Abstract
Dear Editor,
We thank Drs. Muzurović et al 1 for their scholarly and constructive commentary on our work. 2 Their observations meaningfully contextualize our findings within the broader cardio-kidney-liver-metabolic continuum and raise several points we are pleased to address.
The commentators draw attention to an independent retrospective cohort of 321 MINOCA (myocardial infarction with non-obstructive coronary arteries) patients followed for a median of 26.6 months, in which elevated FIB-4 (fibrosis-4; >2.63) was independently associated with long-term MACE (major adverse cardiovascular events), with a significantly higher cumulative incidence of events in the high FIB-4 group. 3 This external replication of our core finding, across a separate patient population, distinct study design, and different cutoff threshold, provides important external support for the generalizability of FIB-4 as a prognostic tool in MINOCA and directly addresses the single-center limitation inherent to our original work.
Regarding the MASLD (metabolic dysfunction-associated steatotic liver disease) nomenclature transition, we acknowledge this important point. Our study was designed and initiated in September 2022, before the formal publication of the multisociety Delphi consensus statement establishing MASLD as the preferred terminology in June 2023. 4 Importantly, published evidence confirms that approximately 99% of patients with NAFLD (non-alcoholic fatty liver disease) under the old definition meet MASLD criteria, such that the natural history, biomarker associations, and cardiovascular risk relationships described under NAFLD terminology remain fully applicable to MASLD-defined populations. 5 Nonetheless, we agree that future prospective studies—including external validation efforts for our model—should align with MASLD diagnostic criteria to ensure consistency with the evolving cardio-hepatic literature and facilitate integration with the cardio-kidney-liver-metabolic syndrome framework. 6
The commentators’ emphasis on multimarker approaches incorporating biomarkers such as GDF-15 (growth differentiation factor-15) resonates with a central message of our study. 7 Our comprehensive integrated model, which achieved AUC (area under the curve) 0.834 by combining FIB-4, HSI (hepatic steatosis index), cardiac troponin, and conventional clinical parameters, already demonstrates the incremental value of combining hepatic indices with established cardiovascular markers. Whether GDF-15 or other emerging biomarkers provide meaningful incremental reclassification benefit specifically in MINOCA populations—where metabolic dysfunction assumes disproportionate pathogenic importance relative to atherosclerotic burden—is an important question warranting prospective investigation. 8
We are grateful for the engagement of Drs. Muzurović, Zečević, and Mantzoros, whose extensive contributions to the steatotic liver disease and cardiometabolic risk literature provide an important intellectual framework for our findings.
