Dapagliflozin Influences Ventricular Hemodynamics and Exercise-Induced Pulmonary Hypertension in Type 2 Diabetes Patients　- A Randomized Controlled Trial.

BACKGROUND: This prospective randomized multicenter open-label trial evaluated whether sodium-glucose cotransporter-2 inhibitor (SGLT2-i) improves left ventricular (LV) pump function and suppresses elevation of LV filling pressure (LVFP) and right ventricular systolic pressure (RVSP) during exercise in type 2 diabetes mellitus (T2DM) patients.Methods and Results:Based on HbA1c and LV ejection fraction, 78 patients with poorly controlled T2DM were randomly assigned to D-group (dapagliflozin 5 mg/day add-on) or C-group (conventional therapy add-on). Physical examination, home and office blood pressure examination, blood tests, and echocardiography at rest and during ergometer exercise were performed at baseline and at 1.5 and 6 months after treatment. The primary endpoint was defined as the change in RVSP (mmHg) between baseline and 6-month follow up. The secondary endpoints were changes in LVFP (ratio), stroke volume index (SVi; mL/m2), and cardiac index (CI; L/min/m2). Both RVSP and LVFP during exercise significantly decreased from baseline to 6 months after starting treatment in the D-group (P<0.001). No changes to either parameter was observed in the C-group. The SVi and CI did not improve in either group. Both home and office blood pressure significantly decreased in the D-group. Decreases in HbA1c were somewhat greater in the C-group. CONCLUSIONS: Dapagliflozin significantly improved RVSP and LVFP during exercise in patients with T2DM and cardiovascular risk, which may contribute to favorable effects on heart failure.

Cell cycle regulator expression after coronary stenting in humans.

Proliferation of vascular smooth muscle cells (VSMCs) is under the control of cell cycle regulator activity, which is induced by several growth factors. Recent attention has been drawn to treatments that target cell cycle regulators to prevent the proliferation of VSMCs after coronary angioplasty. However, histopathological evaluation of cell cycle regulator expression after human coronary stenting has not been sufficient. Thirty-one coronary arteries of 23 cadavers were examined. Time from stent implantation to patient death ranged from 0 to 235 days. Sections were stained with antibodies against platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), cyclin D1, p16, p21, and p27. Staining for macrophage colony stimulating factor receptor (MCSF-R) was conducted to detect dedifferentiated VSMCs. MCSF-R-positive cells were observed in neointima but decreased in the late stage. PDGF was detected in neointima and decreased gradually. Expression of cyclin D1 appeared to be associated with the proliferation of VSMCs, whereas p27 was downregulated with the proliferation of neointima and upregulated in the late stage. Our results suggest that one of the most promising methods for preventing excessive proliferation of neointima after stenting is to limit the decrease in p27 or the increase in cyclin D1.

[Contribution of monocyte chemoattractant protein-1 and c-fms/macrophage colony-stimulating factor receptor to coronary artery disease: analysis of human coronary atherectomy specimens].

OBJECTIVES: Primary coronary atherosclerotic lesions(de novo lesions) are a type of inflammatory vascular disease. Restenotic lesions after percutaneous coronary intervention mainly consist of proliferative vascular smooth muscle cells. Recent studies have demonstrated that locally synthesized cytokines, including chemokines, are important in both these coronary lesions. Monocyte chemoattractant protein(MCP)-1 and macrophage colony-stimulating factor(M-CSF) are two of the associated chemokines, but their role in coronary artery disease has not been sufficiently clarified. This study investigated the expression of MCP-1 and c-fms/M-CSF receptor in human coronary tissues. METHODS: Histological and immunohistochemical studies used samples obtained from patients who underwent directional coronary atherectomy(28 de novo lesions and 16 restenotic lesions). The following primary antibodies were used: anti-MCP-1, anti-c-fms, anti-macrophages and anti-alpha-smooth muscle actin. RESULTS: Focal accumulation of macrophage-derived foam cells, thrombus, cholesterol clefts and calcification tended to be more frequent in de novo lesions than in restenotic lesions. On the other hand, restenotic lesions mainly consisted of stellate vascular smooth muscle cells and extracellular matrix. The expression of MCP-1-positive cells almost coincided with the macrophages. In contrast, staining for MCP-1 was little seen in the stellate vascular smooth muscle cells. Expression of c-fms was found in both macrophages and stellate vascular smooth muscle cells. Expression patterns of MCP-1 and c-fms exhibited no difference between the two lesion types. CONCLUSIONS: Both MCP-1 and the M-CSF/c-fms system are involved in the atherogenesis of de novo lesions. However, the M-CSF/c-fms system, rather than MCP-1, is more important in the late stage of restenosis.

Hepatocyte growth factor and vascular endothelial growth factor in ischaemic heart disease.

BACKGROUND: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors, but the production of these growth factors in cardiomyocytes has also been demonstrated. However, there have been no reports focusing their attention on the changes in these growth factors after coronary intervention. We investigated the time-course changes of the serum VEGF and HGF levels in angina pectoris (AP) and acute myocardial infarction (AMI). METHODS: The serum HGF and VEGF levels were measured in 60 patients with AP, in 62 patients with AMI (AP, before heparin administration, and at 24 and 48 hours, and one week after intervention; AMI, before heparin, and at 48 and 72 hours, and one, two, three and four weeks) and in 56 patients with neurocirculatory asthenia as controls. We defined the patients with remodelling who showed an increase in left ventricular end-diastolic volume index (LVEDVI) in the sub-acute phase of AMI. RESULTS: Hepatocyte growth factor levels in the AP and AMI were significantly higher than that in the control (p<0.0001). The AMI level was also significantly higher than AP (p<0.001). In the AMI and AP, HGF peaked at 48 hours. Vascular endothelial growth factor level in the AMI was significantly higher than that in the control and AP (p<0.0001). In the AMI, VEGF peaked at two weeks. There was a significant positive correlation between the peak VEGF and LVEDVI in the sub-acute phase of AMI (p=0.0089, r=0.436). Peak VEGF in the remodelling (+) group was significantly higher than that in the remodelling (-) group (p<0.001). In the AP, VEGF was unchanged. CONCLUSION: While both myocardial and vascular damage contribute to an increase in HGF level, vascular damage is not associated with the increase in VEGF. Vascular endothelial growth factor might be related to left ventricular remodelling in the sub-acute phase of myocardial infarction.

Significance of small dense low-density lipoproteins and other risk factors in patients with various types of coronary heart disease.

BACKGROUND: It remains unclear how closely the small dense low-density lipoprotein (LDL) (diameter < or =25.5 nm) is associated with various types of coronary heart disease (CHD) in Japanese patients, an ethnic group with lower serum cholesterol levels and less massive obesity compared with Western populations. METHODS AND RESULTS: We measured mean LDL particle diameter by gradient gel electrophoresis in 571 patients with CHD and in 263 healthy subjects who served as control patients. Patients with CHD were classified into acute coronary syndrome (ACS), stable CHD and vasospastic angina. High-density lipoprotein cholesterol and apolipoprotein-A1 and -B were significantly different between patients with CHD and controls. LDL size in patients with CHD was markedly smaller than that in controls in both men and women (25.5 +/- 0.7 vs 25.9 +/- 0.4 and 25.7 +/- 0.7 vs 26.0 +/- 0.5 nm, respectively). LDL cholesterol was significantly higher in patients with ACS than in other groups. Plasma levels of high-density lipoprotein cholesterol decreased as the number of diseased vessels or angiographic coronary severity evaluated by Gensini score increased, but the LDL size was comparable irrespective of the type of CHD and the extent and severity of the lesions. Multiple logistic regression analysis revealed that small dense LDL was independently associated with the incidence of CHD in both sexes (odds ratio [OR] 3.5, 95% CI 2.1-5.7, and OR 2.9, 95% CI 1.5-5.6, P <.005). CONCLUSION: Our study suggests that the small dense LDL is strongly associated with various types of CHD, independent of traditional and nontraditional coronary risk factors, but is not related to the severity and extent of the coronary lesions.

Comparison of the morphological changes of restenosis after the implantation of various types of stents in a swine model.

BACKGROUND: Stent design causes the differences of restenosis rate, but the morphological differences after the various types of stent implantation have not been clarified. DESIGN: Seven types of stents were implanted in pig coronary arteries to clarify how the mechanism of restenosis differs with coil stents and tube stents. METHODS: The left anterior descending coronary arteries (LADs) of pigs were injured using coronary angioplasty balloons (diameter: 3.0 mm; length: 20 mm; balloon/artery ratio: 1 : 2). Fourteen days after the injury, four types of coil stents (Cordis, Wiktor, GR-I, and GR-II) and three types of tube stents (Palmaz-Schatz, gfx, and Multilink) were implanted, and the LADs were extracted 28 days after the implantation. RESULTS: The proliferated neointima was eccentric in the coil stents and concentric in the tube stents. Although there was no significant difference in the area of neointima, the area of the lumen was significantly larger in the tube stents than in the coil stents ( < 0.01) because of the larger area of stent. Cells positive for anti-proliferating cell nuclear antigen antibody were mainly observed around the stent struts, and most of these cells were also positive for either anti-macrophage or anti-smooth muscle actin antibodies. CONCLUSIONS: Compared to the coil stents, the tube stents induce less negative remodelling including stent recoil, resulting in a wider luminal area. In order to prevent restenosis, it is crucial to implant a stent that will cause less negative remodelling.

Clinical characteristics and follow-up in patients with microvascular angina.

Arteriosclerosis of the small arteries is one of the main causes of microvascular angina, and although some reports have shown favorable prognoses, there is progressive reduction in left ventricular function. The present study evaluated the prognosis of microvascular angina in 86 Japanese patients (51 women, 35 men; average age, 59+/-9 years) who had ischemic ST segment depression, normal coronary angiograms and small artery sclerosis confirmed by endomyocardial biopsies. The mean follow-up period was 7.2+/-3.4 years. Questionnaires regarding their symptoms, cardiac medication, and new events were sent to all patients. Eighty-five patients (98.9%) were still alive at the end of the follow-up period. Chest pain remained in 35.3%; the degree of pain was unchanged in 18.8%, and had lessened in 11.8%. None of the patients died of cardiac events or suffered from a myocardial infarction. At the end of the follow-up period, calcium antagonist was used in 63.5% of patients. Seventeen patients (20.0%) were free of antianginal medication. The prognosis of microvascular angina diagnosed by strict criteria was favorable.