Cardiac Regeneration by Statin‐Polymer Nanoparticle‐Loaded Adipose‐Derived Stem Cell Therapy in Myocardial Infarction

Abstract Clinical trials with autologous adipose‐derived stem cell (AdSC) therapy for ischemic heart diseases (IHDs) are ongoing. However, little is known about combinational therapeutic effect of AdSCs and statin poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles on the ischemic myocardium. We investigated the hypothesis that statins, which have pleiotropic effects, augment the therapeutic potential of AdSCs and that AdSCs also act as drug delivery tools. Simvastatin‐conjugated nanoparticles (SimNPs) significantly promoted migration activity without changing proliferation activity and upregulated growth factor gene expression in vitro. A small number of intravenously administered SimNP‐loaded AdSCs (10,000 cells per mouse) improved cardiac function following myocardial infarction, inducing endogenous cardiac regeneration in the infarcted myocardium. The de novo regenerated myocardium was thought to be derived from epicardial cells, which were positive for Wilms' tumor protein 1 expression. These findings were attributed to the sustained, local simvastatin release from the recruited SimNP‐loaded AdSCs in the infarcted myocardium rather than to the direct contribution of recruited AdSCs to tissue regeneration. SimNP‐loaded AdSCs may lead to a novel somatic stem cell therapy for IHDs. Stem Cells Translational Medicine 2019;8:1055–106

Left Atrial Ball-Shaped Thrombus with Concomitant Biatrial Appendage Thrombi in a Patient with Prior Mitral Valve Replacement

We reported a 67-year-old woman in whom large atrial thrombi were found by chance during discontinuation of therapeutic anticoagulation. The patient, with a history of mitral valve replacement surgery, had stopped anticoagulation for months because of intractable gastrointestinal bleeding, during which she was found to have 3 large thrombi in the atria on transesophageal echocardiography: left atrial free-floating ball-shaped thrombus, left atrial appendage thrombus, and right atrial appendage thrombus. One month following diagnosis, she still had the free-floating thrombus despite adequate anticoagulation. Free-floating ball-shaped thrombus is a rare finding observed on echocardiography in patients with mitral valve disease and an even rarer finding in case of appendage thrombi coexisting

HMG-CoA Reductase Inhibitor, Pitavastatin, Prevents Migration of Cultured Smooth Muscle Cells by Suppressing Myosin Light Chain Phosphorylation

Objective: To clarify the mechanism underlying the protective effect of statins against vascular events, we investigated whether pitavastatin affects the migration, adhesion and myosin light chain (MLC) phosphorylation of pig vascular smooth muscle cells (VSMCs) from the coronary artery. Methods: Migration was assayed by the modified Boyden’s chamber method and MLC phosphorylation was determined with the use of glycerol-PAGE. Results: Pitavastatin strongly inhibited cell migration and cell adhesion. Pretreatment of mevalonate (MVA) prior to the pitavastatin administration totally reversed these inhibitory effects of pitavastatin on VSMCs, whereas pretreatment of geranylgeranylpyrophosphate (GGPP) only partially reversed these inhibitory effects. Morphologically, MVA completely reversed, whereas GGPP partially reversed pitavastatin-inhibited cell spreading. Pitavastatin also inhibited MLC phosphorylation, and MVA completely reversed, whereas GGPP partially inhibited this effect. Y-27632 (a Rho-kinase inhibitor) suppressed VSMC migration and MLC phosphorylation more effectively than ML-9 (a MLC-kinase inhibitor). The inhibitory effects upon VSMC migration and MLC phosphorylation were maximal after incubation with both Y-27632 and ML-9. Conclusions: Pitavastatin inhibited VSMC migration by inhibiting cell adhesion, spreading and MLC phosphorylation. Another pathway in addition to the Rho pathway might be involved in these effects

Serum uric acid is associated with left ventricular hypertrophy independent of serum parathyroid hormone in male cardiac patients.

BACKGROUND: Several studies have shown that serum uric acid (UA) is associated with left ventricular (LV) hypertrophy. Serum levels of parathyroid hormone (PTH), which has bbe shown to be correlated with UA, is also known to be associated with cardiac hypertrophy; however, whether the association between UA and cardiac hypertrophy is independent of PTH remains unknown. PURPOSE: We investigated whether the relationship between serum uric acid (UA) and LV hypertrophy is independent of intact PTH and other calcium-phosphate metabolism-related factors in cardiac patients. METHODS AND RESULTS: In a retrospective study, the association between UA and left ventricular mass index was assessed among 116 male cardiac patients (mean age 65 ± 12 years) who were not taking UA lowering drugs. The median UA value was 5.9 mg/dL. Neither age nor body mass index differed significantly among the UA quartile groups. Patients with higher UA levels were more likely to be taking loop diuretics. UA showed a significant correlation with intact PTH (R = 0.34, P<0.001) but not with other calcium-phosphate metabolism-related factors. Linear regression analysis showed that log-transformed UA showed a significant association with left ventricular mass index, and this relationship was found to be significant exclusively in patients who were not taking loop and/or thiazide diuretics. Multivariate logistic regression analysis showed that log-transformed UA was independently associated with LV hypertrophy with an odds ratio of 2.79 (95% confidence interval 1.48-5.28, P = 0.002 per one standard deviation increase). CONCLUSIONS: Among cardiac patients, serum UA was associated with LV hypertrophy, and this relationship was, at least in part, independent of intact PTH levels, which showed a significant correlation with UA in the same population