Thioredoxin, Adiponectin, and Clinical Course of Acute Fulminant Myocarditis

Study Questions:

Do plasma levels of the cytokines adiponectin and thioredoxin predict patient clinical course in acute fulminant myocarditis (FM)?

Methods:

Plasma levels of adiponectin, thioredoxin, tumor necrosis factor alpha (TNF-α), soluble TNF receptor (sTNF-R), and interleukin-10 (IL-10) from 20 patients with biopsy proven (viral genome positive on reverse transcriptase–polymerase chain reaction [RT-PCR] or myocardial inflammatory infiltrates according to Dallas criteria) FM and 13 with nonfulminant myocarditis (NFM) were measured upon admission and 2 weeks after admission. Cytokine levels from 22 healthy controls without any cardiac disease were also measured. FM was defined as requiring mechanical circulatory support (MCS) or high-dose inotrope support for >1 day for management of cardiogenic shock. NFM patients did not have significant hemodynamic compromise. The correlation between cytokine levels and the duration of MCS was evaluated.

Results:

The mean ± standard deviation patient age was 36 ±15 years and 58% were male. Patients with FM were more likely to present with fever and had lower left ventricular ejection fractions and greater incidences of ventricular dysrhythmias than NFM patients. On histopathology, 19 patients with FM had lymphocytic myocarditis and one had giant cell. Fifteen FM patients had evidence of Coxsackievirus genome on RT-PCR. In the NFM group, eight had lymphocytic myocarditis and five had eosinophilic myocarditis, whereas only three had Coxsackievirus on RT-PCR. Plasma thioredoxin levels were significantly higher on admission in FM patients (3.1 ± 2.2 ng/ml) than NFM (1.6 ± 0.45 ng/ml, ANOVA p = 0.011) and controls (1.8 ± 0.36) as were plasma IL-10, TNF-α, and sTNF-R levels (all ANOVA p < 0.001). There was no significant difference in admission adiponectin levels (FM = 5.1 ± 2.1 ng/ml vs. NFM = 4.9 ± 2.1 ng/ml vs. control = 3.8 ± 0.89 ng/ml, ANOVA p = 0.04). Two weeks after admission, thioredoxin levels significantly dropped in the FM group (1.9 ± 0.62 ng/ml, p = 0.044 compared with admission), but no change was noted in the NFM group. Follow-up sTNF-R levels significantly reduced in both the FM (10.3 ± 1.1 pg/ml to 9.1 ± 1.7 pg/ml, p = 0.011) and NFM groups (7.5 ± 1.5 pg/ml to 5.8 ± 0.69 pg/ml, p = 0.015). No change was noted in adiponectin, IL-10, or TNF-α levels at follow-up. MCS duration was significantly longer in patients who died or required transplant (20 ± 9 days) than that of FM patients who recovered myocardial function (7 ± 5 days, p = 0.002). MCS duration was associated with lower admission systolic blood pressure (odds ratio [OR], 0.86 [0.78-0.94]), higher heart rate (OR, 1.09 [1.03-1.16]), higher admission plasma thioredoxin levels (OR, 5.8 [1.7-20]), and lower admission adiponectin levels (OR, 0.16 [0.055-0.49]).

Conclusions:

Admission thioredoxin levels are higher in FM than NFM. In FM, a higher admission thioredoxin and lower adiponectin may predict worse outcome.

Perspective:

Acute myocarditis portends variable patient outcome, with giant cell myocarditis generally leading to highest risk for death. A means of predicting which acute myocarditis patients will have worse outcome, and therefore benefit from early MCS, would be useful. Because many myocarditis patients are at increased risk for arrhythmias (which are poorly tolerated on left ventricular assist device support) and right ventricular dysfunction, a rapid transition from MCS to transplant in high-risk patients would be favored. In this novel analysis, it appears that admission thioredoxin, a measurement of oxidative stress and inflammation, may predict worse outcome. It would be interesting to know if thioredoxin levels correlated with presence of giant cell myocarditis, which is well known to offer poor prognosis, or if levels correlated with poor outcome regardless of histopathology. While adiponectin levels were not significantly different between FM and NFM patients on admission and levels did not seem to change at follow-up, lower admission adiponectin levels in FM were associated with worse outcome. More studies are needed to tease out adiponectin’s role in myocarditis.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biological Markers, Adiponectin, Heart Failure, Myocarditis, Tumor Necrosis Factor-alpha, Thioredoxins


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