Valerio Zacà

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

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.

Atenolol Is Inferior to Metoprolol in Improving Left Ventricular Function and Preventing Ventricular Remodeling in Dogs with Heart Failure

Objectives: β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β1-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30–40%]. Methods: Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Δ) in EF and volumes between measurements before and after therapy was calculated and compared among study groups. Results: In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. ΔEF was significantly higher and Δend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 ± 0.86% vs. 0.8 ± 0.85%, p < 0.05; end-systolic volume: –4.3 ± 0.81 ml vs. –1 ± 0.52 ml, p <0.05). Conclusions: In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.

Pleiotropic effects of long-term monotherapy with rosuvastatin in dogs with moderate heart failure

Objective: The objective of this study was to investigate the potential pleiotropic effects of rosuvastatin (RSV) in the left ventricular (LV) myocardium of dogs with moderate heart failure (HF). Methods: LV tissue was obtained from HF dogs randomized to 3 months therapy with low-dose RSV (n = 7), high-dose RSV (n = 7) or to no therapy (Control, n = 7) and from 7 normal dogs. mRNA and protein expression of prohypertrophic mediator NGFI-A binding protein 1 (Nab1), phosphatase and tensin homolog (PTEN), phosphoinositide-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) were measured, as well as that of proinflammatory cytokine interleukin-6 (IL-6), bone marrow-derived stem cell markers cKit and Sca1, vascular endothelial and fibroblast growth factors (VEGF and FGF) and nitric oxide synthase (NOS) isoforms. Results: Nab1, PTEN, PI3K, mTOR and IL-6 increased in the controls. High-dose RSV reduced expression of Nab1, PTEN, PI3K, mTOR and IL-6 to near-normal levels. cKit and Sca1 significantly increased, while VEGF and FGF decreased in the controls compared to the normal dogs. RSV therapy further increased expression of cKit, Sca1, VEGF and FGF. High-dose RSV normalized the expression of NOS isoforms. Conclusion: These pleiotropic effects of RSV may account, in part, for the observed beneficial effect of RSV on LV function and structural remodeling.