Inflammation in Right Ventricular Failure: Does It Matter?

Abstract

Right ventricular (RV) failure is a common consequence of acute and chronic RV overload of pressure, such as after pulmonary embolism and pulmonary hypertension. It has been recently realized that symptomatology and survival of patients with pulmonary hypertension are essentially determined by RV function adaptation to increased afterload. Therefore, improvement of RV function and reversal of RV failure are treatment goals. Currently, the pathophysiology and the pathobiology underlying RV failure remain largely unknown. A better understanding of the pathophysiological processes involved in RV failure is needed, as there is no proven treatment for this disease at the moment. The present review aims to summarize the current understanding of the pathogenesis of RV failure, focusing on inflammation. We attempt to formally emphasize the importance of inflammation and associated representative inflammatory molecules and cells in the primum movens and development of RV failure in humans and in experimental models. We present inflammatory biomarkers and immune mediators involved in RV failure. We focus on inflammatory mediators and cells which seem to correlate with the deterioration of RV function and also explain how all these inflammatory mediators and cells might impact RV function adaptation to increased afterload. Finally, we also discuss the evidence on potential beneficial effects of targeted anti-inflammatory agents in the setting of acute and chronic RV failure.

Keywords: chemokines; coupling; cytokines; immune cells; inflammation; pulmonary hypertension; right ventricular failure.

Figure 1

Pathophysiology of right ventricular (RV) failure implicating activation of inflammatory and immune processes. Pulmonary arterial hypertension (as well as acute pulmonary embolism) induces an increased afterload for the RV resulting in RV remodeling. The structural and functional changes during the development of RV failure can be characterized clinically, as summarized on the left hand. RV dysfunction is also probably due the activation of other pathophysiological mechanisms (summarized on the right hand) leading to multiple cellular changes, such as oxidative stress, apoptosis, inflammation, fibrosis, and metabolic remodeling. These factors also contribute to RV dysfunction and subsequent RV failure (characterized by altered coupling between the RV and the pulmonary circulation). The cellular changes are either the result of chronic RV pressure overload or the effect of circulating factors released from the sick lung circulation. RV, right ventricle; BMPR-2, bone morphogenetic protein type 2 receptor; ROS, reactive oxygen species; PA, pulmonary artery; LV, left ventricle.

Figure 2

Schematic overview of the contribution of immune and inflammatory mediators and cells in the pathogenesis of right ventricular (RV) dysfunction/failure. In presence of pulmonary arterial hypertension or pulmonary embolism, circulating inflammatory mediators originating from the pulmonary vasculature may trigger or contribute to local activation of inflammatory processes in the RV. Inflammation in the RV is characterized by activation of immune processes, implying expansion and activation of different cell types and by up-regulation of cytokines, chemokines, and cell adhesion molecules contributing to chronic inflammatory status. Through this upregulation of immune and inflammatory processes, mediators contribute to the development of RV failure. RV, right ventricle; HO-1, heme oxygenase-1; NF-κB, nuclear factor kappa B; IL, interleukin; TNF, tumor necrosis factor; MCP, monocyte chemoattractant protein; ECM, extracellular matrix.

Figure 3

Hypothetical schematic cellular and molecular insights of immune cells and inflammatory mediators on the pathogenesis of right ventricular failure, more precisely on cardiomyocyte hypertrophy and death, as well as on fibrosis. Immune and inflammatory cells are myocardial resident cells or are coming from the blood stream, adhere to endothelial cells and invade the myocardium. Cytokines (e.g., IL-1β, IL-6, and TNF-α), chemokines (e.g., MCP-1), and enzymes (e.g., metalloproteinases and proteases, such as chymase) released by these cells promote cardiomyocyte hypertrophy, fibroblast differentiation/activation, deposition of extracellular matrix and cardiomyocyte apoptosis. Acute-phase inflammatory and immune mediators are represented in red, while late-phase mediators after myocardial injury are represent in blue. ROS, reactive oxygen species; IL, interleukin; TNF, tumor necrosis factor.