In this manuscript, we report the cardiovascular risk of patients presenting with suspected acute MI during a median long-term follow-up of 5 years. As a key finding, we show that patients with myocardial injury are at comparable risk for death and cardiovascular events to those presenting with acute MI. The increased recognition of acute and chronic myocardial injury as separate entities apart from MI has important clinical implications, as has the differentiation of T1MI and T2MI. The ability to differentiate these different types of myocardial injury is partly owed to the increased sensitivity of cardiac troponin assays, hereby frequently revealing slightly elevated troponin concentrations [3]. Considering the increasing availability of hs-cTn assays, a rising number of clinicians is confronted with the interpretation of partly non-ischemic elevations of troponin. Understanding the prevalence of such myocardial injury, as well as their prognosis is of clinical importance to guide further treatment. The present study investigated the long-term outcome of patients admitted to the chest pain unit of a tertiary care center, with final diagnoses adjudicated according to the Fourth Universal Definition of MI [7]. Compared to earlier studies, our study is unique, as it is based on thorough state-of-the-art adjudication and has extended long-term follow-up available. The following observations have important implications for clinical routine:

First, myocardial injury is very common. Overall, 3.2% of patients have been classified with acute myocardial injury (almost comparable to the prevalence of T2MI in the present cohort) and even every fourth patient in the overall cohort had chronic myocardial injury. Thus, myocardial injury was more frequent than all types of MI combined.

Second, despite the absence of infarction at presentation, the crude event rate per 1,000 patient-years for all-cause mortality was highest in those with myocardial injury. As shown in Fig. 2A, the crude rate of all-cause mortality was highest in those with myocardial injury, with STEMI patients having the best survival of all patients with a diagnosis of MI or myocardial injury. The high risk for all-cause mortality remained highly significant for myocardial injury and infraction upon adjustment for age, sex, cardiovascular risk factors, and important clinical conditions. In fact, we did not observe any differences in risk comparing these groups of patients to those with MI.

Third, a previous study reported an equal rate of major adverse cardiovascular events comparing patients with T2MI or myocardial injury with T1MI patients [9]. In the present study, we can confirm a high risk for cardiovascular events in patients with T1MI, STEMI and those with myocardial injury. Yet, in the fully adjusted model, patients with T2MI were not at significantly increased risk for this composite cardiovascular endpoint in our study.

Compared to previous reports, we were able to differentiate acute and chronic myocardial injury, allowing a more specific evaluation of event rates for both types during long-term follow-up. Here we prove that the risk for cardiovascular death, MI or unplanned revascularization was also significantly increased in patients with acute or chronic myocardial injury, despite full adjustment for patient characteristics, cardiovascular risk factors, and underlying comorbidities. Although we observed the sharpest increase in the incidence of the composite cardiovascular endpoint (including cardiovascular death, MI, or unplanned revascularization) in patients with STEMI or T1MI, the risk seemed to decrease over time. If the entire follow-up is considered, the incidence remained largely similar with patients having either acute or chronic myocardial injury. In these groups, particularly those patients with known CAD experienced cardiovascular events, as shown in Fig. 4A and B.

Fourth, out of all diagnoses requiring a troponin elevation exceeding the 99th percentile, the median elevation in troponin concentrations was lowest in patients with chronic myocardial injury (median 19 ng/L, 99th percentile upper reference limit of the hs-cTnT troponin assay 14 ng/L). Also, it was the most frequent diagnosis involving troponin elevation. Irrespective of the comparably low troponin elevation, clinicians should be aware of the high risk for death and cardiovascular events at which these patients are. Identification of patients at higher risk should ideally result in the initiation of therapies aiming at a risk reduction. In the case of patients with myocardial injury, data on this matter are scarce. Yet, presentation to the emergency department and identification of chronic myocardial injury could act as a trigger for intensified primary or secondary preventive therapies. For instance, the prevalence of known CAD in patients with chronic myocardial injury was high. Almost every second patient had a history of CAD, that was associated with the highest risk for cardiovascular events (2.56 [1.97, 3.33], Supplementary Table 5). Identification of those patients should prompt physicians to assess secondary prevention therapies established (for example, lipid lowering therapy) and, ideally, increase those per guidelines to recommended targets and tolerated doses [18, 19]. Although dedicated trials for such an approach (identification of patients by elevated hs-cTn resulting into intensification of therapy) have not been conducted to date, lipid lowering therapy results in a strong risk reduction and sub-studies suggest  that hs-cTn concentrations decrease along with an intensification of lipid lowering therapy accompanied by a risk reduction [20, 21].

In addition to CAD, patients with chronic myocardial injury frequently presented with other important comorbidities as well, among others chronic kidney disease (53.2%), atrial fibrillation (28.4%), heart failure (21.6%), or severe valvular heart defects (17.5%). Thus, one may speculate whether a structured assessment in patients with chronic myocardial injury allows an improvement of therapy, which could translate into a decrease in hs-cTn, as also to a reduction in the high event rate observed. In this regard, previous studies could already demonstrate that a reduction in cardiac troponin parallels a reduction in the risk for cardiovascular events, and that specific therapeutic measures mitigate both [20,21,22].

Fifth, previous studies have reported a rather wide range with respect to the prevalence of T2MI [9, 23,24,25], which might be owed to different settings and patient samples enrolled. Yet, T2MI is very common and in our study, approximately one out of three patients with non-ST-elevation MI had T2MI. In line with previous reports [9], the risk for all-cause mortality is high for patients with T2MI, with even higher crude event rates compared to patients with T1MI or STEMI [9, 25]. While the risk for all-cause mortality remained significantly elevated upon adjustment for patient characteristics and comorbidities in these patients, the risk for the composite cardiovascular endpoint did not, an observation similarly to a report by Chapman et al. [9]. Overall, patients with T2MI were commonly older and presented with multiple cardiovascular risk factors and comorbidities, probably partly explaining the high observed event rate. However, since the risk for cardiovascular events in our model was reduced upon full adjustment for patients with T2MI, it may be hypothesized that most likely non-cardiovascular causes drive the high mortality rate observed in these patients. Considering the high prevalence of cardiovascular risk factors in this group of patients, as also the high prevalence of CAD, it may be speculated whether competing risk, with patients dying due to non-cardiovascular causes before cardiovascular events could happen, might also explain some of the observations in our study and others [9]. Irrespective of the multiple cardiovascular risk factors, the ambulatory therapy as provided in Supplementary Table 1 leaves room for appropriate secondary prevention therapies.