Myocardial infarction caused by surgery: Blame inflammation not the surgeon
2016; Elsevier BV; Volume: 255; Linguagem: Inglês
10.1016/j.atherosclerosis.2016.08.044
ISSN1879-1484
AutoresCarlos G. Santos‐Gallego, Maria Wallert, Karlheinz Peter,
Tópico(s)Lipoproteins and Cardiovascular Health
ResumoThe connection between major surgery and cardiovascular (CV) events has been proposed for a long time. Already in 1912, Wilson reported for the first time a fatal case of coronary embolic occlusion one day after non-cardiac surgery [[1]Wilson L.B.I. Fatal post-operative embolism.Ann. Surg. 1912; 56: 809-817Crossref PubMed Google Scholar]. In the following decades, the connection of major surgery and increased CV events such as myocardial infarction (MI) has been confirmed in many publications and is part of basic clinical knowledge. However, the exact mechanisms remain elusive. Hip and knee replacement surgeries are prototypical examples for increased CV risk after major surgery [2Lalmohamed A. Vestergaard P. Klop C. Grove E.L. de Boer A. Leufkens H.G. et al.Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study.Arch. Intern Med. 2012; 172: 1229-1235Crossref PubMed Scopus (59) Google Scholar, 3Gandhi R. Petruccelli D. Devereaux P.J. Adili A. Hubmann M. de Beer J. Incidence and timing of myocardial infarction after total joint arthroplasty.J. Arthroplasty. 2006; 21: 874-877Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. In the present issue of Atherosclerosis, Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar] shed light on the mechanisms of the association between this major orthopedic surgery and increased MI risk. As mentioned, there is a strong (up to 25-fold) increased risk of MI after hip and knee replacement surgeries [2Lalmohamed A. Vestergaard P. Klop C. Grove E.L. de Boer A. Leufkens H.G. et al.Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study.Arch. Intern Med. 2012; 172: 1229-1235Crossref PubMed Scopus (59) Google Scholar, 3Gandhi R. Petruccelli D. Devereaux P.J. Adili A. Hubmann M. de Beer J. Incidence and timing of myocardial infarction after total joint arthroplasty.J. Arthroplasty. 2006; 21: 874-877Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar], so marrow embolization due to surgical invasion of the medullary canal was originally proposed as a mechanism [2Lalmohamed A. Vestergaard P. Klop C. Grove E.L. de Boer A. Leufkens H.G. et al.Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study.Arch. Intern Med. 2012; 172: 1229-1235Crossref PubMed Scopus (59) Google Scholar, 3Gandhi R. Petruccelli D. Devereaux P.J. Adili A. Hubmann M. de Beer J. Incidence and timing of myocardial infarction after total joint arthroplasty.J. Arthroplasty. 2006; 21: 874-877Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. However, given that non-orthopedic surgery also increased CV risk [[5]Poldermans D. Schouten O. Vidakovic R. Bax J.J. Thomson I.R. Hoeks S.E. et al.A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: the DECREASE-V Pilot Study.J. Am. Coll. Cardiol. 2007; 49: 1763-1769Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar], a different mechanism had to be responsible. Imbalance between myocardial oxygen supply and consumption (due to hypovolemia, vasodilation, hypoxemia, anemia, tachycardia, stable coronary stenosis) was subsequently blamed, but post-mortem pathological studies conclusively demonstrated that at least half of the perioperative MI were due to unstable atherosclerotic plaques with superimposed thrombosis [6Gualandro D.M. Campos C.A. Calderaro D. Yu P.C. Marques A.C. Pastana A.F. et al.Coronary plaque rupture in patients with myocardial infarction after noncardiac surgery: frequent and dangerous.Atherosclerosis. 2012; 222: 191-195Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 7Dawood M.M. Gutpa D.K. Southern J. Walia A. Atkinson J.B. Eagle K.A. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention.Int. J. Cardiol. 1996; 57: 37-44Abstract Full Text PDF PubMed Scopus (300) Google Scholar]. The question remains, why do so many atheroma plaques rupture perioperatively? As early on reported by Virchow, inflammation is a driver of atherosclerotic disease [[8]Ross R. The pathogenesis of atherosclerosis–an update.N. Engl. J. Med. 1986; 314: 488-500Crossref PubMed Scopus (4015) Google Scholar]. Indeed, inflammation has been described as a causal link between traditional risk factors and modification of the arterial wall, which leads to atherosclerosis and its clinical complications such as MI and stroke [[9]Libby P. Inflammation in atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2045-2051Crossref PubMed Scopus (1530) Google Scholar]. Many studies corroborate the increase of CV risk by a wide range of inflammatory diseases in humans. First, acute respiratory infections in general [[10]Smeeth L. Thomas S.L. Hall A.J. Hubbard R. Farrington P. Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination.N. Engl. J. Med. 2004; 351: 2611-2618Crossref PubMed Scopus (1047) Google Scholar] and influenza in particular [[11]Naghavi M. Barlas Z. Siadaty S. Naguib S. Madjid M. Casscells W. Association of influenza vaccination and reduced risk of recurrent myocardial infarction.Circulation. 2000; 102: 3039-3045Crossref PubMed Scopus (250) Google Scholar] are associated with increased risk of MI, while, conversely, influenza vaccination reduces CV events [[12]Gurfinkel E.P. de la Fuente R.L. Mendiz O. Mautner B. Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study.Circulation. 2002; 105: 2143-2147Crossref PubMed Scopus (170) Google Scholar]; community-acquired pneumonia is an additional example of infection resulting in increased MI risk [[13]Corrales-Medina V.F. Musher D.M. Wells G.A. Chirinos J.A. Chen L. Fine M.J. Cardiac complications in patients with community-acquired pneumonia: incidence, timing, risk factors, and association with short-term mortality.Circulation. 2012; 125: 773-781Crossref PubMed Scopus (287) Google Scholar]. Moreover, patients with chronic infections such as Helicobacter pylori [[14]Shmuely H. Wattad M. Solodky A. Yahav J. Samra Z. Zafrir N. Association of Helicobacter pylori with coronary artery disease and myocardial infarction assessed by myocardial perfusion imaging.Isr. Med. Assoc. J. 2014; 16: 341-346PubMed Google Scholar] also experienced more CV events. Furthermore, autoimmune diseases such as systemic lupus erythematosus [[15]Lin C.Y. Shih C.C. Yeh C.C. Chou W.H. Chen T.L. Liao C.C. Increased risk of acute myocardial infarction and mortality in patients with systemic lupus erythematosus: two nationwide retrospective cohort studies.Int. J. Cardiol. 2014; 176: 847-851Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar], rheumatoid arthritis [[16]Chung W.S. Lin C.L. Peng C.L. Chen Y.F. Lu C.C. Sung F.C. et al.Rheumatoid arthritis and risk of acute myocardial infarction–a nationwide retrospective cohort study.Int. J. Cardiol. 2013; 168: 4750-4754Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar], psoriasis [[17]Patel R.V. Shelling M.L. Prodanovich S. Federman D.G. Kirsner R.S. Psoriasis and vascular disease-risk factors and outcomes: a systematic review of the literature.J. Gen. Intern Med. 2011; 26: 1036-1049Crossref PubMed Scopus (74) Google Scholar] and likely inflammatory bowel disease [[18]Andersen N.N. Jess T. Risk of cardiovascular disease in inflammatory bowel disease.World J. Gastrointest. Pathophysiol. 2014; 5: 359-365PubMed Google Scholar] are also associated with increased CV risk. Seeing this close connection between inflammation and CV risk, the question then arises whether surgery-induced acute inflammation can explain the increased risk of perioperative MI? In this issue of Atherosclerosis, Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar] investigate potential mechanisms causing CV events during major surgery. Orthopaedic surgery is mimicked in ApoE-KO mice on high fat diet. The authors show that serum amyloid A (SAA), which is a measure of systemic inflammation, is reversibly increased of up to 100 fold after surgery. The authors then provide impressive proof of increased atherosclerotic plaque and necrotic core areas. The piloting work by Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar] provides strong evidence of a direct connection between major surgery and atherogenesis. However, it also leaves several unanswered questions that are of central importance for the understanding of plaque instability and thus warrant further investigations.1)Classically, high macrophage infiltration and increased macrophage apoptosis in the plaque causes fibrous cap thinning and plaque rupture. However, the authors do not report increased macrophage infiltration in the mice undergoing surgery. In fact, there are less macrophages; moreover, M1 (proinflammatory)-polarized macrophages are also reduced (at 5 days) in mice with surgery. A possible explanation is that there is increased macrophage infiltration in the first days after surgery but most of those macrophages die quickly before day 5 (i.e., before the first time point analyzed by the authors), thus contributing to the enlargement of the necrotic core. Furthermore, an increase in apoptosis in the plaques of mice with surgery, as determined by immunohistology for caspase-3, could not be detected. This could be explained because the macrophages could undergo necrosis but not apoptosis. Furthermore, using more sensitive detection systems of apoptosis (e.g., TUNEL or cleaved caspase-3), smaller changes might have been detected.2)Mice with “orthopedic surgery” did not present with thinner fibrous cap, which is a classical sign of plaque vulnerability. This might well be explained by the fact that the ApoE-KO mouse is a model that typically develops stable atherosclerotic plaques, in which cap measurements are not a measure of plaque instability (see discussion below). However, CV events have also been described in humans to be caused by plaque erosion [[19]Santos-Gallego C.G. Picatoste B. Badimon J.J. Pathophysiology of acute coronary syndrome.Curr. Atheroscler. Rep. 2014; 16: 401Crossref PubMed Scopus (202) Google Scholar], not only by plaque rupture. In fact, a high percentage of CV events are probably caused by plaque erosion, especially in young women. Therefore, MI after surgery could be caused by an inflammatory burst resulting in plaque erosion. These explanations reconcile the lack of fibrous cap thinning in the manuscript by Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar], but also suggest interesting avenues for further research. The data from Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar] indicate that increased atherogenesis is associated with enhanced systemic inflammation induced by surgery. This association has indeed been recently confirmed by convincing experimental approaches with various other inflammatory insults. ApoE-KO mice subjected to experimental MI developed 40% larger atherosclerosis lesions with markedly vulnerable phenotype (enlarged necrotic core size, increased protease activity, and enhanced plaque infiltration by macrophages, neutrophils and lymphocytes) [[20]Dutta P. Courties G. Wei Y. Leuschner F. Gorbatov R. Robbins C.S. et al.Myocardial infarction accelerates atherosclerosis.Nature. 2012; 487: 325-329Crossref PubMed Scopus (751) Google Scholar]. Increased sympathetic activity after MI (which might well be a central mechanism of other insults such as surgery) results in both monocytosis and atheroma plaque infiltration with macrophages [[20]Dutta P. Courties G. Wei Y. Leuschner F. Gorbatov R. Robbins C.S. et al.Myocardial infarction accelerates atherosclerosis.Nature. 2012; 487: 325-329Crossref PubMed Scopus (751) Google Scholar]. Augmented inflammation is also the central mechanism of atherosclerotic progression after other insults, both acute (stroke) [[21]Courties G. Herisson F. Sager H.B. Heidt T. Ye Y. Wei Y. et al.Ischemic stroke activates hematopoietic bone marrow stem cells.Circ. Res. 2015; 116: 407-417Crossref PubMed Scopus (141) Google Scholar] or chronic (prolonged stress) [[22]Heidt T. Sager H.B. Courties G. Dutta P. Iwamoto Y. Zaltsman A. et al.Chronic variable stress activates hematopoietic stem cells.Nat. Med. 2014; 20: 754-758Crossref PubMed Scopus (450) Google Scholar]. The necessary role of inflammation in worsening of atherosclerosis after MI is mechanistically corroborated since inhibition of adhesion molecules expression attenuated plaque progression after MI, reduced macrophage infiltration and decreased protease activity [[23]Sager H.B. Dutta P. Dahlman J.E. Hulsmans M. Courties G. Sun Y. et al.RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction.Sci. Transl. Med. 2016; 8 (342ra80)Crossref PubMed Scopus (129) Google Scholar]. Experimental data also clearly indicate that therapeutic targeting of inflammatory pathways attenuates atherosclerosis, as shown by inhibiting various NLRP3 inflammasome-associated proteins [24Duewell P. Kono H. Rayner K.J. Sirois C.M. Vladimer G. Bauernfeind F.G. et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (2567) Google Scholar, 25Zheng F. Xing S. Gong Z. Mu W. Xing Q. Silence of NLRP3 suppresses atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice.Mediat. Inflamm. 2014; 2014: 507208Crossref PubMed Scopus (98) Google Scholar]. In clinical practice, an elevated level of C reactive protein (CRP) is one of the most important systemic markers of inflammation (indeed also increased after surgery) and it has been shown to be also associated with an increased risk of CV events [[26]Ridker P.M. From C-Reactive protein to Interleukin-6 to Interleukin-1: moving upstream to identify novel targets for atheroprotection.Circ. Res. 2016; 118: 145-156Crossref PubMed Scopus (507) Google Scholar]. Whereas the circulating form of CRP, pentameric CRP, seems not to be a proinflammatory factor itself, its dissociation product monomeric CRP seems to be a strong proinflammatory factor that has the potential to drive inflammation in atherosclerotic plaques. The postoperative acute increase in circulating pentameric CRP might result in enhanced monomeric CRP that additionally aggravates atheroma lesion vulnerability, thus also representing a potential therapeutic target [27Thiele J.R. Zeller J. Bannasch H. Stark G.B. Peter K. Eisenhardt S.U. Targeting C-Reactive protein in inflammatory disease by preventing conformational changes.Mediat. Inflamm. 2015; 2015: 372432Crossref PubMed Scopus (76) Google Scholar, 28Eisenhardt S.U. Habersberger J. Murphy A. Chen Y.C. Woollard K.J. Bassler N. et al.Dissociation of pentameric to monomeric C-reactive protein on activated platelets localizes inflammation to atherosclerotic plaques.Circ. Res. 2009; 105: 128-137Crossref PubMed Scopus (199) Google Scholar]. Overall, there is a multitude of evidence available that inflammation drives atherosclerotic plaque instability and experimental work on understanding the mechanisms and identifying therapeutic targeting are an important focus of research [[29]Chen Y.C. Huang A.L. Kyaw T.S. Bobik A. Peter K. Atherosclerotic plaque rupture: identifying the straw that breaks the Camel's back.Arterioscler. Thromb. Vasc. Biol. 2016; 36: e63-72Crossref PubMed Scopus (57) Google Scholar]. The classical ApoE-KO mouse model, used by Fuijkschot et al. [[4]Fuijkschot W.W.M. Martine C. van der Linden Rianne Krijnen Paul A.J. Zethof Ilse P.A. Theyse Lars F.H. Kleemann Robert Niessen Hans W.M. Smulders Yvo M. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE-/- mice.Atherosclerosis. 2016; PubMed Google Scholar], does not exhibit characteristics of plaque instability as seen in humans but rather exhibits stable atherosclerosis. Features such as intraplaque hemorrhage, luminal thrombosis or thin fibrous caps and their disruption leading to plaque rupture are missing. However, mouse models that reflect plaque instability as seen in humans have recently been developed [30Chen Y.C. Bui A.V. Diesch J. Manasseh R. Hausding C. Rivera J. et al.A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.Circ. Res. 2013; 113: 252-265Crossref PubMed Scopus (135) Google Scholar, 31Jin S.X. Shen L.H. Nie P. Yuan W. Hu L.H. Li D.D. et al.Endogenous renovascular hypertension combined with low shear stress induces plaque rupture in apolipoprotein E-deficient mice.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 2372-2379Crossref PubMed Scopus (38) Google Scholar]. Their use in the context of inflammatory insults such as major surgery might provide further insights into the mechanisms of how plaque instability and rupture is provoked perioperatively [[30]Chen Y.C. Bui A.V. Diesch J. Manasseh R. Hausding C. Rivera J. et al.A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling.Circ. Res. 2013; 113: 252-265Crossref PubMed Scopus (135) Google Scholar]. Based on the discussed experimental and clinical data, indicating a direct connection between inflammatory status and CV events, one of the most interesting perspectives for patients going into major surgery is a potentially prophylactic approach using anti-inflammatory drugs. Statins with their pleiotropic anti-inflammatory effects have just recently been reported to reduce CV events given pre-operatively in patients undergoing non-cardiac surgery [[32]Berwanger O. Le Manach Y. Suzumura E.A. Biccard B. Srinathan S.K. Szczeklik W. et al.Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study.Eur. Heart J. 2016; 37: 177-185Crossref PubMed Scopus (87) Google Scholar]. Furthermore, currently large-scale clinical trials with anti-inflammatory drugs such as methotrexate, colchicine and anti-IL1β receptor antibody canakinumab are currently underway; ultimately testing whether inflammation is the driving force of plaque instability and whether anti-inflammatory drugs are able to achieve plaque stabilization. If these trials show a reduction of CV events with anti-inflammatory therapy, then these drugs hold great promise as “prophylactic perioperative therapy”. Certainly, potential side effects of such perioperative anti-inflammatory therapy have to be monitored. However, so far anti-inflammatory therapy with statins and methotrexate did not increase infection rate but rather demonstrated a significant decrease of surgical site infection [[33]Saitoh M. Matsushita K. [Prevention of surgical site infection for orthopaedic surgery in rheumatoid arthritis].Nihon Rinsho. 2016; 74: 993-999PubMed Google Scholar], pneumonia and sepsis [[32]Berwanger O. Le Manach Y. Suzumura E.A. Biccard B. Srinathan S.K. Szczeklik W. et al.Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study.Eur. Heart J. 2016; 37: 177-185Crossref PubMed Scopus (87) Google Scholar]. In summary, understanding the mechanisms of increased CV risk with major surgery (cardiac and non-cardiac) and identifying inflammation as a major determinant of this risk may thus ultimately help identify novel therapeutic, in particular anti-inflammatory, approaches that have the potential to substantially reduce perioperative CV mortality and morbidity.(see Fig. 1) The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE−/− miceAtherosclerosisVol. 255PreviewObservational studies show a peak incidence of cardiovascular events after major surgery. For example, the risk of myocardial infarction increases 25-fold early after hip replacement. The acuteness of this increased risk suggests abrupt enhancement in plaque vulnerability, which may be related to intra-plaque inflammation, thinner fibrous cap and/or necrotic core expansion. We hypothesized that acute systemic inflammation following major orthopedic surgery induces such changes. Full-Text PDF
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