Prognostic value of extraaortic-valvular cardiac damage in patients with moderate aortic stenosis and reduced left ventricular ejection fraction.

PURPOSE: The extraaortic-valvular cardiac damage (EVCD) Stage has shown potential for risk stratification for patients with aortic stenosis (AS). This study aimed to examine the usefulness of the EVCD Stage in risk stratification of patients with moderate AS and reduced left ventricular ejection fraction (LVEF). METHODS: Clinical data from patients with moderate AS (aortic valve area, .60-.85 cm2/m2; peak aortic valve velocity, 2.0-4.0 m/s) and reduced LVEF (LVEF 20%-50%) were analyzed during 2010-2019. Patients were categorized into three groups: EVCD Stages 1 (LV damage), 2 (left atrium and/or mitral valve damage), and 3/4 (pulmonary artery vasculature and/or tricuspid valve damage or right ventricular damage). The primary endpoint included a composite of cardiac death and heart failure hospitalization, with non-cardiac death as a competing risk. RESULTS: The study included 130 patients (mean age 76.4 ± 6.8 years; 62.3% men). They were categorized into three groups: 26 (20.0%) in EVCD Stage 1, 66 (50.8%) in Stage 2, and 48 (29.2%) in Stage 3/4. The endpoint occurred in 54 (41.5%) patients during a median follow-up of 3.2 years (interquartile range, 1.4-5.1). Multivariate analysis indicated EVCD Stage 3/4 was significantly associated with the endpoint (hazard ratio 2.784; 95% confidence interval 1.197-6.476; P = .017) compared to Stage 1, while Stage 2 did not (hazard ratio 1.340; 95% confidence interval .577-3.115; P = .500). CONCLUSION: The EVCD staging system may aid in the risk stratification of patients with moderate AS and reduced LVEF.

Effect of the Xanthine Oxidase Inhibitor, Febuxostat, on WBC Count in Asymptomatic Hyperuricemia: Subanalysis of the Randomized PRIZE Study.

AIMS: The anti-inflammatory effects of the xanthine oxidase inhibitor, febuxostat, a urate-lowering agent, have been reported in animal studies. However, the anti-inflammatory effects of urate-lowering therapy and its associated cardiovascular protective effects have not been fully determined in actual clinical practice. This study aimed to investigate the effect of febuxostat on white blood cell (WBC) count in patients with asymptomatic hyperuricemia and to assess for potential correlations between changes in WBC count and inflammatory biomarkers and atherosclerosis in this patient population. METHODS: This was a post hoc subanalysis of the PRIZE study, a multicenter, prospective, randomized, open-label clinical trial. In the PRIZE study, asymptomatic hyperuricemia patients were randomized to febuxostat group or control group with non-pharmacological therapy and evaluated the effect on vascular. The primary endpoints of this study were the assessment of the time course of WBC count over 24 months and its changes from baseline. Correlations of WBC count with high-sensitivity C-reactive protein (hs-CRP) and mean common carotid artery (CCA)-IMT were also exploratorily examined in the febuxostat group. RESULTS: A total of 444 patients (febuxostat group, n=223; control group, n=221) with WBC measurements available at baseline and at least one of the follow-up time points of 12 or 24 months, were enrolled. Febuxostat modestly, but significantly, reduced WBC counts at 12 and 24 months compared with the baseline levels (P=0.002 and P=0.026, respectively). Notably, the WBC count in the febuxostat group at 12 and 24 months was significantly lower than that in the control group (P=0.007 and P=0.023, respectively). The changes in WBC count were associated with those of hs-CRP (P=0.038), but not with CCA-IMT (P=0.727). CONCLUSIONS: Febuxostat therapy for 24 months modestly, but significantly, decreased WBC count in patients with asymptomatic hyperuricemia. This might potentially reflect a modest anti-inflammatory action of febuxostat in clinical settings.

Impact of Stent Expansion Index on Stent Failure After Left Main Stenting.

Impact of the stent expansion index (EXPI) in percutaneous coronary intervention (PCI) for unprotected left main distal bifurcation lesions (ULMD) has been not completely understood especially in current-generation drug-eluting stent (cDES) era. We evaluated the impact of EXPI on clinical outcomes after PCI with cDES for ULMD. We identified 342 patients treated with cDES for ULMD and postintervention intravascular ultrasound between January 2010 and December 2019. In this study, the ratio of minimum stent area (MSA) to reference vessel area at the MSA site was adopted to assess the stent expansion. We defined the patients with the first and second tertile as low-intermediate EXPI group and those with the third tertile as high EXPI group and compared the clinical outcomes between both groups. The primary end point was target lesion failure (TLF). TLF was defined as a composite of cardiac death, target lesion revascularization (TLR) ,and myocardial infarction. The MSA was located in the ostium of left anterior descending coronary artery in most cases (318 of 342 patients; 93.0%). There were no significant differences between both groups in the baseline clinical, lesion, and procedural characteristics. The high EXPI group had lower TLF rate than the low-intermediate EXPI group (10.2% vs 19.9%, log-rank p = 0.033). In conclusion, this is the first report that the higher ratio of MSA to reference vessel area at the MSA site, which was defined as stent EXPI, was associated with more favorable clinical outcomes after PCI for ULMD.

The estimation of coronary artery calcium thickness by computed tomography angiography based on optical coherence tomography measurements.

Optical coherence tomography (OCT) is recommended to be the most appropriate modality in assessing calcium thickness, however, it has limitations associated with infrared attenuation. Although coronary computed tomography angiography (CCTA) detects calcification, it has low resolution and hence not recommended to measure the calcium size. The aim of this study was to devise a simple algorithm to estimate calcium thickness based on the CCTA image. A total of 68 patients who had CCTA for suspected coronary artery disease and subsequently went on to have OCT were included in the study. 238 lesions of them divided into derivation and validation dataset at 2:1 ratio (47 patients with 159 lesions and 21 with 79, respectively) were analyzed. A new method was developed to estimate calcium thickness from the maximum CT density within the calcification and compared with calcium thickness measured by OCT. Maximum Calcium density and measured calcium-border CT density had a good correlation with a linear equation of y = 0.58x + 201 (r = 0.892, 95% CI 0.855-0.919, p < 0.001). The estimated calcium thickness derived from this equation showed strong agreement with measured calcium thickness in validation and derivation dataset (r2 = 0.481 and 0.527, 95% CI 0.609-0.842 and 0.497-0.782, p < 0.001 in both, respectively), more accurate than the estimation by full width at half maximum and inflection point method. In conclusion, this novel method provided the estimation of calcium thickness more accurately than conventional methods.

Biomarkers associated with coronary high-risk plaques.

Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-α, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p < 0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy.Clinical Trial Registration https://www.umin.ac.jp/ctr/ , UMIN000041692. Biomarkers and high-risk plaques hsCRP, PAI-1, fibrinogen, IL-6, homocysteine, amyloid A, HDL, and bile acid were useful for detecting patients with TCFA. hsCRP, fibrinogen, IL-6, homocysteine, amyloid A, creatinine, TNFα, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques" (plaque which has both TCFA and large plaque burden). White arrowhead denotes TCFA. Red and green dashed lines denote lumen area and external elastic membrane area, respectively.

Gut Microbiota and Coronary Plaque Characteristics.

Background The relationship between gut microbiota and in vivo coronary plaque characteristics has not been reported. This study was conducted to investigate the relationship between gut microbiota and coronary plaque characteristics in patients with coronary artery disease. Methods and Results Patients who underwent both optical coherence tomography and intravascular ultrasound imaging and provided stool and blood specimens were included. The composition of gut microbiota was evaluated using 16S rRNA sequencing. A total of 55 patients were included. At the genus level, 2 bacteria were associated with the presence of thin-cap fibroatheroma, and 9 bacteria were associated with smaller fibrous cap thickness. Among them, some bacteria had significant associations with inflammatory/prothrombotic biomarkers. Dysgonomonas had a positive correlation with interleukin-6, Paraprevotella had a positive correlation with fibrinogen and negative correlation with high-density lipoprotein cholesterol, Succinatimonas had positive correlations with fibrinogen and homocysteine, and Bacillus had positive correlations with fibrinogen and high-sensitivity C-reactive protein. In addition, Paraprevotella, Succinatimonas, and Bacillus were also associated with greater plaque volume. Ten bacteria were associated with larger fibrous cap thickness. Some were associated with protective biomarker changes; Anaerostipes had negative correlations with trimethylamine N-oxide, tumor necrosis factor α, and interleukin-6, and Dielma had negative correlations with trimethylamine N-oxide, white blood cells, plasminogen activator inhibitor-1, and homocysteine, and a positive correlation with high-density lipoprotein cholesterol. Conclusions Bacteria that were associated with vulnerable coronary plaque phenotype and greater plaque burden were identified. These bacteria were also associated with elevated inflammatory or prothrombotic biomarkers. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000041692.

Impact of Left Main Calcium With Chronic Kidney Disease on Outcomes After Percutaneous Coronary Intervention for Left Main Narrowings (from the Milan and New-Tokyo Registry).

Limited data are available about the association between coronary artery calcification and chronic kidney disease severity on clinical outcomes after percutaneous coronary intervention (PCI). This study aimed to assess the association between coronary artery calcification and chronic kidney disease severity on clinical outcomes after PCI. We identified 1,391 patients treated with drug-eluting stent for unprotected left main distal bifurcation lesions (ULMD), including 604 without calcified lesions (noncalcified left main group) and 787 with calcified ULMD (calcified left main group) in Japan and Italy. We divided the calcified group into the following 2 groups: estimated glomerular filtration rate (eGFR) ≥30 (n = 687) and <30 (n = 100) and compared the clinical outcomes. The primary end point was target lesion failure (TLF) at 3 years. TLF was defined as a composite of cardiac death, target lesion revascularization, and myocardial infarction. TLF occurred more frequently in the calcified group (adjusted hazard ratio 1.36, 95% confidence interval 1.08 to 1.71, p = 0.01), especially in calcified ULMD with eGFR <30 (adjusted hazard ratio relative to the other 2 groups 2.59, 95% confidence interval 1.60 to 4.18, p <0.001). In conclusion, the calcified ULMD treated with PCI was associated with poorer clinical outcomes than noncalcified ULMD, especially in those with eGFR <30.

Impact of directional coronary atherectomy followed by drug-coated balloon strategy to avoid the complex stenting for bifurcation lesions.

Although the simple single stenting rather than complex double stenting is recommended on percutaneous coronary intervention (PCI) for bifurcation lesions, double stenting cannot always be avoided. We investigated the impact of directional coronary atherectomy (DCA), followed by drug-coated balloon (DCB) treatment to reduce the number of stents and avoid complex stenting in PCI for bifurcation lesions and short-term patency. DCA treatment without stents was attempted for 27 bifurcation lesions in 25 patients, of those, 26 bifurcation lesions in 24 patients were successfully treated and 3-month follow-up angiography and optical coherence tomography (OCT) were performed. Sixteen lesions (59.3%) were related to left main trunk distal bifurcations, and 7 (25.9%) were true bifurcation lesions. Among the true bifurcation lesions, 4 lesions (57.1%) needed 1 stent, and the other 3 lesions (42.9%) needed no stents. Among the non-true bifurcation lesions, 1 lesion (5.0%) needed bailout stent and other lesions (95.0%) needed no stents. According to DCA followed by DCB treatment, the angiographic mean diameter stenosis improved from 65.5 ± 15.0% to 7.8 ± 9.8%, and the mean plaque area in intravascular ultrasound improved from 80.4 ± 10.5% to 39.0 ± 11.5%, respectively. Angiographic and OCT late lumen loss values were 0.2 ± 0.6 mm and 1.4 ± 1.9 mm, respectively. No patient had in-hospital major adverse cardiac events (MACE) and 3-month MACE. In conclusion, compared with standard provisional side branch stenting strategy, DCA followed by DCB treatment might reduce the number of stents, avoid complex stenting for major bifurcation lesions and provide good short-term outcomes.

The Impact of Aortic Valvular Calcium on Transcatheter Heart Valve Distortion.

OBJECTIVES: To investigate the relationship between the eccentric calcification of aortic valve and transcatheter heart valve (THV) distortion and the impact of THV distortion on echo parameters and clinical outcomes. BACKGROUND: The effects of eccentric calcification of the aortic valve on the THV distortion and the relationship between THV distortion and clinical impact were not fully understood. METHODS: Patients with symptomatic severe aortic stenosis who were undergoing THV implantation were enrolled. Patients underwent preprocedural, postprocedural multislice computed tomography (MSCT), and follow-up transthoracic echocardiogram (TTE). Delta calcium score (ΔCS) is defined as the difference between the maximum and minimal calcium scores of the three cusps, while valve distortion score (VDS) is defined as the difference between the longest and shortest stent frame, as obtained using MSCT. Patients were divided into two groups according to ΔCS: "noneccentric calcification group" and "eccentric calcification group." RESULTS: A total of 118 patients were enrolled (59 patients in noneccentric and 59 in eccentric calcification groups). VDS was significantly lower in the noneccentric calcification group than in the eccentric calcification group (1.31 ± 0.82 mm vs. 1.73 ± 0.76 mm, p=0.004). VDS was not associated with the degree of paravalvular leak (PVL) and aortic valvular mean pressure gradient (AVPG) at 30-day and 1-year follow-up TTE and the cumulative rates of all-cause death and rehospitalization at 2-year clinical follow-up. CONCLUSIONS: Eccentric valvular calcification was associated with longitudinal THV distortion. However, THV distortion was not associated with PVL, AVPG, and adverse clinical events during midterm follow-up.

Practical utilization of cardiac computed tomography for the success in complex coronary intervention.

Percutaneous coronary intervention (PCI) for complex lesions is still technically demanding and is associated with less favorable procedural parameters such as lower success rate, longer procedural time, higher contrast volume and unexpected complications. Because the conventional angiographic analysis is limited by the inability to visualize the plaque information and the occluded segment, cardiac computed tomography has evolved as an adjunct to invasive angiography to better characterize coronary lesions to improve success rates of PCI. Adding to routine image reconstructions by coronary computed tomography angiography, the thin-slab maximum intensity projection method, which is a handy reconstruction technique on an ordinary workstation, could provide easy-to-understand images to reveal the anatomical characteristics and the lumen and plaque information simultaneously, and then assist to build an in-depth strategy for PCI. Especially in the treatment of chronic total occlusion lesion, these informations have big advantages in the visualization of the morphologies of entry and exit, the occluded segment and the distribution of calcium compared to invasive coronary angiography. Despite of the additional radiation exposure, contrast use and cost for cardiac computed tomography, the precise analysis of lesion characteristics would consequently improve the procedural success and prevent the complication in complex PCI.

Impact of intravascular ultrasound-guided minimum-contrast coronary intervention on 1-year clinical outcomes in patients with stage 4 or 5 advanced chronic kidney disease.

This study aims to elucidate 1-year clinical outcomes using this technique for patients with stage 4 or 5 advanced chronic kidney disease (CKD). Research has proven that imaging-guided percutaneous coronary intervention (PCI) reduces contrast volume significantly; however, only short-term clinical benefits have been reported. Minimum-contrast (MINICON) studies are based on the registry design pattern to enroll PCI results in patients with advanced CKD stage 4 or 5 comorbid with coronary artery disease. We excluded cases of emergency PCI or maintenance dialysis from this study. In this study, we compared the intravascular ultrasound (IVUS)-guided MINICON PCI group (n = 98) with the angiography-guided standard PCI group (n = 86). Enrollment of the MINICON studies started in 2006. Before 2012, IVUS-guided MINICON PCI was performed only in 14% (stage 1), but it was 100% after 2012 (stage 2). The enrollment finished in 2016. The IVUS-guided MINICON PCI group exhibited a significantly reduced contrast volume (22 ± 20 vs. 130 ± 105 mL; P < 0.0001) and contrast-induced acute kidney injury (CI-AKI; 2% vs. 15%; P = 0.001). The PCI success rate was similarly high (100% vs. 99%; P = 0.35). At 1 year (follow-up rate, 100%), we observed less induction of renal replacement therapy (RRT; 2.7% vs. 13.6%; P = 0.01), but all-cause mortality or myocardial infarction was similar in both groups. The IVUS-guided MINICON PCI reduces CI-AKI significantly and induction of RRT at 1 year in patients with stage 4 or 5 advanced CKD.

Long-term use of carvedilol in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention.

BACKGROUND: Despite its recommendation by the current guidelines, the role of long-term oral beta-blocker therapy has never been evaluated by randomized trials in uncomplicated ST-segment elevation myocardial infarction (STEMI) patients without heart failure, left ventricular dysfunction or ventricular arrhythmia who underwent primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: In a multi-center, open-label, randomized controlled trial, STEMI patients with successful primary PCI within 24 hours from the onset and with left ventricular ejection fraction (LVEF) ≥40% were randomly assigned in a 1-to-1 fashion either to the carvedilol group or to the no beta-blocker group within 7 days after primary PCI. The primary endpoint is a composite of all-cause death, myocardial infarction, hospitalization for heart failure, and hospitalization for acute coronary syndrome. Between August 2010 and May 2014, 801 patients were randomly assigned to the carvedilol group (N = 399) or the no beta-blocker group (N = 402) at 67 centers in Japan. The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to 6.3±4.3 mg at 1-year. During median follow-up of 3.9 years with 96.4% follow-up, the cumulative 3-year incidences of both the primary endpoint and any coronary revascularization were not significantly different between the carvedilol and no beta-blocker groups (6.8% and 7.9%, P = 0.20, and 20.3% and 17.7%, P = 0.65, respectively). There also was no significant difference in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P = 0.06). CONCLUSION: Long-term carvedilol therapy added on the contemporary evidence-based medications did not seem beneficial in selected STEMI patients treated with primary PCI. TRIAL REGISTRATION: CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) ClinicalTrials.gov.number, NCT 01155635.

Predictive performance of dual modality of computed tomography angiography and intravascular ultrasound for no-reflow phenomenon after percutaneous coronary stenting in stable coronary artery disease.

Attenuated plaque on intravascular ultrasound (IVUS) and low attenuation plaque on computed tomography angiography (CTA) are associated with no-reflow phenomenon during percutaneous coronary intervention (PCI). However, evaluation by a single modality has been unable to satisfactorily predict this phenomenon. We investigated whether the combination of IVUS and CTA findings can ameliorate the predictive potential for no-reflow phenomenon after stent implantation during PCI in stable coronary artery disease (CAD). A total of 988 lesions of 707 stable CAD patients who underwent coronary CTA before PCI were enrolled. PCI was performed with preprocedural IVUS and stent implantation. As for plaque characters, very low attenuation plaque (CTA v-LAP) whose minimum density was < 0 Hounsfield units on CTA and attenuated plaque (IVUS AP) on IVUS were evaluated. No-reflow phenomenon was observed in 22 lesions (2.2%) of 19 patients (2.7%). Both CTA v-LAP and IVUS AP were much more frequently observed in patients with no-reflow phenomenon. Positive (PPV) and negative predictive values (NPV) and accuracy for prediction of no-reflow were almost equivalent between CTA v-LAP (13.2, 99.6, and 87.0%) and IVUS AP (15.7, 99.8, and 89.0%). The combination of CTA v-LAP and IVUS AP markedly ameliorated PPV (31.7%) without deterioration of NPV (99.7%) and increased the diagnostic accuracy (95.5%). These findings showed that the combination of CTA v-LAP and IVUS AP improved the predictive power for no-reflow phenomenon after coronary stenting in stable CAD patients, suggesting the usefulness of combined estimation by using CTA and IVUS for predicting no-reflow phenomenon during PCI in clinical practice.

Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II)　- A Randomized Controlled Clinical Trial.

BACKGROUND: Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. CONCLUSIONS: Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

Safety margin of minimized contrast volume during percutaneous coronary intervention in patients with chronic kidney disease.

Maximum allowable contrast dose (MACD) calculated as body weight × 5/serum creatinine has been a standard contrast dye volume (CV) used to decrease contrast-induced acute kidney injury. Recent advances in intravascular ultrasound-guided percutaneous coronary intervention (PCI) can dramatically minimize CV. The safe threshold when using an extremely low-dose CV is unknown. This study was designed as a multicenter, retrospective study of chronic kidney disease (CKD) patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m(2) undergoing elective PCI. We divided the patients into three groups according to following criteria: (1) low dose, CV/eGFR ratio <1.0; (2) medium dose, CV/eGFR ratio ≥1 and

Coexistence of visceral fat and multiple risk factor accumulations is strongly associated with coronary artery disease in Japanese (the VACATION-J study).

AIM: Multiple risk factor syndrome is a target for the prevention of coronary artery disease (CAD). A cluster of multiple risk factors, such as hypertension, glucose intolerance, and/or dyslipidemia, is encountered in Japanese without and with excess visceral fat. The present study investigated the relationship between multiple risk factor accumulation and CAD in Japanese without and with visceral fat accumulation. METHODS: The study subjects comprised 257 Japanese with suspected CAD (males/females= 153/ 104), who underwent 64-row multislice computed tomography (CT) coronary angiography and visceral fat area (VFA) measurement by CT. Based on the Japanese criteria for visceral fat accumulation, they were divided into those with VFA <100 and ≥10 cm(2). RESULTS: In subjects with VFA <100 cm(2), the age- and sex-adjusted odds ratios (ORs) for 2 and 3 risk factors were 5.33 (95% confidence intervals; 1.04-27.38, p=0.0449) and 4.07 (0.72-23.15, p=0.1138), respectively, compared with VFA <100 cm(2) and 0 risk factor set at 1.0 (p=0.0569 for trend). In contrast, the respective ORs for subjects with VFA ≥100 cm(2) were much higher [6.46 (1.25-33.44, p=0.0261) and 20.42 (3.60-115.73, p=0.0007)] (p<0.0001 for trend). The multivariate adjusted model demonstrated a significant relative excess CAD risk of 1.08 (p=0.0484) and 5.01 (p<0.0001) for the interactions of 2 risk factors and VFA ≥100 cm(2), and 3 risk factors and VFA ≥100 cm(2), whereas multiple risk factor accumulation was not related with the increase of CAD risk in subjects with VFA <100 cm(2). CONCLUSIONS: Coexistence of visceral fat and risk factor accumulations is strongly associated with CAD in Japanese.

Increased productivity of tumor necrosis factor-alpha in helper T cells in patients with systolic heart failure.

BACKGROUND AND AIMS: Whereas increased circulating proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), play an important role in heart failure, where and how TNF-alpha production is upregulated remains largely unknown. We studied the productivity of TNF-alpha in peripheral lymphocytes and underlying mechanisms in patients with heart failure. METHODS: Symptomatic NYHA II-IV patients with chronic heart failure with systolic dysfunction (n=39, aged 74+/-11, ejection fraction [EF]<==50%) were compared with asymptomatic NYHA I patients (n=18, aged 72+/-10, EF>50%) and normal subjects (n=15, aged 67+/-11). Lymphocyte subsets (CD3, CD4, and CD8) and intracellular production of TNF-alpha in peripheral leukocytes were quantified by immunofluorescent flow cytometry, and relationships between these parameters and circulating proinflammatory cytokines were analyzed. RESULTS: Subpopulation of TNF-alpha-producing CD4 was larger in NYHA II-IV patients (23.7% [18.0-28.6]) than in normal subjects (17.1% [6.5-19.5], p<0.05) and was correlated with plasma TNF-alpha levels (r=0.26, p<0.05), EF (r=-0.26, p<0.05), CD4/CD8 ratios (r=0.42, p<0.001), and subpopulation of TNF-alpha-producing monocytes (r=0.47, p<0.0001). Plasma levels of soluble CD14 and interleukin-12 (IL-12) were significantly higher in NYHA II-IV patients than in normal subjects (1971 ng/mL [1740-2375] vs. 1607 ng/mL [1530-1930], p<0.01; and 121 pg/mL [62-230] vs. 62 pg/mL [54-99], p<0.05, respectively), and plasma IL-12 levels were correlated with plasma TNF-alpha levels (r=0.41, p<0.001). CONCLUSIONS: Increased productivity of TNF-alpha in helper T cells, associated with their dominance over cytotoxic T cells, may partially contribute to an increase in circulating TNF-alpha levels in heart failure.