Toshiharu Kawamoto

Association of Hypoadiponectinemia With Coronary Artery Disease in Men

Background—Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD). Methods and Results—The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (P <0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquartile cutoff points were 4.0, 5.5, and 7.0 &mgr;g/mL. The multivariate-adjusted odds ratios for CAD in the first, second, and third quartiles were 2.051 (95% confidence interval [CI], 1.288 to 4.951), 1.221 (95% CI, 0.684 to2.186), and 0.749 (95%CI, 0.392 to 1.418), respectively. Conclusions—Male patients with hypoadiponectinemia (<4.0 &mgr;g/mL) had a significant 2-fold increase in CAD prevalence, independent of well-known CAD risk factors.

Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation—double-blind placebo-controlled trial

BACKGROUND It has been clarified that visceral fat accumulation leads to atherosclerosis through multiple risk factors such as insulin resistance, glucose intolerance, hyperlipidemia and hypertension. So far, it has been reported that a thaizolidinedione derivative, troglitazone, improves the insulin resistance in subjects with diabetes, glucose intolerance and obesity. However, it has not been reported yet that troglitazone affects fat distribution in subjects concomitant with visceral fat accumulation and multiple risk factors. METHODS Twenty-nine subjects with visceral fat accumulation who had at least two risk factors including glucose intolerance, hyperlipidemia and hypertension were investigated. They were randomly assigned to receive either 200 or 400 mg per day of troglitazone or placebo for 12 weeks. A 75 g oral glucose tolerance test (OGTT) was performed before and after the treatment for 12 weeks. Fasting plasma glucose, insulin, HbA(1c), total serum cholesterol (T-chol), triglyceride (TG), HDL-cholesterol (HDL-C), and blood pressure, as well as the number of risk factors were measured periodically during the treatment. The change of the abdominal fat distribution was evaluated using computed tomographic scanning (CT scan) at the umbilicus level. RESULTS After the treatment for 12 weeks, the area under the curve (AUC) of plasma glucose from a 75 g OGTT decreased dose-dependently. HbA(1c) and TG decreased significantly in the high-dose troglitazone group (400 mg per day) compared with the placebo group (P<0.05). Systolic blood pressure was significantly lower in subjects with hypertension in the pooled troglitazone group than in the placebo group (P<0.05). Therefore, the number of risk factors decreased with the troglitazone treatment. The ratio of visceral fat area (VFA) to subcutaneous fat area (SFA) (V/S ratio) decreased in the troglitazone groups due to decreased VFA and increased SFA. CONCLUSION These results suggest that thiazolidinedione derivative may be a useful drug to improve multiple risk factors by changing the fat distribution in subjects with visceral fat accumulation.

Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement.

Left ventricular ejection performance, wall stress, and contractile state were evaluated in 35 patients with chronic aortic regurgitation. Cineangiography and pressure measurements were obtained before and a mean of 26 months after aortic valve replacement, and data were compared with those from 30 normal control subjects. The relation between quantitative changes in wall stress and changes in ejection fraction after surgery was determined. Preoperatively, end-systolic stress was elevated in patients with aortic regurgitation (218 +/- 45 vs. 160 +/- 23 kdynes/cm2 [mean +/- SD] for control subjects, p less than 0.01), and ejection fraction was depressed (0.46 +/- 0.11 vs. 0.65 +/- 0.05, p less than 0.01). End-systolic stress decreased postoperatively (151 +/- 41 kdynes/cm2, p less than 0.01) and ejection fraction increased (0.58 +/- 0.11, p less than 0.01). The magnitude of increase in ejection fraction correlated significantly and negatively (r = -0.65) with the quantitative change in end-systolic stress after surgery. Contractile function, as assessed by the ejection phase index-end-systolic stress relation, did not significantly change: 23 of 35 patients preoperatively and 18 of 35 patients postoperatively had values that clearly fell below the 95% confidence limit of the ejection fraction-end-systolic stress relation for controls. After surgery, individual ejection fraction-end-systolic stress relationships demonstrated a shift parallel to the regression curve for the control subjects. Moreover, persistent postoperative left ventricular hypertrophy was significantly associated with persistent contractile dysfunction. Thus, late improvement in left ventricular ejection performance after aortic valve replacement can be attributed to the reduction in end-systolic stress. Contractile function itself was not improved by surgery. Persistent postoperative hypertrophy may be a marker for myocardial contractile dysfunction.

Clinical Significance of High-Molecular Weight Form of Adiponectin in Male Patients With Coronary Artery Disease

BACKGROUND It has been reported previously that the measurement of plasma total adiponectin level is clinically useful to estimate the risk of coronary artery disease (CAD). Here, the relevance of high molecular weight (HMW) adiponectin with risk factors for atherosclerosis is investigated METHODS AND RESULTS A total of 186 consecutive male CAD patients participated in the study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. In contrast, low molecular weight adiponectin levels (which were calculated as the Total - HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. On the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. Multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. CONCLUSIONS Change in the HMW isoform reflects a change in total adiponectin level. Measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients.

Correlation of fasting serum apolipoprotein B-48 with coronary artery disease prevalence

Eur J Clin Invest 2012; 42 (9): 992–999

Relationship between Platelet Indexes and Coronary Angiographic Findings in Patients with Ischemic Heart Disease

To understand the mechanisms linking platelets to the risk of coronary artery disease, we investigated the relation between coronary angiographic morphology and platelet indexes – platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW) – in patients with ischemic heart disease. Eighty-four patients with ischemic heart disease and 120 aged controls (AC) were enrolled in the study. The patients without any signs of acute myocardial infarction and acute coronary syndromes who underwent coronary angiography were divided into two groups, an ‘angiographically negative group’ (group 0) and an ‘angiographically positive group’ (group 1), with positive coronary obstruction depending on the diagnostic criteria in our hospital. Platelet indexes were measured in peripheral venous blood. The mean platelet counts were significantly lower in groups 1 and 0 than in AC (p = 0.0128 and p = 0.0041, respectively). MPV, P-LCR and the PDW were significantly higher in group 0 than in group 1 and AC (p = 0.0352 and 0.0433, p = 0.0059 and 0.0052, p = 0.00461 and 0.0146, respectively). The indexes of group 1 were almost the same compared with AC with respect to MPV, P-LCR and PDW. In conclusion, these findings suggest that the measurement of platelet indexes may reflect the underlying pathophysiological state and subsequent clinical events in the patients. In particular, lower P-LCR seems to identify patients with positive coronary angiography.

Relationship between Hemostatic Factors and the Platelet Index in Patients with Ischemic Heart Disease

To understand the heterogeneity of platelets, we investigated the correlation between hemostatic factors and the platelet index [platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW)] in patients with ischemic heart disease (IHD). Ninety-seven patients with IHD and 120 aged controls (AC) were enrolled in the study. D-dimer, thrombin-antithrombin III complex (TAT), von Willebrand factor antigen (VWF:Ag) and platelet indexes were measured in the peripheral venous blood. The D-dimer and TAT levels in the patients were significantly elevated compared to the AC. VWF:Ag was also elevated, but not significantly so. However, no differences were observed in the platelet index between the patients and the AC. In the patients, the level of VWF:Ag was significantly inversely correlated with the platelet count, but such correlations were not observed in the D-dimer and TAT. TAT was significantly positively correlated with MPV, P-LCR and PDW. VWF:Ag was also correlated, though not significantly, with MPV, P-LCR and PDW. The D-dimer was not correlated with the platelet index. In the AC, the platelet count was inversely correlated with VWF:Ag, but not significantly so. VWF:Ag showed significant positive correlations with MPV, P-LCR and PDW. However, the D-dimer and TAT were not correlated with the platelet index in AC. These findings suggest that VWF:Ag and TAT seem to be profoundly related to platelet volume.

Relationship between hemostatic markers and platelet indices in patients with aortic aneurysm.

The purpose of this study was to investigate whether platelet indices [platelet count, mean platelet volume (MPV), platelet-large cell ratio (P-LCR) and platelet distribution width (PDW)] could serve as diagnostic tools to evaluate the potential significance of platelet heterogeneity on thrombus formation in patients with aortic aneurysm (AA). Blood samples were obtained from 54 patients with AA (mean age 73 years; 40 males and 14 females), and from 120 age-matched controls (AC; mean age 74 years; 61 males and 59 females). Blood platelet indices were measured using an automated counter for all AC (n = 120) and AA (n = 54). Plasma thrombin-antithrombin III complex (TAT), α2-plasmin inhibitor-plasmin complex (PIC), D-dimer, von Willebrand factor antigen (vWF:Ag) and interleukin-6 (IL-6) were also measured in part of AC and AA. In AA patients, TAT, PIC, D-dimer, vWF:Ag and IL-6 levels were significantly (p ≤0.0005) higher than in AC. In the patients, TAT was significantly inversely correlated with platelet count (ρ = –0.302, p = 0.038, n = 48), and significantly positively correlated with MPV (ρ = 0.329, p = 0.0373, n = 48), P-LCR (ρ = 0.361, p = 0.0134, n = 48) and PDW (ρ = 0.315, p = 0.0466, n = 48). PIC was negatively correlated with platelet count and inversely correlated with MPV, P-LCR and PDW. vWF:Ag was not correlated with platelet count, and inversely correlated with MPV, P-LCR and PDW in the patients. IL-6 was positively correlated with platelet count, and significantly inversely correlated with MPV, P-LCR and PDW in the patients. In AC, vWF:Ag was inversely correlated with platelet count and significantly positively correlated with MPV, P-LCR and PDW. However, PIC, TAT and IL-6 were not correlated with platelet indices in AC. D-dimer was not at all correlated with platelet indices both in AA and AC. In conclusion, the correlation between platelet indices and plasma hemostatic factor levels, e.g. TAT, PIC, D-dimer, vWF:Ag and IL-6, will be important factors for the understanding of platelet heterogeneity in patients with AA.

Relationship between Hemostatic Markers and Circulating Biochemical Markers of Collagen Metabolism in Patients with Aortic Aneurysm

Our objective was to determine the relationship between plasma levels of hemostatic molecular markers – D-dimer and thrombin-antithrombin III complex (TAT) – and circulating biochemical markers of collagen metabolism – aminoterminal propeptide of type III procollagen (PIIIP) and carboxyterminal propeptide of type I procollagen (PICP) – in patients with aortic aneurysm. The subjects were 43 patients with aortic aneurysm (AA; mean age 71 years) and 26 age-matched controls (mean age 75 years). The mean D-dimer, TAT and PIIIP levels were higher in the patients than in the controls (p < 0.0001, 0.0001 and 0.012, respectively), while the mean PICP level was similar to that in the controls. Increased D-dimer had a significant correlation with PIIIP (r = 0.412, p = 0.006) and PICP (r = 0.342, p = 0.0246), while TAT correlated with PIIIP (r = 0.3194, p = 0.0374), but not with PICP. There was also a significant correlation (r = 0.306, p = 0.0463) between PIIIP and PICP. As shown by the significant positive correlations among D-dimer, TAT and PIIIP, accelerated fibrinolysis and thrombogenesis induce an increase of collagen degradation and procollagen synthesis in atherosclerotic lesions. These findings show that D-dimer and TAT, especially the former, may be useful markers to monitor the progression and predict the prognosis of AA.

A 31-year-old woman with homozygous familial hypercholesterolemia without significant lesions in the coronayry arteries

Cardiovascular complications were examined in a 31-year-old woman with homozygous familial hypercholesterolemia (FH) (LDL receptor defective type), who had had no clinical symptoms of coronary artery disease. She had delivered 2 children without any cardiac complications, and her exercise electrocardiogram showed no positive findings for ischemic heart disease. Coronary angiography showed no significant arterial lesions, and left ventriculography revealed good contraction of the left ventricle (ejection fraction: 67%). This is considered to be a very rare case of homozygous FH without significant lesions in the coronary arteries. This might be attributed at least in part to her dietary regimen consisting of a very low fat and low calorie diet, to the residual LDL receptor activity or to the low value of prothrombin time.