Comprehensive Mechanism, Novel Markers and Multidisciplinary Treatment of Severe Acute Pancreatitis-Associated Cardiac Injury - A Narrative Review

Abstract

Acute pancreatitis (AP) is one of the common acute abdominal inflammatory diseases in clinic with acute onset and rapid progress. About 20% of the patients will eventually develop into severe acute pancreatitis (SAP) characterized by a large number of inflammatory cells infiltration, gland flocculus flaky necrosis and hemorrhage, finally inducing systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Pancreatic enzyme activation, intestinal endotoxemia (IETM), cytokine activation, microcirculation disturbance, autonomic nerve dysfunction and autophagy dysregulation all play an essential role in the occurrence and progression of SAP. Organ dysfunction is the main cause of early death in SAP. Acute kidney injury (AKI) and acute lung injury (ALI) are common, while cardiac injury (CI) is not, but the case fatality risk is high. Many basic studies have observed obvious ultrastructure change of heart in SAP, including myocardial edema, cardiac hypertrophy, myocardial interstitial collagen deposition. Moreover, in clinical practice, patients with SAP often presented various abnormal electrocardiogram (ECG) and cardiac function. Cases complicated with acute myocardial infarction and pericardial tamponade have also been reported and even result in stress cardiomyopathy. Due to the molecular mechanisms underlying SAP-associated cardiac injury (SACI) remain poorly understood, and there is no complete, unified treatment and sovereign remedy at present, this article reviews reports referring to the pathogenesis, potential markers and treatment methods of SACI in recent years, in order to improve the understanding of cardiac injury in severe pancreatitis.

Keywords: biomarkers; cardiac dysfunction; cardiac injury; inflammatory mediators; severe acute pancreatitis; treatment.

Figure 1

Data related to acute pancreatitis. (A and B): proportion and mortality in acute pancreatitis of different severity. (C and D): proportion and mortality of acute pancreatitis complicated with organ failure.

Figure 2

Pathophysiological mechanisms influencing the development of cardiac injury in SAP. Various risk factors (gallstones, alcohol, diet and drugs) cause acinar cell damage and the release of pancreatic hydrolase, leading to excessive activation and autocrine of macrophages and neutrophils, resulting in the accumulation of a large number of pro-inflammatory factors. Then the local inflammation at the lesion is amplified through the inflammatory cascade effect, which eventually results in necrosis and hemorrhage of most pancreatic tissue, releasing more and more cytokines, and induces hypercytokinemia (a cytokine storm). As the disease progresses and pancreatic inflammation involves the intestine, it causes dysfunction of intestinal barrier, which leads to the migration of intestinal flora to the pancreas and blood, followed by pancreatic infection and sepsis. These high levels of risk factors (including trypsin, endotoxin and cytokines) in the blood can damage vascular endothelial cells, trigger systemic inflammatory response, lead to myocardial microcirculatory disturbance, autonomic nerve dysfunction and abnormal autophagy, and eventually result in myocardial injury and cardiac dysfunction.

Figure 3

The specific pathways of myocardial injury and cardiac dysfunction caused by inflammation-related factors. DAMPs and PAMPs such as HMGB1, ATP and endotoxin from the pancreas and intestine act on membrane receptors such as TLR and P2X7R to recruit inflammatory cells (macrophages, neutrophils and dendritic cells) in serum, activate classical inflammatory pathways such as NF-κB and NLRP3 inflammasome in inflammatory cells, release a large number of pro-inflammatory cytokines, and form a cascade reaction (upper). These inflammatory factors eventually act on cardiomyocytes, causing myocardial energy metabolism disorder, systolic myocardial dysfunction, myocardial hypertrophy, apoptosis and fibrosis through a complex network of signaling pathways (lower).