Imatinib mesilate inhibits neointimal hyperplasia via growth inhibition of vascular smooth muscle cells in a rat model of balloon injury.

Restenosis is a major problem in percutaneous catheter intervention (PCI) for coronary artery stenosis in patients with acute myocardial infarction. Coronary restenosis arises from intimal hyperplasia, i.e., hyperplasia of the vascular smooth muscle cells (SMCs) caused by endothelial cell (EC) damage due to PCI. Drug eluting stent (DES), a novel stent coated with a cell-growth inhibitor, such as rapamycin, has been utilized to block SMC proliferation, but DES also blocks EC repair and thus requires the administration of anti-platelets for a long time to prevent thrombus formation after PCI. Moreover, insufficient prevention of platelet aggregation sometimes induces restenosis after PCI. One of the signal transduction inhibitors, imatinib mesilate, blocks tyrosine kinase activity of platelet-derived growth factor receptor (PDGFR), and therefore it may block the development of neointima through growth inhibition of SMCs without the obstructive effect on EC-repair. We therefore studied the effects of imatinib on neointimal hyperplasia in a balloon injury model of rat carotid arteries. Rats were orally administered with imatinib for 14 days after balloon injury, and sacrificed to analyze the neointimal formation. Intimal hyperplasia was inhibited by imatinib in a dose-dependent manner. Therefore imatinib presumably obstructed the growth of SMCs via interception on growth-signaling of PDGFR. The administration of imatinib after coronary stenting or the use of an imatinib-eluting stent may further reduce the risk of restenosis in patients.

ST-segment abnormalities and premature complexes are predictors of new-onset atrial fibrillation: the Niigata preventive medicine study.

BACKGROUND: Left ventricular hypertrophy is a known risk factor for atrial fibrillation (AF). However, it is not well understood whether other electrocardiogram abnormalities are associated with development of AF. METHODS: This was a community-based cohort study based upon a database of annual health examinations. We included 63,386 subjects aged > or = 50 years, without baseline AF (including atrial flutter), structural heart disease, or heart failure, who completed the annual examination during a 10-year follow-up period (1991-2002). The electrocardiographic risk factors for AF were studied in the subjects. RESULTS: Atrial fibrillation developed in 873 subjects. Age, male sex, body mass index, hypertension, systolic and diastolic blood pressure, and diabetes were significant risk factors for the development of AF. In multivariable logistic regression analysis adjusted for these risk factors, electrocardiographic left ventricular hypertrophy (odds ratio [OR], 1.43), ST-segment abnormality without left ventricular hypertrophy (OR, 1.89), and the presence of premature complexes during a 10-second recording (OR, 2.89) were significantly associated with AF, whereas either right (OR, 0.84) or left bundle branch block (OR, 0.96) was unrelated. The risk for AF increased progressively with the severity of both ST-segment change and premature complexes. CONCLUSIONS: ST-segment abnormality and comparably high-frequency premature complexes were each associated with increased risk for the development of AF. These electrocardiographic findings may be useful to stratify high-risk subjects for new-onset AF.

Erythroid cells play essential roles in angiogenesis by bone marrow cell implantation.

Bone marrow cell implantation (BMI) has been utilized to treat patients with limb and heart ischemia. BMI provides angiogenic precursors and angiogenic cytokine-producing cells, especially erythroid cells. In this study, we induced in vitro angiogenesis cultures and in vivo BMI simulation using a murine limb ischemia model to examine the role of erythroid cells and the effect of erythropoietin (EPO). Human erythroid colonies (BFU-e) induced capillary networks around the colonies in vitro. Erythroid cells in human bone marrow produced vascular endothelial growth factor and placental growth factor. The angiogenic effects of erythroid cells were further amplified in the presence of EPO. Limb-ischemic mice were treated with BMI +/- EPO, and limb survival, blood flow recovery, and muscle histology were analyzed. Treatment with whole bone marrow cells + EPO significantly improved limb survival and blood flow. The cumulative effects of EPO on BMI induced and increase in capillary number and artery enlargement. Erythroid cells were essential for the in vivo effects of BMI, and CD14-positive cells supported the biological effects. In addition to the direct effect of EPO on angiogenesis, EPO showed indirect effect on angiogenesis through amplifying the angiogenic effects by erythroid cells supported by CD14-positive cells.

Marked decrease of plasma VEGF after implantation of autologous bone marrow mononuclear cells in a patient with critical limb ischemia--a case report.

The authors performed autologous bone marrow mononuclear cells implantation (BMI) in a 79-year-old man with critical limb ischemia. After BMI, the resting pain of the ischemic leg improved gradually. They measured the plasma concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and serum hepatocyte growth factor (HGF) in the blood from bilateral femoral veins. Before BMI, the plasma VEGF and bFGF concentrations were much greater in the ischemic leg than in the other lower limb, but decreased to the same concentrations as those in the contralateral lower extremity after BMI. The large concentrations of the angiogenic factors VEGF and bFGF in plasma indicate the severity and extent of the leg ischemia. BMI resulted in lower levels of VEGF and bFGF, and this fall is the hallmark of the effectiveness of BMI in the treatment of peripheral artery disease.

Cardiovascular risk factors are really linked in the metabolic syndrome: this phenomenon suggests clustering rather than coincidence.

BACKGROUND: The accumulation of cardiovascular risk factors can be seen in a single person but it needs to be determined if this occurs more frequently than might be explained by mere coincidence. METHODS: This study involved 119,412 adults: 41,819 males and 77,593 females, who were 40 years of age or older and who underwent an annual health examination. From the clinical and biochemical data, the actual prevalence of a combination of 3 or more factors: abnormal body mass index (> or =25.0), hypertension, high triglyceride (> or =150 mg/dl), low HDL cholesterol (<40 mg/dl) and abnormal fasting glucose metabolism (fasting blood sugar > or =110 mg/dl or HbA1c. > or =5.5%) was determined. Then, the prevalence of a corresponding combination of 3-5 factors was predicted from the prevalence of each factor on the assumption that their combination occurs as a result of coincidence. RESULTS: The criteria of metabolic syndrome (> or =3 risk factors) was met in 17,842 (14.9%) of the examinees. The actual prevalence of any combination of 3-5 factors of metabolic syndrome was more frequent than those expected to occur by coincidence (P < 0.001). When compared with the prevalence of the total examinees, the prevalence of obesity and insulin resistance was 2.5 and 2.9 times higher in metabolic syndrome compared to that in the total examinees but it was 1.7 to 2.1 times higher in hypertension and high triglyceride. The former two were clustering more than hypertension or high triglyceride in metabolic syndrome. Abnormal levels of serum creatinine and total cholesterol were found more often in metabolic syndrome. CONCLUSION: Combinations of risk factors of metabolic syndrome were found more frequently than coincidental phenomenon in the subjects from the general population. These finding suggest that these risk factors do cluster and obesity and insulin resistance were suggested to be linked with metabolic syndrome more than hypertension or high triglyceride.

Guidewire-induced coronary artery perforation treated with transcatheter delivery of subcutaneous tissue.

In three cases of small coronary artery perforation by guidewires during percutaneous coronary intervention, coronary leakage continued despite prolonged balloon inflation and reversal of heparin. Subcutaneous tissue was selectively delivered to perforated vessels by means of microcatheters in a successful attempt to stop leakage. This method appears to be extremely effective for treating guidewire-induced perforations of distal coronary arteries.

Relationship between serum lipoprotein(a) concentrations and coronary vasomotion in coronary spastic angina.

BACKGROUND: Elevated lipoprotein(a) (Lp(a)) concentrations are reported to impair endothelium-dependent vasodilatation of the epicardial coronary artery. However, the effects on vasomotor abnormalities in coronary spastic angina (CSA) have not been thoroughly investigated. METHODS AND RESULTS: In the present study 80 sites of spasm (spastic sites) without significant organic stenosis (% diameter stenosis <50%) were assessed in 80 patients with CSA diagnosed by intracoronary ergonovine (EM) test. Spastic sites were divided into 2 groups: Group 1 included 30 sites provoked by the full dose (=50 microg) of EM, and Group 2 included 50 sites provoked with less than 50 microg (34.7+/-8.2 microg). Control subjects (n=22) did not show coronary spasm with the EM test. Serum Lp(a) concentrations were measured in all patients. Group 2 had a significantly greater basal coronary artery tone in the spastic sites than Group 1 (p<0.001). Lp(a) level in Group 2 was significantly higher compared with both the control group and Group 1 (p<0.05 by analysis of variance). Multivariate analysis confirmed that only serum Lp(a) concentration was associated with low-dose EM spasm provocation. CONCLUSIONS: Serum Lp(a) concentration could be a marker for high disease activity in CSA.

Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells.

BACKGROUND: There have been a number of recent reports on the use of autologous bone marrow implantation (BMI) in the treatment of peripheral arterial disease, with a clinical response rate of approximately 70%. However, the factors that influence efficacy have not yet been clarified. We have analyzed the relationship between the number of implanted bone marrow cells and the clinical efficacy of BMI. METHODS AND RESULTS: Eight patients with arteriosclerosis obliterans were treated with BMI. Bone marrow was aspirated from the ilium (500-1,000 ml), the mononuclear cells were separated and then were implanted. The clinical effectiveness of BMI was evaluated by assessing changes in the ankle-brachial pressure index (ABI) and the transcutaneous oxygen pressure (TcO2) between the pre-treatment baseline, with follow-up testing at 4 weeks. These changes were defined as DeltaABI and DeltaTcO2. The mean number of CD34-positive cells was 1.04+/-0.60 x10(6) /kg body weight. There was a strong correlation between the number of CD34-positive cells and DeltaABI (r=0.754, p=0.028). CONCLUSIONS: It is likely that the number of implanted CD34-positive cells is one of the primary factors that influence the clinical efficacy of BMI.