1 Introduction

Visfatin is an adipokine that elicits paracrine and autocrine effects on the cardiovascular system. Previously, visfatin has been considered to be identical to pre-B cell colony-enhancing factor (PBEF) that promotes the maturation of early B-lineage precursor cells (Adeghate 2008). Further, visfatin has intrinsic enzyme activity as nicotinamide phosphoribosyl transferase (NAMPT) (Rongvaux et al. 2002). NAMPT catalyses the rate-limiting step in NAD+ (nicotinamide adenine dinucleotide) biosynthetic salvage pathway, wherein NAD + is an essential cofactor in several redox reactions (Revollo, Grimm, and Imai 2004). As shown in Fig. 1, NAMPT converts nicotinamide to nicotinamide mononucleotide (NMN); then nicotinamide/nicotinic acid mononucleotide adenyl transferase (NMNAT) transforms NMN to NAD+ (Formentini, Moroni, and Chiarugi 2009).

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Fig. 1

NAD + biosynthesis by salvage pathway. CD38-cyclic ADP ribose hydrolase; NAD + -Nicotinamide adenine dinucleotide; NAM-nicotinamide; NR-nicotinamide riboside; NMN-nicotinamide mononucleotide’; iNAMPT-intracellular nicotinamide phosphoribosyltransferase (visfatin); NMNAT-nicotinate mononucleotide adenylyltransferase’ PARP-poly-ADP ribose polymerase; PPi-pyrophosphate; Vit B3-vitamin B3.

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Visfatin exists in two forms, intracellular and extracellular. Intracellular form exhibits NAMPT enzyme activity so as to maintain the enzyme activities of NAD + -dependent enzymes, hence, the intracellular visfatin regulates cellular metabolism and energy homeostasis (Ho et al. 2009). Whereas the extracellular form, which is synthesised and secreted by adipocytes and several other cell types (Romacho, Sánchez-Ferrer, and Peiró 2013) (including cardiac fibroblasts, cardiomyocytes, vascular smooth muscle cells, endothelial cells, cells in the atherosclerotic plaque, activated immune cells, circulating blood cells), is an adipocytokine which is associated with hormone-like signalling pathways and intracellular signalling cascades (Verdin 2015). As circulating visfatin has been considered as a biomarker of inflammation and endothelial dysfunction (Romacho et al. 2013), here the focus is on the extracellular circulating visfatin and its association with the pathogenesis of heart failure (HF). Interestingly, a recent report has shown that extracellular circulating visfatin does not elicit enzymatic activity (for NMN biosynthesis) due to the insufficient concentration of ATP (the activator of enzymatic activity of visfatin/NAMPT) in the extracellular spaces (Hara et al. 2011), which shows that circulating visfatin functions as an adipocytokine rather than an enzyme (NAMPT).

The physiological relevance and function of circulating visfatin remains controversial. However, enhanced circulating visfatin concentration has been reported in several pathologies (Romacho et al. 2013) including, obesity, type 2 diabetes (T2D), hypoxia, chronic kidney disease, preeclampsia, acute coronary syndromes, cerebrovascular diseases and non-metabolic chronic inflammatory diseases, among the others. Further, strategies to normalize the elevated circulating visfatin concentration are less explored. TMZ also exhibited antiinflammatory activities (Liang et al., 2020; Engin etal., 2022).

Trimetazidine (TMZ), a cytoprotective and an anti-ischemic agent, is a pharmacological drug that was previously approved for angina pectoris (Milinković et al. 2016). Eventually, the direct influence of TMZ in improving the myocardial metabolism via beta oxidation was established (Kantor et al. 2000), besides the other benefits of TMZ. Hence, the European Society of Cardiology (ESC, 2016 guidelines) has included TMZ for the treatment of angina pectoris with HF (Milinković et al. 2016). Since then, experimental and clinical studies have reported on the efficacy of TMZ in HF (Brottier et al. 1990). Different mechanisms by which TMZ exerts its cardioprotective effect includes sirt1 activation (Brottier et al. 1990), energy metabolism (Heggermont et al. 2016), apoptosis of cardiomyocytes, myocardial autophagy (Yang et al. 2019), myocardial interstitial fibrosis, myocardial inflammation, expression of atrial natriuretic peptide (Morgan et al. 2006), modifying the phosphate levels in left ventricle (Fragasso et al. 2006) and electrophysiological influence (Cera et al. 2010). Nevertheless, whether or not TMZ can influence the circulating visfatin concentration is yet to be understood.

2 Mechanisms associated with circulating visfatin and heart failure

Abdominal obesity occurs due to an imbalance between the energy intake and energy expenditure. Further, obesity is associated with T2D and insulin resistance (IR) (LinPark et al. 2017). The two major cellular events that occur in abdominal obesity are white adipose tissue (WAT) inflammation and hypoxia, as shown in Fig. 2. In cardiovascular disease, classically excessive oxidative stress occurs as an underlying molecular mechanism. Such elevated oxidative stress leads to more tissue inflammation and reduced ejection fraction, which cumulatively leads to HF development. Majority of the reports (Erten 2021; Hara et al. 2011; Peiró et al. 2010) show that visfatin concentration is up-regulated in HF. Besides these oxidative stress induced effects, excess reactive oxygen species down-regulates the sirt1 enzyme activity and expression which in-turn leads to increase in circulating visfatin concentration (Vargas-Ortiz, Pérez-Vázquez, and Macías-Cervantes 2019). Therefore, it is possible that excess circulating visfatin contributes to HF development.

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Fig. 2

Flowchart summarizes the reported effects of circulating visfatin in the cardiovascular system and the potential cardioprotective effects of trimetazidine (TMZ) and adjuvant therapy. EC-endothelial cells; ED-endothelial dysfunction; eNOS-endothelial nitric oxide synthase; FGF2-fibroblast growth factor-2; HFrEF-heart failure with reduced ejection fraction; IL-6-interleukin-6; iNOS-inducible nitric oxide synthase; LV-left ventricle; MCP-1-Monocyte chemoattractant protein-1; Mg-magnesium; MMP-matrix metalloproteinase; NAC-N-acetylcysteine; NAD+ - Nicotinamide adenine dinucleotide; NO-nitric oxide; NOx-NADPH oxidase; ONOO-peroxynitrite; ROS-reactive oxygen species; Sirt1-siruin-1; TNFα-tumor necrosis factor-alpha; VSMC-vascular smooth muscle cells; WAT-white adipose tissue; ↑-upregulation; ↓-downregulation.

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3 Potential strategies to alter the concentration of circulating visfatin for ameliorative effect in cardiovascular disease

In obesity, adipose tissue dysfunction and hypoxia, among the other cellular events, are crucial factors in creating imbalances in the ratio of oxidants/antioxidants and pro-/anti-inflammatory molecules. It is evident that TMZ, one of the established conventional drugs in HF therapy, normalizes the circulating visfatin concentration [11]. Further, the effect of selected nutritional supplements, such as niacin (as NAD + booster) (Pirinen et al. 2020), magnesium (as sirt1 activator and anti-inflammatory molecule) (Martins 2016; Veronese et al. 2022) and NAC (as anti-oxidant and anti-inflammatory) (Tenório et al. 2021) are well established. In this context, our proposition is that along with TMZ, inclusion of an adjuvant therapy which comprises of a multi-ingredient nutritional supplement [such as niacin (vitamin B3 form; an NAD + booster), magnesium (sirt1 activator and anti-inflammatory) and N-acetylcysteine (anti-inflammatory and anti-oxidant)] could improve the adverse outcomes in patients with HF, obesity and IR, than TMZ alone. Possibly, TMZ + multi-ingredient nutritional supplement could address the unfavourably altered biochemical parameters (circulating concentrations of visfatin, NAD + and biomarkers of oxidative stress and inflammation) and cardiac structure and function (Fig. 2).

In support of the inclusion of nutritional supplements, one study has reported that Quercetin, a sirt1 activator, reduces visfatin secretion (Vargas-Ortiz et al. 2019). Hence it is possible that TMZ as a sirt1 activator could directly reduce the circulating concentration of visfatin. Interestingly, exercise is known to activate sirt1 (Shu et al. 2021) and TMZ has been reported to improve HF symptoms by sirt1 activation (Milinković et al. 2016). Therefore, based on these reports, it is only logical to consider sirt1 activators as adjuvants for therapeutic effect in HF.

Deficiencies of magnesium and NAD + are prevalent in HF (Zhu et al. 2016). In this regard, based on our hypothesis, supplementation of NAC and magnesium could address the elevated oxidative stress and pro-inflammatory milieu. Parallelly, as a consequence of elevated circulating visfatin and locally generated visfatin in the cardiovascular system, cardiomyocyte cell death could be triggered. Such an apoptosis-induced augmented in vitro cell death has been reported to be abrogated by exogenous NAD + treatment (Zhu et al. 2016). Thus, therapeutically, NAD + booster could potentially mitigate the excess visfatin-induced cell death. Besides this in vitro cytoprotective effect of NAD+, repletion of NAD + in mice fed with nicotinamide riboside (NAD + precursor and direct activator of NAD + biosynthesis) resulted in the reversal of HF with preserved ejection fraction (HFpEF) (Ziobrowski, Hannah N., Sonneville, Kendrin R. Eddy, Kamryn T., Crosby, Ross D., Micali, Nadia, Horton, Nicholas J., Field 2019). For these HF-associated cellular events, supplementation of magnesium for anti-inflammatory effect and niacin as NAD + booster could potentially mitigate the onset or pathogenic progression in HF.

In HF, oxidative stress induces a reduction in the expression and activity of sirt1 (the deacetylase enzyme). This sirt1-deficiency then leads to hyper-acetylated proteins. In addition to the sirt1-deficiency-induced hyper-acetylated proteins, myocardial hyper-acetylated proteins accumulate due to impaired NAD + biosynthesis pathway (causing NAD + deficiency) and compromised sirt3 expression (Ziobrowski, Hannah N., Sonneville, Kendrin R. Eddy, Kamryn T., Crosby, Ross D., Micali, Nadia, Horton, Nicholas J., Field 2019). Besides the NAD + deficiency-mediated hyperacetylation, elevated oxidative stress compromises the sirt1 enzyme activity (Salminen, Kaarniranta, and Kauppinen 2013) which consequently results in accumulation of hyperacetylated proteins. To counter the hyperacetylation milieu, magnesium as sirt1 activator has been reported to be effective. Thus, magnesium supplementation could restore the physiological status of acetylated/de-acetylated proteins in the myocardium.

Together, TMZ and the nutritional supplements including sirt1 activators, antioxidants, anti-inflammatory molecules and NAD + booster could potentially normalize the concentrations of visfatin, NAD+, free radicals and pro-inflammatory molecules, to eventually improve the adverse symptoms of HF. Besides the influences of nutrient supplements, it is possible that TMZ could reduce the excess circulating visfatin level via potential sirt1 activation.

4 Conclusion

To sum up, while the routine HF therapy with TMZ supports the improvement of clinical manifestations of HF and cardiac function, in terms of ejection fraction(Brottier et al. 1990) and the potential reduction of circulating visfatin concentrations, the adjuvant therapy with multiple nutritional supplements could have an additive effect to TMZ, as the individual supplement(s) is/are known for their effect to normalize the adverse cellular events associated with oxidative stress, inflammation, mitigated sirt1 activity and modified circulating concentrations of analytes (visfatin and NAD + ) that leads to the development and progression of HF (Fig. 2). Hence, TMZ with the said nutritional supplements may have therapeutic and preventive effects in HF.

Compliance with ethical standards

Funding None.

Ethical Approval Not applicable.

Research involving human participants and/or animals Not applicable.