Recent research from the Maastricht Cardiomyopathy Registry included 795 consecutive DCM patients who underwent extensive phenotyping, including extensive clinical data on aetiology and comorbidities, imaging, and endomyocardial biopsies ^[6][9]. On the basis of unsupervised hierarchical clustering of principal components, the authors found four mutually exclusive and clinically distinct phenogroups (PG):

• PG1 included 331 patients with mild systolic dysfunction
• (Mean ejection fraction: 43%  ±  9%),
• PG2 included 83 patients with auto-immune disease background
• PG3 included 165 patients with cardiac arrhythmias (mainly atrial fibrillation and ventricular tachycardias), including patients with genetic causes (Familial cardiomyopathy)
• PG4 included 216 patients with severe systolic dysfunction (Mean ejection fraction: 23%  ±  8%)

RNA-sequencing of cardiac biopsy samples (n = 91) revealed a unique molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3, arrhythmia), and metabolic (PG4, low EF) gene expression. In addition, event-free survival varied between the four phenogroups, even after adjustment for well-known clinical predictors. Using decision tree modelling, four clinical parameters (autoimmune disease, ejection fraction, atrial fibrillation, and renal function) were identified by which every DCM patient from two independent DCM cohorts could be assigned to one of the four phenogroups with corresponding outcomes.

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 CX₃C 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.