Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Abstract

Objectives: Therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV systolic and diastolic function in dogs with heart failure (HF). This study examined the effects of CCM therapy on mRNA and protein expression of cytoskeletal proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the LV myocardium of dogs with HF. Methods: HF was produced in 14 dogs by coronary microembolizations. Dogs were randomized to 3 months of CCM therapy (n = 7) or to sham-operated controls (n = 7). LV tissue from 6 normal (NL) dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction and protein expression using Western blots. Results: Compared with NL dogs, controls showed upregulation of mRNA and protein expression of the cytoskeletal proteins tubulin and fibronectin and MMP-1, MMP-2 and MMP-9, and downregulation of the cytoskeletal protein titin. Normalized expression of all these genes and proteins was seen after CCM therapy. No differences in expression of TIMP-1 and TIMP-2 were observed among groups. Conclusions: CCM therapy normalizes expression of key cytoskeletal proteins and MMPs and may partly explain the improvement in LV function seen in HF following CCM therapy.