HF is based on a complicated interplay of inflammation, neurohormonal stimulation, and immune system alterations. Various important underlying processes have been proven. First of all, inflammation contributes significantly to the genesis of HF and HF with preserved ejection fraction (HFpEF) in particular [4,5]. In addition, it has been observed that an innate increased systematic or cardiac immune response runs throughout the entire inflammatory process on multiple HF subtypes. Inflammation in turn, which is often a chronic issue, is one of the major risk factors for cardiovascular disease (CVD) and the pro-inflammatory molecules in HF that cause a vicious cycle and disrupt the calcium homeostasis and mitochondrial function, thereby impacting myocardial contractility [5]. The pathogenesis and persistency of HF involves inflammatory cytokines, immune cells, and signaling pathways. Cytokine activation and its cross-talk with the adrenal axis, renin-angiotensin aldosterone system (RAAS), as well as the endothelin system, have been considered important elements in the development and exacerbation of HF. Cytokine response involving the participation of IL-1β and IL-6, TNFα, and Transforming Growth Factor-β (TGFβ) is known to be highly critical in the pathogenesis of HF and in regulating its inflammation-based process. As such, the modulation of cardiac inflammation has been identified as an attractive target for the treatment of HF, and has also been the focus of numerous clinical trials.

Secondly, HF progression is also strongly associated with the stimulation of neuro-hormonal processes, including the Sympathetic Nervous system (SNS), endocrine and immune systems. Insulin sensitivity disturbance, microvascular dysfunction and cardiac remodeling that cause aggravation of the disease may be associated with the activation of the above-mentioned processes. Thirdly, there is an increasing body of evidence that focuses on gut microbiota as well as their metabolites, which also plays a significant part in the physiopathology HF. Derived from gut microbiota metabolism imbalance, gut microbial-derived metabolites could be involved in cardiac dysfunction and inflammation. The heart may be connected with gut failure through heart–gut axis [6]. Moreover, Toll-like receptors (TLRs) and nod-like receptors (NLRs), as part of the innate immune response system, have also been suggested to be a new therapy target of HF. They act as upstream regulators of cytokine activation during the pathogenic inflammation associated with HF, and the role of these receptors in HF has been a recent area of intensive research with potential therapeutic applications [7].

In focusing on the underlying inflammatory processes of the disease, it is worth mentioning that inflammation occurs due to a complex interaction between pro-inflammatory cytokines, adhesion molecules, and oxidative stress. The disorder is characterized by a dysregulated immune response, which results in myocardial remodeling and, finally, cardiac dysfunction [1]. Patients with HF show high levels of pro-inflammatory cytokines, all of which are secreted in a continuous manner [8]: TNF-α, IL-1, -6, -8, -10, -10R, -33 and -18 [1], vascular endothelial growth factor (VEGF), high-sensitivity C-reactive protein (hs-CRP), brain natriuretic peptide (BNP), vascular cell adhesion molecule 1 (VCAM-1), C-C Motif Chemokine Ligand 2 (CCL2), monocyte chemoattractant protein (MCP)-1 [9], intercellular adhesion molecule-1 (ICAM-1) [10], myeloperoxidase (MPO), and inducible nitric oxide synthase (iNOS) [3]. They also activate various cells within the myocardium; which shows that they are not only confined to the immune system [8]. The severity, course of development and prognostic evaluation of the disease and its exacerbations are associated with them [3]. Additionally, higher levels of these inflammatory mediators injure the endothelium, resulting in decreased smooth muscle cell activity promoting vascular tone. However, other studies have reported higher levels of anti-inflammatory substances such as adiponectin and soluble Fas/soluble Fas ligand, which were associated with unfavorable outcomes [10,11,12].

It is pertinent to mention some specific molecules, which play a key role in the pathogenesis of HF. Firstly, IL-1 action in cardiovascular disease depends upon molecular pathways of IL-1R1-IL-1RAcP and activation of interleukin-1 receptor-associated kinases (IRAKs), as well as tumor necrosis factor receptor associated factor 6 (TRAF6) [13]. It causes the translation of these transcriptional messenger RNA factors p38 mitogen activated protein kinase (p38 MAPK) and nuclear factor kappa B (NF-kB) and, hence, its migration into the nucleus. Secondary messengers are molecules that are coded by hundreds of target genes and come at this point to create different kinds of signaling pathways [13]. Among the mechanisms linking IL-1 to impaired systolic function, IL-1 inhibits L-type calcium channels, uncouples the β-adrenergic receptor (β-AR) from the adenylyl cyclase (AC), and induces transcriptional and posttranslational changes in phospholamban and sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) [13]. IL-1 also increases NOS expression, leading to increased nitric oxide (NO) activity. This further disrupts calcium and β-AR signaling and impairs mitochondrial function. These molecular mechanisms contribute to inflammation and cardiac dysfunction by promoting the production of proinflammatory cytokines and chemokines, and also by inducing contractile dysfunction in cardiomyocytes and reversible cardiomyopathy in animal models. Additionally, IL-1 has been shown to increase within hours in ischemic models of HF and is associated with the progressive nature of the cardiac dysfunction [13].

Other inflammatory markers such as MPO and CRP serve as indicators of cardiac stress and remodeling through their association with the pathophysiological processes of the disease. MPO, an enzyme released by activated neutrophils, has been linked to ventricular dysfunction and remodeling after myocardial infarction (MI), indicating its role as a marker of cardiac stress and remodeling [14,15]. On the other hand, CRP, an acute-phase reactant produced by the liver in response to inflammation, has been associated with the inhibition of pyruvate dehydrogenase activity and mitochondrial function of cardiomyocytes, further contributing to cardiac dysfunction and remodeling [14,15]. These mediators modulate the phenotype and function of myocardial cells. They have negative inotropic effects, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrix-degrading phenotype in fibroblasts. Additionally, they may exert chronic fibrogenic actions, leading to interstitial fibrosis, which may increase myocardial stiffness, further contributing to the pathogenesis of HFpEF [9]. Likewise, continuing the reference to interleukins, the continuous activation of oncostatin M (OSM), a cytokine of the IL-6 family, is implicated in cardiac remodeling and inflammatory cardiomyopathy [1]. It induces dedifferentiation of the cardiomyocytes, promoting the progression of HF in dilative cardiomyopathy [8].

Lastly, Bcl-2 interacting protein 3 (BNIP3) plays a significant role by mediating cell death caused by inflammatory cytokines. It has been found to be induced by TNF-α and NO molecules. It also mediates the detrimental effects of inflammatory agents, inducing IL-6 and resulting in the progression of HF. Additionally, its activation during stress or injury depletes endoplasmic reticulum Ca²⁺ and induces mitochondrial dysfunction and apoptosis [16]. The expression of BNIP3 is altered in human HF during inflammation response. Additionally, TNF-α has been found to up-regulate BNIP3 expression, further establishing the association between inflammatory mediators and BNIP3 [16]. Epigenetic regulation of BNIP3 has been shown to play a crucial role in the progression of various types of diseases, including the cardiovascular disorders. Hypomethylation of BNIP3 causes the up-regulation of the protein’s expression level and contributes to the development of coronary artery diseases (CAD) that profoundly provokes cardiac dysfunction [17].

Inflammatory markers contribute to cardiac dysfunction through various mechanisms. For instance, TNF-α has been shown to have negative inotropic effects on the adult mammalian heart, leading to impaired cardiac function and, thus, exacerbation of HF symptoms [14]. Additionally, IL-1 and IL-6, as well as CRP, have been associated with the inhibition of pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes, further contributing to cardiac dysfunction. Furthermore, MPO has been linked to ventricular dysfunction and remodeling after MI, while iNOS inhibition has been found to improve ventricular function and remodeling post-MI [14].

It is worth noticing the pivotal role that vascular endothelium has in the pathophysiology of HF by regulating vascular tone, inflammation, and thrombotic mechanisms. Altered endothelial function is a result of the reduced synthesis and release, along with increased degradation of NO, and elevated production of endothelin-1 (ET-1). Some measures that have a positive effect on the endothelial function are physical activity, along with the traditional and adjunctive treatments for HF [3]. An additional condition that contributes to the formation of inflammation in the context of all phases of HF is oxidative stress. It is generated by the induction of eNOS uncoupling, in addition to the regulation of apoptosis among endothelial cells [18].

Many other aspects of HF are triggered by the underlying inflammatory processes, and they have been observed in both HF with reduced ejection fraction (HFrEF) and HFpEF [10]. These include the left ventricular (LV) function, LV remodeling, cachexia, and hematopoiesis [10,12]. Thus, inflammatory biomarkers can serve as a prognostic clue to the appearance of all these alterations. In HFpEF, inflammation plays a crucial role, particularly in response to cardiac pressure overload (e.g., hypertension). In such conditions, inflammation is one of the earliest pathophysiologic findings; it appears with the elevation of endothelial adhesion molecules levels, with an increased production of inflammatory cytokines, and with the inflammatory infiltration (activated inflammatory cells) of the myocardium [19].

Cytokines aggravate chronic HF symptoms (e.g., hemodynamic imbalances), induce weight loss, and are directly cardiotoxic, resulting in a decline in myocardial tissue [17]. Chronic inflammation with elevated proinflammatory cytokine levels is considered to have a pathogenesis role in myocardial remodeling. This is established by impairing myocardial contraction, causing ventricular hypertrophy, and activating apoptosis mechanisms. The persistent inflammation involving increased levels of inflammatory cytokines plays a pathogenic role by influencing heart contractility, inducing hypertrophy, and promoting apoptosis, contributing to myocardial remodeling. The inflammatory mediators may, in giving significant prognostic information and increased levels of cytokines in HF patients, indicate major pathogenetic mechanisms [20]. It is shown that NF-κB activation and increased levels of CRP highlight the pathogenesis of immune perturbance in chronic HF. Comparatively, the development of HF is usually based on chronic inflammation processes, which occur, for example, among patients suffering from CAD. Necrosis is another type of cell death (the most frequent) associated with cellular pathology and HF, LV dysfunction, negative inotropic effects, changes in the cardiac metabolism, myocardial remodeling, and HF progression [16]. Activating signals, like heat shock proteins, High-mobility group box 1 (HMGB1), Adenosine Triphosphate (ATP), and ROS released by damaged myocytes and extracellular matrix work as initiators of inflammatory response. Furthermore, NO and Reactive Oxygen Species (ROS), mainly in the highly inflamed environment of ischemic heart disease, interact to cause increased cell injury, as well as maintain the inflammation. The latter ultimately leads to function failure of the myocardium [16].

There are certain comorbidities that contribute to persistent low-grade inflammation and exert deleterious effects on organ systems beyond the heart, such as skeletal muscle oxygen extraction during exercise, anemia, sarcopenia, sodium retention in the kidneys, and increased pulmonary pressures during exercise due to pulmonary vasoconstriction, all of which contribute to dyspnea and reduced exercise tolerance in HF [21]. It is equally interesting that evidence of viral infection in patients with HF and the associated immune response suggests a direct link between inflammation and HF. Additionally, chronic immune disorders like rheumatoid arthritis have been associated with an increased risk of HF, particularly the nonischemic type, indicating that chronic inflammation may directly lead to HF. In terms of immune response, while certain CD4+ regulatory T cells have been found to be cardioprotective, preventing the progression of HF, the balance of immune-mediated injury and repair remains poorly understood, especially in the chronic phase of myocardial injury [22]. If inflammation is a direct cause of HF, treatments targeting the immune response may be beneficial. However, if inflammation primarily serves as a marker of disease, immune modulatory treatment may not be effective, but targeting patients with documented inflammation to identify and treat unrecognized LV dysfunction could be beneficial [22].

The use of anti-inflammatory medications in HF has been prompted by the recent finding that abnormally high levels of specific inflammatory biomarkers (e.g., NT-proBNP, CRP, pentraxin 3, and a combination of other serum markers) might predict future cardiovascular events. Prognostic biomarkers can be used for the evaluation and the guidance of any given treatment. However, challenges with their clinical surveillance have made a more focused strategy for identifying individuals who would benefit from specific approaches necessary [23]. CRP has been linked with characteristics of more severe stages of HF and has been found to be independently related to unfavorable outcomes, suggesting that it may be beneficial for determining if patients would benefit from treatment with statins [24]. Moreover, Anand et al. [25] showed that both CRP and TNF can independently predict morbidity and mortality. Additionally, Food and Drug Administration (FDA) recently approved two prognostic inflammatory biomarkers in HF, soluble ST2 and galectin-3, for the prediction of outcomes in HF patients. There is even greater growing interest in pentraxin-3 as a novel cytokine biomarker, further expanding the repertoire of inflammatory biomarkers used for prognostication [25]. In addition, the CD14+ + CD16+ monocyte population has been implicated as a potential inflammatory biomarker, with its levels correlating to the severity of HF, LV ejection fraction (LVEF), and pro-BNP levels. This suggests the potential of this monocyte population as an inflammatory biomarker [25]. IL-1 also plays a significant role in HF, as it is upregulated in HF and associated with a worse prognosis. IL-1 has been shown to induce contractile dysfunction in isolated cardiomyocytes and reversible cardiomyopathy in mice, as well as increase within hours in ischemic models of HF, and is associated with the progressive nature of cardiac dysfunction. Additionally, IL-1 blockade has been found to limit postinfarction ventricular remodeling, improve ventricular systolic and diastolic function, and increase survival in animal models. It has been also identified as a cardiodepressant factor in severe sepsis and has been linked to the presence of a circulating cardiodepressant factor of acute decompensated HF patients [13]. Hofmann and Frantz also pointed out that it is necessary to identify novel biomarkers, as well as novel imaging modalities to characterize the immunological status of each patient and to provide individualized treatment. If this happens, the suitability of patients with HF for the targeted immuno-modulation therapy will be determined more easily [26].