Predictive value of nesfatin-1 in heart failure mortality

Introduction

Advanced heart failure (HF) occurs in a period when patients’ complaints and HF findings persist even during light exercise and/or rest despite optimal medical treatment, device therapy, or surgical interventions, necessitating many important decisions in the management of the disease, such as recurrent hospitalizations, the need for inotropic therapy, placement of mechanical support devices or heart transplantation, consequently leading to significantly shortened survival in many patients [1]. Although there is no clear data on its actual prevalence, large registry studies, including cases of chronic HF, have reported the prevalence of advanced HF as 5–10 % [2]. The newly published European Society of Cardiology (ESC) -HF Pilot study (EURObservational Research Program: the Heart Failure Pilot Survey) reported 1 year mortality at 7.2 % in chronic HF and 1 year survival at 25 % in patients with advanced HF [3]. Many mortality predictors have been identified in advanced heart failure, such as hyponatremia, elevated N-terminal fragment brain natriuretic peptides (NT-pro-BNP) and troponin I, deterioration in right ventricular systolic functions, increased pulmonary arterial pressure [4, 5]. Weight loss due to increased inflammation and neurohumoral activity was also detected to be closely related to mortality in advanced heart failure [6].

Oh et al. [7] characterized nesfatin-1 as an 82 amino acid satiety molecule, which was discovered in the hypothalamus with a molecular weight of 9.7 kDa [7]. Studies have shown that the suppression of feeding by nesfatin-1 is by a mechanism independent of leptin but dependent on the melanocortin receptor [8]. As an anorectic peptide, nesfatin-1 has been shown to suppress appetite. Moreover, experimental studies have shown that exogenous application of nesfatin-1 causes considerable reductions in food consumption, body weight, and mesenteric, subcutaneous, and epidermal fat mass [9]. A negative correlation has been reported between body mass index (BMI) and nesfatin-1 in non-obese individuals, with significantly lower nesfatin-1 concentration in groups with high BMI [10]. In addition, nesfatin-1 amounts in plasma were detected to be lower in anorexia nervosa patients, which is characterized by chronic food intake restriction [11]. These findings collectively suggest that nestatin-1 is closely associated with weight loss and gain.

Nesfatin-1 regulates blood pressure and heart rate, regulates cardiomyocyte metabolism and permeability, protects against ischemia/reperfusion injury, decreases circulatory levels in patients with acute myocardial infarction (AMI) and peripheral artery disease, and raises circulatory levels in incident parotid hemorrhage. These are just some of the cardiovascular effects of nesfatin-1 on heart physiology [12].

Nesfatin-1 also has peripheral effects on a number of areas, including the cardiovascular system, in addition to a central modulation of blood pressure and heart rate management, nutrition and energy balance, and nervous system circuits [13]. The metabolism of heart failure patients is shifted towards catabolism due to neurohumoral mechanisms that result in increased levels of norepinephrine and epinephrine. The weight loss observed in patients with heart failure can be attributed to a reduction in anabolic hormones and an elevation in catabolic hormones [14]. Assessing weight loss and BMI in advanced heart failure patients during the decompensated stage is challenging and frequently produces imprecise outcomes due to the heightened volume load.

Therefore, nesfatin-1 appears to be of interest for monitoring the status of metabolic pathways in patients with advanced heart failure compared to other markers used in heart failure monitoring.

In advanced heart failure patients, determining weight loss during hospital admission is difficult due to the increased volume load in the patients. This study aims to reveal the association of nesfatin-1 level, which is closely related to weight loss and gain and, therefore, to metabolic pathways, with mortality in patients with advanced heart failure.

Materials and methods

This prospective observational research was executed with 74 patients who had decompensated heart failure and applied to the emergency clinic of Kahramanmaras Sutcu Imam University Medical Faculty Hospital; they were then taken to the coronary intensive care clinic between June 2021 and June 2022 because of the identification of advanced heart failure. The criteria of inclusion in the study were as follows; being over 18 years of age and being voluntary to join the study, symptoms of severe HF such as shortness of breath and/or fatigue at rest or mild exercise (Functional Classification of New York Heart Association, class III or IV), two objective proof of severe cardiac dysfunction (elevated plasma quantities of NT-proBNP in the absence of non-cardiac causes, left ventricular ejection fraction <30 %), decreased cardiac output at rest (peripheral hypoperfusion) and/or fluid retention (systemic and/or pulmonary congestion, peripheral edema), inability to exercise and walking less than 300 m in the six-minute walk test, ≥1 hospitalization due to HF in the last six months, and persistence of symptoms despite attempts to optimize therapy with guideline medications such as beta-blockers, diuretics, and renin-angiotensin-aldosterone system inhibitors, and cardiac resynchronization treatment when necessary. Patients with active cancer, acute coronary syndrome on admission, sepsis, patients who were admitted to the emergency clinic due to cardiac arrest and underwent resuscitation, patients with advanced heart failure due to congenital cardiac disease, advanced heart failure patients who were hospitalized due to cerebrovascular incident or pulmonary thromboembolism, and patients with right heart failure secondary to primary pulmonary hypertension were the exclusion criteria from the study. Patients’ clinical findings at admission, demographic characteristics, laboratory results, treatment, and follow-ups were recorded using a standardized questionnaire by researchers blinded to biomarker levels. Electrocardiography was taken on admission, and transthoracic echocardiographic evaluation was performed by a blinded researcher. In addition to routine blood parameters, venous blood for nesfatin-1 was taken from the subjects during hospitalization in the coronary intensive care unit. Patients’ in-hospital mortality outcomes were recorded. The endpoint of the research was in-hospital mortality. The study group was divided into two groups: those who developed in-hospital mortality and those who did not. This research was ruled in line with the Declaration of Helsinki and was ratified by the Kahramanmaras Sutcu Imam University Ethics Committee (25/07/2018-302). All patients gave informed consent.

Results

The study included 74 cases of advanced heart failure. Of these cases, 19 were female, 55 were male, and 22 (5 females and 17 males) died during follow-up. The cases were split into two different groups; In-hospital mortality and survivors. Baseline characteristics, echocardiographic parameters, and laboratory data are shown in Table 1. The mortality group had a much older age distribution [(74 (66–95) vs. 67 (26–90); p=0.019)]. Of the echocardiographic parameters, left atrial diameter was significantly higher in the mortality group, while TAPSE was significantly lower (43.8 ± 5.5 vs. 40.5 ± 6.1; p=0.027, 13.5 ± 1.9 vs. 16.2 ± 2.6 p=0.001, respectively). Laboratory findings showed that serum nesfatin-1 level [31.4 (9.62–31.4) vs. 14.2(11.5–25.5); p=0.002] and hemoglobin (10.1 ± 1.6 vs. 11 ± 1.2; p=0.045, respectively) were statistically lower in the group with mortality. On the other hand, serum uric acid level, NT-proBNP, blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate transaminase (AST) were significantly elevated in the mortality group (9.4 ± 2.9 vs. 7.3 ± 3.0; p=0.026, 13,600 (850–38000) vs. 4,910 (474–3,500); p=0.0032, 28 (9–1,188) vs. 18 (5–73); p=0.046; 33 (16–834) vs. 22 (8–337); p=0.0015 and 36.5 (16–122) vs. 22.5 (8–79) p=0.022, respectively). Other basal characteristics, laboratory values, and echocardiographic parameters were similar between the groups.

The outcomes of multivariate and univariate logistic regression analysis for in-hospital mortality are given in Table 2. Serum nesfatin-1 (pg/mL), age (years), BUN (mg/dL), hemoglobin (g/dL), left atrial diameter (cm) TAPSE (cm), NT-proBNP(ng/L) and ALT (U/L) were found related with the existence of in-hospital mortality in univariate analysis. nesfatin-1 and TAPSE (OR=0.899, 95 % CI=0.826–0.997, p=0.013, OR=0.510, 95 % CI=0.314–0.828, p=0.006, respectively) remained related with the existence of in-hospital mortality in the multivariate logistic regression model after adjustment for statistically significant values in univariate analysis. ROC curve analysis showed that the optimum cut-off level for nesfatin-1 in determining in-hospital mortality was ≤23.57 (pg/mL) with a specificity of 73.1 % and a sensitivity of 77.3 % (AUC=0.763, 95 % CI=0.647–0.879, p<0.001, Figure 1).

Figure 1:

Receiver operator characteristic (ROC) curve of nesfatin-1 to predict mortality in advanced heart failure.

Discussion

This research determined that low nesfatin-1 level is related to mortality in patients with advanced heart failure and seems to be an independent predictor of mortality. In addition to low nesfatin-1, low TAPSE, an echocardiographic indicator of advanced right ventricular systolic dysfunction, was related to mortality in advanced heart failure patients and became an independent predictor for in-hospital mortality.

Nesfatin-1 is principally thought of as a hormone of satiety. This peptide has been demonstrated to decrease food intake in mice when administered intraperitoneally [16]. Endogenously, nesfatin-1 deficiency has been shown to be associated with obesity and weight gain. Despite being a satiety hormone, recent studies have revealed that this peptide is tightly associated with diabetes, hypertension, neurological diseases, coronary artery disease, and psychiatric diseases through various pathophysiological mechanisms [17], [18], [19]. Our study also determined that the level of nesfatin-1 was low in the in-hospital mortality group in advanced heart failure patients.

Metabolic disorders such as malnutrition, malabsorption, and nutrient losses through the urinary and digestive systems cause weight loss in advanced heart failure patients [20]. In addition, cellular hypoxia in heart failure causes inefficient functioning of the intermediate metabolism, leading to increased catabolism, decreased anabolism, and protein loss [21]. In heart failure patients, increased norepinephrine and epinephrine levels with neurohumoral mechanisms shift the metabolism towards catabolism. A decrease in anabolic hormones and an increase in catabolic hormones result in weight loss in heart failure patients [14]. This catabolic process is manifested by weight loss and a decrease in BMI. A decrease in BMI and weight loss are tightly related to mortality in heart failure patients [22]. However, due to the increased volume load in advanced heart failure patients, assessing weight loss and BMI in the decompensated stage is difficult and often yields inaccurate results.

As in our study, evaluating this process with the nesfatin-1 hormone, which is closely related to metabolism, may yield more accurate results. Low levels of this peptide in acquired diseases, whose endogenous deficiency results in weight gain, maybe a defense mechanism to prevent weight loss. In patients with advanced heart failure, a low nesfatin-1 level can be considered a predictor of increased catabolic process and hence mortality. Similar to the findings in our research, serum nesfatin-1 quantities were detected to be lower in anorexia nervosa patients with severe food intake restrictions. The reduced quantities of nesfatin-1 may also be attributed to the inflammatory process in advanced heart failure patients. Previous studies have shown that nesfatin-1-expressing neuron activation and inflammation in the brain stem and hypothalamus are related [23]. A study comparing nesfatin-1 levels in acute myocardial infarction, stable coronary artery disease, and the control group showed that nesfatin-1 level was low in the group with acute myocardial infarction and attributed this to the inflammatory process [24]. In subcutaneous adipose tissue, Osaki et al. demonstrated that chemical sympathectomy using 6-hydroxydopamine boosted the expression of nesfatin/NUCB2 [25]. In light of these data, it is possible to say that nesfatin-1 levels can be suppressed by increased sympathetic activity. In advanced heart failure, increased sympathetic activity may be the cause of low nesfatin-1.

Right-sided heart failure is indeed a common condition in left-sided heart failure. Left ventricular dysfunction causes pulmonary hypertension in the natural course of left-sided heart failure, allowing right-sided heart failure to occur [26]. Right ventricular functions are of prognostic importance in advanced heart failure. TAPSE provides information about right ventricular base-to-apex contraction and right ventricular functions. The relationship of low TAPSE with mortality in advanced heart failure has been shown in various studies [27]. Consistent with the literature, our study also defined TAPSE to be an independent predictor of mortality in advanced heart failure. In general, both congestive and acute HF are associated with a worse prognosis when pulmonary hypertension and right ventricular (RV) dysfunction are present. In fact, Ghio et al. demonstrated in an outpatient context that the presence of pulmonary hypertension [systolic pulmonary artery pressure (sPAP)>40 mmHg] and RV dysfunction (TAPSE<14 mm) was related to a poor prognosis in CHF [28]. Aronson et al. revealed that the coexistence of RV dysfunction and pulmonary hypertension (sPAP>50 mmHg) in HF patients, including individuals with both reduced and preserved EF, was linked with the worst mortality [29].

The present research had some limitations. The study’s relatively small patient enrollment was the most significant of these. In addition, the markers of the inflammatory process, except for C-reactive protein (CRP), could not be evaluated in the participating patients. The BMI of the patients could not be calculated due to excessive volume overload in the patients during their admission to the hospital. Yet, not calculating BMI during the follow-ups following the removal of the volume load is also a limitation. Another limitation is the intermix classification of the patients and not determining the nesfatin-1 levels accordingly. However, it was thought that classification-based analysis would be weak because of the small sample size.

Conclusions

In patients with heart failure, weight loss caused by accelerated catabolism is strongly associated with mortality. In advanced heart failure, the nesfatin-1 level, which is a hormonal signal of weight loss concealed by volume load during hospitalization, can be utilized as a mortality indicator.