Hisashi Murakami

Implantation of Adipose-Derived Regenerative Cells Enhances Ischemia-Induced Angiogenesis

Objective—Therapeutic angiogenesis using autologous stem/progenitor cells represents a novel strategy for severe ischemic diseases. Recent reports indicated that adipose tissues could supply adipose-derived regenerative cells (ADRCs). Accordingly, we examined whether implantation of ADRCs would augment ischemia-induced angiogenesis. Method and Results—Adipose tissue was obtained from C57BL/6J mice, and ADRCs were isolated using standard methods. ADRCs expressed stromal cell–derived factor 1 (SDF-1) mRNA and proteins. Hind limb ischemia was induced and culture-expanded ADRCs, PBS, or mature adipocytes (MAs) as control cells were injected into the ischemic muscles. At 3 weeks, the ADRC group had a greater laser Doppler blood perfusion index and a higher capillary density compared to the controls. Implantation of ADRCs increased circulating endothelial progenitor cells (EPCs). SDF-1 mRNA abundance at ischemic tissues and serum SDF-1 levels were greater in the ADRC group than in the control group. Finally, intraperitoneal injection of an anti–SDF-1 neutralizing antibody reduced the number of circulating EPCs and therapeutic efficacies of ADRCs. Conclusions—Adipose tissue would be a valuable source for cell-based therapeutic angiogenesis. Moreover, chemokine SDF-1 may play a pivotal role in the ADRCs-mediated angiogenesis at least in part by facilitating mobilization of EPCs.

Impact of the high-molecular-weight form of adiponectin on endothelial function in healthy young men

Objective  Adiponectin is an adipocyte‐derived, antiatherogenic protein that is present in plasma as a large multimeric structure of high molecular weight (HMW) and in a trimer or hexamer form (non‐HMW). The biological activities of these isoforms have not yet been elucidated. We therefore examined the effect of these isoforms on endothelial function in healthy young men.

Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Impact of coronary stent designs on acute stent recoil

BACKGROUND Acute stent recoil has been often observed following stent delivery balloon deflation in coronary arteries and the recoil rate varies by stent design. Accordingly, the purpose of the present study was to evaluate the impact of stent designs on acute stent recoil after new generation drug-eluting stent implantation. METHODS AND RESULTS A total of 154 lesions [56 treated with biolimus-eluting stent (BES), 46 with cobalt chromium everolimus-eluting stent (CoCr-EES), and 52 with platinum chromium everolimus-eluting stent (PtCr-EES)] were evaluated. Quantitative coronary angiography was used to measure the minimal lumen diameter (MLD). MLD1 was defined as a MLD of complete expansion of the last stent delivery balloon at the highest pressure. MLD2 was defined as a MLD immediately after the last stent delivery balloon deflation. Acute stent recoil was determined by the calculation as (MLD1-MLD2)/MLD1. Acute stent recoil was significantly higher in the CoCr-EES group versus the BES group and PtCr-EES group (10.1 ± 6.9%, 6.7 ± 5.5%, and 6.5 ± 4.8%, respectively, p = 0.01). Multivariate linear regression analysis demonstrated that the use of CoCr-EES and the number of stent delivery balloon inflations were independent predictors of acute stent recoil (r = 0.26, β = 0.21, p = 0.01 and r = -0.51, β = -0.58, p < 0.01, respectively). CONCLUSION Acute stent recoil occurred more frequently with the CoCr-EES compared with both BES and PtCr-EES. Strategies with multiple balloon inflation might be needed to overcome this recoil phenomenon.

Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes

AIMS A lipid-lowering agent, fenofibrate, has been reported to reduce hepatic glucose production and the expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme for gluconeogenesis in the liver. However, the precise mechanisms of these effects have remained unclear. MAIN METHODS Rat hepatoma-derived H4IIE cells and murine myoblast-derived C2C12 cells were incubated with the ester form of fenofibrate and fenofibric acid, a metabolite of fenofibrate ester, and the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), PEPCK mRNA expression and glucose production were assessed. KEY FINDINGS Incubation of H4IIE hepatoma cells with the ester form of fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and decreased PEPCK mRNA expression and glucose production. Fenofibrate-induced reductions in PEPCK expression and glucose production were abrogated by compound C, a specific AMPK inhibitor. Fenofibric acid, a metabolite of fenofibrate ester, had no effects on AMPK phosphorylation, PEPCK gene expression, or glucose production in H4IIE cells. Fenofibrate-treated mice exhibited increases in AMPK phosphorylation and a decrease in PEPCK expression in the liver but not in skeletal muscles, suggesting that unmetabolized fenofibrate accumulated and affected AMPK only in the liver. SIGNIFICANCE These results demonstrate that fenofibrate inhibits PEPCK gene expression and hepatic glucose production in the liver via AMPK activation, even though the metabolite loses its effects on AMPK and does not work in vivo in myocytes. This novel feature of fenofibrate may provide additional benefit for the treatment of patients with disorders of both lipid and glucose metabolism.

Unruptured Left Coronary Sinus of Valsalva Aneurysm Causing Mitral Valve Obstruction

A 77-year-old man was admitted for congestive heart failure. He had started to have palpitations after eating supper 2 days before the admission and had experienced dyspnea on exertion since then. He visited his family physician, who referred him to the cardiology clinic of our hospital. The patient was under the family physicians care for diabetes mellitus, hypertension, and paroxysmal atrial fibrillation. He had never been diagnosed as having any organic heart disease. He was an ex-smoker and drank alcohol on social occasions. The patient was on β-blockers and Coumadin. His cardiovascular physical examination was significant for a 3/6 systolic murmur and a rapid, irregular heart beat. His ECG showed atrial fibrillation with a ventricular rate of 150 bpm. His portable chest x-ray (Figure 1A) showed bilateral pleural effusion and pulmonary edema. An emergency transthoracic echocardiogram showed normal left and right ventricular function. A large mass in the left atrium was seen that was causing functional mitral stenosis. The patient was admitted to the hospital, given digoxin, and started on intravenous diuresis. His ECG on normal sinus rhythm (Figure 1B), which was …

Acute improvement of left ventricular relaxation as a predictor of volume reduction after cardiac resynchronization therapy: a pilot study assessing the value of left ventricular hemodynamic parameter.

Cardiac resynchronization therapy (CRT) improves cardiac function, but CRT recipients with advanced heart failure (HF) do not always respond well. Because the best parameters for the prediction of CRT response are not established, we investigated whether improvement of invasive left ventricular (LV) hemodynamic diastolic parameters could identify CRT responders.