Akihiro Nakagomi

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.

Elevated peripheral blood mononuclear cell count is an independent predictor of left ventricular remodeling in patients with acute myocardial infarction

OBJECTIVES Peripheral blood mononuclear cells (PBMCs) increase after acute myocardial infarction (AMI) and infiltrate to the infarct region. However, its impact on left ventricular (LV) remodeling remains unclear. The purpose of the present study was to clarify whether elevated PBMC count contributed to LV remodeling in patients with AMI. SUBJECTS AND METHODS A total of 131 patients with AMI were recruited. White blood cell (WBC), monocyte, and lymphocyte counts were measured at presentation and every 24h for five days after presentation. The correlation between PBMC count and LV remodeling was evaluated. LV remodeling was defined as an increase of LV end-diastolic volume index ≥ 10% at the 6-month follow-up left ventriculography. RESULTS Forty-eight patients had LV remodeling. Peak WBC (p=0.008), peak monocyte (p=0.001), and peak PBMC (p<0.001) counts were significantly greater in patients with LV remodeling than those without remodeling. Multivariate analysis revealed the peak PBMC count ≥ 3600/mm(3) was an independent predictor of LV remodeling [relative risk (RR) 3.243, p=0.011]. CONCLUSION Increased PBMC count is significantly correlated with LV remodeling, thus suggesting that PBMCs play a pivotal role for the development of LV remodeling after AMI.

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.

Utility of rapid D-dimer measurement for screening of acute cardiovascular disease in the emergency setting

BACKGROUND Rapid and accurate methods for screening are necessary for the diagnosis of acute cardiovascular diseases (ACVD), including acute coronary syndrome (ACS), pulmonary thromboembolism, and acute aortic dissection. In this study, the utility of rapid D-dimer measurement for the screening of ACVD was evaluated. METHODS AND RESULTS Consecutive 279 emergent patients in whom ACVD was suspected or not ruled out were enrolled. The median D-dimer concentration of ACVD group (1.10 μg/ml) was significantly higher than that in the non-ACVD group (0.69 μg/ml, p<0.05). Sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer (with cut-off level of 0.75 μg/ml) for the discrimination of ACVD from non-ACVD was 75%, 55%, 38%, and 85%, respectively. In ACVD group, the level of D-dimer in the large vessel disease subgroup was significantly higher than that in the ACS subgroup (6.99 μg/ml and 0.89 μg/ml, respectively; p<0.05). The well-balanced cut-off point for discriminating the two subgroups was D-dimer level of 5.0 μg/ml. D-dimer (with cut-off level of 0.75 μg/ml) showed significantly higher positive test rate for the detection of ACS in very early phase (within 2 h from the onset) compared with troponin T (p<0.05). CONCLUSIONS Rapid measurement of D-dimer is useful for the screening of ACVD in the emergency setting.

Effect of insulin resistance associated with compensatory hyperinsulinemia on the long-term prognosis in patients with vasospastic angina.

BACKGROUND Insulin resistance associated with compensatory hyperinsulinemia plays a significant role in the pathogenesis of cardiovascular diseases, including vasospastic angina (VSA). However, the effects of insulin resistance associated with hyperinsulinemia on the long-term prognosis in patients with VSA remain unclear. METHODS A total of 265 selected patients with VSA and 56 control subjects with atypical chest pain were enrolled in the present study. Patients with VSA had a positive acetylcholine (ACh) provocation test with normal coronary angiograms, and control subjects had a negative ACh test and normal coronary angiograms. A 75-g oral glucose tolerance test was performed, and the plasma glucose and immunoreactive insulin (IRI) levels were measured before, and 30 min and 120 min (IRI 120) after the 75-g glucose load. RESULTS During the median follow-up period of 90.0 months, thirty-one patients developed cardiac events, including 6 sudden cardiac deaths and 25 readmissions for acute coronary syndrome. Cardiac events occurred in 38.9% of the patients with an IRI 120 ≥ 80 μU/ml and only 1.6% of the patients with an IRI 120<80 μU/ml (log rank 77.220, p<0.001). A multivariate analysis showed that an IRI 120 ≥ 80 μU/ml (hazard ratio 27.49, 95% confidence interval: 4.66-162.10, p<0.001) was an independent predictor of cardiac events. CONCLUSIONS These data indicate that insulin resistance associated with compensatory hyperinsulinemia increases the risk of cardiac events in VSA patients.

Differential Effects of Atorvastatin and Pitavastatin on Inflammation, Insulin Resistance, and the Carotid Intima-Media Thickness in Patients with Dyslipidemia

AIMS 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have multiple pleiotropic effects, such as anti-inflammatory and vascular endothelium protection, that are independent of their low-density-lipoprotein (LDL) cholesterol lowering effects. However, whether different statins exert diverse effects on inflammation, insulin resistance, and the progression of carotid atherosclerosis [as indicated by the intima-media thickness (CIMT)] in patients with dyslipidemia remains unclear. METHODS A total of 146 patients with hypercholesterolemia without known cardiovascular disease were randomly assigned to receive 5 mg/day of atorvastatin (n=73) or 1 mg/day of pitavastatin (n=73). RESULTS At baseline, age, gender, blood pressure, lipid profiles, and the serum monocyte chemoattractant protein (MCP)-1, homeostasis model assessment of insulin resistance (HOMA-IR) and CIMT values were comparable between the groups. After 12 months of treatment, atorvastatin and pitavastatin equally reduced the LDL cholesterol levels; however, atorvastatin increased the HOMA-IR by ＋26% and pitavastatin decreased this parameter by －13% (p＜0.001). The MCP-1 values were reduced by －28% in the patients treated with pitavastatin and only －11% in those treated with atorvastatin (p=0.016). A greater percent decrease in the mean CIMT from baseline was observed in the patients treated with pitavastatin than in those treated with atorvastatin (－4.9% vs. －0.5%, p=0.020). CONCLUSIONS These data indicate that, while these agents significantly and equally reduce the LDL cholesterol levels, atorvastatin and pitavastatin have different effects on inflammation, insulin resistance, and the progression of carotid atherosclerosis in patients with dyslipidemia.

Inflammation and Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. Accumulating evidence indicates a link between inflammation and AF, and important advances in understanding mechanisms of AF are arising from studies of the critical components involved in the modulation of the immunoinflammatory balance within the atrium. However, molecular mechanisms remain unclear. Indeed, although preclinical and clinical studies suggest that chronic inflammation may promote development of AF, the roles of inflammation in the process are complex and incompletely understood. The purpose of this review is to briefly highlight current evidence on relationships between inflammation and AF, and to discuss possible mechanisms of development of AF and/or possible therapeutic approaches targeting components of the inflammatory response.

Serum Tartrate-resistant Acid Phosphatase-5b Levels are Associated with the Severity and Extent of Coronary Atherosclerosis in Patients with Coronary Artery Disease

Aims: Tartrate-resistant acid phosphatase (TRACP)-5b and osteoprotegerin (OPG) are specific and sensitive markers of bone resorption in patients with rheumatoid arthritis (RA) and chronic kidney disease (CKD). The TRACP-5b level is associated with the severity of RA and CKD, while the OPG level is associated with the severity of coronary atherosclerosis and calcification, and can predict a poor outcome in patients with coronary artery disease (CAD). However, the impact of TRACP-5b on coronary atherosclerosis in CAD patients remains unclear. Methods: A total of 71 CAD patients (57 men, 14 women; mean age: 69.0 ± 9.7 years) and 28 age- and gender-matched healthy subjects were investigated. The number of diseased vessels (a marker of the severity of coronary atherosclerosis) and the Gensini score (a marker of the extent of coronary atherosclerosis), as well as the OPG and TRACP-5b levels were measured in CAD patients. The TRACP-5b levels were classified into quartiles. Results: The TRACP-5b levels were significantly higher in CAD patients than in healthy subjects. Patients with higher TRACP-5b levels had higher OPG levels and Gensini scores than those with lower TRACP-5b levels. Higher TRACP-5b levels were associated with an increased number of diseased vessels. A multivariate linear regression analysis showed that the OPG level and the number of diseased vessels or the Gensini score were significantly and independently associated with the TRACP-5b level. Conclusions: These data indicate that the TRACP-5b level is significantly associated with the OPG level and with the severity and extent of coronary atherosclerosis in CAD patients.