Hrev_master [page 38] [Emergency Care Journal 2015; 11:5397] Heart in acute pancreatitis: facts and fictions Raffaele Pezzilli,1 Bahjat Barakat,2 Alessandra Barassi3 1Department of Digestive System, S. Orsola-Malpighi University Hospital, Bologna; 2Department of Emergency, S. Orsola-Malpighi University Hospital, Bologna; 3Department of Health Sciences, University of Milan - San Paolo Hospital, Italy Abstract Pain is the hallmark of acute pancreatitis and it is localized in the epigastrium in more than 60% of patients having mild or severe dis- ease. Acute pancreatitis may mimic other dis- eases such as acute coronary syndrome. In addition, the acute illness of the pancreas is associated with a number of metabolic abnor- malities, such as hypocalcemia and hypophos- phatemia, which may cause hemodynamic changes and variations in the concentration of ionized calcium. In turn, these have been directly correlated to changes in myocardial contractility. The aim of this paper is to review the current literature on the involvement of heart during the course of acute pancreatitis and also to evaluate experimental and clinical data on this topic. Introduction Pain is the hallmark of acute pancreatitis and it is localized in the epigastrium in more than 60% of patients having mild or severe disease.1 Sometimes acute pancreatitis may mimic other diseases and, in particular, acute coronary syn- drome.2 In addition, the acute illness of the pan- creas is associated with a number of metabolic abnormalities, such as hypocalcemia and hypophosphatemia which may cause hemody- namic changes and variations in the concentra- tion of ionized calcium have been directly corre- lated to changes in myocardial contractility.3 Our aim is to review the current literature on the involvement of heart during the course of acute pancreatitis and to evaluate experimental and clinical data on this topic. Pathogenesis of acute pancre- atitis The main etiology of acute pancreatitis, at least in Western countries remains that of bil- iary origin. In fact, biliary forms represented the most frequent etiological category (69.3%), while alcoholic forms occurred in only 6.6%; all together the remaining etiologies (post- surgery, post-endoscopic cholangiopancreatog- raphy, traumatic, hyperlipemic, drug-induced and pancreas divisum) accounted for 7.1% of cases and 17.1% remained without a definite etiological factor.4 The current theory of acute biliary pancreatitis is the common bile duct obstruction, which increases pancreatic duct pressure that led to trypsin activation and pan- creatic auto-digestion.5 Although pancreatic duct obstruction may play an important role in the pathogenesis of gallstone pancreatitis, it is not sufficient to cause the morphological changes of acute pancreatitis,6 indicating that other events must occur if the changes induced by pancreatic duct obstruction lead to acute pancreatitis. ossible that pancreatic aci- nar hyperstimulation, in the presence of duct obstruction, triggers and exacerbates acute pancreatitis.7 Probably a common pathogenic pathway that triggers various forms of acute pancreatitis may involve exocrine increased pancreatic hyperstimulation, pancreatic duct pressure, active trypsin reflux, and unregulat- ed activation of trypsin within pancreatic aci- nar cells. When intracellular protective mecha- nisms aimed to prevent trypsinogen activation or reduce trypsin activity are overwhelmed, acute pancreatitis occurs. Pathophysiology of acute pancreatitis From experimental studies it has been postu- lated that acute pancreatitis evolves in 3 phas- es:7 in the first phase, there are intrapancreatic trypsinogen activation and acinar cell injury as a result of release of trypsin; subsequently, there is an intrapancreatic inflammatory reac- tion that leads to the third phase characterized by development of system inflammatory response syndrome and multiple organ system dysfunction.8 Proteolytic enzymes such as trypsin, lipase and phospholipase A, kinins such as bradykinin, cytokines, and other active pep- tides such as trypsinogen activation peptide and carboxypeptidase activation peptide are liberat- ed from the inflamed pancreas and they trans- form a single-organ disease into a multisystem disease.8 As shown in Figure 1 the pathogenesis and evolution of acute pancreatitis correlate with the clinical phases of the disease.8 The experimental evidence In experimental animals, myocardium pro- duces cytokines locally under stress events and IL-6 production is an early event. In addition other cytokines are also produced by the heart and could be correlated with the echocardio- graphic left ventricular change; for example the production of TNF-alpha occurs in the same period of histological findings as acute myocardial damage, whereas TGF-beta is released in the subsequent period.9 In addi- tion, there is experimental evidence in support of the existence of an intrinsic renin- angiotensin system in the pancreas. The pan- creatic renin-angiotensin system is activated in experimental acute pancreatitis and may cause cardiac and alterations10 in humans as well.11 The clinical evidence Drummond first reported electrocardio- graphic changes in patients with abdominal pain.12 The causes of these alterations were hypothesized due to sympathetic adrenergic activation from a parasympathetic reflex, reduction of intra-cellular potassium, activa- tion of enzymatic systems, reabsorption of toxic substances.13 Clinical studies have identified electrocardiographic changes and pericardium alterations due to hemodynamic status.14,15 Experimental studies have also reported that in acute pancreatitis there are myocardial ultrastructural disturbances, including interstitial edema and cardiomy- ocyte hypoxia,16 myofiber overcontractility, intercellular edema between the cardiomy- ocytes, and cardiomyocyte hypertrophy with Emergency Care Journal 2015; volume 11:5397 Correspondence: Raffaele Pezzilli, Pancreas Unit, Department of Digestive System, Sant’Orsola- Malpighi University Hospital, via G. Massarenti 9, 40138 Bologna, Italy. Tel: +39.051.1244148 - Fax +39.051.1244148. E-mail: raffaele.pezzilli@aosp.bo.it Key words: Acute pancreatitis; Cardiac markers; Severity assessment; Acute myocardial infarc- tion. Conflict of interest: the authors declare no poten- tial conflict of interest. Received for publication: 25 June 2015. Revision received: 22 September 2015. Accepted for publication: 28 September 2015. This work is licensed under a Creative Commons Attribution 3.0 License (by-nc 3.0). ©Copyright R. Pezzilli et al., 2015 Licensee PAGEPress, Italy Emergency Care Journal 2015; 11:5397 doi:10.4081/ecj.2015.5397 Non co mmerc ial us e o nly collagenization of myocardial stroma.17 The electrocardiographic alterations in acute pancreatitis are various, say tachyarrhythmia or bradyarrhythmias, atrial flutter and atrial fibrillation, supraventricular premature con- tractions, short PR interval, QRS prolonga- tion, various bundle-branch blocks (such as left and right bundle-branch block, and left anterior hemiblock), non-specific changes in depolarization, decreased T-wave voltage, T- wave changes, and ST-segment abnormali- ties. These alterations are often seen in approximately 50% of patients.18,19 Evaluation of left ventricular function in the early phas- es of acute pancreatitis has also been inves- tigated, showing an impairment of contractil- ity in a significant portion of patients with acute pancreatitis.20 Echocardiographic assessment based on clinical parameters of severity may help to select those patients who merit highly intensive treatment.20 The laboratory evidence Easy and largely available serum markers are required to rapidly identify those patients having a cardiac involvement during the course of acute pancreatitis.21 In a recent study, we evaluated the presence of elevated levels of high-sensitivity cardiac Troponin (hs-TnT) in patients with acute pancreati- tis,22 and we found that more than 35% of them had high serum levels of this cardiac marker. The time course of serum troponin T in the early phases of acute pancreatitis is reported in Figure 2.22 However, the absence of any clinical and electrocardiographic fea- tures of acute coronary syndrome in our patients suggests that abnormally high results should be interpreted as of non- ischemic origin.23,24 In conclusion, we believe that troponin I should be used in assessing cardiac damage in acute pancreatitis patients, but additional studies exploring this possibility are needed. The future way Other markers of cardiac damage should be evaluated in clinical practice for a more in-depth evaluation of cardiac involvement in acute pancreatitis of different severity. For example, arginine vasopressin (AVP) also known as antidiuretic hormone (ADH) is one of the key hormones for cardiovascular homeostasis. Despite its pivotal role in car- diovascular diseases, both the measurement and the diagnostic use of AVP have never reached clinical practicability due to the technical problems related mainly to three reasons: its short plasma half-life, its interac- tion with platelets in the serum, and its small circulating quantity. Another interesting mol- ecule to test in clinical practice is copeptin, a glycosylated 39-amino acid long peptide with a leucine-rich core segment.25 Copeptin and AVP share the same precursor peptide, the 164-amino acid long preprovasopressin and copeptin is the C-terminal part of pro-AVP (CT-pro-AVP) and it is released together with AVP during precursor processing. In contrast to AVP, copeptin is very stable in serum or plasma at room temperature, and is easy to measure. In contrast to many other biomark- ers, the copeptin plasma concentration was similar in different age groups and showed no correlation with age. A particularly inter- esting observation was the response of circu- lating copeptin levels as a result of an acute myocardial infarction26 since these protein [Emergency Care Journal 2015; 11:5397] [page 39] Review Figure 2. Mean and standard deviation of troponin T in 37 patients with acute pancreati- tis (22 with mild acute pancreatitis and 15 with severe acute pancreatitis). *Indicates P values of serum concentrations of troponin T at days 2 and 3 compared to day 1. The other P values refer to the comparison of serum concentrations of troponin T between mild and severe acute pancreatitis during the three days of the study. Figure 1. Pathophysiology of acute pancreatitis. Non co mmerc ial us e o nly [page 40] [Emergency Care Journal 2015; 11:5397] levels were higher in patients who died or were readmitted with heart failure as com- pared to event-free survivors. Thus, the measurement of plasma copeptin should be investigated in acute pancreatitis patients in order to select those who require more inten- sive support. Finally, adrenomedullin (ADM), a 52- amino-acid peptide elevated in plasma of patients having heart failure and/or post- acute coronary syndrome, has been isolated in human pheochromocytoma and it is also present in the heart, brain, lung, kidney and gastrointestinal organs; it has a potent vasodilator activity due to an increase in cyclic adenosine monophosphate levels.27 It should be underlined that the quantification of ADM is quite difficult due to a short half- life and the lack of the reliable laboratory techniques. The identification of mid-region- al pro-adrenomedullin (MR-proADM)28,29 has overcome these problems, because it is a sta- ble peptide possibly reflecting the concentra- tion of ADM. MR-proADM is probably secret- ed in equimolar amounts to those of ADM, and it does not have any physiological effects which might explain its apparent stability. Plasma MR-proADM concentrations predict an adverse outcome in patients in the recov- ery phase of myocardial infarction and appear to add information beyond the strong predictor N-Terminal pro-B-Type natriuretic peptide (NT-proBNP). There are no studies on the ADM circulating concentration in acute pancreatitis patients and this topic should be explored in order to obtain more accurate information regarding cardiac involvement in acute pancreatitis. In any way, it has been recently reported that MR- proADM is a strong predictor of rehospital- ization and mortality in patients with septic shock28,30 and we believe that this molecule may have a practical role in patients with infected pancreatic necrosis. Regarding NT- proBNP, we have found that this molecule is abnormally elevated in acute pancreatitis and its elevation persists for at least 72 hours (Figure 3). In addition, similar high levels of serum NT-proBNP are present in patients with mild acute pancreatitis as well as in those with severe disease.22 Thus, we should be aware that elevated values of NT-proBNP in patients with acute pancreatitis cannot be useful to detect hearth failure. Conclusions The exact mechanism of myocardial injury during the course of acute pancreatitis still remains unclear. In clinical practice, laborato- ry examinations are needed to distinguish in the emergency room patients with epigastric pain having acute pancreatitis from those with acute myocardial infarction because the treat- ment strategy of the two diseases differs markedly. In addition, further efforts should be made to identify acute pancreatitis patients at high risk of cardiovascular disease and the new above-mentioned markers need to be explored for their possible use in clinical prac- tice. References 1. Uomo G. La pancreatite acuta in Italia. Studio osservazionale su 1005 casi. Firenze, Italy: Press Service; 2001. 2. Pezzilli R, Bellacosa L, Barakat B. Abdominal pain and ECG alteration: a simple diagnosis? Adv Med Sci 2010;55:333-6. 3. Swaminathan R. Magnesium metabo- lism and its disorders. Clin Biochem Rev 2003;24:47-66. 4. Pezzilli R, Uomo G, Gabbrielli A, et al. A prospective multicentre survey on the treatment of acute pancreatitis in Italy. Digest Liver Dis 2007;39:838-46. 5. Saluja A, Saluja M, Villa A, et al. Pancreatic duct obstruction in rabbits causes digestive zymogen and lysosomal enzyme colocalization. J Clin Invest 1989;84:1260-6. 6. Meyerholz DK, Samuel I. Morphologic characterization of early ligation- induced acute pancreatitis in rats. Am J Surg 2007;194:652-8. 7. Pezzilli R. Pharmacotherapy for acute pancreatitis. Expert Opin Pharmaco 2009;10:2999-3014. 8. Pezzilli R, Fantini L, Morselli-Labate AM. New approaches for the treatment of acute pancreatitis. JOP 2006;7:79-91. 9. Meyer A, Kubrusly MS, Salemi VM, et al. Severe acute pancreatitis: a possible role of intramyocardial cytokine production. JOP 2014;15:237-42. 10. Leung PS. Local renin-angiotensin sys- tem in the pancreas: the significance of changes by chronic hypoxia and acute pancreatitis. JOP 2001;2:3-8. 11. Pezzilli R, Fantini L. Proteases of the renin-angiotensin system in human acute pancreatitis. In: Leung PS, ed. Frontiers in research of the renin- angiotensin system on human disease. Amsterdam, Netherlands: Springer; 2007. pp 55-71. 12. Drummond J. Cardiac abnormalities of abdominal origin. S Afr Med J 1934;8:520-6. 13. Tullio D, Staniscia GC, Di Bartolomeo A, Paolucci A. Electrocardiographic changes in acute abdomen. Minerva Med 1981;72:1951-8. 14. Gullo L, Labriola E, Di Benedetto S, et al. Acute pancreatitis associated with parox- ysmal atrial fibrillation. A case report. Review Figure 3. Mean and standard deviation of NT-pro-BNP in 37 patients with acute pancre- atitis (22 with mild acute pancreatitis and 15 with severe acute pancreatitis). **Indicates normalized values of NT-pro-BNP: values from 0 to 1 represent values within the refer- ence range, and values greater than 1 represent values above the upper reference limit. *Indicates P values of serum concentrations of troponin T at days 2 and 3 compared to day 1. The other P values refer to the comparison of serum concentrations of troponin T between mild and severe acute pancreatitis during the three days of the study. Non co mmerc ial us e o nly [Emergency Care Journal 2015; 11:5397] [page 41] Panminerva Med 1988;30:111-3. 15. Di Carlo V, Nespoli A, Chiesa R, et al. Hemodynamic and metabolic impair- ment in acute pancreatitis. World J Surg 19815:329-39. 16. Banks PA. Epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis. Gastrointest Endosc 2002;56:26-30. 17. Saulea A, Costin S, Rotari V. Heart ultra- structure in experimental acute pancre- atitis. Rom J Phys 1997;34:35-44. 18. Pezzilli R, Barakat B, Billi P, Bertaccini B. Electrocardiographic abnormalities in acute pancreatitis. Eur J Emerg Med 1999;6:27-9. 19. Rubio-Tapia A, García-Leiva J, Asensio- Lafuente E, et al. Electrocardiographic abnormalities in patients with acute pancreatitis. J Clin Gastroenterol 2005; 39: 815-8. 20. Pezzilli R, Billi P, Bertaccini B, Gullo L. Pericardial effusion and left ventricular function in acute pancreatitis. Am J Gastroenterol 1996;91:997-1000. 21. Pezzilli R, Barassi A, Iammarino MT, Melzi d’Eril GV. Is troponin T a useful marker of myocardial damage in acute pancreatitis? A prospective time course study. Digest Liver Dis 2013;45:347-8. 22. Barassi A, Pezzilli R, Romanelli MC, et al. Serum markers of myocardial damage in acute pancreatitis: a prospective time course study. Pancreas 2015;44:678-80. 23. Pezzilli R, Billi P, Cappelletti O, Barakat B, et al. Rhabdomyolysis and acute pan- creatitis. J Gastroen Hepatol 1999;14:168-71. 24. Casagranda I, Cavazza M, Clerico A, et al. Proposal for the use in emergency departments of cardiac troponins meas- ured with the latest generation methods in patients with suspected acute coro- nary syndrome without persistent ST- segment elevation. Clin Chem Lab Med 2013;51:1727-37. 25. Holwerda DA. A glycopeptide from the posterior lobe of pig pituitaries.Isolation and characterization. Eur J Biochem 1972;28:334-9. 26. Khan SQ, Dhillon OS, O’Brien RJ, et al. C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study. Circulation 2007;115:2103-10. 27. Asakawa H, Nishikimi T, Suzuki T, et al. Elevation of two molecular forms of adrenomedullin in plasma and urine in patients with acute myocardial infarction treated with early coronary angioplasty. Clin Sci 2001;100:117-26. 28. Pezzilli R, Barassi A, Pigna A, et al. Time course of proadrenomedullin in the early phase of septic shock. A comparative study with other proinflammatory pro- teins. Panminerva Med 2012;54:211-7. 29. Palladini G, Barassi A, Perlini S, et al. Midregional proadrenomedullin (MR- proADM) is a powerful predictor of early death in AL amyloidosis. Amyloid 2011;18:216-21. 30. Travaglino F, Russo V, De Berardinis B, et al. Thirty and ninety days mortality pre- dictive value of admission and in-hospi- tal procalcitonin and mid-regional pro- adrenomedullin testing in patients with dyspnea. Results from the VERyfing DYspnea trial. Am J Emerg Med 2014;32: 334-41. Review Non co mmerc ial us e o nly