Anti‐Inflammatory and Antiarrhythmic Effects of Beta Blocker in a Rat Model of Rheumatoid Arthritis

Abstract

Background Patients with rheumatoid arthritis are at twice the risk of ventricular arrhythmia and sudden cardiac death as the general population. We hypothesize that β‐blocker treatment of rheumatoid arthritis is antiarrhythmic by producing synergistic anticatecholaminergic and anti‐inflammatory effects. Methods and Results Collagen‐induced arthritis (CIA) was induced in Lewis rats by immunization with type II collagen in Freund's incomplete adjuvant. The treatment with propranolol (4 mg/kg) started on the first day of immunization. We evaluated the ventricular vulnerability to ventricular arrhythmia using in vivo programmed stimulation and performed ex vivo optical mapping to measure the electrical remodeling of the heart. The ventricular tissue was further processed for immunohistochemical staining and protein array analysis. The assessment of ventricular vulnerability showed that the number and duration of the induced ventricular arrhythmia episodes were increased in CIA rats, which were improved with propranolol treatment. The sympathovagal index and the plasma level of catecholamines significantly increased in CIA rats, whereas the use of propranolol attenuated sympathetic hyperactivity. In the optical mapping study, electrical remodeling, characterized by prolonged action potential duration, slow conduction velocity, and steepened action‐potential duration restitution, were noted in CIA rats and reversed in the propranolol‐treatment group. The propranolol treatment was associated with decreases in paw thickness, fewer inflammatory cell infiltrations in the heart, reduced levels of cardiac inflammatory cytokines, and less cardiac fibrosis as compared with the CIA group. Conclusions CIA increased ventricular arrhythmia vulnerability through sympathetic hyperinnervation and proarrhythmic ventricular electrophysiological remodeling. Treatment with propranolol in CIA rats was both anti‐inflammatory and antiarrhythmic.

Activation of Hypothalamic AMP‐Activated Protein Kinase Ameliorates Metabolic Complications of Experimental Arthritis

“…Thus, activation of the same centers may promote both BAT thermogenesis and immune activation in the spleen. This connection is functionally supported by our data and a recent report showing that propranolol (a nonselective beta blocker) promotes, in addition to antiarrhythmic effects, a systemic antiinflammatory action in a model of collagen-induced arthritis in Lewis rats (48). Overall, this evidence seems to indicate that reduced sympathetic tone ameliorates EA symptoms, offering a possible alternative mechanism to the antiinflammatory effect of AMPKα1 adenoviral treatment in the VMH.…”

Saussurea involucrata oral liquid regulates gut microbiota and serum metabolism during alleviation of collagen‐induced arthritis in rats

“…Seven days after primary immunization, the same emulsion was re‐injected percutaneously for booster immunization, thereby inducing the generation of the RA rat model (Wang et al, 2018). The occurrence and severity of arthritis were recorded using the arthritis index (AI) score, which is graded on a 5‐point scale (0–4): 0 for normal conditions, 1 for marked redness and swelling of the ankle, 2 for moderate redness and swelling of the ankle or wrist, 3 for severe redness and swelling of the whole paw including the toes, and 4 for the most severe inflammation involving multiple joints (Lin et al, 2020). Successful establishment of the RA model was dependent on the occurrence of swelling in at least 1 foot (including the ankle) and an AI score of up to 4, the successful rate of the model was 87%.…”

24 h Holter ECG Monitoring of Patients with Rheumatoid Arthritis—A Potential Role for a Precise Evaluation of QT Interval Duration and Associated Arrhythmic Complications

“…In patients with systemic autoimmune diseases, the prevalence of QT interval prolongation can be up to 30% [5]. In RA, QT interval prolongation and arrhythmic risk are increased by chronic systemic inflammation responsible for an accelerated atherosclerotic process, followed by ischemic heart disease, but there is increasing clinical and experimental evidence that inflammation is associated with abnormal ventricular repolarization and cardiovascular autonomic system dysfunction (increased sympathetic outflow with stimulation of β1 adrenergic receptors on myocytes), which contribute to an increased rate of ventricular arrhythmias associated with the increased rate of sudden cardiac death (SCD) observed in patients with RA [6][7][8][9]. The direct effect of inflammation on ventricular repolarization and QT duration is mediated by the action of inflammatory cytokines on calcium and potassium channels in myocytes with alteration of action potential duration (APD) [5].…”