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

Figures & data

Table 1 Characteristics of Severe Acute Pancreatitis-Associated Cardiac Injury

Characteristics	Supplements	Check Type	References
Cardiomyocytes: a rough type, hypoxia, edema, hypertrophy and apoptosis	Over contracted myofibrils caused by supercharging with calcium Deficiencies in the sarcolemma structure. Affection of the microcirculation vessels structure	Histopathological changes	[^Citation11,^Citation30,^Citation38,^Citation45,^Citation47,^Citation67,^Citation82,^Citation88,^Citation116]
Myocardium stroma: edema and collagenization	Deficiencies in the sarcoma structure compensatory response of connective tissue to lesions		[^Citation11,^Citation39,^Citation46,^Citation47,^Citation82]
Electrocardiogram	Arrhythmia: prolonged QTc interval	Laboratory and imaging changes	[^Citation5,^Citation135,^Citation155]
Biochemical examination	CK-MB, LDH, cTnI		[^Citation114,^Citation161]
Echocardiography	Myocardial contractile dysfunction: decreased ejection fraction, poor contraction response to volume load, decreased peak systolic pressure/end-systolic volume ratio, enlarged heart and pericardial effusion		[^Citation4,^Citation30]
Other complications	Increased blood flow and permeability of pulmonary capillaries, increased adhesion and infiltration of leukocytes and thickening of alveolar septum	Histopathological changes	[^Citation14,^Citation52,^Citation106,^Citation119,^Citation122,^Citation165]
	Decreased renal blood flow and acute renal failure		[^Citation6,^Citation122,^Citation164]

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).

Table 2 Markers with Predictive or Prognostic Value for SAP-Associated Cardiac Injury

Symbols	Sample Size	Clinical Implication	P value	References
Antiendotoxin core antibody	45	Assess the severity of acute pancreatitis (edematous/necrotic)	P < 0.05	[^Citation139]
	33	Identify patients with SAP complicated with MOF	P < 0.01	[^Citation140]
	20	Predict poor outcome in patients with AP	P < 0.01	[^Citation141]
HMGB1	80	Determine the intestinal barrier dysfunction and infection in SAP	P < 0.01	[^Citation143]
sST2	295	Predict mortality in myocardial infarction patients	P = 0.048	[^Citation145
PAP	98	To be an indicator of the course of AP	P < 0.001	[^Citation147]
	70	To be a prognostic marker for disease severity in heart failure	P < 0.001	[^Citation148]
sTREM-1	48	Correlated with disease severity and early organ dysfunction in patients with AP	P < 0.01	[^Citation149]
	838	Associated with all-cause mortality and major adverse cardiovascular event	P < 0.001	[^Citation150]
Heart rate variability	41	A good predictor of SAP complicated with IPN and multiple organ dysfunction	P < 0.01	[^Citation153]

Table 3 Prevention and Treatment of SAP-Associated Cardiac Injury

Treatment Methods	Study Type	Therapeutic Effect	Validity Parameter	Reference
Inhibit the activation and release of pancreatin and inflammatory mediators
Somatostatin	Experimental study	Reduce the internal and external secretion of the pancreas and the pressure in the pancreatic duct		[^Citation154]
Prostaglandin E1	Clinical study	Inhibit proinflammatory cytokines production during cardiac surgery	–	[^Citation156]
Octreotide	Experimental study	Inhibit the apoptosis of cardiomyocytes	P <0.05 (Survival rate)	[^Citation157]
Fentanyl	Experimental study	Improve the swollen and disordered cardiac fibers and congested vessels in SAP rats	–	[^Citation158]
ERCP	Clinical study	Identify the etiology of obstructive pancreatitis and implement corresponding interventional therapy	–	[^Citation159]
Laparotomy	Case report	Decompression laparotomy at an appropriate time is useful for abdominal compartment syndrome caused by SAP	–	[^Citation160]
APD	Experimental study	Inhibit oxidative stress, reduce myocardial enzymes and cardiomyocyte apoptosis to improve the morphological changes of cardiomyocytes and alleviate cardiac dysfunction	–	[^Citation161]
Fluid resuscitation	Clinical study	Reasonable and timely fluid resuscitation is the basis for preventing vascular endothelial cells from releasing inflammatory mediators	P <0.05 (Survival rate)	[^Citation162]
Dextran	Clinical study	Improve pancreatic anoxia and prevent microthrombus generation on based on adequate fluid resuscitation	–	[^Citation166]
Salvia miltiorrhizae	Experimental study	Improve myocardial pathological changes and reduce the content of PLA2 in blood	P>0.05 (Survival rate)	[^Citation167]
Blood purification therapy	Guide	Reduce the level of pro-inflammatory cytokines in the blood of SAP patients and prevent subsequent MODS	–	[^Citation170]
Reduce endotoxin translocation and prevent infection
Rhubarb	Experimental study	Reduce intestinal flora and endotoxin translocation as well as maintain intestinal mucosal barrier function	–	[^Citation173]
Preventive antibiotics	Conference literature	The third- and fourth-generation cephalosporins, and carbapenems could cross blood-pancreas barrier to prevent infection, reduce the production of endotoxin and avoid the expansion of systemic inflammatory response	–	Conference literature
Drug treatment of myocardial injury
Ulinastatin	Experimental study	Decrease the production of peroxide and superoxide	–	[^Citation175]
	Experimental study	Reduce the release of inflammatory factors (TNF-α and IL-6)	–	[^Citation176]
	Clinical study	Decrease the secretion of inflammatory mediators by inhibiting trypsin, elastase, fibrinolytic enzyme and hyaluronidase	P <0.05 (Survival rate)	[^Citation177]
	Experimental study	Stabilize lysosomal membrane and scavenge oxygen free radicals	P <0.05 (Survival rate)	[^Citation178]
Statins	Review	Regulate cellular immunity, improve endothelial cell function, and resist oxidative stress	–	[^Citation179]
	Experimental study	Inhibit NLRP3 inflammasome activation and relief oxidative stress to against myocardial ischemia-reperfusion injury	–	[^Citation180]
	Experimental study	Regulatory T cells contribute to rosuvastatin-induced protective effect against myocardial ischemia-reperfusion injury	–	[^Citation181]
Positive inotropic drugs and vasoactive drugs	Guide	Norepinephrine/epinephrine to maintain blood pressure	–	[^Citation184]
	Guide	Dobutamine is recommended for recurring cardiac dysfunction	–	[^Citation184]
	Experimental study	Milrinone and levosimendan with special advantages	–	[^Citation185]
Traditional Chinese medicine
Qingyi decoction	Experimental study	Confer cardio-protection against SAP-induced MI by regulating myocardial-associated protein expression	P <0.05 (Survival rate)	[^Citation187]
Lai Fu Cheng Qi decoction	Experimental study	Decrease the rate of apoptosis of myocardial cells in SAP rats	–	[^Citation188]
Sheng-jiang powder	Experimental study	Alleviate multiple-organ inflammatory injury in AP in rats fed a high-fat diet	P <0.01 (cardiac pathological damage)	[^Citation189]

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