Abstract
Background
The aim of this study was to determine whether spironolactone therapy has an effect on serum apelin-12 levels in heart failure with reduced ejection fraction (HFrEF) patients.
Methods
Eighty outpatients previously diagnosed with HFrEF were enrolled in the current study. Included patients were taking only standard heart failure therapy (ST) (angiotensin converting enzyme or angiotensin receptor blocker, beta-blockers, loop diuretics and anticoagulant or antiagregan agents) without a mineralocorticoid receptor antagonists (MRA) because of its side effects, and were designated the non-MRA group; those patients taking 25 mg/daily spironolactone in addition to the ST were deemed the MRA group. Patient blood samples were collected to measure serum apelin-12 levels.
Results
After adjustment for all clinical and demographic factors, plasma apelin-12 levels were significantly higher and NT pro-BNP levels were significantly lower in the MRA group compared to the non-MRA group (p < 0.001, p < 0.001; respectively). In multiple linear regression analyses, there was no association between baseline apelin-12 level and clinical parameters. MRA using initial apelin-12 levels were lower and NT pro-BNP levels were higher in patients with stricken event than in event-free patients (p = 0.042, p < 0.001, and p < 0.001; respectively).
Conclusions
Blocking the aldosterone receptors by spironolactone, in addition to maximal standard therapy, may increase serum apelin-12 levels among patients with HFrEF.
Keywords: Aldosterone antagonist, Apelin-12, Heart failure
INTRODUCTION
Heart failure (HF) is an abnormality of cardiac structure and function that results in a failure of oxygen to be supplied to the metabolizing tissues, despite normal filling pressures (or only at the increased filling pressures).1 The chronic neurohormonal changes such as renin-angiotensin-aldosterone system activation in HF with reduced ejection fraction (HFrEF) is crucial to address the deterioration of heart structure and management of heart failure. Aldosterone is a steroid hormone synthesized by the adrenal glands and possessing several regulatory functions which maintain normal volume status and electrolyte balance. Aldosterone plays a major role in the pathophysiology of HFrEF.2 Studies have shown that patients with HFrEF have significantly higher levels of plasma aldosterone than patients with normal ejection fraction.3 Girerd et al. showed that serum aldosterone levels correlated with worsening post-discharge outcomes in patients with acute decompensation of systolic HF.4 For this reason, mineralocorticoid receptor antagonists (MRAs) are used in systolic HF as a treatment cornerstone. Mineralocorticoid receptor antagonists compete with aldosterone for binding to the mineralocorticoid receptors. It was previously shown that MRAs reduce hospitalizations and mortality in HFrEF as well as during acute decompensation.5 Additionally, mineralocorticoid receptor antagonists have been recommended for systolic HF patients with reduced ejection fraction (EF) as ≤ 35% and patients with reduced EF as ≤ 40% after acute myocardial infarction, when persisting symptoms occur despite treatment with an angiotensin converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB), beta-blocker (BBs) and a diuretic combination (I-A recommendation).6-8
There is a significant correlation between excess aldosterone and altered serum adipokine (cytokine derived from adipose tissue) levels. When aldosterone levels are chronically elevated in plasma, visceral fat tissue may display disturbed pro-inflammatory and anti-inflammatory adipokine profiles. Apelin has been proposed as a novel beneficial adipokine that is related to insulin resistance, cardiovascular risk factors, hypertension, and obesity.9-11 Apelin is the most potent positive inotropic agent (among all identified inotropic agents) in normal hearts and acts by reducing apelin levels on pathogenesis and worsening HFrEF.12 Plasma apelin levels were found higher in early stages of HFrEF patients and decreased in late stages of HFrEF patients.13
An unfavorable adipokine profile can be also created by hyperaldosteronism in HFrEF patients. It has been previously shown that aldosterone overloading was inversely related to adipose tissue apelin production and plasma apelin levels via down-regulation of apelin expression in mice adipocytes.14 In the present study, we attempted to evaluate the physiological basis of spironolactone. Our study was based solely one hypothesis that elevated levels of aldosterone may also cause a decrease in serum apelin-12 levels in HFrEF patients. When considering the potentially favorable effects of apelin-12, increasing apelin-12 levels by administering an MRA analog may provide a positive impact on treatment of HFrEF. Spironolactone may increase serum apelin-12 levels by blocking the aldosterone effects on adipose tissue.
METHODS
Study population
Eighty outpatients previously diagnosed with HFrEF were enrolled in the current study. Patients received only standard heart failure therapy (ST) (ACE or ARB, BBs, loop diuretics and anticoagulant or antiplatelet agents) without a mineralocorticoid receptor antagonists (MRA) because of its side effects was labeled the non-MRA group, and patients who recived 25 mg/daily spironolactone in addition to the ST were called the MRA group.
HFrEF was defined in patients strickened with continuous symptoms and/or signs of heart failure, or history of symptoms and/or signs of heart failure controlled by therapy in the presence of reduced left ventricular (LV) EF (≤ 40%) on echocardiography in the absence of any other causes for symptoms.15,16 Age, gender and heart failure duration of all participants were recorded. Complete physical examinations and New York Heart Association (NYHA) functional class were assessed in all patients.
Patients with a history of type 2 diabetes mellitus (DM) using insulin therapy, acute or chronic infectious diseases, other comorbid situations such as acute or chronic renal failure, acute or chronic hepatic failure, presence of any chronic inflammatory and autoimmune diseases and any known malignancy were excluded from the study. Informed consent was obtained from all participants and the study protocol was approved by the local ethics committee.
Clinical follow-up was performed for a period of 12 months. Heart failure events were defined as death and re-hospitalization due to cardiac dyspnea or any sign of decompensation of HF. Additionally, we asked patients to be aware of and disclose if they had any re-hospitalization to another clinic during the follow-up period.
Laboratory tests
Serum samples were collected at the outpatient clinic by a peripheral venous route and measured by commercially available automated chemistry analyzer kits (Roche Diagnostics, Indianapolis, IN, USA). The levels of N-terminal pro-brain natriuretic peptide (NT pro-BNP) and high sensitivity C-reactive protein (hs-CRP) were assessed by using immunoturbidimetry (Beckmann Assay 360, Bera, California, USA). Hematological parameters were measured from tripotassium ethylenediaminetetraacetic acid-based anticoagulated blood samples and assessed by a Sysmex K-1000 Autoanalyzer (Block Scientific, Bohemia, NY, USA) within 30 minutes of sampling. Serum Apelin-12 (EK-057-23) levels were measured by using EIA kits (Phoenix Pharmaceuticals, Inc., California, USA) following the manufacturer’s instructions by using DSXTM Four-Plate Automated enzyme-Linked ImmunoSorbent Assay (ELISA) Processing System micro ELISA (Dynex Technologies, Chantilly, Virginia, USA). A standard curve of known concentrations can be established accordingly. The concentration of standards was 0.01 ng/ml, 0.1 ng/ml, 1 ng/ml, 10 ng/ml, 100 ng/ml, and 1000 ng/ml. The unknown concentration in samples can be determined by extrapolation to this standard curve.
Statistical analysis
For purposes of statistical analysis, SPSS statistical software program (version 16.0, Chicago, IL, USA) was used. The variables were investigated by using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov and Shapiro-Wilk test) to determine if they were normally distributed, and were expressed as mean ± standard deviation (SD) or the median and interquartile range (IQR, range from the 25th to the 75th percentile). The Mann-Whitney U test was used for comparison of two groups with abnormal distribution of variables, and the Chi-square test was used for comparison of qualitative data. Comparisons between the two groups were carried out using an independent sample T-test. Pearson’s correlation was used for numerical data, and Spearman’s correlation was used for purposes of nominal data. Additionally, log transformation was performed for NT pro-BNP values, and multiple linear regression analysis was applied to identify whether admission apelin-12 was independently associated with other study parameters. Kaplan-Meier curves of event-free survival among the groups were compared using the log-rank test. The univariate effects of study parameters on survival of study patients were investigated using the log-rank test. The possible factors identified with univariate analyses were thereafter applied to the Cox regression analysis, with backward selection, to determine independent predictors of 1-year HF events.
RESULTS
The baseline characteristics and laboratory findings of two groups were summarized in Table 1. The mean age was similar between groups (63.1 ± 10.5 in MRA group vs. 60.9 ± 10.4 in non MRA group; p = 0.346). Overall, 49 patients were male (61%) and the gender ratios (female/male: 16/24, 15/25, respectively, p = 0.817) were similar between the MRA and non-MRA groups. Fifty-seven patients (72%) had ischemic etiology. The mean left ventricular ejection fraction, duration and type of HF, systolic and diastolic blood pressures and hematological-biochemical parameters were similar between groups.
Table 1. Baseline and laboratory characteristics of the study patients.
| MRA group (n = 40) | Non-MRA group (n = 40) | p value | |
| X ± SS | X ± SS | ||
| Age, years | 63.1 ± 10.5 | 60.9 ± 10.4 | 0.346 |
| Gender, female/male, % | 16/24 | 15/25 | 0.817 |
| Tip 2 DM, n | 20 | 17 | 0.508 |
| Hypertension, n | 22 | 16 | 0.183 |
| Smoke, n | 20 | 19 | 0.827 |
| Duration of HF, mean month | 50.3 | 42.6 | 0.106 |
| HF type, ischemic/nonischemic, n | 11567 | 26/14 | 0.217 |
| NYHA functional class | 2.63 ± 0.76 | 2.97 ± 0.8 | 0.018 |
| Mean LVEF, % | 34.7 ± 6.44 | 33.8 ± 6.15 | 0.538 |
| Heart rate, bpm | 82.9 ± 13.47 | 84.5 ± 12.71 | 0.594 |
| Initial rhythm, n, AF/SR | 6/34 | 8/32 | 0.556 |
| Systolic BP, mmhg | 129.2 ± 19.74 | 124.6 ± 14.48 | 0.234 |
| Diastolic BP, mmhg | 74.3 ± 11.07 | 74.1 ± 8.51 | 0.910 |
| BMI, kg/m2 | 29.4 ± 4.76 | 27.6 ± 4.61 | 0.091 |
| Follow up events, death/rehospitalization | 11 (3/8) | 25 (7/18) | 0.031 |
| Plasma glucose, mg/dL | 129.8 ± 51.92 | 141.5 ± 65.35 | 0.427 |
| Creatinine, mg/dL | 0.89 ± 0.25 | 0.94 ± 0.35 | 0.498 |
| ALT, U/L | 22.4 ± 13.42 | 19.8 ± 11.35 | 0.246 |
| Total cholesterol, mg/dL | 174.9 ± 36.74 | 185 ± 68.14 | 0.415 |
| Triglyceride, mg/dL | 159.8 ± 79.33 | 173.4 ± 98.25 | 0.497 |
| LDL-C, mg/dL | 116.1 ± 28.41 | 123.5 ± 52.26 | 0.846 |
| HDL-C, mg/dL | 42.4 ± 9.44 | 41.9 ± 9.56 | 0.434 |
| Hemoglobin, g/dL | 13.0 ± 1.77 | 13.5 ± 1.85 | 0.143 |
| hsCRP, mg/dL | 1.62 ± 0.78 | 1.75 ± 0.75 | 0.474 |
| Sedimentation | 24.3 ± 13.94 | 22.7 ± 14.69 | 0.655 |
| NT pro-BNP, pg/mL | 492.0 (323.0-647.5) | 993.0 (598.5-1605.0) | < 0.001 |
| Apelin-12 level, ng/ml | 4.2 ± 2.64 | 2.3 ± 1.81 | < 0.001 |
AF, atrial fibrillation; ALT, alanin aminotranspherase; BMI, body mass index; BP, blood pressure; bpm, beat per minute; DM, diabetes mellitus; HDL-C, high density lipoprotein cholesterol; HF, heart failure; hsCRP, high sensitive c-reactive protein; LDL-C, low density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT pro-BNP, N terminal brain natriuretic peptide; NYHA, New York heart association; SD, standard deviation; SR, sinus rhythm; WB, white blood cell; X, average. p < 0.05 was accepted as significant.
In multiple linear regression analysis, there was no association between baseline apelin-12 levels and clinical parameters (Table 2). After adjusting for all clinical and demographic factors, plasma apelin-12 levels were significantly higher and NT pro-BNP levels were significantly lower in the MRA group compared to the non-MRA group [4.2 ± 2.64 ng/mL vs. 2.3 ± 1.81 ng/mL; p < 0.001 for apelin-12, and 492.0 (323.0-647.5) vs. 993.0 (598.5-1605.0), p < 0.001 for NT pro-BNP, respectively] (Table 1).
Table 2. The association of admission apelin-12 level with study parameters.
| r | p value | |
| Age, year | 0.09 | 0.20 |
| BMI | 0.14 | 0.10 |
| SBP | -0.09 | 0.20 |
| LVEF | 0.042 | 0.35 |
| Glucose | 0.11 | 0.09 |
| Creatinine | -0.04 | 0.36 |
| Total cholesterol | -0.1 | 0.19 |
| Heart rate | 0.007 | 0.47 |
| NYHA functional class | -0.17 | 0.21 |
| CRP | -0.06 | 0.29 |
| NT pro-BNP | -0.274 | 0.02 |
BMI, body mass index; CRP, C-reactive protein; LVEF, left ventricle ejection fraction; NT pro-BNP, N terminal brain natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure. p < 0.05 was accepted as significant.
Ultimately, there was a significant negative correlation between apelin-12 levels and NT pro-BNP levels (r = -0.441, p < 0.001) (Figure 1).
Figure 1.
Correlation between admission apelin-12 and logNT pro-BNP level.
All patients were followed-up for a period of 12 months. Re-hospitalization and/or death observed during this period were defined as follow-up events. During the follow-up period, 36 patients were re-hospitalized and 10 of those patients died. The patients were categorized into two groups according to 1-year HF events in order to assess and compare the initial apelin-12 levels. MRA using initial apelin-12 levels were lower and NT pro-BNP levels were higher in patients who had suffered an eventrather than event-free patients (p = 0.042, p < 0.001, and p < 0.001; respectively). Other parameters were not different between event-driven groups (Table 3).
Table 3. The characteristics of patients with and without follow-up event.
| Patients with event (n: 36) | Patients without event (n: 40) | p value | |
| Gender, male, % | 43 | 57 | 0.62 |
| Age, year | 59.8 ± 11.7 | 63.8 ± 9.1 | 0.09 |
| BMI | 27.7 ± 4.3 | 29.2 ± 4.8 | 0.17 |
| DM, % | 58 | 42 | 0.07 |
| HT, % | 37 | 63 | 0.18 |
| MRA using, % | 32 | 68 | 0.042 |
| Smoke, % | 44 | 56 | 0.49 |
| Glucose, mg/dl | 142.7 ± 75.7 | 130.4 ± 53.9 | 0.42 |
| Serum sodium, mmol/l | 141.0 ± 2.3 | 140.3 ± 2.4 | 0.25 |
| WBC, ×10/μL | 8.2 ± 2.5 | 7.9 ± 2.2 | 0.59 |
| Hemoglobin, g/dl | 13.2 ± 2.1 | 13.3 ± 1.4 | 0.95 |
| Creatinine, mg/dl | 0.92 ± 0.28 | 0.91 ± 0.30 | 0.92 |
| Hs-CRP, mg/dl | 0.81 ± 1.01 | 0.58 ± 0.46 | 0.19 |
| SBP, mmhg | 129.1 ± 17.7 | 125.0 ± 16.9 | 0.29 |
| NT pro-BNP, pg/ml | 477.1 ± 385.1 | 155.8 ± 121.6 | < 0.001 |
| Heart rate, bpm | 83.2 ± 11.4 | 84.1 ± 14.3 | 0.76 |
| Apelin-12, ng/ml | 2.7 ± 1.1 | 5.1 ± 2.5 | < 0.001 |
BMI, body mass index; BP, blood pressure; DM, diabetes mellitus; hs-CRP, high sensitive C-reactive protein; HT, hypertension; MRA, mineralocorticoid receptor antagonist; NT pro-BNP, N terminal brain natriuretic peptide; SBP, systolic blood pressure; SD, standard deviation; WBC, white blood cell, X, average. p < 0.05 was accepted as significant.
The mean apelin-12 level was 3.71 ± 1.88 ng/mL for all study patients. Based on the mean value of apelin-12 concentration, patients were divided into 2 groups; the high levels of apelin-12 group (apelin-12 level > 3.71 ng/mL; n = 40 patients) and the low apelin group (apelin-12 level < 3.71 ng/mL, n = 40 patients). Kaplan-Meier analysis revealed that the event-free rate was significantly lower in patients with low apelin-12 than those with high apelin-12 group (p < 0.001, log rank analyses) (Figure 2).
Figure 2.
Kaplan-Meier analysis for event rate based on the serum apelin level of patients. This figure shows the event-free survival rates in the patients with low (< 3.7 ng/ml) and high (> 3.7 ng/ml) serum apelin levels. Our data shows that low apelin serum level is significantly associated with lower event-free survival rate (p < 0.001, log rank analyses).
To determine the predictors of follow-up events, we performed the multivariate Cox proportional hazard analysis, and the variables that showed significance by univariate analysis were adopted as covariates. Our data revealed that serum apelin-12 is a predictor for follow-up events [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.61-0.91, p = 0.004]. The other unfavorable prognostic predictors were DM (HR = 2.3, 95% CI 1.1-4.9, p = 0.02) and NT pro-BNP (HR = 1.02, 95% CI 1.01-1.03, p < 0.001) (Table 4).
Table 4. The univariate and multivariate Cox regression analysis results.
| Univariate | Multivariate | |||
| HR (95%CI) | p value | HR (95%CI) | p value | |
| Age, year | 0.97 (0.94-1.05) | 0.1 | 0.98 (0.95-1.02) | 0.98 |
| DM | 1.9 (1.01-3.7) | 0.04 | 2.3 (1.1-4.9) | 0.02 |
| HT | 0.71 (0.36-1.4) | 0.32 | ||
| Hemoglobin, g/dL | 0.95 (0.77-1.2) | 0.61 | ||
| Creatinine, mg/dL | 1.15 (0.42-3.45) | 0.78 | ||
| SBP, mmHg | 1.01 (0.98-1.04) | 0.14 | 1.01 (0.99-1.03) | 0.13 |
| NT pro-BNP, pg/mL | 1.05 (1.01-1.12) | 0.02 | 1.02 (1.01-1.03) | < 0.001 |
| Heart rate, bpm | 0.99 (0.97-1.02) | 0.71 | ||
| Apelin-12, ng/ml | 0.65 (0.52-0.80) | < 0.001 | 0.74 (0.61-0.91) | 0.004 |
bpm, beats per minute; CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; HT, hypertension; NT pro-BNP, N terminal brain natriuretic peptide; SBP, systolic blood pressure. p < 0.05 was accepted as significant.
DISCUSSION
The main finding of this study was that apelin-12, which has beneficial effects on cardiovascular system and hemodynamic status, may be altered by spironolactone therapy in HFrEF patients. This is the first study reporting an association between plasma apelin-12 levels and MRA treatment in HFrEF patients.
Previous studies have shown that HFrEF patients had significantly higher levels of aldosterone compared with the normal population.17 While aldosterone has been shown to be an integral part of maintaining fluid and electrolyte balance, it is also recognized to be a trigger that causes damage to the cardiovascular system and worsening heart failure. Actually, elevated levels of aldosterone have been repeatedly shown to be associated with increasing blood pressure, causing left ventricular hypertrophy and promoting cardiac fibrosis in HFrEF.18 Hence, MRAs such as spironolactone or eplerenone have been used for decades in the management of excess volume.9,18 In HFrEF patients are not already receiving MRA, treatment should be initiated as soon as possible as recommended within current guidelines, unless renal function and potassium levels are within abnormal limits. Although MRAs have been recommended for all heart failure patients with persistent symptoms (NYHA Class II-IV) and a LVEF ≤ 35% despite appropriate treatment [ACE inhibitor/ARB, BBs and a diuretic combination] to reduce the risk of heart failure hospitalization and premature death (I-A recommendation), previous large registry studies have shown that only 64% of HF patients have taken MRAs.6,7
A variety of cytokines (adipokines) were secreted from adipose tissue, one of which was apelin. In these circumstances, apelin is the endogenous ligand of the G-protein-coupled receptor (APJ), and has been proposed as a novel beneficial adipokine related to insulin resistance, cardiovascular risk factors, hypertension, and obesity.10-12,19 Apelin and APJ mRNAs are widely expressed in various tissues and have multiple protective functions in cardiovascular homeostasis and metabolism.11
The excess plasma aldosterone levels can also alter serum adipokine levels. For example, patients with primary aldosteronism displayed reduced leptin and adiponectin levels, as well as increased resist in levels.20 Also, it has been previously shown that an acute aldosterone overloading was inversely related to plasma apelin levels, production of apelin and down-regulation of apelin expression in mice adipocytes.21 Recently, Chong et al. showed that plasma apelin concentrations were significantly lower in patients with chronic systolic heart failure, irrespective of NYHA class, ejection fraction or etiology.22 In our study, we found that initial apelin-12 levels were significantly higher in the MRA group than in the non-MRA group. The study groups were well-adjusted for outpatient medications included ACE inhibitor/ARB, BB and a diuretic therapy. The doses of used drugs were similar between the groups. We attempted to homogenize the groups particularly for ACE inhibitor or ARB dosing, arising from a recent study which show that angiotensin II synthesis inhibition or using an ARB increases apelin-12 expression and secretion.10,23 Also, we excluded patients with insulin-dependent type 2 DM because recent studies demonstrated that insulin exerts a direct control on apelin gene expression in adipocytes. The groups were also well-matched regarding demographic parameters such as age, gender and BMI. After adjusting all of these factors which can effect serum apelin levels, we found that elevated serum apelin-12 levels in HFrEF patients may only be dependent on using of spironolactone.
At the end of patient follow-up, those study subjects who were exposed to heart failure events during the 1-year follow-up period had lower apelin levels than those patients without event. This may be explained by the fact that apelin, which has inotropic, vasodilator and diuretic properties, has some favorable effects on cardiovascular hemostasis. Actually, apelin causes nitric oxcite (NO)-dependent vasorelaxation on human arteries both in vitro and in vivo studies.24,25 In vivo exogenous apelin administration has been shown to cause a rapid NO-dependent fall in blood pressure in a rodent model.26 Furthermore, apelin is a potent endogenous positive inotropic agent. Szokodi et al. suggested that apelin causes activation of phospholipase C-dependent signal transduction pathway, which ultimately affects Ca2+ availability and/or Ca2+ responsiveness of the myofilaments.10 Indeed, plasma apelin levels increase in the early stages and decrease in the end stages of heart failure.13 More recently, it has been shown that apelin has diuretic properties through counteracting the actions of arginine vasopressin.27 A combination of inotropi, vasodilatation and natriuretic effects may suggest that apelin could play an important role in lowering left ventricular end-diastolic pressure and reducing NT pro-BNP levels, eventually improving patient outcomes. In the current study, the MRA group had lower NT pro-BNP levels than the non-MRA group. Elevated NT pro-BNP levels reflect high left ventricular end-diastolic pressure and its concentrations are strongly predictive of short and long-term clinical outcomes. On the other hand, a decrease in aldosterone levels by using spironolactone results in decreased NT pro-BNP levels via reduce intravascular volume and diminished preload in HFrEF patients. Additionally, it is generally understood that aldosterone can cause left ventricular hypertrophy, and promotes cardiac fibrosis.18
Study limitations
There were several limitations to our investigation, including the small number of enrolled patients. Although we only measured serum apelin-12 levels, we were able to measure some important adipokines associated with inflammation and could show their association with the current study results. Our hypothesis was based on an elevation of serum apelin-12 levels by reducing the effect of aldosterone on adipose tissue by a MRA. Therefore, plasma aldosterone levels may be able to be measured to support our results, but this measurement was not performed in our study. Additional further in vivo or in vitro studies are also required to confirm this hypothesis.
CONCLUSIONS
Our study suggested that apelin-12, which has beneficial effects on cardiovascular system and hemodynamic status, may be altered by spironolactone therapy. The results obtained from this study may provide novel clues about beneficial effects of apelin-12 on hemodynamic status in HFrEF patients, and also reconfirms the importance of spironolactone use as a diuretic agent in HFrEF patients. From this study, we cannot assuredly state that measurement of apelin-12 level is crucial, and that decreasing of apelin level promotes an MRA response. However, we did find that apelin can be used as an independent predictor of follow-up events in HF patients. When new pathways are discovered associated with apelin-12, heart failure treatment can be adjusted and modified to achieve the most beneficial patient outcome.
Acknowledgments
No funding supported this study.
CONFLICTS OF INTEREST
None declared.
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