Simvastatin preserves diastolic function in experimental hypercholesterolemia independently of its lipid lowering effect

Abstract

Objective: Isolated diastolic dysfunction is present in 40% of heart failure patients. It has been attributed to myocardial fibrosis and related to cardiovascular risk factor exposure. We hypothesized that simvastatin will improve these dynamics in experimental hypercholesterolemia (HC). Methods: Three groups of pigs were studied after 12 weeks of normal (N) diet, HC diet, or HC diet with simvastatin (80 mg/day) treatment. Cardiac function was assessed by electron beam computed tomography (EBCT) and percentage of myocardium occupied by microvessels (myocardial vascular fraction) was calculated by micro-CT. Collagen content was determined by Sirius red staining and confirmed by a quantitative, hydroxyoproline-based assay. Results: Compared with N, LDL serum concentration was higher in HC and HC + simvastatin (1.0 ± 0.1 vs. 7.9 ± 1.7 and 9.6 ± 1.2 mmol/L, p < 0.05 for both). Cardiac early diastolic filling was reduced in HC compared with N (102.4 ± 11.3 vs. 151.1 ± 12.1 mL/s; p < 0.05) but restored in HC + simvastatin (176.8 ± 21.3 mL/s, p < 0.05 vs. HC). Compared with N, myocardial vascular fraction was higher in HC but not in HC + simvastatin (1.98 ± 0.84 vs. 4.48 ± 0.31 and 2.95 ± 0.95%; p < 0.05 for HC vs. N). Myocardial collagen content was higher in HC than in HC + simvastatin and N (4.72 ± 1.03 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p < 0.05 for HC vs. N), which was attributable mainly to an increase in collagen III (2.90 ± 0.48 vs. 1.62 ± 0.12 and 1.21 ± 0.24% area staining; p < 0.05 for HC vs. N). Conclusions: Simvastatin is able to prevent diastolic dysfunction in experimental HC independent of its lipid lowering effect. This beneficial effect is, at least partially, due to a decrease in myocardial fibrosis and angiogenesis.

Primary proteasome inhibition results in cardiac dysfunction

“…23 Characteristically, this pattern follows the vasculopathy of the coronary circulation with progressive accumulation of collagen, first in the perivascular regions and then in the interstitium, as observed in hypercholesterolaemic pigs. 14,17,23 In agreement with this, we found a marked reduction in the myocardial perfusion response and a marked increase in vascular permeability in response to stressors, especially dobutamine. Previously, in the same animals, we noted prominent endothelial dysfunction and even changes consistent with early atherosclerosis.…”

“…The contribution of rapid early diastolic filling and reduced late atrial to LV filling, hence a significantly elevated E/A ratio, is the hallmark of a restrictive filling pattern . EBCT can be used to assess diastology, and previously we reported on its abnormality in pigs subjected to hypercholesterolaemia ,,. Similarly, the current study shows diastolic dysfunction in animals undergoing chronic proteasome inhibition and, additionally, even more collagen deposition and yet no increase in oxidative stress and no stimulation of the TGF‐β pathway.…”

“…This technique has been validated against echocardiography . For diastolic function determination, we calculated the volume of the LV at 16 points through the cardiac cycle and plotted the global LV volume vs. time; the resulting slope of the curve was traced to determine the early (E) and late (A) diastolic filling rate ,,. Myocardial perfusion and permeability studies were conducted as described before and are detailed in the Supplementary material …”

“…Electron beam computed tomography (Imatron C-150, South San Francisco, CA, USA) was performed as reported before. 13,14 In brief, during suspended respiration, an ECG-triggered, contrastenhanced cine sequence was obtained with 8 mm thick tomographic slices in the neutral axis from the LV apex through the base. The images were reconstructed and analysed using the Analyze w software package (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN, USA).…”

Rosuvastatin Inhibits TIMP-2 and Promotes Myocardial Angiogenesis

“…A recent porcine study showed decreased myocardial angiogenesis following high-dose simvastatin (80 mg/kg) treatment [25]. The conflicting results seen in our study compared with the porcine model could be due to differences in the hydrophilicity of the studied statins, as RSV is a hydrophilic statin and simvastatin a highly lipophilic statin.…”