Japanese Circulation Society
Scientific Sessions Activities Publications
index
Congress Report
the 71st Scientific Session
Symposia
Symposium 10

Diabetic Cardiovascular Complications and Therapeutic Strategy

Vessel Oxidative Stress as a Therapeutic Target in Diabetes
Keith M. Channon
Department of Cardiovascular Medicine, University of Oxford John Radcliffe Hospital, UK

Detrimental Effect of Postprandial Hyperglycemia on Long-Term Prognosis in Patients with Acute Myocardial Infarction but no Previous Diabetes
Koichi Tamita
Department of Cardiology, Kobe General Hospital Takagi Cardiovascular Clinic, Kobe, Japan

Role of Mitochondrial ROS Production Associated with Glucose Metabolism in Development of Diabetic Cardiomyopathy
Hidetoshi Yonemochi
Department of Cardiovascular Science, Oita University School of Medicine, Oita, Japan

 

Vessel Oxidative Stress as a Therapeutic Target in Diabetes

Keith M. Channon

Department of Cardiovascular Medicine, University of Oxford John Radcliffe Hospital, UK


Loss of normal nitric oxide (NO)-mediated endothelial function is a cardinal feature of early diabetes. In this keynote lecture, Dr. Keith M. Channon, University of Oxford John Radcliffe Hospital, discussed the mechanisms of NO loss in diabetes and potential therapeutic targets.

NO is produced from endothelial nitric oxide synthase (eNOS), but eNOS expression is maintained in early diabetes and vascular disease. However, NO loss is associated with a marked increase in the production of reactive oxygen species (ROS), notably superoxide. In patients with diabetes the decrease in NO-mediated vasorelaxation is paralleled by an increase in vascular superoxide production. The NADPH oxidases and eNOS are important sources of vascular superoxide in diabetic patients. A deficiency of cofactor tetrahydrobiopteran (BH4) can result in uncoupling of eNOS. In the absence of BH4, the stability of eNOS is impaired, resulting in reduction of oxygen, which leads directly to superoxide production. 

Dr. Channon’s group generated transgenic mice with increased GTP cyclohydrolase (GTPCH) mRNA expression (GCH-Tg mice). Endothelial BH4 levels were two- to four-fold higher in organs rich in vascular endothelium in the GCH-Tg mice than in wild-type (WT) mice. GCH-Tg and WT mice were injected with streptozotocin (STZ) to induce diabetes or a citrate buffer control. After four weeks, aortas were harvested and evaluated for superoxide production, biopteran chemistry, and endothelial function.

Figure 1. Endothelial superoxide was increased 17-fold in diabetic WT endothelium compared to WT control.
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Figure 2. Detectable BH4 levels were maintained in diabetic GCH-Tg mice.
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Figure 3. Endothelial function in the diabetic GCH-Tg mice was nearly identical to that in the non-diabetic mice.
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Endothelial superoxide was increased 17-fold in diabetic WT endothelium compared to WT control (Figure 1). In contrast, superoxide was increased only three-fold in diabetic GCH-Tg endothelium compared to the GCH-Tg control. In WT diabetic aorta, total biopteran levels remained constant but BH4 was almost completely oxidized. In diabetic GCH-Tg mice, detectable BH4 levels were maintained despite considerable oxidative loss because of increased BH4 synthesis (Figure 2).

Endothelial function was the same in the non-diabetic WT and GCH-Tg mice but impaired in the diabetic WT mice. In contrast, endothelial function in the diabetic GCH-Tg mice was almost identical to that in the non-diabetic mice (Figure 3). These results indicate that increased endothelial BH4 in the diabetic GCH-Tg mice prevented endothelial dysfunction.

In humans with coronary disease, patients with the highest vascular BH4 levels have the lowest superoxide production and the best endothelial function.

The results of these studies suggest that maintaining BH4 levels can reduce  superoxide production and improve endothelial function in patients with diabetes. The ongoing OXBIO study is investigating the effects of oral BH4 supplementation on endothelial function in coronary artery disease patients with and without diabetes.

 

 


Detrimental Effect of Postprandial Hyperglycemia on Long-Term Prognosis in Patients with Acute Myocardial Infarction but no Previous Diabetes  

Koichi Tamita

Department of Cardiology, Kobe General Hospital Takagi Cardiovascular Clinic, Kobe, Japan


Patients with diabetes have an approximately two-fold higher risk of short-term mortality after acute myocardial infarction (AMI).  Recent studies have demonstrated that newly diagnosed postprandial hyperglycemia is common in patients with AMI. The purpose of this prospective study, presented by Dr. Koichi Tamita, Kobe General Hospital, was to determine the influence of this previously unrecognized postprandial hyperglycemia on long-term outcomes after AMI.

A total of 275 consecutive patients admitted to the hospital with AMI were enrolled. The patients were divided into three groups based on their medical history and fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT) at discharge. A total of 85 patients (31%) had previously diagnosed diabetes (DM), 112 (41%) had newly diagnosed postprandial hyperglycemia (PPHG+), and 78 patients (28%) did not have postprandial hyperglycemia (PPHG–).

The primary endpoint was time to measurable adverse cardiac event (MACE), which included cardiac mortality, non-fatal MI/acute coronary syndrome (ACS), stroke, or cardiac intervention due to non-target vessel revascularization (TVR). The composite secondary endpoints included all-cause mortality, non-fatal MI/ACS, stroke, cardiac intervention due to TVR or non-TVR, congestive heart failure episode, or hospitalization for peripheral vascular disease.

Figure 1. Patients without PPHG had the highest cardiac event-free rate while those with PPGH and previous DM had similar rates, after 7 years follow-up.
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Figure 2. The percentage of patients free of composite secondary endpoints was highest in the PPHG– group and similar in the PPHG+ and DM groups.
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Figure 3. The strongest predictors for future cardiovascular events were diagnosis of PPHG, previous DM, and previous CABG surgery.
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At discharge, patients with PPHG had higher two-hour plasma glucose (P<0.0001) and higher triglycerides (P=0.003) than patients without PPHG. During the hospital stay and at discharge, treatment for cardiovascular disease (CVD) among all three groups was similar, except that more patients with PPHG received lipid lowering agents than patients without PPHG or DM patients.

After seven years follow-up, patients without PPHG had the highest cardiac event-free rate while those with PPGH and previous DM had similar rates (P=0.002) (Figure 1). Similarly, the percentage of patients free of composite secondary endpoints was highest in the PPHG– group and similar in the PPHG+ and DM groups (P=0.0001) (Figure 2). Multivariate analysis showed that the strongest predictors for future cardiovascular events were diagnosis of PPHG (hazard ratio to PPGH– 2.65, P=0.004), previous DM (hazard ratio to PPGH– 3.27, P=0.0005), and previous CABG surgery (hazard ratio 3.86, P=0.0018) (Figure 3).

The cardiovascular event-free 5-year survival rate was 70% in the newly diagnosed PPHG group compared to 70% in the non-PPHG group (P<0.01) and equivalent to the previous DM group (60%, P=0.09).

Dr. Tamita concluded that newly diagnosed PPHG is a major risk factor for future cardiovascular events in patients with AMI. The prognostic potential of newly diagnosed PPHG is equivalent to that of pre-diagnosed DM in patients with AMI.

 

 


Role of Mitochondrial ROS Production Associated with Glucose Metabolism in Development of Diabetic Cardiomyopathy  

Hidetoshi Yonemochi

Department of Cardiovascular Science, Oita University School of Medicine, Oita, Japan


Hyperglycemia is a major contributing factor to development of cardiomyopathy in patients with diabetes. However, the mechanisms of this  effect are unclear. Dr. Hidetoshi Yonemochi, Oita University School of Medicine, reported on a study that tested the hypothesis that hyperglycemia induced production of reactive oxygen species (ROS) in mitochondria regulates myocardial survival during oxidative stress.

Neonatal rat cardiomyocytes were incubated with normal or high levels of glucose. The rate of cardiomyocyte apoptosis, mitochondrial inner membrane potential, and production of ROS were assessed by flow cytometry.

High glucose exposure exerted an initial anti-apoptotic effect at 72 hours, followed by a late pro-apoptotic effect at 96 hours. Mild ROS production preceded or paralleled the anti-apoptotic effect, while the pro-apoptotic effect was preceded by massive ROS production. Co-treatment with ROS scavengers up to 60 or 72 hours normalized the early mild ROS production and eliminated the early anti-apoptotic effect of high glucose. Co-treatment with ROS scavengers for 96 hours attenuated the late increased rate of apoptosis.

Treatment with the metabolic inhibitors, 4-OHCA and TTFA, restored ROS production, mitochondrial membrane potential, and the rate of apoptosis to control levels. This demonstrated that the high glucose-induced ROS production was associated with increased metabolic influx in the mitochondria. Increased, normal, and decreased glucose conditions were simulated by adding 4-OHCA at various concentrations. With increased glucose influx, ROS production was mild and the rate of apoptosis decreased. Decreased glucose influx resulted in massive ROS production and significantly increased apoptosis.

Prolonged exposure to high glucose reduced myocardial glutathione (GSH) in a time-dependent manner. Depletion of GSH was prevented by co-treatment with ROS scavengers.

The cardiomyocytes were exposed to hydrogen peroxide to determine the effect of external oxidative stress.  After 72 hours the rate of apoptosis increased significantly in the high glucose group in a glucose dose-dependent manner. The increased response to hydrogen peroxide was inhibited by treatment with ROS scavengers or 4-OHCA. Hydrogen peroxide exposure rapidly decreased intracellular GSH content in both the normal and high glucose groups, with a greater decrease in the high glucose group. ROS scavenger pretreatment normalized GSH levels in the high glucose group. These results suggest that cardiomyocytes adapt to hyperglycemia at the expense of decreased antioxidant reserves; thus, they are more prone to apoptosis from oxidative stress.

Dr. Yonemochi concluded that hyperglycemia regulates myocardial survival and susceptibility to oxidative stress through ROS production in mitochondrial electron transfer chains. This may explain the high incidence of heart failure and poor prognosis in patients with diabetes.

 

 

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