM, VeC,
LB, DP, RM, TM, FA, GS, FV, and AS read and agreed to the pub-
lished version of the manuscript.
Funding Open access funding provided by Università degli studi
"Magna Graecia" di Catanzaro within the CRUI-CARE Agreement.
This manuscript received no external funding.
Data availability Not applicable.
Code availability Not available.
Declarations
Conflict of interest The authors declare that they have no competing
interests.
Ethical approval The ethics committee Azienda Ospedaliera universi-
taria “Mater Domini” approved the protocol in date 17/10/2012, and
informed written consent was obtained from all participants (code pro-
tocol number 2012.63).
Informed consent Informed consent was obtained from all subjects
involved in the study.
Human and animal rights statement The study procedures were car-
ried out in accordance with the principles of the Declaration of Hel-
sinki.
Consent for publication Not applicable.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
References
1. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach
A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O et al
(2021) ESC Guidelines for the diagnosis and treatment of acute
and chronic heart failure. Eur Heart J 42(36):3599–3726. https://​
doi.​org/​10.​1093/​eurhe​artj/​ehab3​68
2. Gale SE, Mardis A, Plazak ME, Kukin A, Reed BN (2021) Man-
agement of noncardiovascular comorbidities in patients with
heart failure with reduced ejection fraction. Pharmacotherapy
41(6):537–545. https://​doi.​org/​10.​1002/​phar.​2528
3. Sciacqua A, Succurro E, Armentaro G, Miceli S, Pastori D, Rengo
G, Sesti G (2023) Pharmacological treatment of type 2 diabe-
tes in elderly patients with heart failure: randomized trials and
beyond. Heart Fail Rev 28(3):667–681. https://​doi.​org/​10.​1007/​
s10741-​021-​10182-x

4. Liang L, Zhao X, Huang L, Tian P, Huang B, Feng J, Zhou P,
Wang J, Zhang J, Zhang Y (2023) Prevalence and prognostic im-
portance of malnutrition, as assessed by four different scoring
systems, in elder patients with heart failure. Nutr Metab Cardio-
vasc Dis 33(5):978–986. https://​doi.​org/​10.​1016/j.​numecd.​2023.​
01.​004
5. Pasini E, Aquilani R, Gheorghiade M, Dioguardi FS (2003) Mal-
nutrition, muscle wasting and cachexia in chronic heart failure:
the nutritional approach. Ital Heart J 4(4):232–235
6. Araújo JP, Lourenço P, Rocha-Gonçalves F, Ferreira A, Betten-
court P (2011) Nutritional markers and prognosis in cardiac ca-
chexia. Int J Cardiol 146(3):359–363. https://​doi.​org/​10.​1016/j.​
ijcard.​2009.​07.​042
7. Allen LA, Felker GM, Pocock S, McMurray JJ, Pfeffer MA, Swed-
berg K, Wang D, Yusuf S, Michelson EL, Granger CB, CHARM
Investigators (2009) Liver function abnormalities and outcome in
patients with chronic heart failure: data from the Candesartan in
Heart Failure: Assessment of Reduction in Mortality and Morbid-
ity (CHARM) program. Eur J Heart Fail 11(2):170–177
8. von Haehling S, Lainscak M, Springer J, Anker SD (2009) Cardiac
cachexia: a systematic overview. Pharmacol Ther 121(3):227–252.
https://​doi.​org/​10.​1016/j.​pharm​thera.​2008.​09.​009
9. Chojkier M (2005) Inhibition of albumin synthesis in chronic dis-
eases: molecular mechanisms. J Clin Gastroenterol 39(4 Suppl
2):S143–S146. https://​doi.​org/​10.​1097/​01.​mcg.​00001​55514.​
17715.​39
10. Adlbrecht C, Kommata S, Hülsmann M, Szekeres T, Bieglmayer
C, Strunk G, Karanikas G, Berger R, Mörtl D, Kletter K et al
(2008) Chronic heart failure leads to an expanded plasma vol-
ume and pseudoanaemia, but does not lead to a reduction in the
body’s red cell volume. Eur Heart J 29(19):2343–2350. https://​
doi.​org/​10.​1093/​eurhe​artj/​ehn359
11. Arques S, Ambrosi P (2011) Human serum albumin in the
clinical syndrome of heart failure. J Card Fail 17(6):451–458.
https://​doi.​org/​10.​1016/j.​cardf​ail.​2011.​02.​010
12. Roche M, Rondeau P, Singh NR, Tarnus E, Bourdon E (2008)
The antioxidant properties of serum albumin. FEBS Lett
582(13):1783–1787. https://​doi.​org/​10.​1016/j.​febsl​et.​2008.​04.​
057
13. Liu M, Chan CP, Yan BP, Zhang Q, Lam YY, Li RJ, Sanderson
JE, Coats AJ, Sun JP, Yip GW et al (2012) Albumin levels predict
survival in patients with heart failure and preserved ejection frac-
tion. Eur J Heart Fail 14(1):39–44. https://​doi.​org/​10.​1093/​eurjhf/​
hfr154
14. Metra M, Cotter G, El-Khorazaty J, Davison BA, Milo O, Caru-
belli V, Bourge RC, Cleland JG, Jondeau G, Krum H et al (2015)
Acute heart failure in the elderly: differences in clinical character-
istics, outcomes, and prognostic factors in the VERITAS Study. J
Card Fail 21(3):179–188. https://​doi.​org/​10.​1016/j.​cardf​ail.​2014.​
12.​012
15. Uthamalingam S, Kandala J, Selvaraj V, Martin W, Daley M,
Patvardhan E, Capodilupo R, Moore S, Januzzi JL Jr (2015)
Out-comes of patients with acute decompensated heart failure
managed by cardiologists versus noncardiologists. Am J Cardi-ol
115(4):466–471. https://​doi.​org/​10.​1016/j.​amjca​rd.​2014.​11.​034
16. Arques S, Roux E, Stolidi P, Gelisse R, Ambrosi P (2011) Useful-
ness of serum albumin and serum total cholesterol in the predic-
tion of hospital death in older patients with severe, acute heart
failure. Arch Cardiovasc Dis 104(10):502–508. https://d​ oi.o​ rg/1​ 0.​
1016/j.​acvd.​2011.​06.​003
17. Yanagisawa S, Miki K, Yasuda N, Hirai T, Suzuki N, Tanaka T
(2010) Clinical outcomes and prognostic factor for acute heart
failure in nonagenarians: impact of hypoalbuminemia on mortal-
ity. Int J Cardiol 145(3):574–576. https://​doi.​org/​10.​1016/j.​ijcard.​
2010.​05.​061
Internal and Emergency Medicine
18. Horwich TB, Kalantar-Zadeh K, MacLellan RW, Fonarow GC
(2008) Albumin levels predict survival in patients with systolic
heart failure. Am Heart J 155(5):883–889. https://​doi.​org/​10.​
1016/j.​ahj.​2007.​11.​043
19. Lau GT, Tan HC, Kritharides L (2002) Type of liver dysfunction
in heart failure and its relation to the severity of tricuspid re-
gurgitation. Am J Cardiol 90(12):1405–1409. https://​doi.​org/​10.​
1016/​s0002-​9149(02)​02886-2
20. Arques S, Roux E, Sbragia P, Gelisse R, Pieri B, Ambrosi P
(2008) Usefulness of serum albumin concentration for in-hospital
risk stratification in frail, elderly patients with acute heart failure.
Int J Cardiol 125(2):265–267. https://​doi.​org/​10.​1016/j.​ijcard.​
2007.​07.​094
21. Uthamalingam S, Kandala J, Daley M, Patvardhan E, Capodilupo
R, Moore SA, Januzzi JL Jr (2010) Serum albumin and mortality
in acutely decompensated heart failure. Am Heart J 160(6):1149–
1155. https://​doi.​org/​10.​1016/j.​ahj.​2010.​09.​004
22. Kinugasa Y, Kato M, Sugihara S, Hirai M, Kotani K, Ishida K,
Yanagihara K, Kato Y, Ogino K, Igawa O et al (2009) A sim-
ple risk score to predict in-hospital death of elderly patients with
acute decompensated heart failure–hypoalbuminemia as an addi-
tional prognostic factor. Circ J 73(12):2276–2281. https://​doi.​org/​
10.​1253/​circj.​cj-​09-​0498
23. Arques S, Pieri B, Biegle G, Roux E, Gelisse R, Jauffret B (2009)
Comparative value of B-type natriuretic peptide and serum al-
bumin concentration in the prediction of in-hospital mortality
in elderly patients admitted for acute severe heart failure. Ann
Cardiol Angeiol (Paris) 58(5):279–283. https://​doi.​org/​10.​1016/j.​
ancard.​2009.​09.​003
24. Domínguez JP, Harriague CM, García-Rojas I, González G, Apa-
ricio T, González-Reyes A (2010) Acute heart failure in patients
over 70 years of age: Precipitating factors of decompensation. Rev
Clin Esp 210(10):497–504. https://​doi.​org/​10.​1016/j.​rce.​2010.​04.​
020
25. López Castro J, Almazán Ortega R, De Juan P, Romero M,
González Juanatey JR (2010) Mortality prognosis factors in heart
failure in a cohort of North-West Spain. EPICOUR study. Rev
Clin Esp 210(9):438–447. https://​doi.​org/​10.​1016/j.​rce.​2010.​02.​
009
26. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D,
Knosalla C, Davos CH, Cicoira M, Shamim W, Kemp M et al
(2003) Uric acid and survival in chronic heart failure: validation
and application in metabolic, functional, and hemodynamic stag-
ing. Circulation 107(15):1991–1997. https://​doi.​org/​10.​1161/​01.​
CIR.​00000​65637.​10517.​A0
27. Jackson CE, Bezlyak V, Tsorlalis IK et al (2009) Multimarker
laboratory testing in acute decompensated heart failure (ADHF)
how much prognostic information do novel biomarkers BNP, tro-
ponin and CRP provide in addition to routine laboratory tests? Eur
Heart J 30:711
28. Feng KY, Ambrosy AP, Zhou Z, Li D, Kong J, Zaroff JG, Mishell
JM, Ku IA, Scotti A, Coisne A, Trial Investigators COAPT et al
(2023) Association between serum albumin and outcomes in heart
failure and secondary mitral regurgitation: the COAPT trial. Eur
J Heart Fail 25(4):553–561. https://​doi.​org/​10.​1002/​ejhf.​2809
29. Gotsman I, Shauer A, Zwas DR, Tahiroglu I, Lotan C, Keren A
(2019) Low serum albumin: A significant predictor of reduced
survival in patients with chronic heart failure. Clin Cardiol
42(3):365–372. https://​doi.​org/​10.​1002/​clc.​23153
30. El Iskandarani M, El Kurdi B, Murtaza G, Paul TK, Refaat
MM (2021) Prognostic role of albumin level in heart failure:
A systematic review and meta-analysis. Medicine (Baltimore)
100(10):e24785
31. Schupp T, Behnes M, Rusnak J, Ruka M, Dudda J, Forner J,
Egner-Walter S, Barre M, Abumayyaleh M, Bertsch T et al
(2023) Does albumin predict the risk of mortality in patients with
Internal and Emergency Medicine
cardiogenic shock? Int J Mol Sci 24(8):7375. https://​doi.​org/​10.​
3390/​ijms2​40873​75
32. Chao P, Cui X, Wang S, Zhang L, Ma Q, Zhang X (2022) Serum
albumin and the short-term mortality in individuals with conges-
tive heart failure in intensive care unit: an analysis of MIMIC. Sci
Rep 12(1):16251. https://​doi.​org/​10.​1038/​s41598-​022-​20600-1
33. Vellas B, Villars H, Abellan G, Soto ME, Rolland Y, Guigoz Y,
Morley JE, Chumlea W, Salva A, Rubenstein LZ et al (2006)
Overview of the MNA - Its history and challenges. J Nutr Health
Aging 10(6):456–463
34. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher
DF, Turner RC (1985) Homeostasis model assessment: insulin
resistance and beta-cell function from fasting plasma glucose
and insulin concentrations in man. Diabetologia 28(7):412–419.
https://​doi.​org/​10.​1007/​BF002​80883
35. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd,
Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T et al
(2009) CKD-EPI (Chronic Kidney Disease Epidemiology Col-
laboration) A new equation to estimate glomerular filtration rate.
Ann Intern Med 150(9):604–612. https://​doi.​org/​10.​7326/​0003-​
4819-​150-9-​20090​5050-​00006
36. Thygesen K, Alpert JS, White HD (2007) Joint ESC/ACCF/AHA/
WHF Task Force for the Redefinition of Myocardial Infarction.
Universal definition of myocardial infarction. J Am Coll Cardiol
50(22):2173–2195. https://​doi.​org/​10.​1016/j.​jacc.​2007.​09.​011
37. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L,
Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, et al.
American Heart Association/American Stroke Association Stroke
Council; American Heart Association/American Stroke Associa-
tion Clinical Cardiology Council; American Heart Association/
American Stroke Association Cardiovascular Radi-ology and
Intervention Council; Atherosclerotic Peripheral Vascular Disease
Working Group; Quality of Care Outcomes in Research Interdis-
ciplinary Working Group. Guidelines for the early management of
adults with ischemic stroke: a guideline from the American Heart
Association/American Stroke Association Stroke Council, Clini-
cal Cardiology Coun-cil, Cardiovascular Radiology and Interven-
tion Council, and the Atherosclerotic Peripheral Vascular Dis-
ease and Quality of Care Outcomes in Research Interdisciplinary
Working Groups (2007) The American Academy of Neurology
affirms the value of this guideline as an educational tool for neu-
rologists. Circulation. 115(20):e478–e534. doi: https://d​ oi.o​ rg/1​ 0.​
1161/​CIRCU​LATIO​NAHA.​107.​181486.
38. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS
(1995) Congestive heart failure in dialysis patients: prevalence,
incidence, prognosis and risk factors. Kidney Int 47(3):884–890.
https://​doi.​org/​10.​1038/​ki.​1995.​132
39. Filippatos GS, Desai RV, Ahmed MI, Fonarow GC, Love TE,
Aban IB, Iskandrian AE, Konstam MA, Ahmed A (2011) Hypoal-
buminaemia and incident heart failure in older adults. Eur J Heart
Fail 13(10):1078–1086. https://​doi.​org/​10.​1093/​eurjhf/​hfr088
40. Sciacqua A, Andreozzi F, Succurro E, Pastori D, Cammisotto
V, Armentaro G, Mannino GC, Fiorentino TV, Pignatelli P,
Angiolillo DJ et al (2021) Impaired clinical efficacy of aspirin in
hypoalbuminemic patients with diabetes mellitus. Front Pharma-
col 22(12):695961. https://​doi.​org/​10.​3389/​fphar.​2021.​695961
41. Violi F, Novella A, Pignatelli P, Castellani V, Tettamanti M,
Mannucci PM, Nobili A. REPOSI (REgistro POliterapie SIMI,
Società Italiana di Medicina Interna) Study Group (2023) Low
serum albumin is associated with mortality and arterial and ve-
nous ischemic events in acutely ill medical patients. Results of a
retrospective observational study, Thromb Res. 225:1–10, doi:
https://​doi.​org/​10.​1016/j.​throm​res.​2023.​02.​013.
42. Herrmann FR, Safran C, Levkoff SE, Minaker KL (1992) Serum
albumin level on admission as a predictor of death, length of stay,
and readmission. Arch Intern Med 152:125e30
43. Lyons O, Whelan B, Bennett K, O’Riordan D, Silke B (2010)
Serum albumin as an outcome predictor in hospital emergency
medical admissions. Eur J Intern Med 21(1):17–20. https://​doi.​
org/​10.​1016/j.​ejim.​2009.​10.​010
44. Silverdal J, Sjöland H, Bollano E, Pivodic A, Dahlström U, Fu
M (2020) Prognostic impact over time of ischaemic heart disease
vs. non-ischaemic heart disease in heart failure. ESC Heart Fail
7(1):264–273. https://​doi.​org/​10.​1002/​ehf2.​12568
45. Sciacqua A, Perticone M, Tassone EJ, Cimellaro A, Miceli S,
Maio R, Sesti G, Perticone F (2015) Uric acid is an independent
pre-dictor of cardiovascular events in post-menopausal women. Int
J Cardiol 15(197):271–275. https://​doi.​org/​10.​1016/j.​ijcard.​2015.​
06.​069
46. Nguyen M, Rumjaun S, Lowe-Jones R, Ster IC, Rosano G, Ander-
son L, Banerjee D (2020) Management and outcomes of heart
failure patients with CKD: experience from an inter-disciplinary
clinic. ESC Heart Fail 7(5):3225–3230. https://​doi.​org/​10.​1002/​
ehf2.​12796
47. Ronit A, Kirkegaard-Klitbo DM, Dohlmann TL, Lundgren J,
Sabin CA, Phillips AN, Nordestgaard BG, Afzal S (2020) Plasma
albumin and incident cardiovascular disease: results from the
CGPS and an updated meta-analysis. Arterioscler Thromb Vasc
Biol 40(2):473–482. https://​doi.​org/​10.​1161/​ATVBA​HA.​119.​
313681
48. Maclouf J, Kindahl H, Granström E, Samuelsson B (1980) Inter-
actions of prostaglandin H2 and thromboxane A2 with human
serum albumin. Eur J Biochem 109(2):561–566. https://​doi.​org/​
10.​1111/j.​1432-​1033.​1980.​tb048​28.x
49. Agostoni P, Corrà U, Cattadori G, Veglia F, La Gioia R, Scar-
dovi AB, Emdin M, Metra M, Sinagra G, Limongelli G, et al.
MECKI Score Research Group (2013) Metabolic exercise test data
combined with cardiac and kidney indexes, the MECKI score: a
multiparametric approach to heart failure prognosis. Int J Cardiol.
167(6):2710–2718. doi: https://​doi.​org/​10.​1016/j.​ijcard.​2012.​06.​
113.
50. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Køber L, Squire
IB, Swedberg K, Dobson J, Poppe KK, Whalley GA et al (2013)
Predicting survival in heart failure: a risk score based on 39 372
patients from 30 studies. Eur Heart J 34(19):1404–1413. https://​
doi.​org/​10.​1093/​eurhe​artj/​ehs337
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