Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-α

Abstract

. Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiac-specific overexpression of tumor necrosis factor-␣. Am J Physiol Heart Circ Physiol 289: H1456 -H1467, 2005. First published May 27, 2005; doi:10.1152/ajpheart.00733.2004.-Transgenic mice overexpressing the inflammatory cytokine TNF-␣ in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-␣ mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n ϭ 8/32) in TNF1.6 but not in control mice (n ϭ 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n ϭ 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca 2ϩ normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca 2ϩ handling. Thus abnormalities in action potential propagation and Ca 2ϩ handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure. heart failure; atrium; atrial fibrillation; cytokines INFLAMMATORY CYTOKINES, including TNF-␣, are increased in the serum and hearts of patients with congestive heart failure (CHF) and may contribute to the pathophysiology of the disease (18,24,25). We recently engineered mice that overexpress TNF-␣ in the heart under the control of the ␣-myosin heavy chain promoter (TNF1.6 mice) and develop a cardiomyopathy characterized by biventricular dilatation, decreased left ventricular ejection fraction, ventricular arrhythmias, and decreased survival compared with nontransgenic littermates (28). Most of the mice exhibit symptoms of CHF before death (tachypnea, cyanosis, and ascites) and evidence of decompensated heart failure at autopsy (pleural effusions, hepatic congestion, and severe atrial and ventricular dilatation).We have previously used optical mapping of voltage and calcium in ventricles from the TNF1.6 mice to show prolongation of action potential duration (APD), prolongation of calcium transient duration, and elevated diastolic and depressed systolic calcium (33). Premature beats had depressed action potential amplitude and slowed conduction velocities that contributed to initiation of reentrant arrhythmias. Lowering extracellular calcium reversed the abnor...

Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor

“…Indeed, studies in Cx40-deficient mice are consistent with the electrical phenotype observed in our MHCsTNF mice, including depressed sinus node activity, increased AV Wenckebach periodicity, increased inducibility of atrial tachyarrythmias, and reduced conduction in the His-Purkinje system with preserved conduction velocity in the ventricular myocardium (4,12,30,35,36). Our results of atrial arrhythmias in a mouse model with overexpression of TNF confirm previous observations by others (27). However, a novel finding of our study was the role of Cx40 in the setting of inflammation.…”

“…However, a novel finding of our study was the role of Cx40 in the setting of inflammation. Furthermore, while myocardial tissue fibrosis was evident in TNF mice aged 2-9 mo (27), it is unlikely that fibrosis played a major role in the pathogenesis of atrial arrhythmias in our model, insofar as fibrosis does not develop significantly in this model until 12 wk of age (32). Ion channel currents are altered in heart failure; specifically, it is thought that L-type calcium currents are upregulated and transient outward potassium currents are downregulated (14).…”

Atrial Fibrillation Promotion in a Rat Model of Rheumatoid Arthritis

“…TNF‐α has been demonstrated to induce atrial fibrosis by increasing atrial myofibroblast proliferation and metalloproteinase secretion 23, 24. Saba et al25 found that cardiac‐specific overexpression of TNF‐α could cause atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model. Moreover, a recent study has revealed that enhanced expression of TNF‐α in the murine atrial cardiomyocyte HL‐1 cell line promoted cardiomyocyte apoptosis by activating CASP‐3 26.…”

Hepatorenal Syndrome

“…In one study of 52 decompensated patients with cirrhosis, natriuretic peptide level correlated with the Child-Pugh score and the ventricular wall thickness (39). The mechanism of impaired cardiac function is complex and may include (1) neurohumoral hyperactivity leading to myocardium growth and fibrosis with disturbed relaxation; (2) diminished myocardial ␤ adrenergic receptor signal transduction; and (3) an inhibitory effect of circulating cytokines, including TNF-␣ and nitric oxide (NO), on ventricular function (37,40,41). In alcoholic patients, a variable degree of alcoholic cardiomyopathy also can be a contributing factor.…”