Naoyoshi Aoyama

Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease

BackgroundGlucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.MethodsTo examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).ResultsFasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.ConclusionCirculating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

A Peptide Fragment of β Cardiac Myosin Heavy Chain (β-CMHC) Can Provoke Autoimmune Myocarditis as well as the Corresponding a Cardiac Myosin Heavy Chain (α-CMHC) Fragment

The validity of the general belief that a cardiac myosin heavy chain (α-CMHC) is primarily responsible for causing experimental autoimmune myocarditis because of the more profound tolerance induction to β-CMHC due to its expression during the embryonic stage has been examined. In order to completely avoid cross-contamination among components of the two myosin heavy chains, recombinant myosin fragments were synthesized in Escherichia coli using cDNA fragments of rat a- and (J-CMHC cloned by reverse transcription polymerase chain reaction (RT-PCR). Two fragments corresponding to amino acid residues 1107-1164 derived from a-and β-heavy chains were equally capable of provoking severe myocarditis in Lewis rats when immunized in complete Freunďs adjuvant. No significant differences in the severity, as judged from histological scoring, were observed between the diseases induced by the two different peptide fragments, indicating conclusively that β-CMHC is as pathogenic as α-CMHC.

Two-week interval optical coherence tomography: imaging evidence on neointimal coverage completion after implantation of the Endeavor zotarolimus-eluting stent.

To obtain imaging evidence by 2‐week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus‐eluting stent (E‐ZES).

Extremely prolonged elimination of cibenzoline at toxic plasma concentrations in patients with renal impairments

Three patients (age: 36, 68, and 80 years) treated with a standard oral dose of cibenzoline (300 mg/d) developed clinical symptoms being compatible with cibenzoline toxicity (e.g., prolonged QTc, wide QRS, arrhythmias, hypotension and hypoglycemia). Their plasma cibenzoline concentrations (i.e., 1944–2580 &mgr;g/L) were 5 to 10 times greater than the expected therapeutic levels. All patients had severe renal dysfunction (i.e., creatinine clearance: 10–16 mL/min) but had no severe liver damages. They received no drugs that might have inhibited hepatic drug metabolism. Intentional or accidental overdosing of the drug was ruled out in each patient. The elimination half-lives of cibenzoline monitored immediately after its withdrawal (i.e., 69, 116 and 198 hours) were 3–10 times longer than those reported in patients with end-stage renal failure of about 20 hours. In addition, two patients exhibited biphasic plasma drug decay curves. Our report indicates that not only reduced renal excretion but also non-linear kinetics of the drug via non-renal elimination at toxic concentrations may render renal failure patients more susceptible to cibenzoline toxicity.

Clinical Characteristics of Patients on Hemodialysis With Peripheral Arterial Disease.

Patients on hemodialysis (HD; n = 210) were examined for peripheral arterial disease (PAD) using ankle-brachial index (ABI) and toe-brachial index (TBI). The prevalence of PAD was 38.1%. Among patients with PAD, 87.5% were newly diagnosed with PAD, 42.5% were diagnosed with TBI <0.6 despite ABI ≥ 0.9, and 68.7% had no lower limb symptoms. In patients with PAD, the prevalence rate of cerebrovascular disease was 36.3%, coronary artery disease was 42.5%, spinal stenosis was 33.2%, and vertebral fracture 15.0% and was significantly higher than those of the non-PAD patients. Low high-density lipoprotein cholesterol was the most important biomarker among patients with PAD. PAD has been underdiagnosed and untreated in patients on HD because most patients do not have symptoms that could be due to diabetic neuropathy or have insufficient daily activity to experience exertional leg symptoms. Screening for PAD using the ABI and TBI increased diagnostic efficiency in patients on HD and may lead to effective early treatments, including pharmacotherapy, revascularization therapy, and exercise rehabilitation to avoid the worst possible scenario such as lower limb amputation, cardiovascular event, and death.

Effect of charcoal hemoperfusion on clearance of cibenzoline succinate (cifenline) poisoning.

BACKGROUND Management of cibenzoline succinate (cifenline) poisoning by symptomatic treatment is recommended because it has been reported cibenzoline succinate is not effectively removed by hemodialysis. The use of charcoal hemoperfusion for patients with cibenzoline succinate poisoning has not been reported previously. CASE REPORT An 80-year-old woman with permanent right ventricular pacing was admitted to our hospital with general fatigue and clouding of consciousness. She had been receiving cibenzoline succinate for 1 month. The patient was clearly in shock on admission. Electrocardiogram showed a prolonged QRS and QTc interval and pacing failure. Hemodynamic failure, electrocardiographic abnormalities including pacing failure, and liver and renal dysfunction were compatible with cibenzoline succinate poisoning. Symptomatic treatment was provided. On day 4, charcoal hemoperfusion was initiated because of the development of hypoglycemia accompanied by liver and renal dysfunction. After charcoal hemoperfusion, the hypoglycemia, liver and renal dysfunction, prolonged QRS and QTc interval, and pacing threshold resolved. She was discharged on digoxin. We present a case of cibenzoline succinate poisoning treated with charcoal hemoperfusion which resulted in a rapid reduction of cibenzoline plasma concentrations with a significant clinical improvement.

Effect of Colestimide on Reduction of Body Weight and Waist Circumference in Metabolic Syndrome Patients with Cardiovascular Risk Factors

Background and objective: Insulin resistance is thought to be central to the pathogenesis of abdominal obesity- linked metabolic syndrome (MetS). Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acid- sequestering resin used to lower LDL cholesterol. In recent reports, bile acid-controlled signaling pathways have shown promise as novel drug targets to treat metabolic disorders, such as obesity, type 2 diabetes, hyperlipidemia, and athero- sclerosis. The aim of this study was to evaluate the efficacy of colestimide on weight loss in MetS patients. Methods: Sixty-one patients with MetS who had cardiovascular risk factors were randomized to receive lifestyle counsel- ing with or without colestimide treatment. The primary endpoint was achieved when the reduction in body weight is � 5%. Additionally, differences in the waist circumference and metabolic-associated profiles between the colestimide group and the control group, which received lifestyle modifications alone, were analyzed. Results: The numbers of participants who achieved � 5% weight loss significantly favored the colestimide group over the non-colestimide group (71.4% vs. 33.3%; p < 0.01). The mean reduction in waist circumference during the study period (average 22 weeks) was greater with colestimide than without it (10.1 � 5.4 vs. 7.1 � 5.2 cm, p < 0.05). Conclusions: The colestimide treatment together with lifestyle intervention was associated with reduction in body weight and waist circumference over a relatively short term in obese subjects. The combination of colestimide and lifestyle inter- vention may be useful for weight management in MetS patients with cardiovascular risk factors.

Heat-shock protein 72 promotes platelet aggregation induced by various platelet activators in rats

Increase of thrombus in the coronary arteries is positively correlated with the level of heat-shock protein 72 (HSP72) in the blood of patients with acute myocardial infarction (AMI). Platelet aggregation participates in thrombus formation on ruptured plaque in AMI. In this study, we aimed to clarify the role of HSP72 in thrombus formation by evaluating the effects of HSP72 on platelet aggregation. Platelet aggregation activities were measured in platelet-rich plasma obtained from male Sprague-Dawley rats with or without the platelet activators, such as adenosine diphosphate (ADP), collagen, thrombin receptor-activating peptide-6 (TRAP-6), ristocetin, and arachidonic acid. Changes in aggregation were estimated by the co-addition of recombinant HSP72 and anti-HSP72 antibodies. Our results showed that addition of HSP72 increased platelet aggregation in the presence of low concentrations of ADP, collagen, TRAP-6, ristocetin, and arachidonic acid. Increased platelet aggregation stimulated by ADP and HSP72 was reduced by the co-addition of anti-HSP72 antibodies. Thus, these findings suggested that HSP72 was released extracellularly in response to stress, promoting thrombus formation and AMI. Additionally, treatment with anti-HSP72 antibodies may control platelet aggregation induced by extracellular HSP72.

Is there a relation between triglyceride concentrations in very low density lipoprotein and the index of insulin resistance in nondiabetic subjects

Serum very low density lipoprotein (VLDL) levels increase during the early stages of insulin resistance; therefore, determination of VLDL levels would be useful for evaluating the progression of metabolic syndrome and diabetes mellitus. The aim of this study was to clarify the clinical utility of triglyceride in VLDL (VLDL‐TG) level, determined using a homogeneous assay kit (Shino‐test Corporation, Tokyo, Japan), as an index of insulin resistance.

Modeling of Individual Left Ventricle for Cardiac Resynchronization Therapy

On cardiac resynchronization therapy, the right position for implantation of a pacemaker on the lateral wall of the left ventricle (LV), is the most important point for the surgical success. However, the past researches of the heart modeling have been developed the common heart model which has difficulty in application to individual diagnosis. Therefore the individual heart models which include individual physiological information are expected to use in the preoperative diagnosis by cardiac surgeons. In this paper, we propose a novel method of individual LV modeling which extracts the individual LV information from patients CT images and constructs the individual LV model using the spring mass system. The model based on the patients LV information can simulate his heart beating and suggest the surgical result by modifying the parameters of the model. We performed some experiments to construct the individual heart model of a normal healthy person and simulated the heart failure using it.