Changes in metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy by rapid atrial pacing in dogs

Abstract

Background: It was the aim of this study to investigate the variation in metalloproteinase and tissue inhibitor of metalloproteinase (TIMP) connexin levels during tachycardia-induced cardiomyopathy (TIC).

Methods: Canine models of TIC were established by rapid right atrial pacing at 350-400 beats per min for 8 weeks in 11 dogs, with another 6 dogs acting as sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dt(max) and -dp/dt(max)), as well as intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. The relative abundance of matrix metalloproteinase (MMP)-9 and TIMP-1 was studied by immunoblotting.

Results: The following hemodynamic changes were detected after 8 weeks of rapid pacing: the TIC group had decreased dp/dt(max) (p < 0.05), the left ventricular relaxation time constant (tau) was prolonged (p < 0.05), both left ventricular end-diastolic volume and left ventricular end-systolic volume were decreased (p <0.05), left ventricular end-diastolic pressure was significantly increased (p <0.05), and -dp/dt(max) was significantly decreased (p <0.001) compared with the control group; no statistical differences in the left ventricular ejection fraction between weeks 1, 4 or 8 (p >0.05) were observed, but left ventricular ejection fraction was significantly decreased after 1 week of pacing (p < 0.05). The left ventricular end-diastolic volume was increased after 1 week of pacing compared with the control group (24.15 +/- 8.15 vs.11.19 +/- 4.41 ml; p <0.05), as shown by echocardiography. Compared with the control group, MMP-9 was significantly higher (0.217 +/- 2.16 E-02 vs. 0.314 +/- 5.263 E-02; p < 0.001), while TIMP-1 was decreased (0.230 +/- 8.944 E-02 vs. 0.120 +/- 9.258 E-03; p < 0.001).

Conclusions: Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. Enlarged and disarrayed fibers and mitochondria with disintegrated crystal and an anarchic pattern were observed. Additionally, moderate dilation of the rough endoplasmic reticulum and intercalated disk discontinuity were seen after 8 weeks of pacing, and MMP-9 was increased and TIMP-1 was decreased after the same time period.