Should Myocardial Infarction Type 2 Be Regarded As Two Separate Entities?

Kristian Thygesen; Allan S. Jaffe


Eur Heart J. 2019;40(33):2810-2812. 

According to the Universal Definition of Myocardial Infarction (UDMI), the presence of acute myocardial injury in the setting of acute myocardial ischaemia meets the clinical definition of an acute myocardial infarction (MI). Based on pathological and clinical differences of MIs, a novel classification into five subcategories was introduced in 2007 with subtle adjustments later on.[1–3] However, the treatment strategies of these MI types are incomplete and awaiting outcome studies.

Type 1 MI is the traditional clinical picture of a heart attack. The underlying pathophysiology involves acute atherosclerotic plaque disruption complicated by intraluminal thrombosis resulting in decreased oxygen and nutrient delivery to heart muscle. In contrast, in type 2 MI, oxygen deprivation is not caused by acute atherosclerotic plaque disruption in a coronary artery but rather by an acute stressor that results in a supply/demand imbalance of myocardial oxygen consumption and nutrient supply, leading to ischaemia and myocardial injury. Coronary abnormalities as well as increased cardiac demand often play an important pathophysiological role. Individual ischaemic thresholds vary substantially from one patient to another depending on the magnitude of the stressor, the presence of non-cardiac comorbidities, the extent of underlying coronary artery disease (CAD), abnormalities in vasomotion, and cardiac structural abnormalities.[3] The type 2 MI patients without CAD have substantially lower event-related mortality compared with those with CAD,[4] and there is increasing evidence that the presence of obstructive coronary disease is a powerful predictor of future adverse cardiovascular events.[5,6]

Therapeutic strategies are well established for type 1 MI,[7,8] but no compelling data exist for treatment of other MI categories. Suggestions for the management of the type 2 MI category are based on the underlying illness that has led to an ischaemic imbalance of oxygen supply and demand in the myocardium. Therapy may include volume adjustment, blood pressure management, blood transfusion, heart rate control, and respiratory support.[3] However, therapeutics for type 2 MI or non-ischaemic myocardial injury, independent of the underlying precipitating diagnosis, require a greater understanding of whether and how such myocardial injury results in adverse clinical outcomes independent of the precipitating trigger.

Among patients with an acute coronary syndrome (ACS), thought mostly to be type 1 MI events, the risk of future major adverse cardiovascular events (MACE) and death is elevated although modifiable by lowering atherogenic lipoproteins, reflected by reduction of LDL cholesterol (LDL-C).[9] It is thought that the reduction in LDL-C results in plaque remodelling which reduces the vulnerability of the plaque to rupture. The advent of inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) has given an opportunity to lower LDL-C to levels not previously achievable with statins and/or ezetimibe. Thus, PCSK9 inhibitors are now recommended on top of lipid-lowering therapy in patients with ACS and patients undergoing percutaneous coronary intervention if the LDL-C target is not reached with the highest tolerable statin dose and/or ezetimibe; or alone or in combination with ezetimibe in statin-tolerant patients or in whom a statin is contra-indicated.[9]

Recently, the favourable effect of a PCSK9 inhibitor on recurrent ischaemic cardiovascular events was confirmed in the large ODYSSEY trial, in which patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy had significantly better outcome by treatment with the PCSK9 inhibitor alirocumab compared with placebo in 18 924 patients.[10] The trial population consisted of CAD patients who were 40 years of age or older, had been hospitalized with an ACS (83% had MI and 17% unstable angina), and had undergone coronary revascularization for the index event 1–12 months prior to randomization.[10]

Typological classification of the MIs was not performed at the enrolment of the trial. However, in a pre-specified analysis, the effect of alirocumab was assessed on the types of MI as reported by White et al. in this issue of the European Heart Journal.[11] During a follow-up of a median of 2.8 years, the incidence of first occurrence of MI was tabulated and it appeared that patients with a first type 2 MI event were older, more likely to have a lower glomerular filtration rate, and were more likely to have a history of hypertension, heart failure, chronic obstructive pulmonary disease, peripheral artery disease, or malignant disease, but less likely to be smokers when compared with patients with a first type 1 MI event after randomization.[11] The data showed that alirocumab significantly reduced the occurrence of first MIs (P = 0.003), with reductions in the incidences of both type 1 MI (P = 0.032) and type 2 MI (P = 0.025). The frequencies of the remaining MI types were too small to allow for meaningful statistical evaluation.[11] Nevertheless, the results indicate for the first time that a lipid-lowering therapy can attenuate the risk of type 2 MI. Thus, LDL-C lowering with alirocumab below levels achieved with statins may be an important preventive treatment for both type 1 MI and type 2 MI following ACS provided manifestation of CAD. From that perspective the data are very welcome (Take home figure).

Take Home Figure.

The ODYSSEY OUTCOMES trial indicates that after ACS, LDL-C lowering therapy including alirocumab reduces the incidence of not only type 1 MI events but also of type 2 MI events associated with CAD (depicted on the left). Whether comparable effects of this therapy would be observed in circumstances where type 2 MI evolves without CAD (depicted on the right) requires more research.

The first MIs were prospectively adjudicated in a pre-specified analysis by a Clinical Events Committee (CEC) blinded to the treatment assignment and lipid levels and typed according to the Third UDMI definitions.[2,11] The CEC led by Duke University consists of almost 50 members.[11] It cannot be ruled out that this unusually high number of adjudicators might have influenced the classifications, especially of type 2 MI, in the absence of clearly codified criteria. It is difficult to keep consistency in adjudications when considering views from so many angles, and the ability of even trained adjudicators to agree on the diagnosis of MI subtypes is challenging. It was only 64% in a study from the Swedish myocardial infarction registry (SWEDEHEART),[12] and the literature in this area is substantially heterogeneous.[13] The task is difficult seeing that abnormalities that might cause supply–demand imbalance may be the cause or the response to a given event. Moreover, angiography may not always be definitive as thrombus can occur with either type 1 or type 2 events,[14] and acute-looking lesions are known to exist in those with stable CAD.[15]

It would have been helpful to have information on how often the adjudicators found increases in cardiac troponin concentration without acute myocardial ischaemia, leading to a diagnosis of myocardial injury but not MI. The mere presence of CAD, which by design was the case in all the patients in the ODYSSEY trial, does not imply that every increase in cardiac troponin values is due to MI. Increases due, for example, to infectious disease, heart failure, or kidney disease may also be present.[3] Helping clinicians to understand that by reporting such data would have been useful to those who may think this way.

Nonetheless, the evaluation of individual types of MI will increase the opportunity for identifying new risk factors that themselves may become therapeutic targets, similar to the data on lipid-lowering treatment observed in the ODYSSEY trial. The appropriateness of coronary investigation in myocardial injury and type 2 MI (ACT-2) is now being studied in an ongoing randomized trial of early coronary angiography or computed tomography angiography vs. conservative management on mortality in participants with criteria consistent with type 2 MI or non-ischaemic myocardial injury.[16]

The presence of CAD has important prognostic implications, and the data presented from the ODYSSEY study suggest that for patients with CAD, an aggressive lipid lowering should be part of the management, although the specific criteria as to the appropriate LDL-C target remain to be defined. Beyond the importance of CAD, specific treatments for type 2 MI will require an understanding of the heterogeneous group of conditions that leads to the diagnosis and additionally require consistent criteria. However, as of now, there is growing evidence that for patients with type 2 MI with or without obstructive CAD this differentiation between two separate entities may have important therapeutic implications.