Proinflammatory Cytokine Modulates Intracellular Calcium Handling and Enhances Ventricular Arrhythmia Susceptibility

Abstract

Background: The mechanism of Interleukin-17 (IL-17) induced ventricular arrhythmia (VA) remains unclear. This study aimed to investigate the effect of intracellular calcium (Cai) handling and VA susceptibility by IL-17.Methods: The electrophysiological properties of isolated perfused rabbit hearts under IL-17 (20 ng/ml, N = 6) and the IL-17 with neutralizer (0.4 μg/ml, N = 6) were evaluated using an optical mapping system. The action potential duration (APD) and Cai transient duration (CaiTD) were examined, and semiquantitative reverse transcriptase-polymerase chain reaction analysis of ion channels was performed.Results: There were longer APD80, CaiTD80 and increased thresholds of APD and CaiTD alternans, the maximum slope of APD restitution and induction of VA threshold in IL-17 group compared with those in IL-17 neutralizer and baseline groups. During ventricular fibrillation, the number of phase singularities and dominant frequency were both significantly greater in IL-17 group than in baseline group. The mRNA expressions of the Na+/Ca2+ exchanger, phospholamban, and ryanodine receptor Ca2+ release channel were upregulated, and the subunit of L-type Ca2+ current and sarcoplasmic reticulum Ca2+-ATPase 2a were significantly reduced in IL-17 group compared to baseline and IL-17 neutralizer group.Conclusions: IL-17 enhanced CaiTD and APD alternans through disturbances in calcium handling, which may increase VA susceptibility.

Fir(e)ing the Rhythm

“… 36 Chang et al 37 found that acute IL-17 infusion in rabbits with ischemic heart failure (HF) significantly prolonged APD and induced VAs in vivo and in vitro in a dose-dependent manner. 37 These findings, which were reproduced by Tsai et al 38 in isolated healthy rabbit hearts perfused with IL-17, were prevented/reversed by anti-IL-17–neutralizing antibodies. 37 , 38 Moreover, in a murine model of diabetes mellitus showing APD prolongation associated to I to depression, knockout of IL-17A–encoding gene restored these electrophysiological changes by attenuating the nuclear factor κ light chain enhancer of activated B cells–dependent down-regulation of K + voltage-gated channel interacting protein-2 ( Table 1 ).…”

“…Finally, a very recent study performed on isolated perfused rabbit hearts demonstrated that IL-17 enhances intracellular Ca ++ transient duration and VA susceptibility, along with up-regulation of NCX, RyR2, and phospholamban and inhibition of SERCA2a, and that all these changes were reversed in the presence of anti-IL-17 antibody ( Table 2 ). 38 …”

Prevalence, Outcomes, and Management of Ventricular Arrhythmias in COVID-19 Patients

“…In fact, even though the presence of the virus in cardiac tissue or evidence of myocarditis have been inconsistently detected, 20,21,22 cytokines surge from the systemic immune response are alone sufficient to dysregulate calcium handling, modulate ion channels expression, increase fibrosis and exert a negative inotropic effect, ultimately enhancing the susceptibility to VAs. 23,24,25,26,27 For example, late VAs and epicardial fibrosis at the magnetic resonance were documented in one case months after the resolution of the acute illness. 28 J o u r n a l P r e -p r o o f COVID-19 can provoke cardiac ischemia as well, due to both hypoxia/demanding mechanism, 29 but also as it can eminently be thrombogenic and cause coronary micro-emboli and acute coronary syndromes (ACS).…”

“…--myocite contractile dys-synchrony 18 --COVID-19 related-myocarditis [15][16][17]20,21,26 --ischemia [27][28][29]31 --latent arrhythmic disorders 5,6 --pre-existing cardiac disease 2,10 Secondary --cytokine storm [22][23][24][25][26]42 --hypoxia/hypercapnia 33 --fever/dehydration/acidosis 5,6 --hypokalemia/hypomagnesemia 32,34 --sympatergic tone Extrinsic --hydroxicloroquine/azytrhomicine [35][36][37][38]40,41,54 --adrenergic inotropes 3,10 --bradycardia induced tachyarrhytmias secondary to sedation 3 J o u r n a l P r e -p r o o f…”