(A) Scheme of the physical stress–induced MI protocol: starting at 8 weeks after TAC, once per week, ApoE^–/– mice were physically stressed by a treadmill run (4 minutes, at 13 m/min). ECG traces were recorded at baseline and during and 48 hours after the run on the treadmill by using radiotelemetry devices. Echocardiographic analysis was performed at baseline and at 6, 8, 20, and 25 weeks after TAC, as indicated by the gray arrowheads. (B) Percentage of mice that died before and during the stress test protocol and that survived between 8 and 25 weeks after TAC (n = 35). (C) Survival curve of ApoE^–/– mice after TAC dead during the physical stress–induced MI protocol (from 8–25 weeks after TAC; n = 29). (D) Images of the infarcted ApoE^–/– hearts at postmortem examination. Dotted circles indicate the pale myocardium, indicative of infarct. Scale bar: 5 mm. (E) Representative ECG tracing of TAC-operated ApoE^–/– subjected to the physical stress protocol: (from left to right) during rest; the same mouse a week later showed ST elevation (red arrow) at rest; and following treadmill run ST elevation was further increased. The mouse died with remarkable signs of ST elevation and profound bradycardia (right). (F) Masson’s trichrome staining of (left) the banded WT heart at 12 weeks after TAC, (middle) the TAC-operated ApoE^–/– mouse that survived the physical stress (25 weeks after TAC), and (right) the TAC-operated ApoE^–/– mouse that died during physical stress at 12 weeks after TAC. Scale bar: 1 mm. (G) Fractional shortening (FS) measured at the indicated time points after TAC (n ≥ 5). **P < 0.01, ***P < 0.001, 1-way ANOVA. Representative images of 2-dimensional M-mode echocardiography of the LV of TAC-operated ApoE^–/– mice (H) without infarct and (I) with infarct, showing the thin ventricular wall in the apex (yellow dotted lines).