The role of tumor necrosis factor in the pathophysiology of heart failure
Arthur M. Feldman, MD, PhD, FACCa,
Alain Combes, MDa,
Daniel Wagner, MDa,
Toshiaki Kadakomi, MDa,
Toru Kubota, MD, PhDa,
Yun You Li, PhDa and
Charles McTiernan, PhDa
a Cardiovascular Institute of the UPMC Health System, Pittsburgh, Pennsylvania, USA
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Figure 1 Circulating levels of tumor necrosis factor alpha (TNF alpha) in normal subjects and patients with New York Heart Association (NYHA) functional class I to III heart failure. Adapted after Torre-Amione et al. (33) with permission of the authors.
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Figure 2 Immunodetectable TNF alpha (picograms of TNF alpha per g of cystolic protein) in nonfailing and failing myocardium. Adapted after Torre-Amione et al. (38) with permission of the authors.
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Figure 3 Tumor necrosis factor alpha acutely depresses contractile activity and calcium transients of isolated adult rat cardiomyocytes. Cells were loaded with the calcium sensitive dye, fura-2, and exposed to 200 U/ml rat TNF alpha or diluent (control) for 30 min. Cells were then electrically stimulated to contract (1 HZ) and a video edge-detection system used to record diastolic cell length and contraction to determine fractional shortening. Cells were alternately illuminated at 340- and 380-nm light and emission of the fura-2 measured at 520-nm. The ratio of light emission from the two illuminating wavelengths was used to follow intracellular free calcium transients. (A) Fractional shortening (n = 30 each group). (B) Mean calcium transient amplitude (difference between peak systolic and peak diastolic 340/380 nm ratio; n = 40 per group). (Wagner, Combes, Janczewski, McTiernan and Feldman; unpublished data). Open square = control; solid square = TNF alpha 200 U/ml.
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Figure 4 Transgenic mice with cardiac-specific overexpression of TNF alpha (TNF1.6) develop dilated cardiomyopathy. Representative magnetic resonance image (MRI, coronal view) from 24 week-old wild type (A) and TNF1.6 transgenic mice (B) at equivalent stage of cardiac cycle. (C) Transgenic animals demonstrate significant cardiac hypertrophy with chamber dilation and decreased ejection fraction as determined from MRI data (short-axis images). Adapted after Kubota et al. (50) with author’s permission. BW = body weight; EDV = end-diastolic volume; ESV = end-systolic volume; HW = heart weight. Open square = wild type; solid square = TNF1.6. *p < 0.05.
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