Takeshi Tobiume

Effects of Docosahexaenoic Acid on the Endothelial Function in Patients with Coronary Artery Disease

AIM The consumption of n-3 polyunsaturated fatty acids (PUFA), including docosahexaenoic acid DHA), reduces the incidence of cardiovascular events, and reduced serum levels of n-3 PUFA may be associated with an increased risk of cardiovascular events. However, controversy remains regarding which components of PUFA are associated with the endothelial function in patients with coronary artery disease (CAD). We therefore examined the associations between the n-3 and n-6 PUFA levels and CAD. METHODS We retrospectively reviewed 160 consecutive Japanese patients with CAD whose endothelial function was measured according to the percent change in flow-mediated dilation (FMD) and the serum levels of n-3 PUFA, including eicosapentaenoic acid (EPA) and DHA, and n-6 PUFA, including arachidonic acid (AA) and dihomo-gamma-linolenic acid (DHLA). RESULTS A single regression analysis showed no relationships between the FMD and the serum levels of PUFA, including EPA, DHA, AA and DHLA. In contrast, a multiple regression analysis showed that the DHA level was a positive (＜ 0.01) and age was a negative (P ＜ 0.001) contributor to an increased FMD; however, sex, body mass index, systolic and diastolic blood pressure, current/past smoking and the levels of HbA1c, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, EPA, AA and DHLA did not significantly affect the outcome. CONCLUSIONS The serum level of DHA is associated with the endothelial function evaluated according to the FMD in patients with CAD, thus suggesting that a low serum level of DHA may be a predictive biomarker for endothelial dysfunction.

Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis

OBJECTIVES The promotion of adipose tissue inflammation by lifestyle-related diseases such as obesity and diabetes accelerates atherogenesis; however, the underlying mechanisms remain incompletely understood. Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome contributes to chronic inflammation in adipose tissue. Here, we investigated the link between NLRP3 expression in subcutaneous adipose tissue (SAT) and the severity of coronary atherosclerosis. METHODS AND RESULTS SAT was obtained from 72 patients who underwent heart device implantation and coronary angiography. Expression of NLRP3 inflammasome-related molecules (NLRP3, IL-1β and IL-18) in SAT were evaluated by quantitative RT-PCR. Laboratory markers related to lifestyle-related diseases were measured. Patients with obesity, dyslipidemia (P < 0.05, respectively), diabetes or hyperuricemia (P < 0.01, respectively) had significantly higher expression of NLRP3. Multivariate analysis demonstrated that body mass index and serum level of uric acid were predictors of NLRP3 expression in SAT. The expression of NLRP3 in SAT correlated negatively with serum adiponectin level (r = -0.23, P < 0.05). Patients with coronary artery disease showed higher NLRP3 expression than patients without significant stenosis (P < 0.01). Furthermore, the expression of NLRP3 in SAT correlated positively with the severity of coronary atherosclerosis as determined by Gensini score (r = 0.47, P < 0.0001) or SYNTAX score (r = 0.55, P < 0.0001). Multiple regression analysis revealed that the expression of NLRP3 in SAT remains as an independent predictors for the severity of coronary atherosclerosis. CONCLUSIONS The expression of NLRP3 in SAT, which is affected by lifestyle-related diseases, is associated with the severity of coronary atherosclerosis. Our results suggest that NLRP3 inflammasome in SAT may have a role in atherogenesis.

Serum concentration of eicosapentaenoic acid is associated with cognitive function in patients with coronary artery disease

BackgroundRecent studies have shown that intake of n-3 polyunsaturated fatty acids (PUFAs) is associated with reduced risk of cognitive impairment and coronary artery disease (CAD); however, it is currently unknown whether reduced serum n-3 PUFA is associated with cognitive impairment in patients with CAD.MethodsWe retrospectively evaluated cognitive function with the mini-mental state examination (MMSE), serum levels of PUFAs (including eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], dihomogammalinolenic acid [DGLA], and arachidonic acid [AA]), cardiovascular risk factors (hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, and history of current/previous smoking), and parameters of cardiac function (left ventricular ejection fraction and brain natriuretic peptide levels) in 146 Japanese CAD patients. The associations between the MMSE scores and the other parameters were evaluated.ResultsPearson correlation analysis showed that EPA (R = 0.25, P <0.01), EPA/AA ratio (R = 0.22, P = 0.01), and left ventricular ejection fraction (R = 0.15, P = 0.04) were positively associated with MMSE score, and that age (R = −0.20, P <0.01) and brain natriuretic peptide levels (R = −0.28, P <0.01) were inversely associated with MMSE score. Multiple regression analysis showed that age (P <0.05) was negatively associated with MMSE score, while EPA (P <0.01) and EPA/AA ratio (P <0.05) were positively associated with MMSE score; however, sex; body mass index; left ventricular ejection fraction; levels of DHA, AA, and DGLA; DHA/AA ratio; brain natriuretic peptide; and presence of hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, and history of current/previous smoking were statistically excluded.ConclusionsSerum EPA concentration is associated with cognitive function in patients with CAD, suggesting that a low serum EPA level is a risk factor for cognitive impairment independent of cardiac function, including left ventricular ejection fraction. This correlation potentially lends further support to a role of dietary n-3 PUFAs in preventing the cognitive decline in CAD patients.

Plasma microRNA-100 is associated with coronary plaque vulnerability.

BACKGROUND Although numerous studies have reported altered plasma levels of various microRNAs (miRNAs) in patients with cardiovascular disease, there are no data on the relationship between plasma miRNAs and vulnerable coronary plaque. In this study, we investigated whether plasma miRNAs might be a sensitive marker of coronary plaque vulnerability. METHODS AND RESULTS Integrated backscatter intravascular ultrasound (IB-IVUS) was performed in 32 consecutive patients with angina pectoris who underwent percutaneous coronary intervention. Three-dimensional analysis of IB-IVUS was performed to determine the percentage of lipid volume (%LV) and fibrous volume (%FV). Circulating miRNAs were measured in EDTA-plasma simultaneously obtained from the aorta and the coronary sinus (CS). Muscle-enriched (miR-133a, miR-208a, miR-499), vascular-enriched (miR-92a, miR-100, miR-126, miR-127, miR-145), and myeloid cell-enriched miRNAs (miR-155, miR-223) were measured. Plasma miR-100 was higher in the CS than in the aorta, but there were no significant differences in the levels of other miRNAs between the aorta and CS. Plasma miR-100 in the aorta was positively correlated with %LV (r=0.48, P<0.01) and negatively correlated with %FV (r=-0.41, P<0.05). Importantly, transcoronary concentration gradient of circulating miR-100 was more strongly correlated with %LV (r=0.53, P<0.01) and %FV (r=-0.56, P<0.01). CONCLUSIONS miR-100 might be released into the coronary circulation from vulnerable coronary plaques. This study provides insights into the role of miRNAs in coronary atherosclerotic disease.

Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Incorporating a "Superior" Slow Pathway: A Distinct Supraventricular Tachyarrhythmia

Background— The existence of an atypical fast-slow (F/S) atrioventricular nodal reentrant tachycardia (AVNRT) including a superior (sup) pathway with slow conductive properties and an atrial exit near the His bundle has not been confirmed. Methods and Results— We studied 6 women and 2 men (age, 74±7 years) with sup-F/S-AVNRT who underwent successful radiofrequency ablation near the His bundle. Programmed ventricular stimulation induced retrograde conduction over a superior SP with an earliest atrial activation near the His bundle, a mean shortest spike-atrial interval of 378±119 milliseconds, and decremental properties in all patients. sup-F/S-AVNRT was characterized by a long-RP interval; a retrograde atrial activation sequence during tachycardia identical to that over a sup-SP during ventricular pacing; ventriculoatrial dissociation during ventricular overdrive pacing of the tachycardia in 5 patients or atrioventricular block occurring during tachycardia in 3 patients, excluding atrioventricular reentrant tachycardia; termination of the tachycardia by ATP; and a V-A-V activation sequence immediately after ventricular induction or entrainment of the tachycardia, including dual atrial responses in 2 patients. Elimination or modification of retrograde conduction over the sup-SP by ablation near the right perinodal region or from the noncoronary cusp of Valsalva eliminated and confirmed the diagnosis of AVNRT in 4 patients each. Conclusions— sup-F/S-AVNRT is a distinct supraventricular tachycardia, incorporating an SP located above the Koch triangle as the retrograde limb, that can be eliminated by radiofrequency ablation.

Plasma brain natriuretic peptide levels are elevated in patients with cancer

Background Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. Methods We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Results Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. Conclusions In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients.

Impact of Indoxyl Sulfate, a Uremic Toxin, on Non-Culprit Coronary Plaque Composition Assessed on Integrated Backscatter Intravascular Ultrasound

BACKGROUND Uremic toxin has emerged as an important determinant of cardiovascular risk. The aim of this study was to examine the relationship between serum uremic toxin and coronary plaque composition on integrated backscatter intravascular ultrasound (IB-IVUS). METHODS AND RESULTS IB-IVUS was performed in 47 patients with planned treatment for angina pectoris. Non-culprit intermediate plaque analyzed in this study had to be >5 mm apart from the intervention site. 3-D IB-IVUS analysis was performed to determine percent lipid volume (LV) and fibrous volume (FV). We also measured serum uremic toxins (indoxyl sulfate [IS], asymmetric dimethylarginine [ADMA], and p-cresol [PC]). Glomerular filtration rate correlated with IS (r=-0.329, P=0.04), but did not correlate with ADMA or PC. Percent LV correlated with IS (r=0.365, P=0.02), but did not correlate with ADMA or PC. Percent FV also correlated with IS (r=-0.356, P=0.03), but did not correlate with ADMA or PC. On multivariate regression, only IS was associated with percent LV (r=0.359, P=0.04) and percent FV (r=-0.305, P=0.04) independently of potentially confounding coronary risk factors. CONCLUSIONS Among the uremic toxins, serum IS might be a novel useful biomarker to detect and monitor lipid-rich coronary plaque on IB imaging.

Serial Imaging Changes During Treatment of Immunoglobulin G4–Related Disease With Multiple Pseudotumors

An 80-year-old man noticed a swollen eyelid on his left side and was admitted to our hospital. A chest x-ray showed eccentric cardiomegaly (Figure 1A), and transthoracic echocardiography revealed mild pericardial effusion and a large, low-echoic mass near the inferolateral left ventricular wall (Figure 1B). Other ultrasonic examinations showed thickened outer layers in the bilateral subclavian and iliac arteries (Figure 2B-1). A blood test indicated elevated levels of anti-immunoglobulin G (IgG; 4345 mg/dL), IgG4 (1210 mg/dL), C-reactive protein (7.08 mg/dL), and 60-minute erythrocyte sedimentation rate (100 mm/h). Figure 1. A , Chest x-ray showed eccentric cardiomegaly (arrow). B , Transthoracic echocardiography revealed mild pericardial effusion and a large, low-echoic mass near the inferolateral …

Low Serum Levels of Eicosapentaenoic Acid and Docosahexaenoic Acid are Risk Factors for Cardiogenic Syncope in Patients with Brugada Syndrome

The n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antiarrhythmic effects, possibly via modulation of the cardiac ion channels. Nevertheless, it is unknown whether low serum levels of n-3 PUFAs are risk factors for ventricular fibrillation in patients with Brugada syndrome (BrS). We retrospectively reviewed data from 62 men with BrS and evaluated their serum levels of EPA and DHA, and the risk factors for sudden cardiac death, including a history of cardiogenic syncope. Nineteen patients had a history of cardiogenic syncope, and their EPA and DHA levels were significantly lower than those of the patients without syncope. Multivariate logistic regression analysis revealed that low EPA and DHA levels were associated with the incidence of syncope. The receiver-operator characteristic curve showed the area under the curves of EPA and DHA for history of syncope were 0.84 and 0.72, respectively. In conclusion, low levels of EPA and DHA are risk factors for cardiogenic syncope in patients with BrS, which suggests that n-3 PUFAs play important roles in preventing ventricular fibrillation in BrS.

Clinical, Electrocardiographic, and Echocardiographic Parameter Combination Predicts the Onset of Atrial Fibrillation

BACKGROUND The ability to identify risk markers for new-onset atrial fibrillation (AF) is critical to the development of preventive strategies, but it remains unknown whether a combination of clinical, electrocardiographic, and echocardiographic parameters predicts the onset of AF. In the present study, we evaluated the predictive value of a combined score that includes these parameters. Methods and Results: We retrospectively studied 1,040 patients without AF who underwent both echocardiography and 24-h Holter electrocardiography between May 2005 and December 2010. During a median follow-up period of 68.4 months (IQR, 49.9-93.3 months), we investigated the incidence of new-onset AF. Of the 1,040 patients, 103 (9.9%) developed AF. Patients who developed AF were older than patients who did not. Total heart beats, premature atrial contraction (PAC) count, maximum RR interval, and frequency of sinus pause quantified on 24-h electrocardiography were associated with new-onset AF. LA diameter (LAD) on echocardiography was also associated with the development of AF. On multivariate Cox analysis, age ≥58 years, PAC count ≥80 beats/day, maximum RR interval ≥1.64 s, and LAD ≥4.5 cm were independently associated with the development of AF. The incidence rate of new-onset AF significantly increased as the combined score (i.e., the sum of the risk score determined using hazard ratios) increased. CONCLUSIONS A combined score that includes age, PAC count, maximum RR interval, and LAD could help characterize the risk of new-onset AF.