Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle abnormality, is a major cause of sudden cardiac death (SCD). However, the burden of SCD and risk factors in ARVC are not clearly described. Thus, we estimated the rates and predictors of SCD in ARVC in a meta-analysis. Methods and results PubMed, Embase, and Web of Science were searched through 7 April 2021. Prospective studies reporting SCD from ARVC cohorts were included. Data were independently extracted by two reviewers and pooled in a random-effects meta-analysis. Fifty-two studies (n = 5485 patients) with moderate-to-low risk of bias were included. The pooled annualized rates of SCD were 0.65 per 1000 [95% confidence interval 0.00–6.43, I2 0.00%] in those with an implantable cardioverter-defibrillator (ICD) and 7.21 (2.38–13.79, I2 0.0%) in non-ICD cohorts: 7.14 in probands and 8.44 for 2010 Task Force Criteria (TFC). Multivariable predictors of life-threatening arrhythmic events including SCD were: age at presentation [adjusted hazard ratio 0.98 (0.97–0.99)], male sex [2.08 (1.29–3.36)], right ventricular (RV) dysfunction [6.99 (2.17–22.49)], QRS fragmentation [6.55 (3.33–12.90)], T-wave inversion [1.12 (1.02–1.24)], syncope at presentation [2.83 (2.40–4.08)], previous non-sustained ventricular tachyarrhythmia [2.53 (1.44–4.45)], and the TFC score [1.96 (1.02–3.76)], (P < 0.05). Predictors of appropriate ICD therapy were RV dysfunction, syncope, and inducible ventricular arrhythmia (P < 0.01). Conclusion This meta-analysis demonstrates a high burden of SCD in ARVC patients, especially among probands and ARVC defined by the modified TFC. Better strategies are required to improve patient management and prevent SCD in ARVC. PROSPERO ID: CRD42020211761.

CXCR4 is a G-Protein coupled receptor that is expressed nearly ubiquitously and is known to control cell migration via its interaction with CXCL12, the most ancient chemokine. The functions of CXCR4/CXCL12 extend beyond cell migration and involve the recognition and disposal of unhealthy or tumor cells. The CXCR4/CXCL12 axis plays a relevant role in shaping the tumor microenvironment (TME), mainly towards dampening immune responses. Notably, CXCR4/CXCL12 cross-signal via the T and B cell receptors (TCR and BCR) and co-internalize with CD47, promoting tumor cell phagocytosis by macrophages in an anti-tumor immune process called ImmunoGenic Surrender (IGS). These specific activities in shaping the immune response might be exploited to improve current immunotherapies.

Chemokines engage in heterodimeric interactions to activate or dampen their cognate receptors in inflammatory conditions. The chemokine CXCL12 forms with the alarmin HMGB1 a patho-physiologically relevant heterocomplex (HMGB1-CXCL12), whose formation synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. However, the molecular details of complex formation were still elusive. Through an integrative structural approach (NMR, AUC, ITC, MST, SAXS) we show that HMGB1-CXCL12 represents the first fuzzy chemokines heterocomplex reported so far. HMGB1 and CXCL12 form a dynamic equimolar assembly, rather than involving one HMGB1 and two CXCL12 molecules as previously assumed, with structured and unstructured HMGB1 regions recognizing the dimerization surface of CXCL12. We uncover an unexpected role of the acidic intrinsically disordered region (IDR) in heterocomplex formation and provide the first evidence that the acidic IDR facilitates the ternary HMGB1-CXCL12-CXCR4 interaction on the cell surface. Thus, the interaction of HMGB1 with CXCL12 diverges radically from the classical rigid heterophilic chemokine-chemokine dimerization. Simultaneous interference with the multiple interactions within HMGB1-CXCL12 complex formation might offer novel pharmacological strategies to inhibit its detrimental activity in inflammatory conditions.

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