Impact of Statins Therapy for Ischemic Heart Disease Patients with Low-Density Lipoprotein Cholesterol Levels Less Than 100 mg/dL.

BACKGROUND: The objective of this study was to determine whether the use of statins prevents the progression of ischemic heart disease (IHD) in patients with low levels of low-density lipoprotein cholesterol (LDL-C). METHODS: We reviewed data obtained from IHD patients who underwent first percutaneous coronary intervention (PCI). Patients underwent follow-up coronary angiography (re-CAG) after PCI. However, only patients with LDL-C levels less than 100 mg/dL at PCI were included in this study. Ultimately, 92 patients were enrolled. All patients were divided into two groups: 1) patients who were treated with statins (n = 69), and 2) patients who were not treated with statins (n = 23). RESULTS: The two groups had similar LDL-C levels at PCI. At re-CAG, the ratio of patients who underwent PCI for de novo lesion in the statin group was lower than that in the non-statin group (12% vs. 48%) (p < 0.001). In multiple regression analysis, statin usage and LDL-C level at PCI were independent predictors of the ratio of patients undergoing PCI for de novo lesion. CONCLUSIONS: Statins therapy for patients whose LDL-C levels are less than 100 mg/dL has a beneficial effect on secondary prevention of IHD.

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the progression of renal dysfunction in Japanese hypertensive patients.

AIM: The aim was to determine whether the use of statins prevents the progression of chronic kidney disease (CKD) in hypertensive patients. METHODS: We retrospectively reviewed data obtained from hypertensive patients, and subjects with diabetes mellitus and those undergoing hemodialysis were excluded. At total of 227 patients were enrolled (83 men, mean age 73 years) and 90% of the patients were of CKD stage 2 or 3. The patients were divided into two groups: those treated with statins (n = 93) and those not treated with statins (n = 134). Renal function was evaluated by estimated glomerular filtration rate (eGFR). RESULTS: The statin group and the non-statin group were similar in age, sex, blood pressure, follow-up period and prescriptions of antihypertensive medicines. The eGFR in the statin group increased from 62 +/- 14 to 66 +/- 15 (mL/min per 1.73 m(2)), whereas it decreased in the non-statin group from 69 +/- 16 to 64 +/- 18 (mL/min per 1.73 m(2)). The annual eGFR improved in the statin group (2.5 +/- 6.6 mL/min per 1.73 m(2)/year), but decreased in the non-statin group (-3.3 +/- 6.6 mL/min per 1.73 m(2)/year) (P < 0.001). When the patients were divided into two groups by low-density lipoprotein (LDL) cholesterol levels at the second evaluation, annual eGFR improved in the group of LDL to below 100 mg/dL (n = 99) (0.4 +/- 7.2 mL/min per 1.73 m(2)/year), but decreased in the other group (n = 128) (-1.9 +/- 7.0 mL/min per 1.73 m(2)/year) (P = 0.018). CONCLUSION: Lipid-lowering intervention with statins inhibits the progression of CKD in hypertensive patients.

Granulocyte colony-stimulating factor activates Wnt signal to sustain gap junction function through recruitment of beta-catenin and cadherin.

Our previous study reveals that connexin (Cx) 43 is targeted by ACh to prevent lethal arrhythmia. Granulocyte colony-stimulating factor (G-CSF), used against ischemic heart failure, may be another candidate, however, with unknown mechanisms. Therefore, we investigated the cellular effects of G-CSF. G-CSF activated the Wnt and Jak2 signals in cardiomyocytes, and up-regulated Cx43 protein and phosphorylation levels. In addition, G-CSF enhanced the localization of Cx43, beta-catenin and cadherin on the plasma membrane. G-CSF inhibited the reduction of Cx43 by enhancing Cx43 anchoring and sustained the cell-cell communication during hypoxia. Consequently, G-CSF suppressed ventricular arrhythmia induced by myocardial infarction. As a result, G-CSF could be used as a therapeutic tool for arrhythmia.

Nitric oxide stimulates vascular endothelial growth factor production in cardiomyocytes involved in angiogenesis.

BACKGROUND: Hypoxia-inducible factor (HIF)-1alpha regulates the transcription of lines of genes, including vascular endothelial growth factor (VEGF), a major gene responsible for angiogenesis. Several recent studies have demonstrated that a nonhypoxic pathway via nitric oxide (NO) is involved in the activation of HIF-1alpha. However, there is no direct evidence demonstrating the release of angiogenic factors by cardiomyocytes through the nonhypoxic induction pathway of HIF-1alpha in the heart. Therefore we assessed the effects of an NO donor, S-Nitroso-N-acetylpenicillamine (SNAP) on the induction of VEGF via HIF-1alpha under normoxia, using primary cultured rat cardiomyocytes (PRCMs). METHODS AND RESULTS: PRCMs treated with acetylcholine (ACh) or SNAP exhibited a significant production of NO. SNAP activated the induction of HIF-1alpha protein expression in PRCMs during normoxia. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was induced by SNAP and was completely blocked by wortmannin, a PI3K inhibitor, and NG-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor. The SNAP treatment also increased VEGF protein expression in PRCMs. Furthermore, conditioned medium derived from SNAP-treated cardiomyocytes phosphorylated the VEGF type-2 receptor (Flk-1) of human umbilical vein endothelial cells (a fourfold increase compared to the control group, p < 0.001, n = 5) and accelerated angiogenesis. CONCLUSION: Our results suggest that cardiomyocytes produce VEGF through a nonhypoxic HIF-1alpha induction pathway activated by NO, resulting in angiogenesis.

Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1alpha.

Electrical stimulation of the vagal efferent nerve improves the survival of myocardial infarcted rats. However, the mechanism for this beneficial effect is unclear. We investigated the effect of acetylcholine (ACh) on hypoxia-inducible factor (HIF)-1alpha using rat cardiomyocytes under normoxia and hypoxia. ACh posttranslationally regulated HIF-1alpha and increased its protein level under normoxia. ACh increased Akt phosphorylation, and wortmannin or atropine blocked this effect. Hypoxia-induced caspase-3 activation and mitochondrial membrane potential collapse were prevented by ACh. Dominant-negative HIF-1alpha inhibited the cell protective effect of ACh. In acute myocardial ischemia, vagal nerve stimulation increased HIF-1alpha expression and reduced the infarct size. These results suggest that ACh and vagal stimulation protect cardiomyocytes through the PI3K/Akt/HIF-1alpha pathway.