Increased plasma glutamate in non-smokers with vasospastic angina pectoris is associated with plasma cystine and antioxidant capacity.

Objectives. Endothelial dysfunction caused by oxidative stress plays an important role in the development of vasospastic angina pectoris (VSAP). Glutamate causes endothelial dysfunction by generating oxidative stress, and it inhibits cystine import into endothelial cells via the cystine/glutamate antiporter (XC-), which leads to depletion of antioxidant glutathione. However, whether glutamate and cystine are implicated in the pathogenesis of VSAP remains unclear. We investigated plasma glutamate and cystine levels, oxidative stress markers and antioxidant capacity in non-smoker patients with VSAP to determine whether glutamate and cystine are associated with the development of VSAP. We assessed 49 non-smokers assigned to groups with (n = 27) and without (n = 22) VSAP, and also measured plasma glutamate, cystine, nitrotyrosine, reactive oxygen metabolites and biological antioxidant potential. Results. Plasma glutamate and cystine values were significantly higher in the group with, than without VSAP (59.8 ± 25.7 vs. 43.5 ± 18.7 µmol/L, p = .016 and 35.3 ± 14.2 vs. 25.2 ± 9.1 µmol/L, p = .0056, respectively). Plasma glutamate and cystine values were significantly and positively associated (r = 0.32, p = .027). Levels of the oxidative stress markers nitrotyrosine and reactive oxygen metabolites, and biological antioxidant potential of as a measure of antioxidant capacity, did not significantly differ between the two groups. However, glutamate and biological antioxidant potential values were significantly and negatively associated (r = -0.3, p = .036). Conclusion. Plasma glutamate levels were increased in patients with VSAP who did not smoke, and they were positively associated with plasma cystine and negatively associated with the biological antioxidant potential levels.

Glyceraldehyde-derived advanced glycation end-products are associated with left ventricular ejection fraction and brain natriuretic peptide in patients with diabetic adverse cardiac remodeling.

Objectives: Glyceraldehyde-derived advanced glycation end-products (Glycer-AGEs) have a strong binding affinity for their cognate receptor and elicit oxidative stress and inflammation. However, it remains unknown whether the levels of Glycer-AGEs correlate with the severity of cardiac function and heart failure in patients with diabetic adverse cardiac remodeling (DbCR). Fourteen heart failure patients with type 2 diabetes mellitus (DM) without other cardiac disorders (DbCR group) were enrolled. Another 14 patients with idiopathic dilated cardiomyopathy (DCM) without DM were served as a control (DCM group). All patients were assessed for serum Glycer-AGEs, nitrotyrosine (NT), and tumor necrosis factor alpha (TNFα) and for plasma brain natriuretic peptide (BNP). The left ventricular ejection fraction (LVEF) was evaluated by echocardiography. Results: The mean serum levels of Glycer-AGEs, NT, and TNFα in the DbCR group were significantly higher than those in the DCM group (for Glycer-AGEs, p = .0073; for NT, p = .005; for TNFα, p < .0001, respectively). In the patients with DbCR, the levels of serum Glycer-AGEs and TNFα were closely associated with LVEF and BNP values. Conclusions: Both Glycer-AGEs and TNFα showed close associations with LVEF and the levels of BNP in patients with DbCR. Glycer-AGEs and TNFα may play a pathological role in the development of DbCR.

Nutri-pharmacogenomics of warfarin anticoagulation therapy: VKORC1 genotype-dependent influence of dietary vitamin K intake.

Warfarin is the most widely prescribed oral anticoagulant, but large interindividual variations exist in the dose required to achieve comparable therapeutic effects. Several clinical and genetic variables have been identified that influence warfarin dosing. However, interactions between genotype and nutrition remain uncertain in terms of dietary vitamin K intake. To investigate genotype-nutrient interactions in warfarin anticoagulation therapy, 202 consecutive outpatients (M/F = 142/60, mean age, 69 years) undergoing treatment with warfarin were enrolled. Prevalent single nucleotide polymorphisms in VKORC1 and CYP2C9 were genotyped, and dietary vitamin K intake during the week preceding the blood sampling was quantitatively estimated by a dietitian-assisted questionnaire. Patients were classified according to low, medium, or high vitamin K intake. The mean daily warfarin dose in subjects with a VKORC1-1639 A/A genotype was significantly smaller than that with a -1639A/G genotype (2.74 vs. 3.91 mg/day, respectively, p < 0.0001). Dose requirements did not differ between subjects with a CYP2C9 *1/*3 genotype versus a CYP2C9 *1/*1 genotype. In subjects with a variant VKORC1-1639 G allele, the mean daily warfarin dose was significantly attenuated by low vitamin K intake compared with medium and high intake after adjustment for covariates (3.4 vs. 5.0 vs. 4.0 mg/day, respectively, p = 0.028). No such genotype effects were observed in homozygous patients for the VKORC1-1639 A allele. The results of the present study suggest that the capacity of dietary vitamin K intake to influence warfarin dose requirements during anticoagulation therapy is VKORC1 genotype-dependent, at least in part.

Thrombotic Microangiopathy after a 15-year Treatment with Interferon Beta-1b in a Patient with Multiple Sclerosis: A Case Report and Review of Literature.

A 54-year-old woman with multiple sclerosis treated with interferon-ß (IFN-ß)-1b for 15 years presented with sustained hypertension (240/124 mmHg) and retinal bleeding. She had proteinuria, anemia, thrombocytopenia, elevated serum creatinine levels, and haptoglobin depletion. Intravenous nicardipine stabilized her blood pressure, but her renal function and platelet count deteriorated. The initial disintegrin-like metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity was 28% of normal without its inhibitor. The subsequent peripheral appearance of schistocytes suggested thrombotic microangiopathy (TMA). After IFN-ß-1b cessation, the platelet count increased, and the blood pressure stabilized. The ADAMTS13 activity normalized, although the creatinine level did not. TMA may develop after the long-term use of IFN-ß without adverse events.

The circulating furin-cleaved/mature PCSK9 ratio has a potential prognostic significance in statin-naïve patients with acute ST elevation myocardial infarction.

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, but their biological functions are uncertain. We investigated whether their levels associate with prognosis in patients with acute ST elevation myocardial infarction (STEMI). Methods: We enrolled 160 statin-naïve patients with acute STEMI and followed for 3 years. PCSK9 subtype levels were determined by an enzyme-linked immunosorbent assay before and at five timepoints up to 48 h after emergent coronary intervention. The occurrence of coronary and cardiac events was compared between subjects stratified by the PCSK9 level. Results: One hundred and twenty-six patients completed 3 years of follow-up. In the acute phase, both PCSK9 subtype levels decreased, and thereafter increased from 6 to 48 h (mature: from 198 ± 67 to 334 ± 116 ng/mL, furin-cleaved: from 20 ± 7 to 39 ± 16 ng/mL, both p < 0.01). Major cardiac events occurred in 46 patients. The furin-cleaved/mature PCSK9 ratio at 48 h after coronary intervention predicted the likelihood of experiencing of events; patients in the third tertile had lower event-free survival than those in the first and second tetiles in Kaplan-Meier analysis (p = 0.004). Multivariate Cox regression analysis revealed that this ratio had a greater impact (HR: 1.92; 95% CI: 1.06-3.45, p = 0.03) on events than other known atherosclerosis risk factors. Conclusions: The furin-cleaved/mature PCSK9 ratio was associated with 3-year cardiovascular events in statin-naïve patients with acute STEMI, suggesting a potential link between furin cleavage process of PCSK9 and its effect on prognosis. (249 words).

Diurnal glycemic fluctuation is associated with severity of coronary artery disease in prediabetic patients: Possible role of nitrotyrosine and glyceraldehyde-derived advanced glycation end products.

BACKGROUND: Glucose fluctuation (GF) is a risk factor for coronary artery disease (CAD). However, it remains unknown whether specific indices of GF are risk factors for CAD. Therefore, we evaluated the relationship between GF, as determined by a continuous glucose monitoring system (CGMS) or the glucose level at 2h after a 75-g oral glucose tolerance test (75g OGTT 120), and the severity of CAD in prediabetic patients. We also evaluated whether nitrotyrosine (NT) and glyceraldehyde-derived advanced glycation end-products (Glycer-AGE) were induced by GF. METHODS: Twenty-eight prediabetic patients underwent coronary angiography (CAG), and the Gensini score and the SYNTAX score were evaluated as the severity of CAD, while the mean amplitude of glycemic excursions (MAGE) by CGMS and 75g OGTT 120 were evaluated. Serum NT and Glycer-AGE were measured. RESULTS: The MAGE was closely associated with the Gensini score (r=0.742, p<0.001) and the SYNTAX score (r=0.776, p<0.001), respectively. The 75g OGTT 120 was not associated with the Gensini score (r=0.36, p=0.06), but it was significantly associated with the SYNTAX score (r=0.413, p=0.036). Multiple linear regression analysis showed that the MAGE was the only independent determinant for the severity of CAD. The levels of NT and Glycer-AGE were significantly higher in the high MAGE group than in the low MAGE group. CONCLUSIONS: Diurnal GF is associated with the severity of CAD, even in prediabetic patients. GF, NT, and Glycer-AGE may play a pathological role in the progression of CAD.

Circulating Glutamate and Taurine Levels Are Associated with the Generation of Reactive Oxygen Species in Paroxysmal Atrial Fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but its proarrhythmic mechanism remains to be elucidated. Glutamate (Glu) and taurine (Tau) are present in the myocardium at substantially higher concentrations than in the plasma, suggesting their active role in myocardium. Here, we tested the hypothesis that the metabolism of Glu and Tau is altered in association with the generation of reactive oxygen species (ROS) in patients with AF. Fifty patients with paroxysmal AF and 50 control subjects without a history of AF were consecutively enrolled. Circulating Glu and Tau levels were measured and correlations between Glu/Tau and ROS levels were examined. Glu/Tau content was significantly higher in patients with AF versus controls (Glu: 79.2 ± 23.9 versus 60.5 ± 25.2 nmol/L; Tau: 78.8 ± 19.8 versus 68.5 ± 20.8 nmol/L; mean ± standard deviation (SD), p < 0.001 for both). Glu/Tau levels also showed an independent association with AF by multiple logistic regression analysis. Glu and Tau levels both showed significant positive associations with plasma hydroperoxide concentrations. These data suggest a novel pathophysiological role of Glu and Tau in association with ROS production in paroxysmal AF, providing new insights into the elevated amino acid content in cardiac disease.

Chronic total occlusions of the right coronary and left anterior descending coronary arteries in a young adult patient with antiphospholipid syndrome.

A 36-year-old male appeared to have an old myocardial infarction on electrocardiogram, and coronary angiography (CAG) was performed. The CAG showed total occlusions of the right coronary artery and left anterior descending artery. He was successfully treated with drug-eluting stent implantation for both occluded coronary arteries. Such serious coronary lesions are uncommon for his young age. The patient was diagnosed as having antiphospholipid syndrome (APS) based on elevation of anticardiolipin antibody and anti-ß2 glycoprotein I antibody. Two years after stent implantation, the patient was well without ischemia or thrombosis. APS should be considered a potential cause of serious coronary disease in young adults. .

Increased levels of the oxidative stress marker, nitrotyrosine in patients with provocation test-induced coronary vasospasm.

BACKGROUND: Endothelial dysfunction of the coronary arteries caused by oxidative stress plays an important role in the pathogenesis of coronary vasospasm. However, it is not clear whether circulating biomarkers for oxidative stress are altered after coronary vasospasm. We investigated temporal changes in the levels of oxidative stress biomarkers after coronary vasospasm induced by intracoronary acetylcholine provocation testing, resulting in transient myocardial ischemia. METHODS AND RESULTS: Thirty consecutive patients with suspected vasospastic angina pectoris (VSAP) were enrolled in the study. Patients were categorized into the VSAP-positive group (n=14) and the VSAP-negative group (n=16) on the basis of test results. Serum samples were examined for the levels of the oxidative stress markers 4-hydroxynonenal (HNE) and nitrotyrosine (NT) before, and 15min, 3h, and 12h after the provocation test. The serum HNE levels did not change in either group after the test. The serum NT levels in the VSAP-positive group significantly increased at 3h and 12h after the test (11.3±3.3µg/ml at 3h, p=0.015, and 12.1±5.7µg/ml at 12h, p=0.03), as compared with baseline (8.1±3.2µg/ml). In the VSAP-negative group, the serum NT levels significantly decreased from baseline at each of the 3 time points. CONCLUSIONS: Serum NT significantly increased after coronary vasospasm induced by acetylcholine provocation, suggesting that serum NT could be a biomarker of transient myocardial ischemia and could contribute to the development of VSAP.

Serum deoxyribonuclease I activity can be a useful diagnostic marker for the early diagnosis of unstable angina pectoris or non-ST-segment elevation myocardial infarction.

BACKGROUND AND PURPOSE: Recently, serum deoxyribonuclease I (DNase I) activity has been highlighted as a potential diagnostic marker for transient myocardial ischemia. To evaluate whether serum DNase I activity can be a useful biomarker for diagnosing unstable angina pectoris (UAP) or non-ST-segment elevation myocardial infarction (NSTEMI), we investigated serial changes in DNase I levels after chest pain in UAP and NSTEMI (UAP/NSTEMI) patients. METHODS AND RESULTS: Thirty-three and ten patients classified into the UAP/NSTEMI and the chest pain syndrome (CPS) group, respectively, were enrolled. The serum DNase I activity levels within 3h after chest pain and the absolute median value of percentage differences in serum DNase I activity levels from admission to 3h after hospitalization in the UAP/NSTEMI patients was significantly higher than those in the CPS patients. We evaluated the patients to show positive results for DNase I activity if the serum levels or percentage differences exceeded the corresponding cut-off values. The sensitivity and specificity of DNase I within 6h after chest pain in the UAP/NSTEMI patients without elevated levels of cardiac troponin T and the MB isoenzyme of creatine kinase were 89% and 88%, respectively. CONCLUSIONS: Serum DNase I activity can be a useful marker for the early diagnosis of UAP/NSTEMI after the onset of chest pain, irrespective of the evidence of myocardial injury.