Causal Endotype-Based Classification of Myocardial Infarction

The fourth universal definition of myocardial infarction (UDMI) distinguishes type 1 from type 2 myocardial infarction (MI), but this framework does not fully capture the heterogeneity of underlying mechanisms and prognosis.

To characterize the distribution and clinical features of MI causal endotypes in a large contemporary cohort with a descriptive assessment of associated 1-year outcomes.

Consecutive patients from the prospective, multicenter AMIPE registry with an adjudicated diagnosis of MI according to the fourth UDMI were included between January 1, 2017, and December 31, 2023. Follow-up was 1 year; patients with available 1-year follow-up or who died within the first year were included. Type 3, 4, and 5 MI and nonischemic myocardial injuries were excluded. These data were analyzed from June 2025 to May 2026.

Patients were classified according to the primary etiologic mechanism of MI into 4 causal endotypes: cardiac/coronary, cardiac/noncoronary, systemic, or indeterminate.

The main measures were the distribution of causal endotypes and underlying etiologies. One-year outcomes included all-cause death, major adverse cardiovascular events ([MACE] cardiovascular death or recurrent MI), cardiovascular death, and recurrent MI. Cox and Fine-Gray models used the cardiac/coronary group as reference.

Among 6282 patients, mean (SD) age was 69.8 (13.5) years and 2013 (32.0%) were women. Overall, 5330 patients (84.9%) had a cardiac/coronary cause, including 5158 with acute atherothrombosis and 172 with nonatherothrombotic coronary mechanisms, 302 had a cardiac/noncoronary cause (4.8%), most commonly tachyarrhythmia, 503 had a systemic cause (8.0%), and 147 had an indeterminate cause (2.3%). At 1 year, all-cause mortality was 9.8% in cardiac/coronary MI, 15.9% in cardiac/noncoronary MI, 25.8% in systemic MI, and 1.4% in indeterminate MI. Compared with cardiac/coronary MI, adjusted hazard ratios for all-cause death were 1.46 (95% CI, 1.08-1.96) for cardiac/noncoronary MI, 2.50 (95% CI, 2.05-3.05) for systemic MI, and 0.22 (95% CI, 0.06-0.89) for indeterminate MI. Higher mortality in systemic and cardiac/noncoronary MI was largely related to noncardiovascular death. MACE rates differed less markedly across endotypes, whereas recurrent MI was less frequent in cardiac/noncoronary and systemic MI than in cardiac/coronary MI.

In this study, a causal endotype-based classification of MI identified distinct underlying mechanisms and clinical profiles that were not fully captured by the type 1/type 2 framework. This approach may complement the UDMI by improving characterization of MI heterogeneity.