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Loh, S.X.; Ekinci, Y.; Spray, L.; Jeyalan, V.; Olin, T.; Richardson, G.; Austin, D.; Alkhalil, M.; Spyridopoulos, I. Fractalkine in Cardiovascular Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/47598 (accessed on 08 August 2024).
Loh SX, Ekinci Y, Spray L, Jeyalan V, Olin T, Richardson G, et al. Fractalkine in Cardiovascular Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/47598. Accessed August 08, 2024.
Loh, Shu Xian, Yasemin Ekinci, Luke Spray, Visvesh Jeyalan, Thomas Olin, Gavin Richardson, David Austin, Mohammad Alkhalil, Ioakim Spyridopoulos. "Fractalkine in Cardiovascular Disease" Encyclopedia, https://encyclopedia.pub/entry/47598 (accessed August 08, 2024).
Loh, S.X., Ekinci, Y., Spray, L., Jeyalan, V., Olin, T., Richardson, G., Austin, D., Alkhalil, M., & Spyridopoulos, I. (2023, August 03). Fractalkine in Cardiovascular Disease. In Encyclopedia. https://encyclopedia.pub/entry/47598
Loh, Shu Xian, et al. "Fractalkine in Cardiovascular Disease." Encyclopedia. Web. 03 August, 2023.
Fractalkine in Cardiovascular Disease
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12144821

Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1.  Fractalkine receptor CX3CR1 is associated with microvascular obstruction (MVO) in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and intramyocardial haemorrhage (IMH). 

acute myocardial infarction atherosclerosis inflammation fractalkine CX3CR1

1. Role of Fractalkine and Its Receptor in Atherosclerosis

Atherosclerosis is the pathological basis for coronary artery, peripheral arterial, and cerebrovascular disease. It is a chronic inflammatory process affecting medium- to large-sized vessels which typically contain lipid-rich plaque lesions. Atherosclerosis is thought likely to be an immunomodulatory event, and therefore the prevalence of FKN or its receptor within different types of immune cells is highly relevant to the development of atherosclerosis. Wong et al. investigated coronary arteries in young patients who had died through acute trauma. They compared the presence of FKN staining in normal coronaries, with those from atherosclerotic and diabetic coronaries [1]. Surprisingly, FKN was not found within normal coronary arteries, but CX3CR1 was found to be diffuse in the cytoplasmic staining amongst the smooth muscle cells (SMCs). Comparatively, atherosclerotic coronary arteries demonstrated staining across the board in the intimal, medial, and adventitial layers for both FKN and CX3CR1. When this was compared to diabetic vessels, similar patterns of staining to atherosclerotic coronaries were found, with even heavier staining for FKN in the deep intimal layer demonstrated. This study was backed up when plasma FKN levels were compared between diabetics and non-diabetics, which demonstrated an increased level of FKN in diabetics compared to their non-diabetic counterparts [2]. Therefore, it is clear that FKN and CX3CR1 must play important roles in the pathogenesis of atherosclerosis and can be potentially used to assess cardiovascular risk in patients [3].
As gene silencing would be challenging in humans, controlling monocyte and macrophage action by means of pharmacological inhibition was demonstrated to provide similar and encouraging effects when tested again on rodents, as monocytosis was inhibited by blocking CX3CR1 [4]. All three of the above studies revealed that inhibition of CX3CR1 subsequently leads to prevention of atherogenesis. Whilst the systemic effect of treatment showed promising outcomes, Ali et al. studied the local impact of CX3CR1 by coating a prototype drug-eluting stent with a CX3CR1 antagonist [5]. The authors found reduced vascular inflammation and proliferation of SMCs in porcine models. This was compared to other polymer-coated stents without CX3CR1 antagonists as well as bare metal stents. The study demonstrated a 60% reduction in in-stent restenosis, with further reduction in peri-stent inflammation and accumulation of monocytes and macrophages, and minimal impact of endothelialisation. Hence, these studies demonstrate the proof of concept for the use of CX3CR1 antagonists in inhibiting neointimal hyperplasia. Nonetheless, there are two single nucleotide polymorphisms of the CX3CR1 molecule that have been identified and that contribute towards the risk of developing coronary artery disease, namely CX3CR1-V249I and CX3CR1-T280M [6]. CX3CR1-I249 allele heterozygosity was found to reduce the number of FKN binding sites, therefore actually reducing the risk of acute coronary events, and thus presents an independent genetic risk factor on its own [7]. Another study found a close association between CX3CR1-V249I and T280M polymorphisms, coronary plaque vulnerability, and acute MI, confirming that the subjects with the I249 allele display a low level of T cell inflammation and a reduced risk of developing vulnerable plaques [8]. Therefore, CX3CR1 is likely to amplify the Th1 immune response, directly related to plaque vulnerability, thus standing out as a potential target in fatal AMI prevention. This allows for the risk stratification methods using CX3CR1 gene coding to quantify the risk of coronary artery disease independent of other factors. In addition to leukocyte attraction, FKN expressed by endothelial cells can also activate and degranulate platelets that contain CX3CR1-corresponding receptors [9]. These platelets then trigger P-selectin surface expression, which then attach onto monocytes, allowing for more monocytes to transmigrate [10]. This complex formation can be a key aspect, especially when MI occurs as a consequence of atherosclerotic plaque rupture, causing platelet activation and aggregation [6].

2. Significance of Fractalkine and Its Receptor in Myocardial Infarction

As coronary atherosclerosis progresses further, it can become symptomatic, manifesting clinically as stable angina, or with acute coronary syndromes such as the emergency presentation of ST elevation myocardial infarction (STEMI). Several studies have looked at the relevance of sFKN as well as CX3CR1-expressing cells in the context of plaque rupture. Using intracoronary imaging methodology of either intravascular ultrasound (IVUS) or optical coherence tomography (OCT) to understand plaque morphology, studies have compared the levels of FKN and their corresponding receptors to the instability of plaque disease [11][12][13]. Patients with unstable angina and proven unstable plaque disease were found to have significantly higher levels of FKN and mononuclear cells expressing CX3CR1, as compared to stable angina patients or healthy controls. Hence, it can be surmised that FKN is involved in the pathogenesis of plaque vulnerability and consequently plaque rupture [12]. Additionally, Ikejima also demonstrated an increase in levels of monocytes, T lymphocytes, and NK cells, all of which express CX3CR1, and were seen to be elevated in the unstable angina cohort compared to other patient groups [11]. The evidence of FKN in the presence of a ruptured plaque had already been proven by the studies above; therefore, further investigations of more severe infarcts were performed. A study was performed to identify the different circulating proteins present in the event of an acute coronary syndrome, with the majority being STEMI patients. Helseth et al. identified a significant inverse relationship between total ischaemic time with soluble FKN (sFKN) levels where the cut-off was more or less than 4 h [14]. However, this study was not consistent in terms of timing of venepuncture as it was performed between 6 and 24 h of the PCI procedure with a median time of 18 h. Hence, an important study was subsequently performed by Njerve et al., which managed to demonstrate that in comparison to patients with stable angina, those with an acute MI were found to have statistically significant higher levels of FKN up to 12 h post procedure [15]. Levels then returned to those of patients with stable angina by 24 h and the reverse was seen in gene expression of CX3CR1 in patients with acute MI. However, Njerve failed to demonstrate any relationship between the levels of FKN and CX3CR1 expression with myocardial injury by means of troponin, CK-MB, or even infarct size and left ventricular ejection fraction (LVEF) measured on MRI scans. Another study demonstrated a higher level of sFKN in patients with acute STEMI as compared to stable angina, with a rapid decline in levels of sFKN within 24 h with successful reperfusion during PPCI [16][17]. Patients with an acute STEMI maintained a persistently higher level of sFKN compared to the stable angina group if they had not undergone the PPCI procedure. Moreover, the higher level of sFKN was positively correlated with the NT-proBNP level at 1 month, implying worse cardiac function. Our own studies showed that the level of sFKN dipped to its lowest point at 15 min post reperfusion and its level rapidly rose to a peak at 90 min [18]. This was coincidentally correlated with the lowest level of T-cell lymphopenia, which was shown to have a poorer prognosis for patients due to the larger development of microvascular obstruction (MVO). Aside from a demonstration of increased risk of developing poorer cardiac function, levels of FKN had also been proven to be prognostic for the likelihood of developing major adverse cardiovascular events (MACEs) in STEMI patients. Yao et al. revealed a positive correlation between the level of FKN day 1 post PPCI with the level of troponin at day 7 [16]. FKN levels were also found to be inversely proportional to the LVEF which was taken at 1 month, and that FKN was an independent predictor for MACE, whereby a higher FKN level at day 1 lead to an increased risk of MACE following a year’s follow-up period.

3. History of Myocardial Reperfusion Injury

A timely reperfusion of an occluded coronary artery is crucial to restore myocardial blood flow, as it is a prerequisite for myocardial salvage. In the event of total or partial coronary occlusion, this can cause a myocardial infarction. There are different methods to achieve reperfusion of the blocked artery, such as thrombolysis, emergency coronary angioplasty, or even, in extreme situations, coronary artery bypass grafting (CABG). These procedures are all performed with the intent of minimising myocardial cell death, preventing heart failure, and improving survival benefits [19]. However, the paradoxical evil of reperfusion itself has been demonstrated to cause harm to the myocardium in the form of ischaemia/reperfusion (IR) injury. This makes reperfusion therapy a double-edged sword towards the threatened myocardium of those who have been affected. The theory of IR injury was thought to have been introduced in the 1930s [20]. It was subsequently described by Jennings and his team in the 1960s [21][22]. Their study demonstrated an accelerated histological change in the canine’s myocardium causing myocardial cell death after subjecting canine hearts to a period of ischaemia via coronary ligation. Since then, as scientific experiments have progressed, there have been two reversible and two irreversible factors that have been postulated to contribute to the development of reperfusion injury, as shown in the Table 1 [20][23][24][25].
Table 1. Reversible and Irreversible Factors of IR Injury.
Reversible Factors Irreversible Factors
Reperfusion arrhythmia Microvascular obstruction (MVO)
Myocardial stunning Lethal reperfusion injury
IR injury is considered significant because it contributes up to 50% of the final myocardial infarct size in animal models [23]. This also affects the degree of severity of left ventricular ejection fraction (LVEF) in a patient, subsequently leading to heart failure (HF). However, the exact mechanism and extent of IR injury in patients remains unclear.

4. Role of Fractalkine Signalling in Myocardial Reperfusion Injury

The duration of myocardial ischaemia following coronary artery occlusion is a key determinant of infarct size, and rapid reperfusion by PPCI improves clinical outcome [26][27]. However, even in patients with timely and successful stent PCI and normalised antegrade flow, imaging demonstrates failed myocardial reperfusion in 50% of patients, visible as MVO by cardiac MRI, which is an independent predictor of death and heart failure [28][29]. Severe reperfusion injury leads to intramyocardial haemorrhage (IMH), where disturbed vascular integrity and erythrocyte leakage accumulate iron-degradation products, which trigger persisting inflammation and fibrosis, resulting in adverse ventricular remodelling and, finally, heart failure [30]. Hence, two preventable therapeutic targets warrant clinical research: (a) prevention of reperfusion injury that would abrogate IMH, and (b) reduction in post MI inflammation to prevent adverse remodelling, thereby averting heart failure and death. As myocardial infarction has been implicated to be one of the main causes of heart failure, and one of the independent factors contributing to this is myocardial ischaemia/reperfusion (I/R) injury, the role played by FKN/CX3CR1 has also been assessed. In vitro models of murine neonatal cardiomyocytes were subjected to a period of 3 h anoxia with an anaerobic buffer, and then subsequently reoxygenated for 2 h before being exposed to different quantities of sFKN [31]. The study demonstrated that FKN encouraged myocardial I/R by means of influencing expression of atrial natriuretic peptide (ANP), intracellular adhesion molecule-1 (ICAM-1), and matrix metalloproteinase-9 (MMP-9) which are all involved in causing cardiac dysfunction [31]. Neutralising FKN using a FKN antibody (TP233) leads to an improved heart function and pressure loading in the setting of experimental MI. Recent preclinical studies have implicated senescent cells, induced by ischemia/reperfusion (I/R), as a significant contributor to the inflammatory response and a source of FKN release [32][33][34]. Notably, intriguing findings suggest that the elimination of senescent cells post I/R decreased myocardial FNK expression, and was associated with notable benefits, including improved cardiac function and reduced scar size [32]. Moreover, the level of FKN being expressed correlated with the severity of heart failure expressed by the murine hearts. This hypothesis is consistent with the findings found in past and present studies looking at FKN/CX3CR1 as a pathogenesis for heart failure, irrelevant of the aetiology of the heart failure itself [35][36][37].

5. T Lymphocytes Become Activated in Heart Failure (HF) and Influence Cardiac Inflammation and Fibrosis

Murine models show that CD4 T cells, including regulatory T cells (Treg), are necessary to form a stable, fibrotic scar and prevent LV rupture following myocardial injury [38][39]. After the scar has formed, however, these cells continue to infiltrate the myocardium and their pro-fibrotic properties contribute to the progression to HF. Depletion of either CD4 or Treg cells in established ischaemic HF reduces interstitial fibrosis and halts LV remodelling [40][41], and this is also seen in non-ischaemic heart failure models [42][43][44]. Conversely, adoptive transfer of T cells from mice after MI is sufficient to induce myocardial fibrosis and LV dysfunction in recipient, naïve mice [40][45][46]. Despite this strong evidence for pathogenicity in mice, it is not known whether T cells have the same pro-inflammatory, pro-fibrotic, harmful function in human HF—a translational gap. Immune checkpoint inhibitors (ICIs) have, however, highlighted T cells’ capacity to cause myocardial damage in non-HF patients. By disinhibiting T cells, often through programmed cell death protein 1 (PD-1) blockade, ICIs promote anti-cancer immune activity, but can also provoke fulminant myocarditis—as seen in PD-1 deficient mice [47][48]. Myocardial specimens from patients with ICI-induced myocarditis have abundant T lymphocytes and macrophages [49], and their peripheral blood contains clonally expanded populations of CD8+CCR7-CD45RA+ effector memory T cells (CX3CR1-expressing CD8+ TEMRA cells) [50]. The mechanisms of T cell migration to the myocardium in chronic HF are also not fully understood. 

6. The Fractalkine Receptor CX3CR1 and Previous/Latent Cytomegalovirus Infection Accelerate Immune Ageing and Increases Cytotoxic T Cells in MI

Interestingly, latent cytomegalovirus (CMV) infection is also associated with clonal expansion of CD8+ memory T cells [51], myocardial T cell infiltration, and ventricular remodelling after MI [52]; whether CMV seropositivity contributes to subclinical myocardial inflammation in HF patients is unknown. CMV-seropositive patients demonstrate signs of accelerated immune ageing following myocardial infarction, and this seems to link with impaired myocardial healing [53][54]. Importantly, in patients with previous CMV infection, where there is known abundance of virus-specific cytotoxic T lymphocytes, it was found (i) an increased Th1 pro-inflammatory response, (ii) enhanced infiltration of the heart with T lymphocytes, and, finally, (iii) adverse cardiac remodelling [52][53][54][55][56]. Together, this indicates that cytotoxic CD4 and CD8 T lymphocytes could be instrumental in ongoing vascular as well as myocardial inflammation in reperfused MI patients. Therefore, identification of potential targets, such as CX3CR1, could provide ideal ground for anti-inflammatory immunotherapy, potentially avoiding progression of patients to future heart failure.

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Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Shu Xian Loh
,
Yasemin Ekinci
,
Luke Spray
,
Visvesh Jeyalan
,
Thomas Olin
,
Gavin Richardson
,
David Austin
,
Mohammad Alkhalil
,
Ioakim Spyridopoulos
View Times: 502
Revisions: 2 times (View History)
Update Date: 03 Aug 2023
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