Mast Cell Inhibition Attenuates Myocardial Damage, Adverse Remodeling, and Dysfunction During Fulminant Myocarditis in the Rat

Abstract

Background Myocarditis is a life-threatening heart disease characterized by myocardial inflammation, necrosis and chronic fibrosis. While mast cell inhibition has been suggested to prevents fibrosis in rat myocarditis, little is known about its effectiveness in attenuating cardiac remodeling and dysfunction in myocarditis. Thus, we sought to test the hypothesis that mast cell inhibition will attenuate the inflammatory reaction and associated left ventricular (LV) remodeling and dysfunction after fulminant autoimmune myocarditis. Methods and Results To induce experimental autoimmune myocarditis, we immunized 30 rats with porcine cardiac myosin twice at a 7-day interval. On day 8 animals were randomized into treatment either with an intraperitoneal (IP) injection of 25mg/kg of cromolyn sodium (n=13), or an equivalent volume (~0.5ml IP) of normal saline (n=11). All animals were scanned by serial echocardiography studies before treatment (baseline echocardiogram) and after 20 days of cromolyn sodium (28 days after immunization). Furthermore, serial cardiac magnetic resonance was performed in a subgroup of 12 animals. After 20 days of treatment (28 days from first immunization), hearts were harvested for histopathological analysis. By echocardiography, cromolyn sodium prevented LV dilatation and attenuated LV dysfunction, compared with controls. Postmortem analysis of hearts showed that cromolyn sodium reduced myocardial fibrosis, as well as the number and size of cardiac mast cells in the inflamed myocardium, compared with controls. Conclusions Our study suggests that mast cell inhibition with cromolyn sodium attenuates adverse LV remodeling and dysfunction in myocarditis. This mechanism-based therapy is clinically relevant and could improve the outcome of patients at risk for inflammatory cardiomyopathy and heart failure.

Protective effect of resveratrol against pressure overload‐induced heart failure

“…Although found mainly in the skin, gastrointestinal tract, and airways, they are known to reside in cardiac tissue and have been shown to play a key role in the pathogenesis of HF (Mina et al. ).…”

“…Similarly, mast cells have been implicated in the pathogenesis of HF and play a critical role in the fibrotic response to infectious and inflammatory stimuli (Matsumori et al 1994). Although found mainly in the skin, gastrointestinal tract, and airways, they are known to reside in cardiac tissue and have been shown to play a key role in the pathogenesis of HF (Mina et al 2013). Consistent with the enhanced inflammatory response in the TAC mice compared to their WT counterparts, we also found a striking increase in both interstitial and perivascular fibrosis in the PO hearts.…”

Mast Cells: Key Contributors to Cardiac Fibrosis

“…Palaniyandi et al [ 19 ] demonstrated that the MC stabilizer disodium cromoglycate (also known as cromolyn) could dramatically reduce fibrosis in a model of myocarditis, whereby rats were injected with porcine cardiac myosin emulsified with complete freund’s adjuvant with Mycobacterium tuberculosis H37RA. A subsequent study confirmed the anti-fibrotic effect of cromolyn in myocarditis in rats [ 22 ]. We provided the first causal evidence that MCs play a role in cardiac fibrosis in the hypertensive heart [ 23 ].…”

Mast cells in human and experimental cardiometabolic diseases

“…119 Consequently, stabilizing mast cells using disodium cromoglycate prevented left ventricular dilatation, attenuated left ventricular dysfunction, and reduced myocardial fibrosis compared with controls. In aortocaval fistula-induced internal expansion of the left ventricle in mice, a deficiency of the mast-cell activators substance P and neurokinin-1 reduced left ventricular expansion by nearly eightfold, as well as significantly reducing MMP activity and myocardial collagen degradation.…”