Cardiovascular Outcomes in Patients With Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment With Pioglitazone: Reports of a Randomised Trial From The Japan Working Group for the Assessment Whether Pioglitazone Protects DM Patients Against Re-Infarction (PPAR Study).

BACKGROUND: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. METHODS: In this multicentre, prospective, randomised, open, blinded-endpoint trial, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. FINDINGS: HbA1C levels were 5·9 and 5·8% (p = 0·71) at baseline and 6·0 and 5·8% (p < 0·01) at 2 years for the control and pioglitazone groups, respectively.The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years (95% confidential interval (CI):0.662-1·526, p = 0·98), respectively; the incidence of MI and cerebral infarction was 0·3% and 2·2% (95%CI: 0·786-32·415, p = 0·09) and 1·0% and 0·3% (95%CI: 0·051-3·662, p = 0·44), respectively. Post-hoc analyses of the 7-year observation period showed that these trends were comparable (21·9% and 19·2% in the control and pioglitazone groups, 95%CI: 0.618-1·237, p = 0·45). INTERPRETATION: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI.

Native valve endocarditis caused by Neisseria elongata Subsp. nitroreducens.

Neisseria elongata, a normal resident in the human oral cavity, rarely causes invasive infections. We herein report a case of endocarditis caused by Neisseria elongata subsp. nitroreducens that occurred in a patient without any apparent cardiac complications. The patient received aortic valve replacement following the administration of intravenous beta-lactam for five weeks. To our knowledge, this is the first published case in Japan of N. elongata infection in a patient without a prosthetic device.

The therapeutic importance of home blood pressure assessment and combination antihypertensive therapy for achieving target blood pressure control: Ibaraki hypertension assessment trial.

Tight blood pressure (BP) control is important for the prevention of cardiovascular disease in hypertensive patients. A cross-sectional study of 2339 patients from 101 clinics and hospitals in Ibaraki Prefecture was performed to evaluate BP control with the patients' current antihypertensive medication. Group A (n=892) included high-risk hypertensive patients with at least one of the following risk factors: diabetes mellitus, chronic kidney disease or a history of myocardial infarction. Group B (n=586) included patients <65 years old and Group C (n=859) included patients ≥65 years old. Both groups B and C included hypertensive patients without the above risk factors. A mean of 1.8±1.0 antihypertensive drugs per patient were prescribed. A total of 35.8% of all patients received monotherapy, 40% received a combination of three therapies and 20.3% received more than three kinds of drugs. The percentage of patients achieving the target BP at the office and at home was significantly higher in Group C than in the other groups (P<0.001). A combination of more than two antihypertensive drugs, including a high dose of either an angiotensin receptor blocker or a calcium channel blocker, was frequently prescribed to Group A to achieve the target office BP. Although the target BP should be lower in Group A (given their comorbidities), the absolute BP value and the number of medications were similar to the other groups. In conclusion, we demonstrated that physicians should treat hypertension more intensively with a combination of more than two antihypertensive drugs, using a high dose to achieve the target BP. In addition, it is important to teach hypertensive patients the clinical importance of monitoring their BP at home and the need to achieve home BP targets.

Subarachnoid hemorrhage caused by ruptured dissecting aneurysm arising from the extracranial distal posterior inferior cerebellar artery--case report.

A 50-year-old man presented with a dissecting aneurysm arising from the extracranial portion of the right posterior inferior cerebellar artery (PICA) causing subarachnoid hemorrhage (SAH) and manifesting as sudden onset of disturbed consciousness. Computed tomography showed SAH with ventricular reflux predominantly in the posterior fossa. Angiography revealed a fusiform aneurysm of the right PICA originating extracranially from the right vertebral artery. The aneurysm was isolated and excised. Histological examination showed dissection of the aneurysm wall. Dissecting aneurysm arising from the extracranial portion of the PICA is extremely rare.

Conjunctival vasculature patterns influencing the filtering bleb shape following trabeculectomy with limbal-based conjunctival flaps.

PURPOSE: To investigate the correlation between conjunctival vasculature factors and two types of functional bleb shape, cystic and diffuse, formed after trabeculectomy with limbal-based conjunctival flaps. METHODS: Eighty-five eyes of glaucoma patients were consecutively enrolled. After 6 months, functioning blebs were classified as either cystic or diffuse. For each bleb type, the presence of neovascularized vessels in the dissected area (NVc) or the nondissected area (NVi), an avascular area (AVA), or a posterior tarsal artery (PTA) feeding the conjunctiva was analyzed. RESULTS: In 62 eyes with functioning blebs, there were 54 cystic and eight diffuse blebs. AVA was present in 96.3% of the cystic and 25.0% of the diffuse blebs. NVc was present in 100% of the cystic and 62.5% of the diffuse blebs, and NVi in 96.3% of the cystic and 12.5% of the diffuse blebs. A PTA was present in 87.5% of the diffuse blebs, but in only 3.7% of the cystic blebs. AVA, NVi, and NVc were significantly more frequent in cystic blebs, whereas a PTA was more frequent in diffuse blebs. The presence of a PTA in the blebs was negatively related to the presence of AVA, NVc, or NVi. CONCLUSIONS: Avoidance of damage to the PTA during conjunctival dissection might facilitate the formation of a diffuse filtration bleb. The conjunctival vasculature should be considered to avoid cystic avascular bleb formation in trabeculectomy with limbal-based flaps.

Feasibility and safety of granulocyte colony-stimulating factor treatment in patients with acute myocardial infarction.

BACKGROUND: This study examined feasibility and safety of granulocyte colony-stimulating factor (G-CSF) treatment for patients with acute myocardial infarction (AMI). METHODS: Forty patients with AMI related with the left anterior descending coronary artery, who underwent successful percutaneous coronary intervention (PCI), were randomized into G-CSF group (n=18) or Control group (n=22). G-CSF treatment was started within 24 h after PCI. 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) was performed at 4 days and 6 months after AMI. SPECT data was analyzed for LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF) and myocardial perfusion. RESULTS: LVEF at 6 months was significantly better than that at 4 days in G-CSF group (p=0.013), but not changed in Control group (p=0.245). Although no significant difference was observed for LVEDV between the two groups, LVESV tended to be decreased only in G-CSF group. In G-CSF group, defect score (DS) was significantly decreased from 4 days to 6 months after AMI. Restenosis rate at 6 months after AMI was not significantly different between the two groups. CONCLUSIONS: G-CSF treatment for patients with AMI was effective and did not have any clinical and angiographic adverse effects.

[Usefulness of stress MPI for assessment of PCI indication--comparison with FFRmyo evaluation using pressure sensor wire].

PURPOSE: To examine the usefulness of percutaneous coronary intervention (PCI) indication assessment using stress myocardial perfusion imaging (St-MPI). BACKGROUND: The usefulness of myocardial fractional flow reserve (FFRmyo) using a pressure sensor wire for the assessment of PCI indication has been reported in recent years. However, we have frequently experienced discrepancies between results from FFRmyo and St-MPI. SUBJECTS AND METHODS: Forty-two patients with single-vessel disease with 75-90% (AHA classification) stenosis and chronic ischemic heart disease were enrolled in this study. We measured FFRmyo during coronary angiography (CAG), and determined that it was less than 0.75 in all cases. We separated the cases into groups based on the results of the St-MPI, which was carried out just prior to the CAG: 18 patients showing positive stress test (group P); and 24 patients showing negative stress test (group N). We selected PCI only for the group P. We tracked both groups for 4.4 +/-0.6 years and investigated the existence or non-existence of cardiac events therein. We carried out another St-MPI one year later on the group of cases without cardiac events. RESULTS: Although a fatal cardiac infarction occurred in 1 case in the group P, there were no occurrences of major cardiac events (cardiac death or fatal cardiac infarctions) in the group N. Minor cardiac events (new PCI, target lesion re-vascularization: TLR, coronary artery bypass surgery and heart failure) were detected in 8 cases (44%) in the group P and 3 cases (13%) in the group N, thus being a significantly high percentage in the group P (p<0.05). In group P patients without having restenosis at 1 year after PCI, VO2 was significantly improved as compared to that before PCI. However, no significant difference in VO2 before and after followup was observed in group N. CONCLUSION: Because the prognosis of patients with single-vessel stable ischemic heart disease is good, it can be inferred that the principal cardiac events therein are minor cardiac events. When we define minor cardiac event as endpoint, St-MPI can be a more beneficial test for the assessment of PCI indication than FFRmyo.

Ischemic preconditioning and morphine attenuate myocardial apoptosis and infarction after ischemia-reperfusion in rabbits: role of delta-opioid receptor.

We examined whether ischemic preconditioning (IPC) attenuates ischemia-reperfusion injury, in part, by decreasing apoptosis and whether the delta-opioid receptor (DOR) plays a pivotal role in the regulation of apoptosis. Rabbits were subjected to 30-min coronary artery occlusion (CAO) and 180 min of reperfusion. IPC was elicited with four cycles of 5-min ischemia and 10-min reperfusion before CAO. Morphine (0.3 mg/kg iv) was given 15 min before CAO. Naloxone (Nal; 10 mg/kg iv) and naltrindole (Nti; 10 mg/kg iv), the respective nonselective and selective DOR antagonists were given 10 min before either morphine or IPC. Infarct size (%risk area) was reduced from 46 +/- 3.8 in control to 11.6 +/- 1.0 in IPC and 19.5 +/- 3.8 in the morphine group (means +/- SE; P < 0.001 vs. control). Nal blocked the protective effects of IPC and morphine, as shown by the increase in infarct size to 38.6 +/- 7.2 and 44.5 +/- 1.8, respectively. Similarly, Nti blocked IPC and morphine-induced protection. The percentage of apoptotic cells (revealed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay) decreased in IPC (3.6 +/- 1.9) and morphine groups (5.2 +/- 1.2) compared with control group (12.4 +/- 1.6; P < 0.001). Nti pretreatment increased apoptotic cells 11.2 +/- 2.2% in IPC and 12.1 +/- 0.8% in morphine groups. Nal failed to block inhibition of apoptosis in the IPC group (% of cells: 5.7 +/- 1.3 vs. 3.6 +/- 1.9 in IPC alone; P > 0.05). These results were also confirmed by nucleosomal DNA laddering pattern. We conclude that IPC reduces lethal injury, in part, by decreasing apoptosis after ischemia-reperfusion and activation of the DOR may play a crucial role in IPC or morphine-induced myocardial protection.

Imbalance of sex hormone levels in men with coronary artery disease.

OBJECTIVE: Sex hormones are thought to play a key role in atherogenesis, but the available evidence is inconclusive, partly because of a lack of accuracy in measurement. The aim of the study was to investigate the potential role of sex hormones in coronary atherosclerosis. METHODS: We prospectively applied a simple highly-sensitive method using solid-phase extraction followed by radioimmunoassay. Both phases were carried out using commercially available kits to determine levels of estradiol (E2). We also measured the levels of free testosterone (FT), dehydroepiandrosterone sulfate, luteinizing hormone, follicle-stimulating hormone, and progesterone in 236 consecutive male patients with angiographically-defined stable coronary artery disease and in 143 disease-free and age-matched controls. RESULTS: The levels of highly-sensitive E2 and FT in patients and controls differed slightly in opposing directions, but neither difference reached statistical significance. However, the ratio of FT to highly-sensitive E2 in patients was significantly higher than in the controls (mean +/- SD; 2.50 +/- 1.89 versus 2.06 +/- 1.14, P = 0.018), and this difference remained significant after adjustments for age and body mass index had been made. Multiple regression analysis revealed that age, the association of diabetes, and the presence of coronary atherosclerosis were significantly and independently associated with the values of the FT/highly-sensitive E2 ratio. Other hormones examined did not differ significantly between the patients and the controls. CONCLUSIONS: Highly-sensitive E2 measurement demonstrated a significant imbalance of FT to E2 in male patients with coronary artery disease, but individual sex hormone levels did not differ between the patients and the controls.

Pretreatment with tyrosine kinase inhibitor attenuates the reduction of apoptosis 24 h after ischemic preconditioning.

We investigated whether ischemic preconditioning (PC) attenuates ischemia/reperfusion-induced injury in part by decreasing apoptosis and whether tyrosine kinase (TK) can regulate the signaling pathway leading to apoptosis in delayed cardioprotection. Six groups of rabbits were studied in the early phase (EP) and in the delayed phase (DP): (1) sham-operated control animals were received vehicle only (Veh-sham); (2) rabbits that received I.V. genistein (a nonspecific TK inhibitor) 10 min before ischemia (Gen-sham); (3) rabbits that received I.V. daidzein (an inactive structural analog of genistein) 10 min before ischemia (Dzn-sham); (4) rabbits preconditioned with 4 cycles of 5-min occlusion of left anterior descending coronary artery (LAD) and 10-min reperfusion (PC); (5) rabbits that received I.V. genistein, 10 min before PC (Gen-PC); (6) rabbits that received I.V. daidzein 10 min before PC (Dzn-PC). All rabbits underwent 30-min ischemia followed by 180-min reperfusion. Infarct size in the PC, Gen-PC, and Dzn-PC groups in the EP was significantly (p < 0.0001) reduced relative to controls Gen and Dzn. Delayed cardioprotection was blocked significantly (p < 0.0001) by genistein. In the EP, apoptosis was significantly (p < 0.0001) decreased in PC, Gen-PC, and Dzn-PC groups relative to controls Gen and Dzn. In the DP, a reduction of apoptosis was not seen in the Gen-PC group. This study suggests that PC reduces ischemic injury in part by decreasing apoptosis after ischemia/reperfusion and also that TK phosphorylation is involved in the signal transduction cascade leading to the decline of apoptosis in the DP.

Transient glucose deprivation causes upregulation of heme oxygenase-1 and cyclooxygenase-2 expression in cardiac fibroblasts.

Transient glucose deprivation (TGD) has been shown to induce a resistance to a subsequent ischemia and reperfusion injury in the heart. Induction of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) is known to mediate the powerful defensive adaptation of the heart against oxidative stress. In this study, we found that a 30-min incubation in the absence of glucose resulted in a rapid increased expression of COX-2 and HO-1 in cardiac fibroblasts as examined by real-time quantitative polymerase chain reaction (PCR) and western blot analysis. Interestingly, TGD increased the generation of reactive oxygen species (ROS) and caused the transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as the translocation of protein kinase C (PKC)- from the cytosolic to the membrane fraction. However, no significant change in the distribution of PKC-delta isoform was observed compared with the control. Pretreatment of the cells with an antioxidant, N-acetylcysteine (NAC), resulted in the inhibition of p38 MAPK phosphorylation and PKC- translocation during TGD. In addition, the induction of COX-2 and HO-1 expression by TGD was prevented by pretreatment with NAC or SB203580, a p38 MAPK inhibitor. Surprisingly, pretreatment with chelerythrine, an inhibitor of PKC, strongly augmented the HO-1 mRNA expression but blocked the COX-2 mRNA induction by TGD. These results demonstrate that briefly removing glucose from cultured cardiac fibroblasts induces COX-2 and HO-1 expression via generation of ROS and p38 MAPK phosphorylation, while the translocation of PKC- to the membrane fraction may participate in the induction of COX-2 but not in the HO-1 expression.

Differential activation of protein kinase C between ischemic and pharmacological preconditioning in the rabbit heart.

The objective of the present study was to investigate the differential activation of protein kinase C between ischemic (IPC) and pharmacological preconditioning (PPC) in the rabbit heart. Control, IPC, diazoxide (Diaz), and chelerythrine (Chel)+IPC groups underwent prolonged coronary artery occlusion (CAO) for 30 minutes followed by 180 minutes' reperfusion (protocol I). In protocol II, sham, IPC-only, Diaz-only, and Chel+IPC-only groups did not undergo prolonged CAO. IPC was induced with 4 cycles of 5-min regional ischemia and 10-min reperfusion before prolonged CAO. Diaz (5 mg/kg) was administered 30 min before prolonged CAO. Chel (5 mg/kg) was administered 5 min before the IPC procedure. Infarct size was determined by tetrazolium staining. Assessment of protein kinase C (PKC) isoforms from a left ventricular (LV) sample was conducted by western blotting. Apoptosis in situ was determined by TUNEL assay. The infarction area in the IPC (11.6 +/- 1.0%) and Diaz (19.5 +/- 3.8%) groups was reduced significantly (p< 0.01, p< 0.05) relative to the control group (40.0 +/- 3.8%). The reduction by IPC was abolished by pretreatment with Chel. Apoptosis was significantly decreased (p< 0.01) in the IPC and diazoxide groups compared with the control and Chel+IPC groups (control: 4.78 +/- 0.56% vs. IPC: 2.00 +/- 0.38% vs. Diaz: 2.20 +/- 0.32% vs. Chel+IPC: 4.32 +/- 0.41%) and DNA laddering was attenuated in the IPC and Diaz groups. Membrane PKC-epsilon levels in the IPC and Diaz groups increased significantly relative to the control and Chel+IPC groups. Membrane PKC-epsilon levels in the IPC-only group showed greater increases than the Diaz-only and Chel+IPC-only groups. These findings suggest that whereas PPC suppresses apoptosis when diazoxide opens mitochondrial K(ATP) channels and then activates PKC-epsilon through ischemia-reperfusion, IPC activates PKC-epsilon in the particulate fraction prior to continuous ischemia-reperfusion. We concluded that the difference between IPC and PPC appears to consist in the difference in the timing of PKC-epsilon activation, though both IPC and PPC provide the cardioprotection in ischemia-reperfusion injury.

Effect of pretreatment vitamin D levels on in vivo effects of atorvastatin on bone metabolism in patients with heterozygous familial hypercholesterolemia.

To find the clinical variables associated with atorvastatin's effects on bone metabolism markers, 35 patients with heterozygous familial hypercholesterolemia were treated with atorvastatin for 24 weeks, and the levels of bone formation markers (bone-specific alkaline phosphatase and osteocalcin) and resorption marker (urine collagen type-1 cross-linked N-telopeptide) were determined. Pretreatment vitamin D levels showed significant and positive associations with changes in 2 bone formation markers. The serial changes in 3 markers were favorable-increased bone formation markers and unchanged bone resorption marker-but the changes occurred only in patients with pretreatment vitamin D levels >50 pg/ml.