Refining Myocardial Infarction Diagnosis: A Novel Causal Endotype-Based Classification Beyond Type 1 and Type 2 MI

Highlight

This landmark study elucidates a novel classification framework for myocardial infarction (MI) based on underlying causal endotypes rather than the traditional UDMI type 1/type 2 distinction. It identifies four distinct MI causal endotypes—cardiac/coronary, cardiac/noncoronary, systemic, and indeterminate—with markedly different epidemiologies, clinical characteristics, and 1-year outcomes. The findings emphasize that the systemic and cardiac/noncoronary MI groups carry a higher all-cause mortality predominantly due to noncardiovascular causes, highlighting the need for tailored diagnostic and therapeutic strategies in MI management.

Study Background

Myocardial infarction diagnosis and classification have conventionally relied on the criteria set by the fourth universal definition of myocardial infarction (UDMI), categorizing MIs primarily into type 1 (spontaneous atherothrombotic MI) and type 2 (myocardial oxygen supply-demand mismatch without acute coronary atherothrombosis). However, clinical experience and emerging evidence suggest substantial heterogeneity exists within these broad categories, reflecting varied pathophysiological mechanisms and prognostic implications. Traditional classification inadequately captures this diversity, impeding precise risk stratification and personalized treatment approaches.

This large, multicenter, prospective study aims to overcome these limitations by applying a causal endotype-based classification model to a contemporary cohort of over 6000 patients diagnosed with MI. The goal is to gain a refined mechanistic understanding of MI subtypes, their clinical profiles, and associated 1-year outcomes, thereby providing a framework that might complement and extend the UDMI.

Study Design

The study analyzed data from the AMIPE registry, a prospective, multicenter registry enrolling consecutive patients adjudicated with myocardial infarction according to the fourth UDMI between January 2017 and December 2023. Inclusion criteria required documented MI with available 1-year follow-up data or documented death within the first year. Patients with type 3, 4, or 5 MI subtypes and nonischemic myocardial injury were excluded to focus on acute ischemic MI presentations.

Patients were categorized into four causal endotypes based on the primary etiologic mechanism of their MI: 1) cardiac/coronary (including acute atherothrombosis and nonatherothrombotic coronary causes), 2) cardiac/noncoronary (such as tachyarrhythmia-driven ischemia), 3) systemic causes (such as severe anemia, sepsis, or hypoxia), and 4) indeterminate where a definitive causal mechanism could not be identified.

The primary endpoints assessed were the distribution of causal endotypes and their etiologies. Secondary endpoints included one-year all-cause mortality, major adverse cardiovascular events (MACE, defined as cardiovascular death or recurrent MI), cardiovascular death, and recurrent MI. Comparative hazard ratios were estimated using Cox proportional hazards and Fine-Gray competing risks models, using the cardiac/coronary group as the reference.

Key Findings

The study cohort comprised 6282 patients, with a mean age of 69.8 years and 32% women. Cardiac/coronary causal mechanisms predominated, accounting for 84.9% (5330 patients), mainly from acute atherothrombosis (5158 cases). Cardiac/noncoronary causes explained 4.8% (302 patients), chiefly tachyarrhythmias. Systemic causes contributed 8.0% (503 patients), while 2.3% (147) had indeterminate causes.

One-year all-cause mortality differed significantly among endotypes: 9.8% for cardiac/coronary, 15.9% for cardiac/noncoronary, 25.8% for systemic, and 1.4% for indeterminate MI. Adjusted hazard ratios for death relative to cardiac/coronary MI were 1.46 (95% CI: 1.08-1.96) for cardiac/noncoronary causes and 2.50 (95% CI: 2.05-3.05) for systemic causes, supporting substantially worse prognosis in these groups. Conversely, the indeterminate group had an unexpectedly low mortality risk (HR 0.22; 95% CI: 0.06-0.89).

Notably, excess mortality in cardiac/noncoronary and systemic MI was predominantly due to noncardiovascular causes, underscoring the influence of comorbidities and multisystem illness in these etiologic categories. Major adverse cardiovascular event rates were less variable across groups. However, recurrent MI was less frequent among cardiac/noncoronary and systemic MI patients compared with cardiac/coronary MI, underscoring the different natural histories and pathophysiology between these endotypes.

Expert Commentary

This study provides compelling evidence that the pathophysiologic heterogeneity of myocardial infarction extends beyond the dichotomous type 1 versus type 2 model. The causal endotype approach disentangles underlying mechanisms, enabling more precise phenotyping that aligns with differential prognostic and therapeutic pathways.

Clinicians should recognize that patients categorized under non-cardiac or systemic MI may warrant integrated care focusing on underlying systemic disease rather than conventional coronary interventions alone. The notably high mortality related mostly to noncardiovascular causes in these groups suggests that comprehensive management of comorbidities and systemic insults is crucial.

Limitations include potential misclassification inherent to registry data and the challenges of defining ‘‘indeterminate’’ cases, which may benefit from advanced diagnostics. However, the large, contemporary cohort and rigorous adjudication strengthen the generalizability of findings.

Conclusion

Implementing a causal endotype-based classification of myocardial infarction reveals important mechanistic and prognostic insights beyond traditional type-based definitions. This paradigm shift offers a pathway to greater diagnostic precision and personalized treatment strategies, which may ultimately improve patient outcomes. Future research should explore how integrating causal endotypes into clinical practice influences decision-making, resource utilization, and long-term prognosis.

Clinicians and researchers are encouraged to consider this nuanced framework as a complementary tool alongside the UDMI for comprehensive MI evaluation.

Funding and Clinical Trials

The study was supported by participating institutions within the AMIPE registry framework. Details regarding specific funding sources were not provided. The study is registered under relevant clinical trial registries consistent with observational registry standards.

References

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3. Heitner JF et al. Characteristics and outcomes of patients with type 2 myocardial infarction. J Am Heart Assoc. 2018;7(22):e008814.
4. Chapman AR, et al. High-sensitivity cardiac troponin and the universal definition of myocardial infarction. Circulation. 2017;135(2):158-171.