Yoshiki Kusama

Clinical significance of increased plasma concentration of macrophage colony–stimulating factor in patients with angina pectoris

OBJECTIVES To determine the effect of macrophage colony-stimulating factor (MCSF) on atherogenesis in patients with coronary artery disease (CAD), we assessed the relation between the plasma concentration of MCSF and the incidence of acute coronary events in patients with CAD. BACKGROUND Cytokines such as MCSF play a central role in inflammatory and proliferative responses in patients with acute coronary syndromes. However, the effect of MCSF on the clinical course in patients with CAD is still not known. METHODS We measured the plasma MCSF concentration in 142 patients with documented CAD (62 +/- 9 years) and followed up for a mean period of 14 +/- 6 months. The study included 97 patients with stable angina (SA), 45 patients with unstable angina (UA) and 22 age-matched control subjects. The predictors of coronary events were analyzed by using a Cox proportional hazards model. RESULTS The mean plasma MCSF concentration in patients with UA was significantly higher than that in patients with SA and in control subjects (981 +/- 277 vs. 693 +/- 223 vs. 680 +/- 158 pg/ml, p < 0.001). The mean plasma MCSF concentration in the 20 patients with coronary events was significantly higher than that in patients without coronary events (1,192 +/- 232 vs. 690 +/- 213 pg/ml, p < 0.001). The predictors of unfavorable outcome were an increased MCSF concentration, the presence of CAD and a low ejection fraction. CONCLUSIONS These findings suggest that an increased circulating MCSF concentration reflects atherosclerotic progression in patients with CAD and predicts future cardiac events.

Administration of the Rho-kinase inhibitor, fasudil, following nitroglycerin additionally dilates the site of coronary spasm in patients with vasospastic angina

BackgroundThe Rho/Rho-kinase signaling pathway is known to be involved in the pathogenesis of coronary artery spasm. Previous studies reported the efficacy of the Rho-kinase inhibitor, fasudil, in the prevention and relief of coronary spasm. The usefulness of fasudil in combination with conventional vasodilating agents, however, has not been fully examined in patients with vasospastic angina. Methods and resultsA total of 26 patients (mean age, 61±11 years) with documented vasospasm in the left anterior descending coronary artery were examined by the acetylcholine stress test. Coronary diameter at the spasm site was measured at baseline and after the administration of vasodilator agents in the following order: intracoronary nitroglycerin (NTG) (300 μg), intravenous fasudil (30 mg, n=15, fasudil group) or saline (n=11, saline group), and again NTG during coronary angiography. The increase in diameter observed following the first NTG administration was found to be similar in the fasudil and saline groups (38.3±23.5% and 42.3±17.1%, respectively). The additional change in diameter on fasudil treatment (16.9±11.2% increase over the diameter after the first NTG administration) was significantly larger than that with saline (−2.8±7.6%, P<0.001). The second administration of NTG did not affect the diameter of the spasm site in either group. ConclusionsFasudil further dilated the site of coronary spasm, which had already been treated with NTG in patients with vasospastic angina. These findings support and extend the previous results that showed the feasibility of employing fasudil as a novel therapeutic approach for coronary spasm.

Nutritional Status is Associated with Inflammation and Predicts a Poor Outcome in Patients with Chronic Heart Failure

AIM Malnutrition has been identified to be an independent predictor of morbidity and mortality in patients with chronic heart failure (CHF). However, the pathophysiological mechanisms underlying this pathway remain unclear. METHODS Nutritional screening was performed using the controlling nutritional status (CONUT) score, which was calculated using the serum albumin and total cholesterol levels and lymphocyte number, in 114 CHF patients with a mean left ventricular ejection fraction of 26.6%±6.4%. The carotid intima-media thickness (CIMT) is correlated with carotid atherosclerosis and is a significant predictor of future cardiovascular events. Peripheral blood mononuclear cells (PBMCs) were isolated, and the production of monocyte tumor necrosis factor (TNF)-α was measured and expressed as mean±SD (pg/mL/10(6) PBMCs). RESULTS A multivariate linear regression analysis showed that the production of monocyte TNF-α (β coefficient=0.434, p＜0.001) and mean CIMT (β coefficient=0.204, p=0.006) were independent determinants of the CONUT score. During a median follow-up of 67.5 months, 45 patients experienced cardiac events, including 16 cardiac deaths and 29 readmissions for worsening CHF. A multivariate Cox hazard analysis demonstrated that a monocyte TNF-α level of ≥4.1 pg/mL/10(6) PBMCs (hazard ratio (HR), 14.10; 95% confidence interval (CI), 2.55-77.92; p=0.002) and CONUT score of ≥3 (HR, 11.97; 95% CI, 2.21-64.67; p=0.004) were independently associated with the incidence of cardiac events. CONCLUSIONS These data indicate that a poor nutritional status as assessed using the CONUT score and atherosclerosis as indicated by CIMT is significantly associated with inflammation and predicts poor outcomes in patients with CHF.

Upregulation of Monocyte Proinflammatory Cytokine Production by C-Reactive Protein is Significantly Related to Ongoing Myocardial Damage and Future Cardiac Events in Patients With Chronic Heart Failure

BACKGROUND An elevation of the cardiac troponin T (TnT) level identifies patients with ongoing myocardial damage (OMD) and at increased risk for future cardiac events in chronic heart failure (CHF). C-reactive protein (CRP) upregulates monocyte proinflammatory cytokine production and this upregulation appears to play an important role on OMD. METHODS AND RESULTS Peripheral blood mononuclear cells (PBMCs) were stimulated by 25 microg/mL CRP in 72 patients with CHF. Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 production by monocytes was measured by a specific enzyme-linked immunosorbent assay and expressed as the mean +/- SD (pg x mL x 10(6) PBMCs). The patients were divided into 2 groups according to the TnT levels: 27 patients with OMD (TnT >/= 0.01 ng/mL) and 45 patients without OMD. CRP-induced cytokine production was upregulated significantly more in patients with OMD than in those without OMD (TNF-alpha: 200.6 +/- 100.4 vs. 102.1 +/- 73.6 pg/mL, P < .001, IL-6: 4611.7 +/- 2600.0 vs. 1451.6 +/- 1193.5 pg/mL, P < .001). Multivariate Cox regression analyses revealed that CRP-stimulated monocyte production of TNF-alpha >/= 120 pg/mL and TnT >/= 0.03 ng/mL were independent predictors of cardiac events. CONCLUSIONS The upregulation of monocyte proinflammatory cytokine production by CRP could be significantly related to OMD and future cardiac events in CHF.

Independent Determinants of Second Derivative of the Finger Photoplethysmogram among Various Cardiovascular Risk Factors in Middle-Aged Men

The second derivative of the finger photoplethysmogram (SDPTG) has been used as a non-invasive examination for arterial stiffness. The present study sought to elucidate independent determinants of the SDPTG among various cardiovascular risk factors in middle-aged Japanese men. The SDPTG was obtained from the cuticle of the left-hand forefinger in 973 male workers (mean age: 44±6 years) during a medical checkup at a company. The SDPTG indices (b/a and d/a) were calculated from the height of the wave components. Multiple logistic regression analyses revealed that the independent determinants of an increased b/a (highest quartile of the b/a) were age (odds ratio [OR]: 1.12 per 1-year increase, 95% confidence interval [CI]: 1.09–1.15), hypertension (OR: 1.65, 95% CI: 1.03–2.65), dyslipidemia (OR: 1.51, 95% CI: 1.09–2.09), impaired fasting glucose/diabetes mellitus (OR: 2.43, 95% CI: 1.16–5.07), and a lack of regular exercise (OR: 2.00, 95% CI: 1.29–3.08). Similarly, independent determinants of a decreased d/a (lowest quartile of the d/a) were age (OR: 1.11 per 1-year increase, 95% CI: 1.08–1.14), hypertension (OR: 3.44, 95% CI: 2.20–5.38), and alcohol intake 6 or 7 days per week (OR: 2.70, 95% CI: 1.80–4.06). No independent association was observed between the SDPTG indices and blood leukocyte count or serum C-reactive protein levels. In conclusion, the SDPTG indices reflect arterial properties affected by several cardiovascular risk factors in middle-aged Japanese men. The association between inflammation and the SDPTG should be evaluated in further studies.

Increased accumulation of acidic fibroblast growth factor in left ventricular myocytes of patients with idiopathic cardiomyopathy

To clarify the pathophysiologic role of fibroblast growth factors in idiopathic cardiomyopathy, we evaluated endomyocardial biopsy specimens obtained from 24 patients (nine with hypertrophic cardiomyopathy [HCM], 12 with dilated cardiomyopathy [DCM], and three with hypertensive hypertrophy) and six controls. All the specimens were stained for acidic fibroblast growth factor (aFGF) and basic FGF (bFGF) with immunohistochemistry. In situ hybridization was carried out for detection of aFGF mRNA. The average diameter of the myocytes, the percent area of interstitial fibrosis, and capillary vessel density were assessed in each biopsy specimen with morphometric methods. Positive staining of aFGF was observed in the myocytes of the biopsy specimens taken from 15 of 21 (71%) patients with cardiomyopathy (six of nine HCM, nine of 12 DCM) and all hypertensive hypertrophy patients but in none of the controls (p < 0.01). The average diameter of the myocytes was significantly larger in the patients with positive aFGF staining than in those with negative staining (23.1 +/- 1.5 versus 18.3 +/- 1.2 microm, p < 0.05). The percent area of fibrosis and the density of capillaries did not differ between the two groups. Intense expression of aFGF mRNA was observed in the myocytes from the patients with positive aFGF protein. In conclusion, the expression of FGF was significantly increased in myocytes obtained from the left ventricle of patients with cardiomyopathy. Acidic FGF may contribute to the hypertrophy of myocytes as the repair response to myocardial injury in patients with idiopathic cardiomyopathy.

Obesity as an independent influential factor for reduced radial arterial wave reflection in a middle-aged Japanese male population

This study aimed to examine whether obesity, including abdominal obesity, is an influential factor for radial arterial wave reflection, as expressed by the augmentation index (AI), in middle-aged Japanese men. Radial arterial pressure waveform was measured using automated applanation tonometry in 828 men (mean age: 47±5 years) during an annual health examination at a company. Radial AI was calculated from the waveforms. AI appeared to be similar between subjects with and without obesity (body mass index (BMI) ⩾25 and <25 kg m−2, respectively). However, after adjusting for age, height, heart rate, mean blood pressure, low- and high-density lipoprotein cholesterol, fasting plasma glucose, white blood cell count and other potential confounders, AI was significantly lower in subjects with obesity (71.6%, 95% confidence interval (CI); 70.2–73.0%) than in those without (75.2%, 95% CI; 74.4–76.0%, P<0.001). In a multiple linear regression analysis, BMI was negatively associated with AI (β=−0.20, P<0.001); other factors associated with AI were heart rate (β=−0.56), mean blood pressure (β=0.44), height (β=−0.24), age (β=0.15), current smoking (β=0.09), white blood cell count (β=0.06) and low-density lipoprotein cholesterol (β=0.06). Similar associations were found when waist circumference (WC, an index of abdominal obesity) was substituted for BMI in the analysis (β=−0.12, P<0.001). BMI closely correlated with WC (r=0.87), thus suggesting that approximately 76% (a square of 0.87) of BMI can be explained by WC. In conclusion, although it does not have a major impact, obesity, including abdominal obesity, may be an influential factor for reduced radial AI, independently of well-known confounders, in middle-aged Japanese men.

Osteoprotegerin is Associated With Endothelial Function and Predicts Early Carotid Atherosclerosis in Patients With Coronary Artery Disease

Osteoprotegerin (OPG) is a soluble glycoprotein belonging to the tumor necrosis factor receptor superfamily and is linked to vascular atherosclerosis and calcification. The carotid intima-media thickness (CIMT) correlates with carotid atherosclerosis and is a significant predictor of cardiovascular events. The OPG levels are associated with the CIMT in coronary artery disease (CAD) patients. However, the pathophysiological mechanisms underlying this pathway remain unclear. We investigated 114 CAD patients (89 men, 25 women; mean age: 68.7 ± 10.3 years) and measured the Gensini score (a marker of the extent of coronary atherosclerosis), the mean CIMT and the plasma levels of OPG and asymmetric dimethylarginine (ADMA; a marker of endothelial function). Early carotid atherosclerosis was defined as a mean CIMT > 1.0 mm. Only 33 of the 114 patients (28.9%) had early carotid atherosclerosis. Patients with early carotid atherosclerosis had higher OPG levels than those without. The OPG levels were found to be significantly associated with ADMA (r = 0.191, P = 0.046) and the mean CIMT (r = 0.319, P = 0.001), but not with the Gensini score. A receiver operating curve analysis revealed the optimal cut-off value of the OPG levels for predicting early carotid atherosclerosis to be 100 pmol/L. A multivariate logistic regression analysis showed OPG ≥ 100 pmol/L to be significantly and independently associated with early carotid atherosclerosis (odds ratio: 2.98, 95% confidence interval: 1.22-7.20, P = 0.017). These data indicate that OPG is significantly associated with endothelial function and predicts early carotid atherosclerosis in patients with CAD.

Oscillometric measurement of brachial artery cross-sectional area and its relationship with cardiovascular risk factors and arterial stiffness in a middle-aged male population

An enlarged arterial diameter is associated with an increased risk for cardiovascular disease. This study examined the relationship of noninvasively measured brachial artery cross-sectional area with cardiovascular risk factors and arterial stiffness in a middle-aged male population. Absolute volumetric changes of the brachial artery were measured with a newly developed oscillometric method during a general health examination in 387 men (mean age: 38±9 years) without known cardiovascular disease. Based on the measurement, the estimated area (eA) of the brachial artery at end-diastole was obtained. Brachial artery volume elastic modulus (VE) and brachial–ankle pulse wave velocity (baPWV) were simultaneously measured as indices of arterial stiffness by the same device. The relationships of eA with cardiovascular risk factors, including age, obesity, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus (IFG/DM), hyperuricemia, smoking and their associated continuous variables, as well as VE and baPWV, were examined. Overall, the mean eA was 12.9±2.9 mm2. The eA was significantly higher in subjects with obesity, hypertension or IFG/DM than in those without each of these risk factors. In a multiple linear regression analysis, body mass index (β=0.31, P<0.001), age (β=0.25, P<0.001), systolic blood pressure (β=0.16, P=0.004) and pulse rate (β=−0.13, P=0.005) were independent determinants of eA. In contrast, neither VE nor baPWV were selected as independent determinants of eA. In conclusion, enlarged brachial artery cross-sectional area was significantly associated with cardiovascular risk factors such as age, body mass index and systolic blood pressure, but it was not associated with increased arterial stiffness.

Usefulness of rosuvastatin to prevent periprocedural myocardial injury in patients undergoing elective coronary intervention.

The aim of the present study was to investigate whether percutaneous coronary intervention-related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention-related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins.