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‘Paradox’ of troponin elevations after non-cardiac surgery

2015; Elsevier BV; Volume: 114; Issue: 6 Linguagem: Inglês

10.1093/bja/aev068

1471-6771

Giora Landesberg, Allan S. Jaffe,

Aortic aneurysm repair treatments

Dr Noordzij and colleagues1Noordzij P Van Geffen O Dijkstra I et al.High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery.Br J Anaesth. 2015; 114: 909-918Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar report in this issue of BJA that after major abdominal surgery, elevations in troponin, measured with a high-sensitivity assay, predict non-cardiac complications. This may seem to be an apparently paradoxical result. How can a very sensitive and specific diagnostic assay for myocardial injury and infarction predict postoperative non-cardiac rather than cardiac complications? However, those who carefully follow the literature on postoperative troponin elevations should not find this surprising at all. In a study published in 20032Landesberg G Shatz V Akopnik I et al.Association of cardiac troponin, CK-MB, and postoperative myocardial ischemia with long-term survival after major vascular surgery.J Am Coll Cardiol. 2003; 42: 1547-1554Crossref PubMed Scopus (403) Google Scholar from a cohort of 447 patients who underwent major vascular surgery, we showed that even low-level troponin elevations, measured with earlier cardiac troponin (cTn) assays during the first 3 days after surgery, presaged mortality at 5 yr, while more marked elevations predicted higher mortality. The vast majority of postoperative troponin elevations were asymptomatic. In fact, among patients with low-level troponin elevations, who were the majority, only 18% had signs or symptoms that could be attributable to myocardial infarction and only 32% had ST-segment depression lasting longer than 15 min on continuous 12-lead ECG monitoring. Even fewer ischaemic events would have been detected if only daily samples of ECGs had been used, which is the common practice of most clinicians. Among the fewer patients with higher postoperative troponin elevations, the incidence of signs or symptoms possibly related to myocardial infarction increased incrementally to 40–60%, and the chance of finding even short (15 min) episodes of ischaemia on continuous 12-lead ECG monitoring increased to 80–90%. The recent VISION study3Botto F Alonso-Coello P Chan MT et al.Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes.Anesthesiology. 2014; 120: 564-578Crossref PubMed Scopus (600) Google Scholar has rediscovered this phenomenon. In VISION, even minor cTnT elevations detected with the fourth-generation assay for cTnT during the first 3 days in 15 065 patients predicted 30 day postoperative mortality, and more marked elevations were incrementally associated with higher mortality. In that study, as in ours, out of 115 patients with troponin elevations who died, only 22 (19%) had cardiac symptoms and only 31 (27%) had ischaemic ECG findings (ST-elevation/depression, new Q-waves or left bundle branch block) on daily ECGs. Similar results were reported by Beattie and colleagues,4Beattie WS Karkouti K Tait G et al.Use of clinically based troponin underestimates the cardiac injury in non-cardiac surgery: a single-centre cohort studying 51,701 consecutive patients.Can J Anesth. 2012; 59: 1013-1022Crossref PubMed Scopus (61) Google Scholar who studied 51 701 patients retrospectively and found that 20.4% had postoperative troponin I elevations. These elevations incrementally predicted 30 day postoperative all-cause mortality. Importantly, only 34% of postoperative deaths in low-risk patients were cardiac deaths, although the proportion of cardiac deaths increased to 42 and 60% in higher-risk patients. Finally, Van Waes and colleagues5Van Waes JA Nathoe HM de Graaff JC et al.Myocardial injury after noncardiac surgery and its association with short-term mortality.Circulation. 2013; 127: 2264-2271Crossref PubMed Scopus (226) Google Scholar recently studied 2216 consecutive patients after major non-cardiac surgery using high-sensitivity troponin I measurements during the first 3 days after surgery. They too confirmed that postoperative troponin elevations strongly and incrementally predicted 30 day mortality. Of the 315 (19%) patients with troponin elevations, 27 (8.6%) died but only 10 (3.2%) had typical chest pain and only 30 (9.5%) had new ischaemic ECG changes. It is clear from the above summary that while postoperative troponin elevations in the first days after surgery are common and strongly predict both 30 day and long-term mortality, they are not strongly associated with cardiac signs or symptoms. Higher postoperative troponin concentrations are better associated with cardiac signs or symptoms, but low-level troponin elevations, although prognostically important, are rarely associated with overt signs of cardiac abnormalities. The publication by Noordzij and colleagues,1Noordzij P Van Geffen O Dijkstra I et al.High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery.Br J Anaesth. 2015; 114: 909-918Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar although a small report of only 203 patients, focuses on non-cardiac complications, which is something that previous studies did not. Postoperative fifth-generation high-sensitivity troponin T (hs-cTnT) elevations ≥14 ng litre−1 (the 99th% upper reference limit for the hs-cTnT assay) in the study by Noordzij and colleague’s1Noordzij P Van Geffen O Dijkstra I et al.High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery.Br J Anaesth. 2015; 114: 909-918Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar occurred in 106 (52%) patients. Only 39 (19%) had hs-cTnT >30 ng litre−1 and only 33 (16%) had a marked (100%) increase from baseline preoperative hs-cTnT concentrations. These troponin elevations are in the very low range compared with those in previously published papers but are consistent with the preliminary report of Kavsak and colleague6Kavsak PA Walsh M Srinathan S et al.High sensitivity troponin T concentrations in patients undergoing noncardiac surgery: a prospective cohort study.Clin Biochem. 2011; 44: 1021-1024Crossref PubMed Scopus (74) Google Scholar with the high-sensitivity troponin T assay. Combining all the studies together, one may conclude that the low range of postoperative troponin elevations is associated with postoperative non-cardiac complications, while the higher ranges of troponin elevations correlate better with cardiac signs and complications, although all troponin elevations incrementally predict mortality. Hence, the paradox with which we started can now be rephrased; how come low-level postoperative troponin elevations correlate mainly with non-cardiac complications and higher levels of troponin concentrations correlate incrementally with cardiac complications, while both predict early and late mortality?. To understand this paradox, we must understand the pathophysiology of postoperative troponin elevations (i.e. the concept of type II myocardial injury and infarction). Up to 2007, the most dominant recognized cause for myocardial infarction was acute coronary event, namely coronary plaque rupture, fissuring, or erosion, and subsequent acute coronary thrombosis. Stable, although severe, coronary artery disease was thought, according to that paradigm, to be the cause of ischaemia, angina pectoris, or heart failure, but rarely if ever the cause of myocardial infarction. This situation has changed dramatically since the introduction of the troponin assays, which have markedly increased the sensitivity and specificity for detection of cardiac injury, and numerous studies have repeatedly shown that an increase in cTn values has major prognostic importance even in the absence of acute coronary thrombosis.7Alpert JS Thygesen K Antman E Bassand JP Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.J Am Coll Cardiol. 2000; 36: 959-969Crossref PubMed Scopus (3841) Google Scholar In 2007, the Universal Definition for Myocardial Infarction guidelines reclassified myocardial infarction and, for the first time, defined spontaneous primary coronary event caused by plaque erosion, rupture fissuring, or dissection and subsequent acute coronary thrombosis as type I myocardial infarction. In contrast, myocardial infarction secondary to ischaemia resulting from an imbalance in myocardial oxygen supply–demand in the absence of a primary coronary event was defined as type II acute myocardial infarction.8Thygesen K Alpert JS White HD et al.Universal definition of myocardial infarction.Circulation. 2007; 116: 2634-2653Crossref PubMed Scopus (2134) Google Scholar The recognition that a prolonged imbalance in supply and demand was by far the most common mechanism of postoperative myocardial infarction and injury had already been noted by us in 2003,9Landesberg G The pathophysiology of perioperative myocardial infarction: facts and perspectives.J Cardiothorac Vasc Anesth. 2003; 17: 90-100Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar based on the observations that ST-segment elevation-type myocardial infarction, which is pathognomonic for acute plaque rupture and coronary thrombosis, rarely occurs in high-risk cardiac patients undergoing major surgery, despite the immense postoperative physiological and emotional stresses. The observation that myocardial injury occurs after prolonged imbalance in myocardial oxygen supply and demand in response to the stress of surgery, particularly in patients with limited coronary or limited myocardial structural reserve, also explains why these patients are at increased risk of mortality from any critical illness or postoperative complication. Critically ill patients admitted to the intensive care unit who have cTnT elevations have a markedly increased rate of both short- and long-term mortality. This has been shown for patients with acute respiratory failure,10Vasile VC Chai HS Khambatta S et al.Significance of elevated cardiac troponin T levels in critically ill patients with acute respiratory disease.Am J Med. 2010; 123: 1049-1058Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar gastrointestinal bleeding,11Vasile VC Babuin L Rio Perez JA et al.Long-term prognostic significance of elevated cardiac troponin levels in critically ill patients with acute gastrointestinal bleeding.Crit Care Med. 2009; 37: 140-147Crossref PubMed Scopus (48) Google Scholar or sepsis.12Landesberg G Vesselov Y Einav S et al.Myocardial ischemia, cardiac troponin, and long-term survival of high-cardiac risk critically ill intensive care unit patients.Crit Care Med. 2005; 33: 1281-1287Crossref PubMed Scopus (74) Google Scholar What a cTn elevation marks in each individual situation is unclear, but it is undeniable that when one has critical illness and troponin elevations, whether detected acutely or after prolonged stress such as surgery, mortality is increased. This is most likely to be the reason for the increased mortality seen in the study by Noordzij and colleague’s.1Noordzij P Van Geffen O Dijkstra I et al.High-sensitive cardiac troponin T measurements in prediction of non-cardiac complications after major abdominal surgery.Br J Anaesth. 2015; 114: 909-918Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar We have recently shown that diastolic dysfunction is common and strongly associated with troponin elevations and mortality in patients with severe sepsis and septic shock.13Landesberg G Gilon D Meroz Y et al.Diastolic dysfunction and mortality in severe sepsis and septic shock.Eur Heart J. 2012; 33: 895-903Crossref PubMed Scopus (280) Google Scholar, 14Landesberg G Jaffe AS Gilon D et al.Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation.Crit Care Med. 2014; 42: 790-800Crossref PubMed Scopus (157) Google Scholar The challenge now is to understand how to modify our treatment of these patients to take these data into account and improve outcomes. There are important caveats in this area that we need to keep in mind. The first is that acute events, such as acute myocardial infarction requires a rising and falling pattern of cTn values and not only isolated cTn elevations. In addition, there are many things that might cause isolated cTn elevations after surgery other than ischaemia, such as pulmonary embolism, infection, the effects of renal dysfunction, structural heart disease, or a combination of these. Thus, clinical integration is essential, lest we fall into the trap of attributing all postoperative cTn elevations to ischaemic heart disease, leading to the potential for excessive intervention. There has been considerable confusion about some of the causes for cTn elevations, and clarifying all of them is beyond the scope of this editorial. Nevertheless, there are several issues that are important to mention in this context. There are frequent elevations of cTn in patients with renal disease,15Jacobs LH van de Kerkhof J Mingels AM et al.Haemodialysis patients longitudinally assessed by highly sensitive cardiac troponin T and commercial cardiac troponin T and cardiac troponin I assays.Ann Clin Biochem. 2009; 46: 283-290Crossref PubMed Scopus (90) Google Scholar and these elevations are a result of cardiac injury16Ooi DS Isotalo PA Veinot JP Correlation of antemortem serum creatine kinase, creatine kinase-MB, troponin I, and troponin T with cardiac pathology.Clin Chem. 2000; 46: 338-344Crossref PubMed Scopus (158) Google Scholar and are a potent risk factor for mortality.17Apple FS Murakami MM Pearce LA Herzog CA Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease.Circulation. 2002; 106: 2941-2945Crossref PubMed Scopus (466) Google Scholar However, as best we can tell, this is not a result of reduced renal clearance, because cTn is not cleared renally. There is only one report of cTnI and cTnT in urine, and that was in patients with massive proteinuria.18Ziebig R Lun A Hocher B et al.Renal elimination of troponin T and troponin I.Clin Chem. 2003; 49: 1191-1193Crossref PubMed Scopus (86) Google Scholar Thus, cTn elevations in kidney disease probably reflect the metabolic effects of renal failure, structural myocardial changes (e.g. left ventricular hypertrophy) and the association of renal disease with coronary artery disease. It is likely that the renal metabolic milieu changes the degradation pathways so that small fragments of cTnT persist, and because the epitopes for binding are so close together (two to six amino acids), the signal persists.19Diris JH Hackeng CM Kooman JP et al.Impaired renal clearance explains elevated troponin T fragments in hemodialysis patients.Circulation. 2004; 109: 23-25Crossref PubMed Scopus (222) Google Scholar Given that the antigen epitopes for cTnI are further apart (30–50 amino acids), that signal is lost with cTnI. In addition, as with any test, there can be analytical false positives. One can have false positives as a result of cross-reacting or heterophilic antibodies, which usually cause marked elevations of cTn that do not change over time, or so-called ‘fliers’, which are usually attributable to fibrin interference.20Apple FS Jesse RL Newby LK et al.National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes.Circulation. 2007; 115: e352-e355Crossref PubMed Scopus (216) Google Scholar These are rare and can be unmasked by good laboratory practices. The other situation is one where there is re-expression of presumably fetal proteins in response to skeletal muscle injury. That is unique to cTnT.21Jaffe AS Vasile VC Milone M et al.Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T.J Am Coll Cardiol. 2011; 58: 1819-1824Crossref PubMed Scopus (218) Google Scholar In summary, postoperative non-cardiac and cardiac complications correlating with low-levels and higher-levels postoperative troponin elevations, respectively, are two sides of the same spectrum of events. Non-cardiac complications pose a higher demand on the patient’s heart, and thus, it is not surprising that mortality is increased in those with underlying heart disease, which is often marked by an elevated cTn. Conversely, primary cardiac injury may lead to cardiac failure and a deterioration in other important systems, such as the kidneys, leading to what may appear to be a non-cardiac cause of death. Our important role in the future is to develop ways to understand the specifics of both situations so that we can devise treatment strategies that take both cardiac and non-cardiac issues into account and improve patient care. A.S.J. has been consultant to many companies dealing with diagnostics.