- Email: [email protected]
Editorial commentary: Improving our understanding of type 2 myocardial infarction and myocardial injury
Author’s Accepted Manuscript Improving our understanding of type 2 myocardial infarction and myocardial injury Yader Sandoval
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(17)30047-6S1050-1738(17)30042-7 http://dx.doi.org/10.1016/j.tcm.2017.03.007 TCM6388
To appear in: Trends in Cardiovascular Medicine Cite this article as: Yader Sandoval, Improving our understanding of type 2 myocardial infarction and myocardial injury, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2017.03.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Improving our understanding of type 2 myocardial infarction and myocardial injury
Yader Sandoval1, 2, MD
1. Division of Cardiology, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA. 2. Minneapolis
Heart
Institute,
Abbott
Northwestern
Hospital,
Minneapolis,
Minnesota, USA.
Disclosure: Yader Sandoval, non-salaried Advisor, Roche Clinical Diagnostics.
Correspondence Yader Sandoval, MD 701 Park Avenue, Orange Building 5th Floor Minneapolis, Minnesota, 55415, USA. Email: [email protected]
Type 2 myocardial infarction, an increasingly recognized condition, occurs in instances of myocardial injury with necrosis plus evidence of myocardial ischemia where a condition other than an acute atherothrombotic event leads to an imbalance between myocardial oxygen supply and/or demand
1-3.
In this issue of Trends in Cardiovascular
Medicine, Mihatov and colleagues summarize the evidence to date on type 2 myocardial infarction and address several common clinical scenarios in which one must distinguish between myocardial injury and myocardial infarction4. Several observations are offered. First, while challenges exist in ascertaining the incidence of type 2 myocardial infarction with a wide range reported across the literature, several studies have demonstrated that type 2 myocardial infarction is frequent1,3. In the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study, a prospective singlecenter investigation examining 1,251 patients undergoing coronary and peripheral angiographic procedures with or without intervention, 73.8% of all myocardial infarctions on follow-up had at least one incident type 2 myocardial infarction 5. Similarly, studies examining all-comers presenting to the emergency department undergoing cTn measurements have shown that type 2 myocardial infarction occurs often, with recent US studies reporting frequencies ranging from 53% to 74% of all myocardial infarctions 6-7
. Even using strict diagnostic criteria with very high thresholds necessary to qualify as
having supply-demand ischemia, Saaby et al. showed that type 2 myocardial occurred in 26% of unselected hospital patients who had cTnI measured8. The heterogeneity in
the reported frequency across studies is multifactorial and explained in part by challenges in distinguishing myocardial injury from myocardial infarction, variations and limitations in adjudication processes, biomarkers and/or thresholds used to support the diagnosis, selected studied population, and distinct diagnosis definitions used with most studies favoring the use of broad criteria, yet others using strict, specific criteria to establish the diagnosis of type 2 myocardial infarction 1,3. In this regard, Mihatov et al. offer their perspectives on various subsets of patients, including those with congestive heart failure, critical illness, and sepsis4, in which it is often challenging to determine whether the diagnosis of myocardial injury or infarction should be favored when cTn concentrations are above the 99th percentile. The key to distinguish myocardial injury from myocardial infarction should be made on the basis of the presence or absence of overt myocardial ischemia1. Second, most studies examining type 2 myocardial infarction have focused on patients presenting to the emergency department, with limited data on the incidence and features of type 2 myocardial infarction in the postoperative setting. The evaluation of patients with suspected myocardial infarction in the postoperative period is particularly challenging because many patients with perioperative myocardial infarction may not experience ischemic symptoms, particularly anesthetized or sedated patients, and moreover, because electrocardiographic changes may be subtle and/or transient, even in those with marked cTn increases9-10. As Mihatov et al. have emphasized, the postoperative period represents a unique clinical scenario in which patients may be at risk for type 2 myocardial infarction4, as numerous circumstances may lead to supplydemand mismatch and myocardial ischemia during this period, particularly if there is
concomitant obstructive coronary artery disease. Limited data exists in the perioperative setting
addressing
the
Universal
Definition
of
Myocardial
Infarction
subtype
classification using high-sensitivity cTn assays. BASEL-PMI (NCT02573532) is an ongoing observational study, estimated to enroll 2000 patients undergoing non-cardiac surgery in which high-sensitivity cTnT is being measured before and after surgery, and in which patients with cTn increases will be classified as type 1 myocardial infarction, type 2 myocardial infarction or myocardial injury that will inform on the long-term outcome of perioperative myocardial infarction. Third, the presence or absence of concomitant significant coronary artery disease among patients with type 2 myocardial infarction is being increasingly recognized as a factor of importance when evaluating these patients1,11. In CASABLANCA, 61.2% and 47.7% of patients with type 2 myocardial infarction had ≥50% and ≥70% coronary stenosis in ≥2 vessels respectively (5). Similarly, in an analysis from the SWEDEHEART study involving 4,083 patients with type 2 myocardial infarction, approximately one-third underwent coronary angiography with 52.8% having ≥50% coronary stenosis
11
. While these studies are prone to selection bias as only a
subset of patients are referred for coronary angiography, if significant coronary artery disease is present, then medical therapy targeting this disease process should be considered1. Fourth, most studies have suggested that patients with type 2 myocardial infarction have poor short- and long-term outcomes, particularly regarding all-cause mortality, with limited data addressing the mode of death1. CASABLANCA offered important insights on this regard by demonstrating that in comparison to those without;
those with incident type 2 myocardial infarction had significantly increased risk not only for all-cause mortality, but also for major adverse cardiac events, heart failure, arrhythmia, stroke or transient ischemia events, and cardiovascular death 5. Lastly, what will happen with the worldwide adoption of high-sensitivity (hs) cTn assays? In a study by the APACE group, Reichlin et al. reported that compared to 22% of patients with increases above the 99th percentile using the contemporary Roche 4th generation assay, 36% of patients had increases above the 99 th percentile using the hscTnT assay12. Conversely, in the UTROPIA study, the use of the Abbott hs-cTnI assay did not lead to more increases above the 99th percentile compared to the contemporary Abbott cTnI assay, but rather, the improvement in analytical sensitivity obtained by the hs-assay was seen in a shift from results below the limit of detection (LoD) to those between the LoD and the 99th percentile13. Such findings reflect that the impact on the incidence of myocardial injury and infarction may largely depend upon the local assay being used prior to implementing a hs-assay. What is needed? Moving forward it is fundamental to develop consensus on what we understand globally as injury and infarction in order to facilitate how research is developed and translated into clinical practice. Future guidance is expected from the Global Task Force in the Fourth Universal Definition of Myocardial Infarction. More importantly, both patients and clinicians urge for evidence-based therapies and strategies that can attenuate the morbid outcomes seen in these patients. Lastly, more education is needed among clinicians on what constitutes myocardial injury and what constitutes myocardial infarction and the use of appropriate nomenclature. The authors
help us move forward in such regard with this review that summarizes the evidence to date, including their insights obtained from the CASABLANCA study.
REFERENCES 1. Sandoval Y, Thygesen K. Myocardial infarction type 2 and myocardial injury. Clin Chem 2017; 63: 101-107. 2. Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581-98. 3. Sandoval Y, Smith SW, Thordsen SE, Apple FS. Supply/demand type 2 myocardial infarction: should we be paying more attention? J Am Coll Cardiol 2014; 63: 2079-87. 4. Mihatov N, Januzzi JL Jr, Gaggin HK. Type 2 myocardial infarction due to supplydemand mismatch. Trends in Cardiovascular Medicine 2017 [in press] 5. Gaggin HK, Liu Y, Lyass A et al. Incident type 2 myocardial infarction in a cohort of patients undergoing coronary angiography or peripheral arterial angiography. Circulation 2017; 135: 116-127. 6. Meigher S, Thode HC, Peacock WF, Bock JL, Gruberg L, Singer AJ. Causes of elevated cardiac troponins in the emergency department and their associated mortality. Acad Emerg Med 2016; 23: 1267-1273. 7. Sandoval Y, Thordsen SE, Smith SW et al. Cardiac troponin changes to distinguish type 1 and type 2 myocardial infarction and 180-day mortality risk. Eur Heart J Acute Cardiovasc Care 2014; 3: 317-25.
8. Saaby L, Poulsen TS, Hosbond S et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction. Am J Med 2013; 126: 789-97. 9. Landesberg G, Beattie WS, Mosserie M, Jaffe AS, Alpert JS. Perioperative myocardial infarction. Circulation 2009; 119: 2936-44. 10. Garcia S, Marston N, Sandoval Y, Pierpont G, Adabag S, Brenes J, Santilli S, McFalls EO. Prognostic value of 12-lead electrocardiogram and peak troponin I level after vascular surgery. J Vasc Surg 2013; 57: 166-72. 11. Baron T, Hambraeus K, Sundström et al. Impact of long-term mortality of presence of obstructive coronary artery disease and classification of myocardial infarction. Am J Med 2016; 129: 398-406. 12. Reichlin T, Twerenbold R, Reiter M et al. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med 2012; 125: 1205-1213. 13. Love SA, Sandoval Y, Smith SW et al. Incidence of undetectable, measurable, and increased cardiac troponin I concentrations above the 99th percentile using a high-sensitivity vs a contemporary assay in patients presenting to the emergency department. Clin Chem 2016; 62: 1115-9.
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(17)30047-6S1050-1738(17)30042-7 http://dx.doi.org/10.1016/j.tcm.2017.03.007 TCM6388
To appear in: Trends in Cardiovascular Medicine Cite this article as: Yader Sandoval, Improving our understanding of type 2 myocardial infarction and myocardial injury, Trends in Cardiovascular Medicine, http://dx.doi.org/10.1016/j.tcm.2017.03.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Improving our understanding of type 2 myocardial infarction and myocardial injury
Yader Sandoval1, 2, MD
1. Division of Cardiology, Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota, USA. 2. Minneapolis
Heart
Institute,
Abbott
Northwestern
Hospital,
Minneapolis,
Minnesota, USA.
Disclosure: Yader Sandoval, non-salaried Advisor, Roche Clinical Diagnostics.
Correspondence Yader Sandoval, MD 701 Park Avenue, Orange Building 5th Floor Minneapolis, Minnesota, 55415, USA. Email: [email protected]
Type 2 myocardial infarction, an increasingly recognized condition, occurs in instances of myocardial injury with necrosis plus evidence of myocardial ischemia where a condition other than an acute atherothrombotic event leads to an imbalance between myocardial oxygen supply and/or demand
1-3.
In this issue of Trends in Cardiovascular
Medicine, Mihatov and colleagues summarize the evidence to date on type 2 myocardial infarction and address several common clinical scenarios in which one must distinguish between myocardial injury and myocardial infarction4. Several observations are offered. First, while challenges exist in ascertaining the incidence of type 2 myocardial infarction with a wide range reported across the literature, several studies have demonstrated that type 2 myocardial infarction is frequent1,3. In the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study, a prospective singlecenter investigation examining 1,251 patients undergoing coronary and peripheral angiographic procedures with or without intervention, 73.8% of all myocardial infarctions on follow-up had at least one incident type 2 myocardial infarction 5. Similarly, studies examining all-comers presenting to the emergency department undergoing cTn measurements have shown that type 2 myocardial infarction occurs often, with recent US studies reporting frequencies ranging from 53% to 74% of all myocardial infarctions 6-7
. Even using strict diagnostic criteria with very high thresholds necessary to qualify as
having supply-demand ischemia, Saaby et al. showed that type 2 myocardial occurred in 26% of unselected hospital patients who had cTnI measured8. The heterogeneity in
the reported frequency across studies is multifactorial and explained in part by challenges in distinguishing myocardial injury from myocardial infarction, variations and limitations in adjudication processes, biomarkers and/or thresholds used to support the diagnosis, selected studied population, and distinct diagnosis definitions used with most studies favoring the use of broad criteria, yet others using strict, specific criteria to establish the diagnosis of type 2 myocardial infarction 1,3. In this regard, Mihatov et al. offer their perspectives on various subsets of patients, including those with congestive heart failure, critical illness, and sepsis4, in which it is often challenging to determine whether the diagnosis of myocardial injury or infarction should be favored when cTn concentrations are above the 99th percentile. The key to distinguish myocardial injury from myocardial infarction should be made on the basis of the presence or absence of overt myocardial ischemia1. Second, most studies examining type 2 myocardial infarction have focused on patients presenting to the emergency department, with limited data on the incidence and features of type 2 myocardial infarction in the postoperative setting. The evaluation of patients with suspected myocardial infarction in the postoperative period is particularly challenging because many patients with perioperative myocardial infarction may not experience ischemic symptoms, particularly anesthetized or sedated patients, and moreover, because electrocardiographic changes may be subtle and/or transient, even in those with marked cTn increases9-10. As Mihatov et al. have emphasized, the postoperative period represents a unique clinical scenario in which patients may be at risk for type 2 myocardial infarction4, as numerous circumstances may lead to supplydemand mismatch and myocardial ischemia during this period, particularly if there is
concomitant obstructive coronary artery disease. Limited data exists in the perioperative setting
addressing
the
Universal
Definition
of
Myocardial
Infarction
subtype
classification using high-sensitivity cTn assays. BASEL-PMI (NCT02573532) is an ongoing observational study, estimated to enroll 2000 patients undergoing non-cardiac surgery in which high-sensitivity cTnT is being measured before and after surgery, and in which patients with cTn increases will be classified as type 1 myocardial infarction, type 2 myocardial infarction or myocardial injury that will inform on the long-term outcome of perioperative myocardial infarction. Third, the presence or absence of concomitant significant coronary artery disease among patients with type 2 myocardial infarction is being increasingly recognized as a factor of importance when evaluating these patients1,11. In CASABLANCA, 61.2% and 47.7% of patients with type 2 myocardial infarction had ≥50% and ≥70% coronary stenosis in ≥2 vessels respectively (5). Similarly, in an analysis from the SWEDEHEART study involving 4,083 patients with type 2 myocardial infarction, approximately one-third underwent coronary angiography with 52.8% having ≥50% coronary stenosis
11
. While these studies are prone to selection bias as only a
subset of patients are referred for coronary angiography, if significant coronary artery disease is present, then medical therapy targeting this disease process should be considered1. Fourth, most studies have suggested that patients with type 2 myocardial infarction have poor short- and long-term outcomes, particularly regarding all-cause mortality, with limited data addressing the mode of death1. CASABLANCA offered important insights on this regard by demonstrating that in comparison to those without;
those with incident type 2 myocardial infarction had significantly increased risk not only for all-cause mortality, but also for major adverse cardiac events, heart failure, arrhythmia, stroke or transient ischemia events, and cardiovascular death 5. Lastly, what will happen with the worldwide adoption of high-sensitivity (hs) cTn assays? In a study by the APACE group, Reichlin et al. reported that compared to 22% of patients with increases above the 99th percentile using the contemporary Roche 4th generation assay, 36% of patients had increases above the 99 th percentile using the hscTnT assay12. Conversely, in the UTROPIA study, the use of the Abbott hs-cTnI assay did not lead to more increases above the 99th percentile compared to the contemporary Abbott cTnI assay, but rather, the improvement in analytical sensitivity obtained by the hs-assay was seen in a shift from results below the limit of detection (LoD) to those between the LoD and the 99th percentile13. Such findings reflect that the impact on the incidence of myocardial injury and infarction may largely depend upon the local assay being used prior to implementing a hs-assay. What is needed? Moving forward it is fundamental to develop consensus on what we understand globally as injury and infarction in order to facilitate how research is developed and translated into clinical practice. Future guidance is expected from the Global Task Force in the Fourth Universal Definition of Myocardial Infarction. More importantly, both patients and clinicians urge for evidence-based therapies and strategies that can attenuate the morbid outcomes seen in these patients. Lastly, more education is needed among clinicians on what constitutes myocardial injury and what constitutes myocardial infarction and the use of appropriate nomenclature. The authors
help us move forward in such regard with this review that summarizes the evidence to date, including their insights obtained from the CASABLANCA study.
REFERENCES 1. Sandoval Y, Thygesen K. Myocardial infarction type 2 and myocardial injury. Clin Chem 2017; 63: 101-107. 2. Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of myocardial infarction. J Am Coll Cardiol 2012; 60: 1581-98. 3. Sandoval Y, Smith SW, Thordsen SE, Apple FS. Supply/demand type 2 myocardial infarction: should we be paying more attention? J Am Coll Cardiol 2014; 63: 2079-87. 4. Mihatov N, Januzzi JL Jr, Gaggin HK. Type 2 myocardial infarction due to supplydemand mismatch. Trends in Cardiovascular Medicine 2017 [in press] 5. Gaggin HK, Liu Y, Lyass A et al. Incident type 2 myocardial infarction in a cohort of patients undergoing coronary angiography or peripheral arterial angiography. Circulation 2017; 135: 116-127. 6. Meigher S, Thode HC, Peacock WF, Bock JL, Gruberg L, Singer AJ. Causes of elevated cardiac troponins in the emergency department and their associated mortality. Acad Emerg Med 2016; 23: 1267-1273. 7. Sandoval Y, Thordsen SE, Smith SW et al. Cardiac troponin changes to distinguish type 1 and type 2 myocardial infarction and 180-day mortality risk. Eur Heart J Acute Cardiovasc Care 2014; 3: 317-25.
8. Saaby L, Poulsen TS, Hosbond S et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction. Am J Med 2013; 126: 789-97. 9. Landesberg G, Beattie WS, Mosserie M, Jaffe AS, Alpert JS. Perioperative myocardial infarction. Circulation 2009; 119: 2936-44. 10. Garcia S, Marston N, Sandoval Y, Pierpont G, Adabag S, Brenes J, Santilli S, McFalls EO. Prognostic value of 12-lead electrocardiogram and peak troponin I level after vascular surgery. J Vasc Surg 2013; 57: 166-72. 11. Baron T, Hambraeus K, Sundström et al. Impact of long-term mortality of presence of obstructive coronary artery disease and classification of myocardial infarction. Am J Med 2016; 129: 398-406. 12. Reichlin T, Twerenbold R, Reiter M et al. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med 2012; 125: 1205-1213. 13. Love SA, Sandoval Y, Smith SW et al. Incidence of undetectable, measurable, and increased cardiac troponin I concentrations above the 99th percentile using a high-sensitivity vs a contemporary assay in patients presenting to the emergency department. Clin Chem 2016; 62: 1115-9.