Cardiac phenotype in mouse models of systemic autoimmunity

Abstract

Patients suffering from systemic autoimmune diseases are at significant risk of cardiovascular complications. This can be due to systemically increased levels of inflammation leading to accelerated atherosclerosis, or due to direct damage to the tissues and cells of the heart. Cardiac complications include an increased risk of myocardial infarction, myocarditis and dilated cardiomyopathy, valve disease, endothelial dysfunction, excessive fibrosis, and bona fide autoimmune-mediated tissue damage by autoantibodies or auto-reactive cells. There is, however, still a considerable need to better understand how to diagnose and treat cardiac complications in autoimmune patients. A range of inducible and spontaneous mouse models of systemic autoimmune diseases is available for mechanistic and therapeutic studies. For this Review, we systematically collated information on the cardiac phenotype in the most common inducible, spontaneous and engineered mouse models of systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis. We also highlight selected lesser-known models of interest to provide researchers with a decision framework to choose the most suitable model for their study of heart involvement in systemic autoimmunity.

Keywords: Heart disease; Heart failure; Mouse model; Myocarditis; SLE; Systemic autoimmunity.

Fig. 1.

Heart structures and their involvement in systemic autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SSc). Numbers in the table indicate frequency of the manifestation in each disease as reported in the literature cited in this article. *, detected clinically due to patient presenting with symptoms; **, detected at post-mortem investigation in asymptomatic patients; +, presence reported without information available on exact incidence; nd, information not available in cited literature; RV, right ventricle; LV, left ventricle.

Fig. 2.

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (SSc) cause immune-mediated damage to the heart, which may manifest as acute inflammation, fibrosis, valve disease, remodelling towards heart failure, endothelial and cardiomyocyte dysfunction or arrhythmias. To study selected or combined cardiac phenotypes, the research community benefits from a wide range of spontaneous, inducible and engineered mouse models, which allow mechanistic studies to improve our understanding and identify targets for new therapeutic approaches. IFN-γ, interferon gamma; ANAs, anti-nuclear antibodies; R-848, resiquimod; PD-1^−/−, programmed cell death 1 knockout mice; TTP^−/−, tristetraprolin knockout mice; Fra-2, fos-related antigen 2 transgenic mice.

Fig. 3.

Cardiac phenotypes in mouse models of systemic lupus erythematosus (SLE). We include a decision tree to aid model choice based on the cellular mechanisms or tissue effect of interest, with a summary of the cardiac information available for each model. C3, complement-component 3 protein; GvHD, graft-versus-host disease; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; R-848, resiquimod; lpr, lymphoproliferation; gld, generalized lymphoproliferative disease; DCs, dendritic cells; Th1, T-helper cell type 1; MI, myocardial infarction; RV, right ventricle; LV, left ventricle; MRL, Murphy Roths Large.

Fig. 4.

Cardiac phenotypes in mouse models of rheumatoid arthritis (RA). We include a decision tree to aid model choice based on the cellular mechanisms or tissue effect of interest, with a summary of the cardiac information available for each model. C3/C5, complement-component 3/5 protein; IIJ, inherited inflamed joint; IL-6, interleukin-6; TTP, tristetraprolin; TNF, tumour necrosis factor; CIA, collagen-induced arthritis; iNOS, inducible nitric oxide synthase overexpression.

Fig. 5.

Cardiac phenotypes in mouse models of systemic sclerosis (SSc). We include a decision tree to aid model choice based on the cellular mechanisms or tissue effect of interest, with a summary of the cardiac information available for each model. GvHD, graft versus host disease; Topo I, type I topoisomerase; Tsk, tight skin; Ang II, angiotensin type II; Fra-2, fos-related antigen 2; uPAR, urokinase receptor.