Causal Endotype-Based Classification of Myocardial Infarction.

IMPORTANCE: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Patients were classified according to the primary etiologic mechanism of MI into 4 causal endotypes: cardiac/coronary, cardiac/noncoronary, systemic, or indeterminate. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.