Abstract
Acute heart failure (AHF) emerges either de novo or from worsening of chronic heart failure (CHF). The aim of the present study was to evaluate the association between worsening of CHF and mortality in AHF patients. Out of 152 included AHF patients, 47 (30.9%) were de novo AHF patients and 105 (69%) were AHF patients with worsening of CHF. The proportion dying in hospital (19.0% vs. 4.3%, p = 0.023) and within 3 months after hospitalization (36.6% vs. 6.7%, p < 0.001) was significantly higher in AHF patients with worsening of CHF. Logistic regression analyses also showed a significant positive association of AHF emerging as worsening of CHF with hospital mortality [odds ratio (OR) and 95% confidence interval (CI): 5.29 (1.46–34.10), p = 0.029] and 3-month mortality [8.09 (2.70–35.03), p = 0.001]. While the association with hospital mortality was no longer significant after adjusting for comorbidities and clinical as well as laboratory parameters known to be associated with mortality in heart failure patients, the association with 3-month mortality remained significant. We conclude that compared to de novo AHF, AHF evolved from worsening of CHF is a more severe condition and is associated with increased mortality.
Subject terms: Outcomes research, Heart failure
Introduction
Heart failure (HF) is a frequent cause of death and disability worldwide1. According to the European Society of Cardiology (ESC) HF denotes an abnormality of the cardiac structure and function, resulting in failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues2,3. Acute heart failure (AHF) denotes the rapid onset, or a massive exaggeration of existing symptoms and signs of HF3. Accordingly, there are patients with de novo AHF and those with AHF as a consequence of the worsening of Chronic Heart Failure (CHF).
HF is a complex syndrome with a versatile underlying pathophysiology, highlighted by disturbed hemodynamics and a deranged metabolism4. Insufficient tissue perfusion due to impaired performance of the failing heart as well as tissue congestion due to venous volume overload, a consequence of right-sided HF, cause impaired intestinal nutrient absorption, diminished biosynthetic capacity of the liver5, and worsened renal function in HF6,7. Consequently, the decreased serum levels of cholesterol, increased concentrations of urea and creatinine, as well as wasting and chronic inflammation reflect the poor overall status associated with an increased mortality rate in HF patients8.
Considering the persistent hemodynamic and metabolic burden imposed on CHF patients we hypothesized that the clinical and laboratory characteristics are worse and the mortality rate higher in AHF patients with worsening of CHF compared to de novo AHF patients. Therefore, we compared the clinical and laboratory characteristics of patients with worsening of CHF with those of de novo AHF patients and evaluated the association between worsening of CHF and mortality in AHF patients.
Results
Clinical characteristics
The patients’ baseline characteristics have been described elsewhere9 and are shown in Table 1. Out of 152 included patients, 105 (69.1%) were patients with worsening of CHF and 47 (30.9%) were de novo AHF patients. As seen in Table 1, both groups were similar regarding age, sex, smoking status, body mass index (BMI) and New York Heart Association (NYHA) functional classification. Compared to de novo AHF patients, patients with worsening of CHF had a significantly lower mean arterial pressure (MAP) and heart rate (Table 1), whereas respiratory rate and the incidence of dyspnoea and ortopnoea were similar in both groups (Supplementary Table 1). Venous congestion, a consequence of right-sided HF, was more frequent in patients with worsening of CHF; this was exemplified by a significantly higher incidence of jugular venous distension (JVD), enlarged liver, and peripheral edema (Table 1). The incidence of ascites was higher, albeit not statistically significantly in patients with worsening of CHF compared to de novo AHF patients (Table 1). Furthermore, systolic pulmonary artery pressure (SPAP) was significantly higher in patients with worsening of CHF compared to de novo AHF patients, whereas ejection fraction (EF) (Table 1), the incidence of aortic insufficiency, aortic stenosis, and dilatation of right or left ventricle did not differ significantly between the groups (Supplementary Table 1).
Table 1.
Baseline characteristics, vital signs and symptoms of AHF patients with worsening of CHF vs. de novo AHF patients.
| All AHF patients (N = 152) |
De novo AHF (N = 47) |
Worsening of CHF (N = 105) |
p-value | |
|---|---|---|---|---|
| Age (years) | 77.3 (45.5–96.7) | 75.7 (45.5–93.0) | 77.5 (50.6–96.7) | 0.312 |
| Female | 79 (52.0%) | 20 (42.6%) | 59 (56.2%) | 0.160 |
| BMI (kg/m2) | 28.5 (16.3–43.5) | 30.1 (16.3–38.6) | 27.7 (17.1–43.5) | 0.113 |
| Weight (kg) | 80.0 (40.0–144.0) | 89.0 (50.0–125.0) | 79.0 (40.0–144.0) | 0.042 |
| Smoking | 38 (25.0%) | 15 (31.9%) | 23 (21.9%) | 0.225 |
| NYHA class | 0.124 | |||
| 2 | 11 (7.2%) | 6 (12.8%) | 5 (4.8%) | |
| 3 | 83 (54.6%) | 27 (57.4%) | 56 (53.3%) | |
| 4 | 58 (38.2%) | 14 (29.8%) | 44 (41.9%) | |
| MAP (mmHg) | 103.3 (53.3–160.0) | 110.0 (70.0–160.0) | 100.0 (53.3–156.7) | 0.007 |
| Heart rate (beats/min) | 100.0 (36.0–160.0) | 110.0 (36.0–160.0) | 99.0 (50.0–150.0) | 0.041 |
| JVD | 52 (34.2%) | 10 (21.3%) | 42 (40.0%) | 0.027 |
| Enlarged liver | 53 (34.9%) | 9 (19.1%) | 44 (41.9%) | 0.009 |
| Peripheral edema | 105 (69.1%) | 26 (55.3%) | 79 (75.2%) | 0.022 |
| Ascites | 21 (13.8%) | 4 (8.5%) | 17 (16.2%) | 0.309 |
| EF (%) | 45.0 (20.0–70.0) | 45.0 (20.0–65.0) | 41.0 (20.0–70.0) | 0.677 |
| SPAP (mmHg) | 45.0 (35.0–80.0) | 40.0 (35.0–60.0) | 47.5 (35.0–80.0) | 0.002 |
Data are presented as n (%) or as median and range (minimum to maximum). Differences between AHF patients with worsening of CHF and de novo AHF patients were tested with Fisher’s exact test or the Mann-Whitney U test, respectively.
AHF, acute heart failure; BMI, body mass index; CHF, chronic heart failure; EF, ejection fraction; JVD, jugular venous distension; MAP, mean arterial pressure; NYHA, New York Heart Association functional classification; SPAP, systolic pulmonary artery pressure.
Regarding comorbidities, the incidence of chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and cardiomyopathy (CM) were significantly higher, and the incidence of acute coronary syndrome (ACS) was significantly lower in AHF patients with worsening of CHF compared to de novo AHF patients (Supplementary Table 2). In contrast, the incidence of hyperlipidemia, hypercholesterolemia, hypertension, type 2 diabetes mellitus (T2DM) as well as coronary and peripheral atherosclerosis was similar in both groups.
Laboratory parameters
The markers of kidney function urea and creatinine, were significantly higher and glomerular filtration rate (GFR) significantly lower in patients with worsening of CHF compared to de novo AHF patients (Table 2). While the N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and interleukin-6 (IL-6) levels were significantly higher, the levels of alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, as well as leukocytes, and platelets were significantly lower in patients with worsening of CHF compared to de novo AHF patients (Table 2). Levels of aspartate transaminase (AST), C-reactive protein (CRP), triglycerides and erythrocytes did not differ significantly between groups (Table 2). While the levels of total serum protein and albumin, as well as glucose, sodium, and potassium were not significantly different between groups, the chloride levels were significantly lower in patients with worsening of CHF compared to de novo AHF patients (Supplementary Table 3).
Table 2.
Laboratory parameters of AHF patients with worsening of CHF vs. de novo AHF patients.
| All AHF patients (N = 152) |
De novo AHF (N = 47) |
Worsening of CHF (N = 105) |
p-value | |
|---|---|---|---|---|
| GFR (ml/min/1.73 m2) | 50.9 (15–0–105.7) | 58.8 (20.0–105.7) | 45.3 (15.0–104.8) | 0.001 |
| Urea (mmol/L) | 8.0 (3.0–64.0) | 7.0 (3.0–64.0) | 9.0 (3.0–41.0) | 0.003 |
| Creatinine (µmol/L) | 106.0 (53.0–273.0) | 100.0 (53.0–255.0) | 117.5 (59.0–273.0) | 0.006 |
| NT-proBNP (ng/mL) | 9570 (171–70000) | 4465 (171–70000) | 12434 (291–70000) | <0.001 |
| ALT (U/L) | 23.0 (6.0–623.0) | 25.0 (6.0–623.0) | 21.0 (7.0–556.0) | 0.034 |
| AST (U/L) | 27.0 (10.0–666.0) | 28.0 (11.0–666.0) | 27.0 (10.0–487.0) | 0.536 |
| IL-6 (pg/mL) | 19.8 (0.4–300.0) | 15.6 (0.4–300.0) | 24.3 (1.2–300.0) | 0.005 |
| CRP (µg/mL) | 9.4 (0.2–247.4) | 5.7 (0.2–247.4) | 10.6 (0.4–169.0) | 0.189 |
| Total cholesterol (mmol/L) | 3.8 (1.7–9.1) | 4.4 (2.5–9.1) | 3.8 (1.7–7.7) | 0.004 |
| LDL cholesterol (mmol/L) | 2.3 (0.8–6.3) | 2.6 (1.3–6.3) | 2.1 (0.8–6.0) | 0.004 |
| HDL cholesterol (mmol/L) | 1.0 (0.3–3.6) | 1.0 (0.4–1.9) | 0.9 (0.3–3.6) | 0.039 |
|
Triglycerides (mmol/L) |
1.1 (0.5–4.3) | 1.1 (0.6–4.3) | 1.0 (0.5–3.2) | 0.390 |
|
Erythrocytes (x 109/L) |
4.6 (2.5–6.6) | 4.6 (3.6–5.9) | 4.6 (2.5–6.6) | 0.938 |
|
Leukocytes (x 109/L) |
9.7 (3.1–48.9) | 11.2 (4.2–21.5) | 9.4 (3.1–48.9) | 0.017 |
|
Platelets (x 1012/L) |
216.5 (61.0–999.0) | 247.0 (71.0–999.0) | 202.0 (61.0–444.0) | 0.002 |
Data are presented as median and range (minimum to maximum). Differences between AHF patients with worsening of CHF and de novo AHF patients were tested with the Mann-Whitney U test.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; AHF, acute heart failure; CHF, chronic heart failure; CRP, C-reactive protein; GFR, glomerular filtration rate; IL-6, interleukin-6; LDL, low-density lipoprotein; HDL, high-density lipoprotein; NT-proBNP, N-terminal pro brain natriuretic peptide.
Mortality
Significantly more patients with AHF caused by worsening of CHF died in the hospital as well as within 3 months after hospitalization compared to de novo AHF patients (Table 3). In line with this, the univariable logistic regression analyses showed a significant positive association of worsening of CHF with hospital and 3-month mortality (Table 4). While this association did not remain significant for in-hospital mortality after adjusting for age, sex, BMI, NT-proBNP, MAP, GFR, and either urea, IL-6, and LDL cholesterol, or COPD, CKD, CM, ACS, and NYHA, the adjustment did not qualitatively change the results for 3-month mortality (Table 4).
Table 3.
Mortality rate of AHF patients with worsening of CHF vs. de novo AHF patients.
| All AHF patients (N = 152) |
De novo AHF (N = 47) |
Worsening of CHF (N = 105) |
p-value | |
|---|---|---|---|---|
| Hospital mortality | 22 (14.5%) | 2 (4.3%) | 20 (19.0%) | 0.023 |
| 3-month mortality* | 40 (27.4%) | 3 (6.7%) | 37 (36.6%) | <0.001 |
*N = 146 observations (45 de novo AHF, 101 worsening of CHF) available.
Data are presented as n (%). Differences between AHF patients with worsening of CHF and de novo AHF patients were tested with Fisher’s exact test; significant differences are depicted in bold. AHF, acute heart failure; CHF, chronic heart failure.
Table 4.
Logistic regression analyses to assess the influence of the AHF class (worsening of CHF compared to de novo AHF) on hospital and 3-month mortality.
| OR (95% CI) | p-value | Events/N | |
|---|---|---|---|
| Hospital mortality | |||
| unadjusted | 5.29 (1.46–34.10) | 0.029 | 22/152 |
| adjusted* | 1.59 (1.33–11.64) | 0.593 | 20/140 |
| adjusted** | 3.38 (0.65–27.86) | 0.188 | 20/140 |
| 3-month mortality | |||
| unadjusted | 8.09 (2.70–35.03) | 0.001 | 40/146 |
| adjusted* | 4.35 (1.20–21.72) | 0.040 | 37/134 |
| adjusted** | 5.90 (1.53–31.68) | 0.019 | 37/134 |
*Model was adjusted for age, sex, BMI, NT-proBNP, MAP, GFR, urea, IL-6, and LDL cholesterol.
**Model was adjusted for age, sex, BMI, NT-proBNP, MAP, GFR, COPD, CKD, CM, ACS, NYHA.
Data presented are ORs and 95% CIs for AHF as worsening of CHF vs. de novo AHF (reference) as well as the number of events and observations left in the analysis.
ACS, acute coronary syndrome; AHF, acute heart failure; BMI, body mass index; CHF, chronic heart failure; CI, confidence interval; CKD, chronic kidney disease; CM, cardiomyopathy; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; IL-6, interleukin-6; LDL, low-density lipoprotein; MAP, mean arterial pressure; NT-proBNP, N-terminal brain natriuretic peptide; OR, odds ratio.
Discussion
The present study clearly shows that AHF developed from CHF represents a more severe condition that is associated with higher mortality when compared to de novo AHF.
Compared to de novo AHF patients, AHF patients with worsening of CHF presented with markedly higher concentrations of NT-proBNP, a marker of heart congestion and elevated left-sided filling pressure10, indicating a more pronounced left ventricular dysfunction, accompanied by a lower MAP and higher SPAP and in turn, more severe right-sided HF with consequently more severe venous congestion.
Interestingly, despite a higher incidence of JVD, enlarged liver and peripheral edema, the body weight in AHF patients with worsening of CHF was significantly lower than in de novo AHF patients. This finding most probably reflects a more pronounced impairment of the intestinal absorption of nutrients due to a more severe intestinal edema, as well as a more severe chronic inflammation, the postulated common link between CHF, wasting syndrome and hypoalbuminemia8,11,12. In line with this, our AHF patients with worsening of CHF had lower serum levels of albumin (albeit not statistically significant) and significantly higher concentrations of IL-6 when compared to de novo AHF patients.
It is generally accepted that the augmented translocation of bacterial endotoxins from the edematous intestine into the circulation13 as well as insufficient binding and neutralization of endotoxines by circulating lipoproteins, whose levels are decreased in HF14,15, underlie the persistent inflammatory response in HF16. Additionally, the pro-inflammatory activation of venous endothelial cells by circumferential stretch due to congestion contributes to the chronic inflammation in HF17. Accordingly, lower serum levels of LDL cholesterol and HDL cholesterol together with a more severe congestion, in patients with worsening of CHF compared to de novo AHF patients may well explain the more pronounced inflammatory response, reflected by higher IL-6 levels.
The augmented inflammatory response, which is known to promote the formation and clearance of leukocyte - platelet complexes18,19, is most likely responsible for the lower leukocyte and platelet levels in our AHF patients with worsening of CHF.
It is well established that decreased cholesterol and lipoprotein serum levels are strongly and independently associated with increased mortality in HF8,14. In contrast to total, LDL, and HDL cholesterol, which were significantly lower in patients with worsening of CHF, triglyceride levels were similar in both studied groups.
Serum levels of lipids and lipoproteins are determined by their intestinal absorption, hepatic synthesis, and removal from the circulation by various catabolic routes. Accordingly, modulation of these physiological processes by the underlying AHF pathophysiology, such as congestion, which was more severe in AHF patients with worsening of CHF, may explain the different levels of total, LDL, and HDL cholesterol in the studied groups. Similar triglyceride levels in the two studied groups may indicate either that the triglyceride synthesis is not affected by the underlying AHF pathophysiology or that the decreased triglyceride synthesis is counterbalanced by a likewise decreased triglyceride catabolism. The latter possibility is likely, because lipoprotein lipase, a serum enzyme responsible for triglyceride degradation, is decreased by inflammation20, which indeed was more severe in AHF patients with worsening of CHF than in de novo AHF patients.
Renal dysfunction, also a strong predictor of mortality in HF21,22, was more pronounced in our AHF patients with worsening of CHF than in de novo AHF patients. This was reflected by a markedly decreased GFR and concomitantly increased serum levels of urea and creatinine. The reduction in GFR may be due to several factors including kidney hypoperfusion23, renal co-morbidities24, renal venous congestion25,26, or inflammatory cytokines such as IL-627. Accordingly, a higher incidence of CKD, together with a more severe venous congestion and a more pronounced inflammatory response, as well as higher serum levels of NT-proBNP, an established predictor of worsening renal function in CHF28, may well explain the more severe impairment of renal function in our AHF patients with worsening of CHF compared to de novo AHF patients.
Besides their deleterious effects on the kidneys, inflammatory cytokines such as IL-6 exert a direct detrimental effect on the myocardial structure and function by promoting oxidative stress and endothelial dysfunction, thus contributing to the progression of HF29. Therefore, a more pronounced inflammatory state, reflected by higher IL-6 levels, seems to be an important underlying pathophysiology responsible for worse clinical status of our AHF patients with worsening of CHF compared to de novo AHF patients.
The above-mentioned differences between the groups regarding the clinical characteristics observed in our AHF patients with worsening of CHF translated into a higher mortality rate, whereby the impact on 3-month mortality was more pronounced than the impact on hospital mortality. This is in line with two recent reports showing a strong association of the chronicity of HF with 6-month and 3-year mortality, but only a weak association with 1-month mortality30,31. In the present study, the strong association of worsening of CHF with 3-month mortality was weakened, but remained significant upon adjustment for comorbidities and established risk factors in HF8,32,33. This implies that other features inherent to this group of patients underlie their increased mortality compared to de novo AHF patients.
There are several limitations to our present study: The design precludes conclusions on the pathophysiological mechanisms in terms of cause and consequence, or temporal development and onset of signs, and symptoms associated with worsened status and increased mortality. Furthermore, our data do not facilitate the examination whether the duration of HF chronicity affects mortality rates. Finally, the limited number of participants in this monocentric study influences the statistical power of our analyses. Therefore, further large studies are needed to confirm our results.
Based on our results, we conclude that AHF developed from CHF is a more severe condition than de novo AHF and is associated with higher mortality rates.
Methods
Study design and patients
Study design, inclusion and exclusion criteria as well as patient characteristics for our AHF cohort have been reported previously9,34. In short, we performed a prospective observational study on hospitalized patients with AHF in Zagreb, Croatia, between 2013 and 2015. Written informed consent was obtained from each patient and the study, which was approved by the Ethics Committees of the University Hospital Centre Sisters of Charity, Zagreb, Croatia and the Medical University of Graz, Austria, was conducted in adherence to the ethical guidelines of the Declaration of Helsinki35. All patients were treated according to the ESC Guidelines for AHF3,36.
Measurements of SPAP
SPAP was approximated the tricuspid valve velocity, estimated central vein pressure (resembling right atrium pressure), and Bernoulli equation from a Doppler echocardiography.
Laboratory procedures
The collection of blood samples, standard laboratory methods, and the determination of the NT-proBNP concentration have been described in our previous reports on our AHF cohort34,37. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined with the Abbott Architect c8000 (Chicago, IL, USA).
Statistical analyses
Categorical data are shown as absolute and relative frequencies, whereas continuous data are summarized as median and range (minimum to maximum) due to the skewed distribution of many of the laboratory parameters. Patients with de novo AHF and with worsening of CHF were compared by Mann-Whitney U test or Fisher’s exact test. The impact of worsening of CHF as compared to de novo AHF on hospital and 3-month mortality was assessed by logistic regression analysis. In addition to a univariable model, we also adjusted for age, sex, BMI, NT-proBNP, GFR, MAP, urea, IL-6, and LDL cholesterol, as well as for age, sex, BMI, NT-proBNP, MAP, GFR, COPD, CKD, CM, ACS, and NYHA, the comorbidities as well as clinical and laboratory parameters known to be associated with mortality in HF patients. We checked the variance inflation factor to prevent multi-collinearity among the covariates. Results are presented as odds ratios (OR) with the respective 95% confidence interval (CI). All analyses are exploratory and a p-value of <0.05 was considered significant. R version 3.4.2. was used for all statistical analyses.
Electronic supplementary material
Acknowledgements
Authors would like to thank Dr. Branimir Frank (cardiologist emeritus) for helpful discussion. This research was supported by the Austrian Science Foundation [P27166-B23 to S.F.] and the Jubilee Foundation of the Austrian National Bank [15858 to S.F.]. They had no roles in the design of the study, data collection, analysis, and interpretation, report writing or article submission.
Author Contributions
Experiments conceived and designed by: V.D., M.T., I.P., S.F. Experiments carried out by: I.P. V.D., M.T., B.R., S.D.T., B.T. Contribution of reagents/ materials/analysis tools: S.F., B.T., B.R. Contributed significantly to the execution, the analysis or both and interpretation of data: I.P., M.T., G.P., A.B., V.D., B.T., S.F., S.D.T. Paper was written by: I.P., V.D., A.B., G.P., M.T., S.F. Participated in reviewing, and/or revising the manuscript for intellectual content: V.D., I.P., M.T., G.P., A.B., S.D.T., B.R., B.T., S.F. The manuscript was approved for submission by: V.D., I.P., M.T., G.P., A.B., S.D.T., B.R., B.T., S.F.
Data Availability
All data generated or analysed during this study are included in this manuscript and accompanied Supplementary materia.
Competing Interests
The authors declare no competing interests.
Footnotes
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
6/5/2019
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Electronic supplementary material
Supplementary information accompanies this paper at 10.1038/s41598-018-28027-3.
References
- 1.Roger VL. Epidemiology of heart failure. Circ Res. 2013;113:646–659. doi: 10.1161/CIRCRESAHA.113.300268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM) Eur Heart J. 2008;29:2388–2442. doi: 10.1093/eurheartj/ehn309. [DOI] [PubMed] [Google Scholar]
- 3.McMurray JJ, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. doi: 10.1093/eurheartj/ehs104. [DOI] [PubMed] [Google Scholar]
- 4.Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014;64:1388–1400. doi: 10.1016/j.jacc.2014.04.083. [DOI] [PubMed] [Google Scholar]
- 5.Seeto RK, Fenn B, Rockey DC. Ischemic hepatitis: clinical presentation and pathogenesis. Am J Med. 2000;109:109–113. doi: 10.1016/S0002-9343(00)00461-7. [DOI] [PubMed] [Google Scholar]
- 6.F. Gnanaraj J, von Haehling S, Anker SD, Raj DS, Radhakrishnan J. The relevance of congestion in the cardio-renal syndrome. Kidney Int. 2013;83:384–391. doi: 10.1038/ki.2012.406. [DOI] [PubMed] [Google Scholar]
- 7.Mullens W, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53:589–596. doi: 10.1016/j.jacc.2008.05.068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol. 2004;43:1439–1444. doi: 10.1016/j.jacc.2003.11.039. [DOI] [PubMed] [Google Scholar]
- 9.Potocnjak I, et al. Metrics of High-Density Lipoprotein Function and Hospital Mortality in Acute Heart Failure Patients. PLoS One. 2016;11:e0157507. doi: 10.1371/journal.pone.0157507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ambrosy AP, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: findings from the EVEREST trial. Eur Heart J. 2013;34:835–843. doi: 10.1093/eurheartj/ehs444. [DOI] [PubMed] [Google Scholar]
- 11.Chang HR, Bistrian B. The role of cytokines in the catabolic consequences of infection and injury. JPEN J Parenter Enteral Nutr. 1998;22:156–166. doi: 10.1177/0148607198022003156. [DOI] [PubMed] [Google Scholar]
- 12.Hasper D, Hummel M, Kleber FX, Reindl I, Volk HD. Systemic inflammation in patients with heart failure. Eur Heart J. 1998;19:761–765. doi: 10.1053/euhj.1997.0858. [DOI] [PubMed] [Google Scholar]
- 13.Anker SD, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96:526–534. doi: 10.1161/01.CIR.96.2.526. [DOI] [PubMed] [Google Scholar]
- 14.Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet. 2000;356:930–933. doi: 10.1016/S0140-6736(00)02690-8. [DOI] [PubMed] [Google Scholar]
- 15.Rauchhaus M, et al. Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure. Int J Cardiol. 2000;76:125–133. doi: 10.1016/S0167-5273(00)00224-2. [DOI] [PubMed] [Google Scholar]
- 16.Niebauer J, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353:1838–1842. doi: 10.1016/S0140-6736(98)09286-1. [DOI] [PubMed] [Google Scholar]
- 17.Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52:1527–1539. doi: 10.1016/j.jacc.2008.07.051. [DOI] [PubMed] [Google Scholar]
- 18.Ed Rainger G, et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets. 2015;26:507–520. doi: 10.3109/09537104.2015.1064881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Glezeva N, Gilmer JF, Watson CJ, Ledwidge M. A Central Role for Monocyte-Platelet Interactions in Heart Failure. J Cardiovasc Pharmacol Ther. 2016;21:245–261. doi: 10.1177/1074248415609436. [DOI] [PubMed] [Google Scholar]
- 20.van Wijk JP, Halkes CJ, Erkelens DW, Castro Cabezas M. Fasting and daylong triglycerides in obesity with and without type 2 diabetes. Metabolism. 2003;52:1043–1049. doi: 10.1016/S0026-0495(03)00106-9. [DOI] [PubMed] [Google Scholar]
- 21.Ruggenenti P, Remuzzi G. Worsening kidney function in decompensated heart failure: treat the heart, don’t mind the kidney. Eur Heart J. 2011;32:2476–2478. doi: 10.1093/eurheartj/ehr242. [DOI] [PubMed] [Google Scholar]
- 22.Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121:2592–2600. doi: 10.1161/CIRCULATIONAHA.109.886473. [DOI] [PubMed] [Google Scholar]
- 23.Schrier RW. Role of diminished renal function in cardiovascular mortality: marker or pathogenetic factor? J Am Coll Cardiol. 2006;47:1–8. doi: 10.1016/j.jacc.2005.07.067. [DOI] [PubMed] [Google Scholar]
- 24.McCullough PA. Cardiorenal risk: an important clinical intersection. Rev Cardiovasc Med. 2002;3:71–76. doi: 10.1016/S1522-1865(02)00125-7. [DOI] [PubMed] [Google Scholar]
- 25.Haddy FJ. Effect of elevation of intraluminal pressure on renal vascular resistance. Circ Res. 1956;4:659–663. doi: 10.1161/01.RES.4.6.659. [DOI] [PubMed] [Google Scholar]
- 26.Dilley JR, Corradi A, Arendshorst WJ. Glomerular ultrafiltration dynamics during increased renal venous pressure. Am J Physiol. 1983;244:F650–658. doi: 10.1152/ajprenal.1983.244.6.F650. [DOI] [PubMed] [Google Scholar]
- 27.Sanchez-Lozada, L. G., Tapia, E., Johnson, R. J., Rodriguez-Iturbe, B. & Herrera-Acosta, J. Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation. Kidney Int Suppl, S9-14 (2003). [DOI] [PubMed]
- 28.Pfister R, et al. NT-pro-BNP predicts worsening renal function in patients with chronic systolic heart failure. Intern Med J. 2011;41:467–472. doi: 10.1111/j.1445-5994.2010.02203.x. [DOI] [PubMed] [Google Scholar]
- 29.Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62:263–271. doi: 10.1016/j.jacc.2013.02.092. [DOI] [PubMed] [Google Scholar]
- 30.AlHabib KF, et al. Long-Term Mortality Rates in Acute De Novo Versus Acute-on-Chronic Heart Failure: From the Heart Function Assessment Registry Trial in Saudi Arabia. Angiology. 2015;66:837–844. doi: 10.1177/0003319714563138. [DOI] [PubMed] [Google Scholar]
- 31.Greene SJ, et al. Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure: From the ASCEND-HF Trial. J Am Coll Cardiol. 2017;69:3029–3039. doi: 10.1016/j.jacc.2017.04.043. [DOI] [PubMed] [Google Scholar]
- 32.Ford I, et al. Top ten risk factors for morbidity and mortality in patients with chronic systolic heart failure and elevated heart rate: The SHIFT Risk Model. Int J Cardiol. 2015;184:163–169. doi: 10.1016/j.ijcard.2015.02.001. [DOI] [PubMed] [Google Scholar]
- 33.Fonarow GC, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. 2005;293:572–580. doi: 10.1001/jama.293.5.572. [DOI] [PubMed] [Google Scholar]
- 34.Radulovic B, et al. Hypochloraemia as a predictor of developing hyponatraemia and poor outcome in acute heart failure patients. Int J Cardiol. 2016;212:237–241. doi: 10.1016/j.ijcard.2016.03.081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.World Medical, A World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194. doi: 10.1001/jama.2013.281053. [DOI] [PubMed] [Google Scholar]
- 36.Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239. doi: 10.1016/j.jacc.2013.05.019. [DOI] [PubMed] [Google Scholar]
- 37.Potocnjak I, et al. Serum Concentration of HDL Particles Predicts Mortality in Acute Heart Failure Patients. Sci Rep. 2017;7:46642. doi: 10.1038/srep46642. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Supplementary Materials
Data Availability Statement
All data generated or analysed during this study are included in this manuscript and accompanied Supplementary materia.