Rotigaptide Infusion for the First 7 Days After Myocardial Infarction–Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border‐Zone and Arrhythmia Inducibility

Figures

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  Figure 1. Incidence of spontaneous ventricular arrhythmias recorded at the end of the healed phase (day 28) post‐myocardial infarction (MI) surgery. A, Number of ventricular premature beats (VPB) occurring during 24‐hour period. B, Composite arrhythmia score including VPB, ventricular tachycardia, and ventricular fibrillation occurring during 24‐hour period. Sham=sham‐operated (n=5), MI+CON=control (n=15), MI+ROT=rotigaptide (n=15). I/R indicates infarction/reperfusion; ns, not significant; and PBS, phosphate‐buffered saline. *P<0.05.

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  Figure 2. Representative optical action potential recordings during PES‐induced VT/VF and susceptibility to arrhythmias studied ex vivo at the end of the healed phase (day 28) post‐MI. A, Black‐and‐white image represents visible epicardial optical mapping surface with (B) 3 action potential transients showing rapid (CL <100 ms) tachyarrhythmia voltage recordings from remote (blue), infarct border zone (black), and infarct (red) myocardium. C, Arrhythmia score from extrastimulus arrhythmia provocation studies. D, Incidence of VT (encompassing both sustained and nonsustained VT) induced by extrastimulus arrhythmia provocation studies. Sham+no drug=sham operated (n=5), MI+CON=control (n=15), MI+ROT=rotigaptide (n=15). *P<0.05 (E) ECG example of nonsustained VT. (F) ECG example of sustained VT. CL indicates cycle length; CON, control; MI, myocardial infarction; NSVT, nonsustained ventricular tachycardia; PES, programmed electrical stimulation; ROT, rotigaptide; SUS, sustained; VF, ventricular fibrillation; and VT, ventricular tachycardia.

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  Figure 3. Representative optical action potential recordings during premature extra stimulus–induced VT/VF. Three examples (A through C) of sustained VT/ VF recorded during programmed electrical stimulation. Black‐and‐white image represents visible epicardial optical mapping surface with 3 action potential transients showing rapid (CL <100 ms) tachyarrhythmia voltage recordings from normal (blue), infarct border zone (black), and infarct (red) myocardium. CL indicates cycle length; VF, ventricular fibrillation; and VT, ventricular tachycardia.

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  Figure 4. Effects of rotigaptide on CV and action potential rise time. A, Reduction in CV at IBZ, comparable between treatment groups. B, Prolongation of rise time in the infarct region, comparable between treatment groups. CON indicates control; CV, conduction velocity; IBZ, infarct border zone; ns, not significant; Rem, remote; and ROT, rotigaptide. *P<0.05.

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  Figure 5. Correlation of MR parameters and histology. A, Regions of collagen deposition on Masson's trichrome–stained histological section and (B) areas of low fractional anisotropy and (C) areas of high mean diffusivity from a single section through the mid‐LV of an infarcted heart. D, Three paired sections of normal myocardium showing (left) histology and (right) 2‐dimensional primary eigenvector. Scale bar (white)=500 μm. (E) Comparison of orientation in normal myocardium between histology and primary eigenvector. LV indicates left ventricle; and MR, magnetic resonance.

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  Figure 6. The effect of rotigaptide on diffusion tensor MRI‐derived measures of tissue architecture. A, Infarct size, B, Histological representations, C, FA and D, MD. CON indicates MI+control (n=4); FA, fractional anisotropy; IBZ, infarct border zone; Inf, infarct; MD, mean diffusivity; Rem, remote; and ROT, MI+rotigaptide (n=3). *P<0.05.

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  Figure 7. Effect of rotigaptide treatment on 3‐dimensional myocardial structure derived from diffusion tensor imaging. Representative single short‐axis slice maps of (A) helix angle and (B) transverse angle in sham‐operated and infarcted (no drug) hearts. Helix angle transitions from right‐handed, positive angle in endocardial fibers to a left‐handed, negative angle in epicardial fibers with a similar pattern in remote and infarct border zone regions of control (C) and rotigaptide‐treated (D) hearts.