There is an ongoing debate about the significance of cardiac troponin T (cTnT) elevation after strenuous exercise: heart muscle cell death versus physiologic mechanism of release through an intact cell membrane. While cTnT is a small molecule (37 kDa), cardiac specific myosin heavy chain-alpha (MHC-α) is much larger (224 kDa) and an increase after exercise could hardly be explained by passage through an intact cardiac cell membrane. PURPOSE: To measure MHC-α, and other biomarkers (C-reactive protein (CRP); cTnT, creatine kinase (CK), myoglobin (MG), creatinine (C), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) before and after a full distance Ironman in order to answer the question of heart muscle cell death versus physiologic changes. METHODS: In 52 non-elite athletes (14 female, 38 male; age 41.1 ± 9.7, range 24-70 years; all completed the race) biomarkers were measured by standard laboratory methods 7 days before, directly after, and day 1, 4 and 6 after the race. MHC-α was measured with a commercially available ELISA with no cross reactivity with other myosins. RESULTS: The course of MHC-α concentration [μg/L] was 1.33 ± 0.53 (before), 2.57 ± 0.78 (directly after), 1.51 ± 0.53 (day 1), 2.74 ± 0.55 (day 4) and 1.83 ± 0.76 (day 6). Other biomarkers showed a one-peaked increase with maximal values either directly after the race or at day 1: cTnT 76 ± 80 ng/L (12-440; reference <15), NT-proBNP 776 ± 684 ng/L (92-4700; ref. < 300), CK 68 ± 55 μkat/L (5-280; ref. < 1.9), MG 2088 ± 2350 μg/L (130-17000; ref. < 72), and creatinine 100 ± 20 μmol/L (74-161; ref. < 100), CRP 49 ± 23 mg/L (15-119; ref. < 5). There was a significant correlation between MHC-α and NT-proBNP (R = 0.48; p < 0.001) but neither between MHC-α and cTnT (R = 0.13; p = 0.36) nor MHC-α and myoglobin (R = 0.18; p = 0.2). CONCLUSION: An Ironman leads to remarkable disturbances in biomarkers as e.g. cTnT was in the range of myocardial infarction in 100% of women and 97% of men. This is to our best knowledge the first investigation of MHC-α after strenuous exercise and its two-peaked increase most likely represents first release from the cytosolic pool and later from cell necrosis including the contractile apparatus. However, many questions remain, not at least why MHC-α baseline levels are as high as 1.33 ± 0.53 μg/L.