Table 5.

Clinical Studies Showing an Association Between Cytokine Levels and QTc Prolongation/VAs/SCD

First Author	Study Population	Subjects, n	Controls, n	Key Findings
Adlan et al144	RA	112	—	QTc duration positively correlated with circulating levels of TNF, IL-1β and IL-6
Lazzerini et al145	RA	17	—	Anti-IL-6 therapy (TCZ) was associated with a rapid (12-week) QTc shortening that correlated with the TNF level decrease
Kobayashi et al146	RA	94	42	Anti-IL-6 therapy (TCZ) was associated with a rapid (24-week) QTc shortening
Pisoni et al148	CTD	73	—	QTc prolongation was independently predicted by elevated IL-1β levels
Lazzerini et al147	Acute infections	41	25	QTc prolongation was common (39%) and QTc duration correlated over time with IL-6 and IL-1 levels; in these patients, Kir2.1 channel mRNA expression in PBMCs (which associated with that measured in the ventricular tissue), inversely correlated to IL-1 blood changes
Wu et al149	HIV infection	774	652	Independent association between increasing tertiles of IL-6 and longer QTc duration
Wu et al150	HIV infection	774	652	QT-interval subcomponents (To-p, Tp-e) were higher in patients with HIV than in control subjects; the highest tertile of IL-6 was associated with a 7.3 ms longer To-p.
Heravi et al151	HIV infection	589	534	QTV was increased in patients with HIV than in control subjects and associated with ventricular arrhythmia burden; higher levels of IL-6 and sTNF-R2 were associated with higher QTV
Lazzerini et al152	Various inflammatory diseases	46	—	QTc prolongation in 26% of patients; CRP reduction was associated with significant QTc shortening, which correlated over time with IL-6 level decrease
Lazzerini. et al152	TdP	40	20	In patients with TdP, circulating IL-6 was ∼15–20× higher than in control subjects and comparable to patients with active RA
Elmas et al153	CAD	50	—	In patients with AMI who developed VF, IL-6 levels were higher than in patients with AMI who were not complicated with VF
Safranow et al154	CAD	167	—	IL-6 plasma concentration was an independent predictor for severe VAs, including sustained VT or VF
Fisman et al155	CAD	3,090	—	Patients with CAD who presented with SCD had higher IL-6 levels than those who did not; each 1 pg/mL IL-6 increase was associated with a 1.70 increased relative odd of subsequent SCD
Streitner et al156	Recipients of ICDs	47	—	IL-6 serum levels were prospectively associated with an increased risk of spontaneous VT/VF events
Streitner et al157	Recipients of ICDs	86	—	Gradual IL-6 increase when subjects without ICD intervention were compared to those with a single VT/VF event and those developing electrical storm
Cheng et al159	Recipients of ICDs	1,189	—	Higher IL-6 levels independently increased the risk of shocks for VT/VF and mortality
Wu et al160	Recipients of ICDs	382	—	Circulating IL-6 was a top predictor for appropriate ICD discharge and SCD
Medenwald et al161	General population	1,716	—	sTNF-R1 levels independently correlated with QTc duration in women
Empana et al162	General population	9,771	—	IL-6 was an independent predictor of SCD in asymptomatic men
Hussein et al163	General population	5,382	—	IL-6 was an independent predictor of SCD, beyond traditional risk factors

AMI = acute myocardial infraction; CAD = coronary artery disease; CRP = C-reactive protein; CTD = connective tissue disease; ICD = implantable cardioverter-defibrillator; mRNA = messenger RNA; PBMCs = peripheral blood mononuclear cells; QTV = QT-interval variability; RA = rheumatoid arthritis; SCD = sudden cardiac death; sTNF-R1/2 = soluble TNF-receptor-1/2; TCZ = tocilizumab; TdP = torsades de pointes; To-p = interval from the onset to the peak of the T-wave; Tp-e = interval from the peak to the end of the T-wave; VAs = ventricular arrhythmias; VF = ventricular fibrillation; VT = ventricular tachycardia; other abbreviations as in Table 1.