Although a genetic basis for familial DCM is well established, the majority of cases of DCM appear to be sporadic; that is, even when the family members of patients newly diagnosed with idiopathic DCM are clinically screened, the majority of family members have no evidence of DCM; thus, patients are ultimately diagnosed with nonfamilial (sporadic) DCM. No large, multicentre study of families whose members have been systematically clinically screened for DCM and also undergone exome or genome sequencing to identify a potential genetic cause has been published to date. A total of 15–30% of patients with DCM may be diagnosed with familial DCM if their family members undertake clinical screening, according to family-based studies
[3]. Historically, large multigenerational familial DCM pedigrees have served as the foundation for the majority of DCM-associated gene discovery. These multigenerational genealogies have provided statistically sound genetic evidence for the causality of variants in DCM-associated genes.
3.2. Autoimmune Myocarditis
Autoimmune myocarditis is a condition in which cardiac muscle is damaged by self-reactive immune cells. This condition is typically associated with numerous genetic and environmental risk factors. Various systemic autoimmune diseases, such as sarcoidosis or SLE (lupus), can compromise cardiac function by a variety of mechanisms
[7][11]. The prognosis for patients with either of these conditions is typically dismal. However, it has been demonstrated that early administration of glucocorticosteroids and immunosuppressive agents improves patients’ conditions
[8][12]. Restoring the equilibrium between autoimmunity and immune tolerance, which is regulated by Th17 and regulatory T cells (Tregs), is one of the primary therapeutic approaches for autoimmune disease
[9][13]. Treg cells are capable of inhibiting autoreactive T cells, and multiple studies have repeatedly identified a deficiency in the quantity or function of Treg cells in autoimmune disorders
[9][13]. Therefore, Treg administration has been demonstrated to be a promising treatment for a variety of autoimmune disorders.
3.3. Post-Viral Myocarditis
Myocarditis is frequently preceded by infection, with viruses being the most prevalent cause of this condition
[10][11][15,16]. There are typically three phases of viral myocarditis. During the first phase, which lasts several days, the virus obtains entry and actively replicates. Therefore, the innate immune response will be triggered against these exogenous substances. During this phase, direct viral burden contributes significantly to myocardial damage. The subsequent phase revealed that an excessive immune response is the leading cause of cardiac damage. During this phase, T cell infiltration has been reported alongside an increase in fibrosis and calcification of the myocardium. In the final phase, patients may experience either remission or progression to dilated cardiomyopathy (DCM), depending on the heart’s capacity to recover from previous insults of direct viral injury and immune persistence
[10][11][15,16].
3.4. Immune Checkpoint Inhibitor-Related Myocarditis
Immune checkpoint inhibitors (ICIs) are a novel type of cancer treatment that is being applied to a growing number of cancer types for example malignant melanoma, Hodgkin’s lymphoma and non small cell lung cancer to name a few. The immune modulators CTLA-4, PD-1, and PD-L1 are the targets of ICIs
[12][19]. ICIs may, however, stimulate T cell activity against host tissues, leading to immune-related adverse events (irAEs). Myocarditis is a rare adverse reaction associated with ICIs, with incidence rates ranging from 0.1% to 2%
[13][20]. With ICI myocarditis, there is a reduction in absolute lymphocyte count and an increase in neutrophils, both of which are associated with subsequent significant adverse cardiac events
[13][20]. Cardiovascular magnetic resonance (CMR) utilising tissue characterisation techniques such as late gadolinium enhancement (LGE) and the presence of myocardial oedema, is the gold standard non-invasive imaging test for diagnosis and risk prediction in myocarditis of other aetiologies.
CTLA-4 is a crucial regulator of T cell inhibition via multiple mechanisms, including negative signalling of B7-CD28, inhibition of IL-2 mRNA expression, and interaction with the TCR-CD3 pathway to inhibit T cell activation
[14][15][22,23]. After IFN-g exposure, PD-1 and PD-L1 were highly expressed to prevent T-cell-mediated signalling on host cells. The FDA has currently approved seven ICI medications for cancer therapy. Although ICI-associated myocarditis is uncommon, its mortality rate can reach 25 to 50 percent
[15][23]. In addition, this adverse event was reported to occur within 1 to 2 months of the initial ICI dose. The underlying pathogenesis of ICI-associated myocarditis remains unknown.
4. Role of Fractalkine Signalling in Cardiovascular Disease
4.1. Fractalkine (CX
3
CL1) and Its Receptor CX
3
CR1 in Atherogenesis
Fractalkine consists of 373 amino acids and is the only member of the CX
3C chemokine subfamily with both membrane-bound and soluble variants
[16][17][18][19][25,26,27,28]. The former is an adhesion molecule with four sections: an extracellular N-terminal domain, a mucin-like stalk, a transmembrane alpha helix, and a brief cytoplasmic tail. Fractalkine can be cleaved at the juncture of its stalk and transmembrane helix my metalloproteinases ADAM 10 or ADAM 17 to produce its soluble form, which functions as a chemoattractant (see
Figure 2) for monocytes, NK cells, and T cells.
Figure 2. Transmembrane chemokine Fractalkine (CX
3CL1). Graphic illustration of the transmembrane chemokine. It contains an extracellular N-domain, mucin stalk and a short cytoplasmic trail. The soluble form is generated by shedding and cleavage by metalloproteinases ADAM 10 and ADAM 17. The resulting release of the mucin-like stalk and chemokine domain acts as a chemoattractant for inflammatory cells.].
4.2. CX
3
CR1 and Myocardial Infarction
The CX
3CR1 receptor is essential for the recruitment of lymphocytes that contribute to cardiac ischaemia/reperfusion injury and subsequent adverse remodelling. A subset of lymphocytes with cytotoxic properties adhere and are marginalised upon interaction with the fractalkine receptor CX
3CR1 expressed on circulating lymphocytes (see
Figure 3).
![Cells 12 02377 g003](/media/item/202310/652106e233e10cells-12-02377-g003-550.jpg)
Figure 3. Soluble fractalkine (CX
3CL1) binds to CX
3CR1, its G-coupled receptor, resulting in lymphocyte activation adhesion and migration across the endothelium, resulting in tissue damage.
4.3. Fractalkine Signalling in Heart Failure
In a study conducted by Nakayama and colleagues, higher myocardial immune activation was found to be associated with a poor prognosis for DCM
[20][8]. Patients with higher counts of CD3
−, CD68
−, and CD163-positive infiltrating cells had substantially worse outcomes (
p = 0.007,
p = 0.011, and
p = 0.022, respectively). The association between M2 macrophages and collagen synthesis suggests that ventricular remodelling in DCM may be associated with the phenotypic polarisation of macrophages towards M2. CX
3CR1 and CX
3CL1 expression is consistently upregulated in cardiac tissue from heart failure patients with various aetiologies, including end-stage DCM. CX
3CR1 and CX
3CL1 gene expression has been found to be elevated in both DCM and ICM patient cardiac tissue
[21][32]. Richter and coworkers measured the plasma levels of CX
3CL1 in 349 patients with advanced systolic heart failure
[22][53].
5. Link between CX3CR1 and Cytomegalovirus
Cytomegalovirus (CMV) is a pervasive herpes virus with a seroprevalence of greater than 60% in individuals aged 50 and older in the majority of studies
[23][54] and 85% in those aged 80 and older
[24][46]. CMV causes an asymptomatic or moderate initial response in immunocompetent hosts, but it is never eliminated from the body, resulting in lifelong latent infection with the possibility of reactivation
[23][54]. Seropositivity for CMV induces significant changes in the T cell composition of the host. CMV-specific CD8
+ and, to a lesser extent, CD4
+ memory T cells, particularly TEMRA cells, account for a disproportionately high proportion of total T cells; this phenomenon is known as memory inflation
[25][26][27][55,56,57]. There is evidence that memory expansion in the CD8 compartment is greater in older patients, indicating that the CMV-specific memory population continues to expand with age, but this is less evident and has been less thoroughly studied in CD4 T cells
[28][48]. Memory inflation may be an adaptive response to suppress reactivations
[29][58], and whether this unbalanced expansion impedes the immune system’s function remains debatable, as some contend that the CD8 compartment is sufficiently plastic to permit expansion of one phenotype without disruption of others
[30][59]. In the presence of viral antigen, CMV-specific CD4
+ T cells have been shown to cause endothelial injury, with more damage occurring in donors with higher frequencies of CMV-specific CD4
+ T cells
[31][32][33][60,61,62]. This injury is caused by the release of IFN-g and TNF-α by T cells at sufficient levels to induce endothelial cell induction of fractalkine, thereby attracting natural killer (NK) cells and monocyte-macrophages, as depicted in
Figure 4.
Figure 4. CMV-specific T cells produce interferon-g and TNF-α, which induce fractalkine expression on the endothelium. The soluble form attracts monocytes and NK cells, and the membrane-bound form catches and internalises them, removing them from the circulation.
6. Conclusions
The evidence base and existing literature suggest that upregulation of fractalkine/CX
3CR1, together with CMV seropositivity and consequent migration of immune and inflammatory cells, is associated with worse outcomes in patients with inflammatory conditions including dilated cardiomyopathy.
ThWe
scholars hypothesise that dilated cardiomyopathy, whether acquired secondary to infection, autoimmunity, drugs and toxins or familial in origin, may lead to cardiac inflammation and fibrosis, resulting in adverse remodelling through the interplay of these factors. Robust observational studies are required to identify a subgroup of at-risk patients with dilated cardiomyopathy through in-depth phenomapping, genotyping, evaluation of immune status, and viral presence, which in turn may inform future drug trials utilising immune modulators to target this pathway.