Type 2 MI Linked to More CV Deaths, Even in Younger Patients

High short-term mortality rates following type 2 MI (T2MI) have been attributed in the past to the older, critically ill patients in whom these kinds of MIs are common, but younger patients with T2MI also face an increased risk of dying over the long term, new research shows. In fact, this report—the longest-running study to date to look at risks of T2MI in younger adults—indicates that both all-cause and cardiovascular mortality were higher for T2MI than for type 1 MI (T1MI).

“Many people have generally felt that type 2 MI is a condition that older people experience, and the reason for that, after all, is that to get a type 2 MI you need to have some kind of supply-demand mismatch with respect to oxygen supply by the coronary vessels,” senior author Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), explained to TCTMD. “And to have that supply-demand mismatch basically means that you have increased demands for oxygen, which usually means some kind of acute medical illness”—illnesses that tend to be more common in the elderly, he added.

“So one of the things I think is interesting,” said Blankstein, “is when you look at all the patients in our cohort, the type 2 MIs [occurred] in nearly one-third of the patients, so it's not uncommon; this actually happens with young MI patients, and it's something that probably we will recognize more and more.”

A rise in the diagnosis of T2MI has followed its clarification as a distinct entity in the Fourth Universal Definition of MI as well as wider use of high-sensitivity troponin assays more sensitive to biomarker changes.

T1MI, according the Fourth Universal Definition, refers to patients with ischemia and cardiac enzyme elevation presumed to result from a spontaneous atherosclerotic event. In T2MI, by contrast, patients have biomarker evidence of myocardial damage and signs of myocardial ischemia, but the cause is an imbalance between oxygen supply and demand unrelated to an acute atherosclerotic event. A third category, myocardial injury, is defined by stable troponin level and oxygen supply/demand mismatch, but no myocardial ischemia and no direct precipitating factor.

This actually happens with young MI patients, and it's something that probably we will recognized more and more. Ron Blankstein

“In our study population, if you combine type 2 MI and myocardial injury, it’s actually a 50/50 split with type 1 MI,” lead author Avinainder Singh, MD (Yale University, New Haven, CT), told TCTMD. “And in my clinical practice, type 2 MI and myocardial injury are probably more common than type 1,” he said, noting that other centers are seeing similar trends.

“We used to see these patients with a troponin rise and we thought there was nothing to worry about. The main message here is that patients with a T2MI actually have very high mortality and that’s understandable—these patients are having gastrointestinal bleeds, septic shock, etc—but they also have very high cardiovascular mortality,” Singh continued. “Here, we show that if you follow T2MI patients for 10 years, they are dying, and a lot of them dying of cardiovascular causes.”

Ten-Year Outcomes

For the current study, Blankstein, Singh, and colleagues drew on data from the YOUNG-MI registry of individuals 50 years or younger at the time of their MI admission to one of two large academic medical centers over a 17-year period. All 3,829 patients had no known history of CAD but were diagnosed at the time of their hospital admission with T1MI (55%), T2MI (32%), or myocardial injury (13%). Patients with T2MI were more likely to be younger than patients with T1MI and more likely to be women.

Over a median follow-up of 10 years, the death rate was lowest for patients initially hospitalized with T1MI (12%), followed by T2MI (34.2%), and highest for patients initially diagnosed with myocardial injury (45.6%).

In a model that adjusted for a range of baseline demographic factors, comorbidities, and prescribed therapies and interventions, T2MI patients had a significantly higher risk of dying over 10-year follow-up than T1MI patients (HR 1.8; 95% CI 1.2-2.7) and as compared to patients initially diagnosed with myocardial injury (HR 2.6; 95% CI 1.7-4.0). Even more striking, said both Singh and Blankstein, is the increased risk of cardiovascular death among these patients—something expected with T1MI, but not for type 2. This was true in the unadjusted analyses, and even more pronounced after adjusting for baseline characteristics (HR 1.8; 95% CI 1.2-2.7 for T2MI and HR 2.6; 95% CI 1.17-4.0 for myocardial injury).

Of note, compared with patients who had T1MI, patients with T2MI were significantly less likely to undergo invasive testing and less likely to be discharged on cardiovascular medications including aspirin, P2Y12 inhibitors, statins, beta-blockers, ACE inhibitors, and/or angiotensin receptor blockers (ARBs).

“The important finding is that [T2MI patients] also have a higher cardiovascular mortality, suggesting that increased risk of CVD is something that hopefully can be modified with more aggressive secondary preventive therapies,” Blankstein said. “Typically with type 2 MI patients . . . we are too concerned about the primary medical process going on, whether it's infection or a burn or trauma, so treatment of preventive treatment for their heart is usually not on the radar of treating physicians.”

A Connection Not Easily Explained

Commenting on the study for TCTMD, Andrew DeFilippis, MD (University of Louisville School of Medicine, KY), stressed the heterogeneity of patients developing T2MI and the difficulty of controlling for all of the potential confounders in a group of patients like this one.

“What’s interesting and new in this study is they show that controlling or adjusting for these risk factors did not make the likelihood of dying from a cardiovascular cause any less likely. It didn’t explain it,” he said. “In fact, when you account for those things and hold those constant, . . . you can’t explain why they are having more cardiovascular events.” Part of this relates to the observational nature of the analysis, despite the best efforts of the authors, DeFilippis noted. “There is something about these patients that can’t be explained by their comorbidities as accounted for in this study.”

Of note, in this analysis, even when the precipitating factor identified by the treating physician at the time of the MI was cardiac in nature—an arrythmia, hypertension, or heart failure, for example—more often than not the actual cause of death down the road was not cardiac in nature. Part of that relates to the fact that the precipitating diagnosis itself might have been secondary to some serious underlying pathology, DeFilippis explained. But it also hammers home the point that the most common cause of death in T2MI patients is still most likely to be non-cardiac in nature.

And the ability for better cardiopreventive therapies to make a dint in those subsequent deaths will depend on the underlying etiology of the T2MI, he said—a point also made by Singh.

“This registry is a very heterogenous group,” Singh said. “We kind of lumped these patients into the category of type 2 MI, but the underlying physiology and processes are very, very different. And in fact the prognosis of these patients and their associated all-cause and cardiovascular mortality really varies by what’s driving their type 2 MI. . . . A one-size-fits-all approach will not work here.”

Asked what might be increasing the risk of cardiovascular death in T2MI patients who subsequently met that fate, Blankstein stressed that the current data don’t offer any answers. “If I had to speculate, I would say that in general these are patients that have atherosclerosis. Since these are all young individuals, if they have atherosclerosis, that's more likely to progress over time, and they are patients who are then more likely to develop plaque rupture and thrombosis,” he suggested.

As such, better blood pressure-lowering, diabetes management, weight control, cholesterol-lowering, and potentially secondary prevention medications that are recommended in T1MI may prove useful, Blankstein said.

Trials like MINOCA-BAT, for example, are currently exploring the potential benefit of beta-blockers and ACE inhibitors/ARBs in patients with myocardial infarction with nonobstructive coronary arteries. In an accompanying editorial, Kristian Thygesen, MD, DSc (Aarhus University Hospital, Denmark) and Allan Jaffe, MD (Mayo Clinic, Rochester, MN), mention another study, known as ACT-2 (Appropriateness of Coronary Investigation in Myocardial Injury and Type 2 Myocardial Infarction), that’s looking at whether using early invasive angiography or CT angiography to guide management, versus usual care, can impact survival and cost-effectiveness.   

“Potentially in some of these patients we're going to learn more if we do some imaging to look for underlying atherosclerosis, which we can do noninvasively with CT or MRI,” Blankstein said. “I think further characterizing the disease burden in these patients may allow us to better understand why they are at increased risk.”