Role of Inflammation in Cardiac Remodeling After Acute Myocardial Infarction

Abstract

Atherosclerosis is defined as an inflammatory disease. Low-grade inflammation is present in all phases of the cardiovascular continuum, since the establishment of cardiovascular risk factors and ischemic heart disease until cardiovascular events, such as myocardial infarction, heart failure and death. Not all inflammatory pathways are linked to cardiovascular outcomes, and thus, not all anti-inflammatory approaches decrease cardiovascular events. The most common cause of ventricular remodeling and heart failure is ischemic heart disease. Biomarkers such as high-sensitivity C-reactive protein can identify individuals at risk of major cardiovascular complications, but this biomarker has no causal effect on cardiovascular disease. On the other hand, interleukin 6 appears to be causally associated with cardiovascular disease. CANTOS was the first proof of concept study showing that anti-inflammatory therapy reduces major cardiovascular outcomes. Based on many anti-inflammatory trials, only therapies acting on the NLRP3 inflammasome, or interleukin 1beta, showed benefits on cardiovascular disease. Ventricular remodeling, particularly after myocardial infarction seems also influenced by the intensity of inflammatory responses, suggesting that anti-inflammatory therapies may reduce the residual cardiovascular risk. Inflammasome (NLRP3) activation, subtypes of lymphocytes, interleukin 6, and some inflammatory biomarkers, are associated with larger infarct size and impaired ventricular function after myocardial infarction. Cardiovascular risk factors commonly present in patients with myocardial infarction, and advanced age are associated with higher inflammatory activity.

Keywords: C-reactive protein; acute myocardial infarction; cardiac magnetic resonance imaging; interleukin-6; lymphocytes.

FIGURE 1

Pivotal role of inflammation in patients with metabolic syndrome. RAS—renin angiotensin system; SNS—sympathetic nervous system; FFA—free fatty acids. Perivascular adipose tissue causes endothelial dysfunction and local inflammation, contributing for atherosclerotic plaque complications. Changes in microbiota composition and higher permeability of the intestinal mucosa to bacterial products such as lipopolysaccharides activate inflammatory pathways. Macrophages and lymphocytes infiltrate visceral adipose tissue and release proinflammatory cytokines, which are related to insulin resistance. These cytokines and FFA change cell signaling related to insulin causing endothelial dysfunction, insulin resistance, and cardiovascular remodeling. The systemic inflammatory status is also related to increased thrombotic risk, leading to ischemic events.

FIGURE 2

NLRP3 activation triggers the inflammatory pathway of atherosclerosis in monocytes and macrophages resident cells. The ischemic insult due to ischemia and reperfusion after acute myocadial infarction activates the inflammatory pathway mediated by NLRP3. ROS—reactive oxygen species; NLRP3 - nucleotide-binding and oligomerization-like receptor pyrin domain-containing protein 3; IL—interleukin; SAA—serum amyloid A; CRP—C-reactive protein; TNF-alpha—tumour necrosis factor—alpha; PAI-1—plasminogen activator inhibitor type 1. NLRP3 inflammasome is a common inflammatory platform where many stimuli (e.g., cholesterol crystals, ischemic conditions) can activate IL-1beta triggering the inflammatory pathway, including IL-6. The activation of IL-1beta reduces contractility in response to beta adrenergic stimuli and is associated with ventricular remodeling. Further, increase in CRP levels can be used for monitoring of the low-grade inflammation.