High Doses of Digitalis Increase the Myocardial Production of Proinflammatory Cytokines and Worsen Myocardial Injury in Viral Myocarditis

Abstract

Results of recent studies suggest that proinflammatory cytokines cause myocardial contractile dysfunction, and that the drugs used to treat heart failure modulate the production of cytokines. This study was designed to examine the effects of digoxin in a murine model of heart failure induced by viral myocarditis. Four-week-old inbred DBA/2 mice were inoculated intraperitoneally with encephalomyocarditis virus (EMCV). Digoxin was given orally in doses of 0.1, 1 or 10 mg/kg daily from the day of virus inoculation. Interleukin (IL)-1 , IL-6 and tumor necrosis factor (TNF)-production in the heart were measured on day 5 after EMCV inoculation by enzyme-linked immunosorbent assay. The 14-day mortality tended to be increased in mice treated with 1 mg/kg, and was significantly increased in the group treated with 10 mg/kg per day. Myocardial necrosis and cellular infiltration on day 6 were significantly more severe in the high-dose digoxin group than in the control group. In the animals treated with 1 mg/kg digoxin, IL-1 was significantly higher than in the control group. Intracardiac TNF-levels were increased in a dose-dependent manner. These results suggest that digoxin worsens viral myocarditis, and that its use in high doses should be avoided in patients suffering from heart failure due to viral myocarditis. (Jpn Circ J 1999; 63: 934 -940)

Diagnosis and Treatment of Myocarditis in Children in the Current Era

“…93 In a similar fashion, nonsteroidal anti-inflammatory drugs are also not recommended because of evidence of increased inflammation and mortality in murine models of myocarditis. 94,95 Current recommendations in adult [2][3][4][5][6] and pediatric 9,10,12 myocarditis emphasize that supportive medical therapy should be the primary therapy for acute myocarditis.…”

Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery

“…Other pro-inflammatory cytokines produced by the heart during cardiac insults include IL-18 and IL-1β (Matsumori, et al, 1999;Pomerantz, Reznikov, Harken, & Dinarello, 2001). IL-1 is produced in response to local or systemic stimuli (Dinarello, Simon, & van der Meer, 2012) and is responsible for cardiac dysfunction in heart failure and the effect is mediated by IL-18 (Toldo, et al, 2014).…”

Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels

“…Specifically, beta-adrenergic blockade was found to interact with the IL-6 and TNFa production in experimental as well as observational clinical studies [9,10,15]. In addition, ACE inhibitors as well as calcium channel blockers may decrease these cytokines whereas digoxin has been shown to elevate their serum levels [12][13][14]16]. Such modulation of the immune response may be of specific interest given that plasma levels of these markers can be used to predict the mortality of the disease [4,17,18].…”