Heart failure is a leading cause of death worldwide. While there are multiple etiologies contributing to the development of heart failure, all cause result in impairments in cardiac function that is characterized by changes in cardiac remodeling and compliance. Fibrosis is associated with nearly all forms of heart failure and is an important contributor to disease pathogenesis. Inflammation also plays a critical role in the heart and there is a large degree of interconnectedness between the inflammatory and fibrotic response. This review discusses the cellular and molecular mechanisms contributing to inflammation and fibrosis and the interplay between the two.

The prevalence of diabetes is rapidly increasing and closely associated with cardiovascular morbidity and mortality. While the major cardiovascular complication associated with diabetes is coronary artery disease, it is becoming increasingly apparent that diabetes impacts the electrical conduction system in the heart, resulting in atrial fibrillation, and ventricular arrhythmias. The relationship between diabetes and arrhythmias is complex and multifactorial including autonomic dysfunction, atrial and ventricular remodeling and molecular alterations. This review will provide a comprehensive overview of the link between diabetes and arrhythmias with insight into the common molecular mechanisms, structural alterations and therapeutic outcomes.

Immune cell β₂-adrenergic receptors (β₂ARs) are important for proinflammatory macrophage infiltration to the heart in a chronic isoproterenol administration model of heart failure. Mice lacking immune cell β₂AR have decreased immune cell infiltration to their heart, primarily proinflammatory macrophage populations. This decrease culminated to decreased cardiac injury with lessened cardiomyocyte death, decreased interstitial fibrosis and hypertrophy, and improved function demonstrating that β₂AR regulation of immune responses plays an important role in the heart’s response to persistent βAR stimulation.

Fibroblasts are an important resident cell population in the heart involved in maintaining homeostasis and structure during normal conditions. They are also crucial in disease states for sensing signals and initiating the appropriate repair responses to maintain the structural integrity of the heart. This sentinel role of cardiac fibroblasts occurs, in part, through their ability to secrete cytokines. β-adrenergic receptors (βAR) are also critical regulators of cardiac function in the normal and diseased state and a major therapeutic target clinically. βAR are known to influence cytokine secretion in various cell types and they have been shown to be involved in cytokine production in the heart, but their role in regulating cytokine production in cardiac fibroblasts is not well understood. Thus, we hypothesized that βAR activation on cardiac fibroblasts modulates cytokine production to influence fibroblast function. Using primary fibroblast cultures from neonatal rats and adult mice, increased interleukin (IL)-6 expression and secretion occurred following β2AR activation. The use of pharmacological inhibitors and genetic manipulations showed that IL-6 elevations occurred through the Gαs-mediated activation of ERK1/2 and resulted in increased fibroblast proliferation. In vivo, a lack of β2AR resulted in increased infarct size following myocardial infarction and impaired wound closure in a murine dermal wound healing assay. These findings identify an important role for β2AR in regulating fibroblast proliferation through Gαs/ERK1/2-dependent alterations in IL-6 and may lead to the development of improved heart failure therapies through targeting fibrotic function of β2AR.

Following injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair; however, leukocytes lacking β ₂ -adrenergic receptor (β ₂ -AR) expression have marked impairments in these processes. Beta blockade is a common strategy for the treatment of many cardiovascular etiologies; therefore, the objective of our study was to assess the impact of prior beta blocker treatment on baseline leukocyte parameters and their responsiveness to acute injury. In a temporal and β-adrenergic receptor isoform–dependent manner, chronic beta blocker infusion increased splenic vascular cell adhesion molecule 1 expression and leukocyte accumulation (monocytes/macrophages, mast cells, and neutrophils) and decreased chemokine receptor 2 (CCR2) expression and migration of bone marrow and peripheral blood leukocytes (PBLs) to, as well as infiltration into, the heart following acute cardiac injury. Further, CCR2 expression and migratory responsiveness were significantly reduced in the PBLs of patients receiving beta blocker therapy compared with beta blocker–naive patients. These results highlight the ability of chronic beta blocker treatment to alter baseline leukocyte characteristics that decrease leukocytes’ responsiveness to acute injury and suggest that prior beta blockade may act to reduce the severity of innate immune responses.