Adipokines Pathogenesis in Heart Failure

Abstract

Many studies have reported that obesity causes heart failure (HF) pathogenesis. The elevated circulating levels of angiopoietin-like protein 2 (ANGPTL2) observed in patients with HF suggest potential links among elevated ANGPTL2 levels, metabolic disturbances, and inflammation. C1q/TNF-related protein 3 and C1q/TNF-related protein 9 are diminished in patients with HF with reduced ejection fraction, in proportion to disease severity, and are associated with elevated morbidity and mortality. In addition, fibroblast growth factor 21 (FGF21) has been suggested to be involved in the pathophysiology of diastolic HF. Further studies are necessary to determine whether FGF21 plays a causal role in HF, and whether measuring circulating FGF21 might effectively improve HF prediction, diagnosis, and prognosis. Osteopontin has also been reported to be upregulated in patients with HF and therefore might potentially serve as a novel prognostic biomarker in patients with chronic HF. A considerable number of patients with community-acquired HF have elevated tumor necrosis factor-alpha, which is associated with significantly diminished survival and significantly elevated risk of HF.

Main article text

Introduction

Increasing rates of obesity are contributing to the rising prevalence of heart failure (HF), a leading cause of morbidity and mortality [1]. HF is associated with obesity in an estimated 11% of cases in men and 14% in women. Obesity can exacerbate HF because of altered heart and blood flow, as well as elevated likelihood of other risk factors. Direct cardiac lipotoxicity is another disorder in which lipid buildup in the heart can cause cardiac failure, even in the absence of additional risk factors [2]. Obesity is characterized by elevated release of adipokines, which are physiologically active molecules, and storage of body fat. When released into the circulation, adipokines function similarly to hormones by binding certain receptors on target cells and consequently affecting metabolism in tissues and organs [3].

Many studies have reported that obesity causes HF pathogenesis [4, 5]. However, this article discusses few major adipokines such as angiopoietin-like protein 2 (ANGPTL2), C1q complement/tumor necrosis factor-associated proteins (CTRPs), fibroblast growth factor 21 (FGF21), osteopontin (OPN), and tumor necrosis factor-alpha (TNF-α) in the pathogenesis of HF, as explained in Table 1 and Figure 1.

Table 1

Overview of Adipokines in HF Pathogenesis

Adipokines	Pathogenesis in HF
Angiopoietin-like protein 2	Angiopoietin-like protein 2 expression is upregulated in the hearts of both mice and humans undergoing pathologic cardiac remodeling. The mice exhibit cardiac dysfunction, attributed to the inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signaling, as well as decreased myocardial energy metabolism. In contrast, mice lacking ANGPTL2 show elevated left ventricular contractility, accompanied by unregulated AKT-SERCA2a signaling and enhanced energy metabolism in the myocardium. ANGPTL2 is known to contribute to chronic inflammation and has been implicated in HF development.
CTRPs	Undetermined
Fibroblast growth factor 21	Preclinical studies have demonstrated that FGF21 is involved in HF development, by preventing oxidative stress, cardiac hypertrophy, and inflammation in heart muscle cells.
Osteopontin	The expression of OPN in the myocardium is significantly elevated in patients with HF. In vitro studies have further demonstrated that OPN significantly increases the expression and activity of lysyl oxidase (LOX) in human cardiac and dermal fibroblasts. An excess of OPN is associated with elevated LOX levels, increased formation of insoluble collagen, and alterations in LV stiffness and systolic dysfunction in patients with hypertensive heart disease (HHD) and HF. Additionally, OPN upregulates LOX in human fibroblasts. The OPN–LOX axis might facilitate the development of collagen that is stiff and resistant to degradation, thus leading to changes in LV mechanical properties and impaired function in patients with HHD and HF.
Tumor necrosis factor-alpha	Inflammation is a major factor in the pathophysiology of HF. The inflammatory cytokine is tumor necrosis factor-alpha that affects cardiac dysfunction and cardiac remodeling, has been associated with the development of HF. Tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) have different and opposing effects in remodeling, hypertrophy, nuclear factor kappa B (NF-κB), inflammation, and apoptosis in heart failure: TNFR1 exacerbates these events, whereas TNFR2 ameliorates them. However, activation through both receptors is necessary to cause oxidative stress and diastolic dysfunction. Locally reduced mitochondrial activity, increased oxidative stress, and myocyte apoptosis are some of the mechanisms by which tumor necrosis factor-alpha increases left ventricular dysfunction in pacing-induced heart failure.

Figure 1

Circulatory Levels of Adipokines in HF Pathogenesis.

Source: Designed by the authors, on the basis of articles cited in the references: (↑) increased levels; (↓) decreased levels.

Role of Adipokines in HF

Angiopoietin-like Protein 2

According to Tian et al., mice and humans experiencing pathologic cardiac remodeling have elevated expression of ANGPTL2 in the heart. In contrast, endurance exercise that causes physiological cardiac remodeling in mice has been found to decrease cardiac ANGPTL2 expression. These animals show diminished myocardial energy metabolism and cardiac dysfunction, as well as inactivation of AKT and sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a signaling. In contrast, mice deficient in ANGPTL2 exhibit elevated left ventricular (LV) contractility and AKT-SERCA2a signaling, and enhanced myocardial energy metabolism. Finally, diminished expression of ANGPTL2 in mice exposed to pressure overload show amelioration of cardiac dysfunction. These results led to the hypothesis that medical suppression of ANGPTL2 might prevent the onset of HF [6].

ANGPTL2 contributes to chronic inflammation and has been implicated in the development of HF. Cardiac rehabilitation (CR), an important component of HF management, has anti-inflammatory effects. However, the effects of CR on serum ANGPTL2 levels in patients with chronic HF have not been investigated [7]. Body weight, body mass index, body fat mass, body fat percentage, anaerobic threshold (AT), C-reactive protein, and total protein (TP) were clinical characteristics that did not correlate with blood NT-proBNP levels but did correlate with serum ANGPTL2 levels. Age, left ventricular ejection fraction, and left atrial dimension were shown to be independently associated with NT-proBNP levels, whereas AT and TP were found to be independent determinants associated with ANGPTL2 levels. It indicated that CR has anti-inflammatory properties and simultaneously enhances exercise tolerance, as demonstrated by decreased blood levels of total protein and ANGPTL2. In individuals with chronic HF, ANGPTL2 might be an important marker of inflammation and impaired exercise tolerance [7].

Similarly, cardiac failure has been associated with certain adipocytokines: obesity, metabolic syndrome, and atherosclerosis are all associated with ANGPTL2, which is expressed primarily in adipose tissue. Individuals with HF have markedly greater serum concentrations of ANGPTL2 than controls. Correlation analysis have demonstrated a positive correlation between ANGPTL2 levels and those of creatinine, fasting glucose, triglycerides, TNF-α, hsCRP, NT-proBNP, and adipocyte fatty acid-binding protein (A-FABP) [8].

In contrast, ANGPTL2 levels are negatively correlated with both left ventricular ejection fraction and high-density lipoprotein cholesterol (HDL-C). Together, the results indicated that ANGPTL2 levels are elevated in the blood in patients with HF, and are potentially associated with inflammation and metabolic derangements [8].

Chronic inflammation and the emergence of age-related illnesses are associated with overexpression of ANGPTL2. ANGPTL2 secretion originates primarily from adipose tissue. Although ANGPTL2 has been associated with the etiology of HF, no research has examined serum ANGPTL2 levels in individuals with HF receiving CR. In patients with chronic HF undergoing the maintenance phase of CR, exercise tolerance might be associated with the inflammatory marker ANGPTL2. Additionally, 6 months after consistent participation in a CR program, individuals with stable chronic HF have been reported to show a substantial decrease in serum ANGPTL2 levels [9].

C1q Complement/Tumor Necrosis Factor-associated Proteins

Biochemical indicators have revolutionized how heart failure is diagnosed. However, assessing patient stability remains difficult. Consequently, new methods for classifying illness severity are needed. Beyond their roles in maintenance of energy balance, the newly identified adipokines C1q/TNF-related protein 3 (CTRP3) and C1q/TNF-related protein 9 (CTRP9) have anti-inflammatory and anti-ischemic properties. One study has indicated diminished CTRP3 and CTRP9 concentrations in patients with HF with reduced ejection fraction (HFrEF) according to the severity of the condition; these changes were associated with elevated rates of morbidity and death [10].

Fibroblast Growth Factor 21

Circulating levels of FGF21 are considerably higher in patients with HF with reduced ejection fraction than in healthy participants. FGF21 staining has been observed in diseased cardiomyocytes, and the levels of FGF21 in the circulation are inversely correlated with the expression of cardiac genes involved in ketone metabolism, thus indicating a potential role of cardiac FGF21 signaling. Remarkably, observations that the FGF21 gene is expressed at extremely low levels in failing and non-failing hearts suggest that the circulating hormone is likely to be synthesized extracardially. B-type natriuretic peptide (BNP) and total bilirubin, indicators of chronic cardiac and hepatic congestion are also positively associated with elevated levels of circulating FGF21. Therefore, the primary source of FGF21 outside of the heart is the liver. These results indicate a putative signaling channel between the liver and heart in human HF, and support that hepatic FGF21 communicates with diseased cardiomyocytes [11].

Evidence had suggested a possible correlation between FGF21 and the prognosis of several cardiovascular disorders, although FGF21 was first identified for its function in controlling glucose and lipid metabolism. However, the link between FGF21 and acute heart failure (AHF) was unknown. Wu et al. therefore investigated whether circulating FGF21 levels might predict the short-term prognosis of patients with AHF. The findings indicated that elevated baseline FGF21 levels were associated with poorer clinical outcomes in patients with AHF. Moreover, serum FGF21 outperformed NT-proBNP in predicting mortality at 3 and 6 months, and therefore might be used as a predictive biomarker for patients with AHF [12].

In addition, Fan et al. have evaluated the relationship between FGF21 and HFrEF, and observed an independent associations between FGF21 and elevated risk of death and readmission in patients with HFrEF. Therefore, FGF21 might be used as a biomarker to track patients HFrEF development [13].

Preclinical research has shown that FGF21 has a role in HF development, by decreasing oxidative stress, cardiac hypertrophy, and inflammation in heart muscle cells. HF is associated with inexplicably high FGF21 levels, similarly to the FGF21 resistance reported in obesity. However, numerous possible confounding variables hinder the interpretation of FGF21 as a clinical biomarker [14].

Osteopontin

A glycoprotein that may be found in plasma, osteopontin, has been shown to be elevated in a number of animal models of heart failure. As a result, it may be a novel biomarker that helps patients with heart failure stratify their risks. Therefore, another study investigated if osteopontin plasma levels are higher in chronic heart failure patients and if they offer a separate prognostic indicator. Thus, osteopontin was proposed as a potential new predictive biomarker for chronic heart failure patients [15].

To investigate the link between the pro-fibrotic matricellular protein osteopontin and the enzymes responsible for the production and cross-linking of collagen type I, which forms fibrils, in hypertensive HF, one study has measured procollagen C-proteinase (PCP), lysyl oxidase (LOX), and OPN expression with histochemical and molecular techniques in cardiac tissue from 21 patients with HF and hypertensive heart disease. The expression of OPN in the myocardium of patients with HF was substantially greater as compared to normal hearts [16].

OPN and LOX, insoluble collagen, and pulmonary capillary wedge pressure have been shown to be directly correlated with LV chamber stiffness but inversely correlated with LV ejection fraction. However, OPN does not exhibit any associations with PCP, or any other factors associated with fibroblast production of collagen or matrix metalloproteinase breakdown. In vitro research has also demonstrated that OPN significantly increases LOX expression and activity in human dermal and cardiac fibroblasts. Therefore, in patients with hypertensive heart disease and HF, an excess of OPN is associated with changes in LV stiffness and systolic dysfunction, elevated LOX levels, and enhanced insoluble collagen production. Furthermore, in human fibroblasts, OPN has been observed to upregulate LOX. Consequently, the OPN–LOX axis may be involved in the production of stiff, resistant-to-degradation collagen, thereby affecting the mechanical characteristics of the left ventricle, and impairing function in patients with HF and hypertrophy [16].

Stawowy et al. have suggested that osteopontin may also be overexpressed in patients with HF. Their results support that aspects and/or processes of dilated cardiomyopathy-associated HF also influence osteopontin expression in humans [17].

Diabetes mellitus (DM) is well recognized to raise the risk of sudden cardiac death (SCD), particularly in individuals with HF with preserved ejection fraction (HFpEF). Currently, no recognized biomarkers can be used to estimate the risk of SCD in patients with both DM and HFpEF. The possibility that osteopontin and several other proteins – low-density lipoprotein receptor (LDLR), dynamin 2 (DNM2), fibronectin-1 (FN1), and 2-oxoglutarate dehydrogenase-like (OGDHL) – might serve as risk indicators for SCD has been examined by Patel et al. That study was additionally aimed at investigating whether these proteins in individuals with DM and HFpEF might be involved in modifiable molecular pathways [18].

OPN, LDLR, FN1, and DNM2 protein expression has been found to be dysregulated in individuals with DM and HFpEF who develop SCD. Specifically, because OPN and soluble LDLR can be detected in the plasma, performing additional prospective investigations might have possible benefits in evaluating the prognostic potential of these plasma biomarkers. Further investigation is required to determine whether changing the expression levels of OPN and LDLR might modify SCD risk in people with both DM and HFpEF [18].

Tumor Necrosis Factor-alpha

Inflammation has a key role in the pathophysiology of HF. TNF-α is an inflammatory cytokine that affects cardiac dysfunction and cardiac remodeling that linked to the development of HF [19, 20]. Tumor necrosis factor receptors 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2) have distinct and opposing effects on remodeling, hypertrophy, nuclear factor kappa B (NF-κB), inflammation, and apoptosis in HF: TNFR1 exacerbates these events, whereas TNFR2 ameliorates them. However, stimulation through both receptors is required to induce diastolic dysfunction and oxidative damage. The effect of TNFR on HF is a crucial consideration in the development of therapeutic anti-TNF approaches [21]. TNF-α increases LV dysfunction in pacing-induced HF, partly by mediating local loss of mitochondrial activity, and increases in oxidative stress and myocyte apoptosis [22].

Pro-inflammatory cytokines are always elevated in congestive HF. TNF-α is an essential pro-inflammatory cytokine that exacerbates HF by causing imbalances via suppressing anti-inflammatory reactions and disrupting the maintenance of homeostasis. The severity of HF is associated with the pro-inflammatory cytokine TNF-α and one of its downstream mediators, interleukin-6, which therefore might potentially serve as biomarkers. Studies focusing on understanding the processes through which pro-inflammatory cytokines cause cardiac dysfunction and failure will be important. This failure can also be due to uncontrolled pro-inflammatory cytokines overriding the anti-inflammatory response and interacting with the sympathetic nervous system [23].

In addition, a substantial portion of patients with community-acquired HF show elevated TNF-α, which is associated with markedly diminished survival and increased risk. TNF-α has been found to be beneficial in risk assessment in patients with HF with preserved and reduced EF [24].

Conclusions

HF is a condition in which obesity is a key risk factor. Several studies have reported that adipokines, such as apelin, adiponectin, chemerin, resistin, RBP4, vaspin, visfatin, leptin, omentin-1, lipocalin-2, and FSTL1, contribute to the onset and development of HF. This article highlights the importance of ANGPTL2, TNF-α, FGF21, Osteopontin, and C1q/TNF-related proteins in the pathophysiology of HF. Nevertheless, additional adipokines, including progranulin, nesfatin-1, monocyte chemotactic protein-1, and plasminogen activator inhibitor-1, remain to be investigated in HF. Critically, further study is necessary to fully understand the intricate interactions among adipokines, adipose tissue, and HF.

Conflict of Interest

No potential conflicts of interest relevant to this article are reported.

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References

1. H Zhao, R Huang, M Jiang, W Wang, Y Chai, Q Liu, et al. Myocardial tissue-level characteristics of adults with metabolically healthy obesity. JACC Cardiovasc Imaging 2023;16(7):889–901.

2. IA Ebong, DC Goff Jr, CJ Rodriguez, H Chen, AG Bertoni. Mechanisms of heart failure in obesity. Obes Res Clin Pract 2014;8(6):e540–8.

3. K Zorena, O Jachimowicz-Duda, D Ślęzak, M Robakowska, M Mrugacz. Adipokines and obesity. Potential link to metabolic disorders and chronic complications. Int J Mol Sci 2020;21(10):3570.

4. S Rafaqat. Adipokines and their role in heart failure: a literature review. J Innov Card Rhythm Manag 2023;14(11):5657–69.

5. S Rafaqat, I Noshair, M Arif, R Hafeez, A Maqbool. Atrial fibrillation and adipokines: a pathophysiological perspective. Cardiovasc Innov Appl 2024;9(1):e946.

6. Z Tian, K Miyata, T Kadomatsu, H Horiguchi, H Fukushima, S Tohyama, et al. ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism. Nat Commun 2016;7(1):13016.

7. C Tanaka, S Kurose, J Morinaga, N Takao, T Miyauchi, H Tsutsumi, et al. Serum angiopoietin-like protein 2 and NT-Pro BNP levels and their associated factors in patients with chronic heart failure participating in a phase III cardiac rehabilitation program. International Heart Journal 2021;62(5):980–7.

8. CL Huang, YW Wu, CC Wu, JJ Hwang, WS Yang. Serum angiopoietin-like protein 2 concentrations are independently associated with heart failure. PLoS One 2015;10(9):e0138678.

9. C Tanaka, S Kurose, N Takao, T Miyauchi, J Iwasaka, I Shiojima, et al. Related factors and changes of angiopoietin-like protein 2 with chronic heart failure patients participating in phase III cardiac rehabilitation. Eur J Prev Cardiol 2022;29(Suppl 1):zwac056.027.

10. C Gao, S Zhao, K Lian, B Mi, R Si, Z Tan, et al. C1q/TNF-related protein 3 (CTRP3) and 9 (CTRP9) concentrations are decreased in patients with heart failure and are associated with increased morbidity and mortality. BMC Cardiovasc Disord 2019;19(1):1–9.

11. S Sommakia, NH Almaw, SH Lee, DK Ramadurai, I Taleb, CP Kyriakopoulos, et al. FGF21 (fibroblast growth factor 21) defines a potential cardiohepatic signaling circuit in end-stage heart failure. Circ Heart Fail 2022;15(3):e008910.

12. G Wu, S Wu, J Yan, S Gao, J Zhu, M Yue, et al. Fibroblast growth factor 21 predicts short-term prognosis in patients with acute heart failure: a prospective cohort study. Front Cardiovasc Med 2022;9:834967.

13. L Fan, L Gu, Y Yao, G Ma. Elevated serum fibroblast growth factor 21 is relevant to heart failure patients with reduced ejection fraction. Comput Math Methods Med 2022;2022:7138776.

14. W Tucker, B Tucker, KA Rye, KL Ong. Fibroblast growth factor 21 in heart failure. Heart Fail Rev 2023;28(1):261–72.

15. M Rosenberg, C Zugck, M Nelles, C Juenger, D Frank, A Remppis, et al. Osteopontin, a new prognostic biomarker in patients with chronic heart failure. Circ Heart Fail 2008;1(1):43–9.

16. B López, A Gonzalez, D Lindner, D Westermann, S Ravassa, J Beaumont, et al. Osteopontin-mediated myocardial fibrosis in heart failure: a role for lysyl oxidase? Cardiovasc Res 2013;99(1):111–20.

17. P Stawowy, F Blaschke, P Pfautsch, S Goetze, F Lippek, B Wollert-Wulf, et al. Increased myocardial expression of osteopontin in patients with advanced heart failure. Eur J Heart Fail 2002;4(2):139–46.

18. M Patel, D Rodriguez, K Yousefi, K John-Williams, AJ Mendez, RB Goldberg, et al. Osteopontin and LDLR are upregulated in hearts of sudden cardiac death victims with heart failure with preserved ejection fraction and diabetes mellitus. Front Cardiovasc Med 2020;7:610282.

19. G Torre-Amione. Immune activation in chronic heart failure. Am J Cardiol 2005;95(11A):3C–8, discussion 38C–40.

20. EJ Armstrong, DA Morrow, MS Sabatine. Inflammatory biomarkers in acute coronary syndromes: part I: introduction and cytokines. Circulation 2006;113(6):e72–5.

21. T Hamid, Y Gu, RV Ortines, C Bhattacharya, G Wang, YT Xuan, et al. Divergent tumor necrosis factor receptor–related remodeling responses in heart failure: role of nuclear factor-κB and inflammatory activation. Circulation 2009;119(10):1386–97.

22. GW Moe, J Marin-Garcia, A Konig, M Goldenthal, X Lu, Q Feng. In vivo TNF-α inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure. Am J Physiol Heart Circ Physiol 2004;287(4):H1813–20.

23. SM Schumacher, SV Naga Prasad. Tumor necrosis factor-α in heart failure: an updated review. Curr Cardiol Rep 2018;20(11):117.

24. SM Dunlay, SA Weston, MM Redfield, JM Killian, VL Roger. Tumor necrosis factor-α and mortality in heart failure: a community study. Circulation 2008;118(6):625–31.