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Consensus on diagnosis, treatment of type 2 MI remains elusive
In 2007, when the second universal definition of MI was formulated by a joint task force of professional societies, the lesser-known cousin of type 1 MI was just beginning to show up on cardiologists’ radar.
According to the universal definition from the task force of the American College of Cardiology, American Heart Association, European Society of Cardiology and World Heart Federation, type 2 MI is defined as “[MI] secondary to ischemia due to either increased oxygen demand or decreased supply.” Possible underlying mechanisms include anemia, arrhythmias, hypertension, hypotension or respiratory failure.
Hanna K. Gaggin, MD, MPH, FACC, a cardiologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, told Cardiology Today that the increasing use and sensitivity of cardiac troponin assays are bringing type 2 MI to the attention of physicians.
Photo credit: Hennepin County Medical Center; printed with permission.
“We know that troponin is a very sensitive and specific biomarker for the diagnosis of MI,” she said. “And when physicians were checking troponin levels on patients who were medically sick, they found that some of these patients had elevated troponin and clinical evidence of a MI — ECG changes, chest pain — consistent with myocardial necrosis or MI, but not the typical ones associated with type 1 MI from coronary artery plaque rupture and thrombosis.”
Now, nearly 10 years after the first coining of the term type 2 MI, research has generated more questions than answers, and there is not enough evidence to formulate specific guidelines for diagnosis and treatment. Many in the cardiology community said they hope that the upcoming fourth universal definition of MI will offer better clarification on how to diagnose and treat type 2 MI and how to better differentiate it from myocardial injury and from type 1 MI.
Defining type 2 MI
The biggest challenge with defining type 2 MI is that it afflicts a heterogeneous group of patients, and there also is heterogeneity in the way the condition is diagnosed and treated.
Yader Sandoval, MD, a cardiology fellow at the Minneapolis Heart Institute at Abbott Northwestern Hospital and Hennepin County Medical Center, Minneapolis, and researcher at the Cardiac Biomarkers Trials Laboratory, Minneapolis Medical Research, told Cardiology Today that if a patient with tachyarrythmia presented with ischemic chest discomfort in the absence of atherothrombosis and had a dynamic rise and/or fall of cardiac troponin with at least one value above the 99th percentile, he and his colleagues would classify the event as type 2 MI; however, whether the diagnosis should be made on the basis of liberal vs. strict criteria remains debated.
“In Europe, some investigators have used strict marked criteria to determine what constitutes a supply-demand imbalance. For example, some researchers have suggested that to qualify as a type 2 MI in the context of a tachyarrhythmia, such needs to be sustained for at least 20 minutes,” Sandoval said.
Another difference between Europe and the United States, according to Sandoval, is that in Europe clinicians often tend to measure cardiac troponin in selected cohorts of patients with chest discomfort who have a higher pre-test probability for type 1 MI than type 2 MI.
In the United States, troponin tests are more broadly utilized in unselected populations. Patients who present with abdominal discomfort and shortness of breath may have their cardiac troponin level measured, which, if combined with other features such as ischemic ECG changes and symptoms, may lead to a type 2 MI diagnosis.
“This contributes to heterogeneity in the diagnosis and incidence observed across studies. Some are calling these events type 2 MI, and others are calling it myocardial injury, with a consensus urgently needed,” Sandoval said.
Moreover, once the FDA clears high-sensitivity cardiac troponin assays in the United States for clinical use, there could be potentially more diagnosis of cardiac injury and type 2 MI, Sandoval said, particularly if transitioning from an older, less sensitive cardiac biomarker assay.
Besides elevation of cardiac troponin, another common diagnosis tool for type 2 MI is coronary angiography. However, David E. Winchester, MD, MS, FACP, FACC, assistant professor of medicine at the University of Florida, Gainesville, and staff cardiologist at the Malcolm Randall VA Medical Center, told Cardiology Today the conundrum is that although it is not practical to perform for every patient, without coronary angiography, a reliable diagnosis is difficult to make.
“Some people are too ill to do PCI, so if they have mildly elevated troponin, the clinician might not be sure what the elevation means. It can be challenging to pin down,” Winchester said.
Allan S. Jaffe, MD, a cardiologist and professor of medicine and laboratory medicine and chair of the division of clinical core laboratory services in the department of laboratory medicine and pathology at Mayo Clinic, said he is against overreliance on the coronary angiogram for diagnosis of MI.
“There is this fantasy I would argue that everybody should have coronary angiography, but I would point out that there is a good deal of ambiguity, even when one does coronary angiography in terms of what the underlying mechanism might be,” Jaffe told Cardiology Today.
“If for some reason you don’t do the angiography as timely as you like, you might miss something that is acute, but, in addition, there is substantial overlap between chronic and acute CAD, and they can sort of look the same angiographically,” said Jaffe, a member of the Cardiology Today Editorial Board. “We need to be terribly careful that we don’t fall into a trap that every time we see CAD and elevated troponin, we decide that it has to be an MI because there are lots of people who have CAD but who could have myocardial injury of another cause even if they have CAD. Even stable patients with CAD can have lesions that appear to be acute lesions. Some of them, a high-risk group, have elevated troponins as well.”
According to Paul Collinson, MD, FACB, FRCP, a consultant chemical pathologist and professor of cardiovascular services at St. George’s Healthcare NHS Trust, London, “Anyone who is severely ill where the illness might have an effect on coronary blood flow is at risk for type 2 MI. Type 2 MI is a bad name because we cannot define it properly. We should call it what it really is, secondary ischemic cardiac injury.
“The problem is, nobody knows how these patients should be treated, and it is likely that the standard treatments for MI may cause harm,” he said.
Prevalence, poor outcomes
Although there is still much unknown about treating and diagnosing type 2 MI, current research has offered some elucidation.
“In current studies, type 2 MI was as frequent as 48% of patients with MI,” Gaggin said. “We are recognizing that there are more [patients with] type 2 [MI] than we realized, but we don’t know what to do about it.”
According to Gaggin, most of the research has been retrospective in design, making it difficult to tell exactly how effective this type of MI is. The only two prospective studies that have followed a well-defined cohort for incidence of type 2 MI so far are the TRITON-TIMI 38 study, which was published in Circulation in 2012, and the CASABLANCA trial.
Marc P. Bonaca, MD, of Brigham and Women’s Hospital, and colleagues analyzed data from TRITON-TIMI 38 of patients with MI undergoing PCI who were randomly assigned prasugrel (Effient, Daiichi Sankyo/Eli Lilly) or clopidogrel and followed them for development of type 2 MI. In this study, undertaken before the 2012 universal definition of MI and before troponin was more commonly measured, the researchers found the frequency of type 2 MI was very low, but correlated with worse outcomes.
In CASABLANCA, results of which Gaggin and colleagues presented at the ACC Scientific Session in April, patients were followed for incidence of MI and major CV outcomes for a median of 3.4 years (maximum follow-up, 7 years). Conventional, not highly sensitive, troponin was used in diagnosing and adjudicating type 2 MI using the third universal definition, Gaggin said.
According to the results, compared with patients without type 2 MI, those with type 2 MI were older and had substantially more comorbidities. Patients with type 2 MI had more diffuse CAD (47.7% vs. 35.3% with disease of at least two vessels with 70% stenosis; P = .006). Baseline myeloperoxidase (482.6 pmol/L vs. 410 pmol/L, P = .002), N-terminal pro–B-type natriuretic peptide (955 pg/mL vs. 293 pg/mL, P < .001) and cystatin C (1 mg/L vs. 0.8 mg/L; P < .001) were higher in those who went on to develop type 2 MI, but there were no significant differences in baseline highly sensitive troponin I levels. Type 2 MI was associated with drastically increased risk for major CV events and death.
“We found that type 2 MI is frequent; 152 of the patients (more than 12%) had at least one incidence of type 2 MI. Among these patients, 56 had more than one type 2 MI. We also found out that people who had an MI, either type 1 or 2, were more likely to develop recurrent type 2 MIs as time passed,” Gaggin said. “And more importantly, we found that once you have type 2 MI, your future risk for CV major events such as death, MI, stroke and HF, was higher.”
In the study, patients with type 2 MI subsequently had 100 major adverse CV events per 100 person-years compared with 17.6 events per 100 person-years in those without type 2 MI (P < .001). There were 23.3 deaths per 100 person-years in patients with type 2 MI vs. 3.4 deaths per 100 person-years for patients with type 1 MI (P .001).
Data from CASBALANCA also have shed light on some predictors of a first type 2 MI. Patients with type 2 MI are more likely to be older, and have lower systolic BP, a history of HF, CAD, chronic obstructive pulmonary disease, diabetes, nitrate use, elevated glucose and elevated NT-proBNP and cystatin C, indicating renal dysfunction.
CASABLANCA only included those undergoing angiography, so the results may not apply to a more generalized population, Gaggin said. “Because patients undergoing angiography are ... selected patients, we may be underestimating the risk of type 2 MI in the general population because you would expect a lower number of type 2 MI in this particular population,” she said.
Other current research on type 2 MI includes a study by Winchester and colleagues on the predictors of short- and long-term mortality in hospitalized veterans with elevated troponin levels, recently published online in the Journal of Hospital Medicine. Winchester and colleagues found that, in this elderly veteran population, elevated troponin due to a type 2 MI was associated with higher mortality at 1 year compared with type 1 MI.
In addition, in a study published in PLoS One in 2014, Gideon Y. Stein, MD, PhD, of Tel Aviv University, and colleagues confirmed that type 2 MI is more frequent than previously thought, especially in older patients with multiple comorbidities and a high ACS risk score. In this study, type 2 MI also was associated with increased short- and intermediate-term mortality.
Not all cardiologists, however, believe the mortality risk for type 2 MI is similar to or higher than type 1 MI. Jaffe questioned whether the higher rate is the result of not separating out critically ill patients.
“The problem of definition also influences what appears to be the very high mortality. I have no doubt it is a serious thing, but I don’t think it is worse than type 1 MI until we find ways to sort this heterogeneous group in a better way,” Jaffe said.
Treatment challenges
Currently, there are no specific guidelines for treating type 2 MI. “Treatment depends on the circumstance,” Jaffe said. “If you think it is all because of an underlying illness, then of course you need to treat the underlying illness first. If a patient presents with a hypertension crisis, then you need to deal with the BP. If they present with tachycardia, then you need to deal with why they have tachycardia.”
Current clinical practice guidelines are geared towards management of acute MI due to atherothrombosis, but, at present, there is an urgent need for evidence-based diagnostic and therapeutic strategies geared towards MI due to supply-demand mismatch in the absence of atherothrombosis, according to Sandoval.
Another obstacle, according to Gaggin, is that type 2 MI is often not treated at all because patients who are treated for underlying causes are often not referred to cardiologists.
“No. 1, we don’t know what to do [about type 2 MI]. But, No. 2, we are not even looking to see if there is anything we can do,” Gaggin said.
Future paths
Although cardiologists wait to see whether the fourth universal definition will offer clearer protocols for diagnosing and treating type 2 MI, larger randomized controlled trials are needed. Gaggin said one area of interest uncovered in her research is that there might not be just one type of patient at risk for type 2 MI, but a heterogeneous group of multiple phenotypes, and treatment might depend on the phenotype.
“We should be radical in our approach of this area,” Collinson said. “We now have a range of other conditions that cause troponin elevation, some of which genuinely will be due to supply–demand mismatch, some of which may be due to supply–demand mismatch plus direct cardiac injury in variable proportions, and some of which clearly will not, such as a knife in the heart. I would like to get rid of the term type 2 MI and replace it with ‘secondary ischemic cardiac injury,’ and then encourage people to exercise clinical judgement.”
Collinson said he also is concerned that using the label “MI” encourages doctors to treat type 2 MI in the same way as they would a typical MI.
“This is not appropriate, we have no evidence and it may cause harm. If it is not a typical MI, then treat the patient and not the troponin,” Collinson said.
For Sandoval, future research should focus on better differentiating between type 2 MI and myocardial injury.
“This is particularly important in patients with renal disease, HF and sepsis,” he said. “One may argue that some troponin elevations occur in the absence of overt ischemic heart disease, and that, therefore, they should be called myocardial injury, instead of type 2 MI.” – by Tracey Romero
- References:
- Bonaca MP, et al. Circulation. 2012;doi:10.1161/CIRCULATIONAHA.111.041160.
- Burke LA, et al. J Am Coll Cardiol. 2015;doi:10.1016/S0735-1097(15)60044-4.
- Gaggin HK, et al. Abstract 1222-117. Presented at: American College of Cardiology Scientific Session; April 2-4, 2016; Chicago.
- Stein GY, et al. PLoS One. 2014;doi:10.1371/journal.pone.0084285.
- Sandoval Y, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.02.541.
- Winchester DE, et al. J Hosp Med. 2016;doi:10.1002/jhm.2619.
- For more information:
- Paul Collinson, MD, FACB, FRCP, can be reached at St. George’s Healthcare NHS Trust, Blackshaw Road, Tooting, London SW170Q7 United Kingdom; email: paul.collinson@stgeorges.nhs.uk.
- Hanna K. Gaggin, MD, MPH, can be reached at Massachusetts General Hospital, 55 Fruit St., Yawkey 5B, Boston, MA 02114; email: hgaggin@mgh.harvard.edu.
- Allan S. Jaffe, MD, can be reached at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: jaffe.allan@mayo.edu.
- Yader Sandoval, MD, can be reached at Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415; email: yader.sandoval@hcmed.org.
- David Winchester, MD, can be reached at the University of Florida, 1600 SW Archer Road, Gainesville, FL 32610; email: david.winchester@medicine.ufl.edu.
Disclosure: Collinson and Sandoval report no relevant financial disclosures. Gaggin reports receiving grants from Portola and Roche; consulting income from American Regent, Amgen, Boston Heart Diagnostics, Critical Diagnostics and Roche; and research payments for clinical endpoint committees from EchoSense. Jaffe reports past or present consulting for most of the makers of cardiac troponin assays. Winchester reports receiving a grant from and serving on an advisory board for Roche.