Diallyl Trisulfide Augments Ischemia-Induced Angiogenesis via an Endothelial Nitric Oxide Synthase-Dependent Mechanism.

BACKGROUND: Hydrogen sulfide (H2S) exerts beneficial actions against the development of cardiovascular disease. Diallyl trisulfide (DATS) is an organic polysulfide found in garlic oil that liberates H2S under physiological conditions. This study investigated whether DATS modulates endothelial cell function, as well as revascularization processes in a mouse model of hind-limb ischemia.Methods and Results:Wild-type (WT), endothelial nitric oxide synthase-deficient (eNOS-KO) and Akt1-heterogenic deficient (Akt-Het) mice were subjected to unilateral hindlimb ischemia (HLI). DATS or a vehicle control was injected into the abdomen of mice for up to 10 days following HLI induction. Treatment with DATS enhanced blood flow recovery and capillary density in the ischemic limbs of WT mice. This was accompanied by a reduction in apoptotic activity and oxidative stress in the ischemic muscles. DATS also increased the phosphorylation of Akt and eNOS in ischemic muscles. In contrast to WT mice, DATS did not improve blood flow of eNOS-KO and Akt-Het mice. In cultured human umbilical vein endothelium cells, DATS decreased apoptotic activity and oxidative stress under hypoxic conditions, and stimulated the phosphorylation of Akt and eNOS. Inhibition of Akt or NOS signaling reversed DATS-stimulated eNOS phosphorylation and blocked the effects of DATS on apoptosis and oxidative stress. CONCLUSIONS: These observations suggest that DATS promotes revascularization in response to HLI through its ability to stimulate the Akt-eNOS signaling pathway.

East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.

BACKGROUND: Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. METHODS AND RESULTS: The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). CONCLUSIONS: East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.

Increased urinary aldosterone excretion is associated with subcutaneous not visceral, adipose tissue area in obese individuals: a possible manifestation of dysfunctional subcutaneous adipose tissue.

BACKGROUND: Aldosterone is reported to be associated with obesity and is a risk factor for metabolic syndrome. Metabolic abnormalities are more strongly associated with visceral adipose tissue (VAT) than with subcutaneous adipose tissue (SAT). OBJECTIVE: We examined whether aldosterone is more closely associated with VAT area than with SAT area in obese individuals. METHODS: We enrolled 81 Japanese patients (46 men, mean age 43 ± 13 years and 35 women, mean age 53 ± 10 years) suspected of metabolic disorders and measured plasma and 24-h urinary aldosterone, as well as SAT and VAT areas. SAT and VAT areas were measured at the umbilical level by computed tomography. RESULTS: Spearman's rank correlation analysis showed that urinary aldosterone was significantly and positively correlated with body mass index, waist circumference, SAT area, alanine aminotransferase, C-reactive protein, plasma immune-reactive insulin, plasma renin activity and estimated glomerular filtration rate, and negatively correlated with age and blood glucose. Urinary aldosterone was not correlated with VAT area (r = 0·013, P = 0·906). Multivariate regression analyses revealed that log SAT area, age and diastolic blood pressure were significant (P = 0·001, 0·001 and 0·032, respectively) predictors of log urinary aldosterone excretion rate. CONCLUSION: Our results indicate that urinary aldosterone excretion is positively associated with SAT but not with VAT area in the middle-aged obese individuals.Urinary aldosterone is also negatively correlated with age.

Detection of coronary artery disease using automated quantitation of myocardial perfusion on single-photon emission computed tomography images from patients with angina pectoris without prior myocardial infarction.

BACKGROUND: Whether or not automated scores obtained from myocardial single-photon emission computed tomography (SPECT) imaging using software correlate with the visual interpretations by experts remains obscure. METHODS AND RESULTS: Eighty-seven consecutive patients with known or suspected angina pectoris underwent (201)thallium stress/rest SPECT followed by coronary angiography and the summed difference scores (SDS) were calculated using Heart Score View software. The SDS was substantially associated with coronary stenosis and accurately detected culprit lesions, because the diagnostic accuracy was comparable to that of expert visual evaluation. CONCLUSIONS: Automated scores obtained from myocardial SPECT can help detect coronary artery disease.

Comparison of exercise electrocardiography and magnetocardiography for detection of coronary artery disease using ST-segment fluctuation score.

BACKGROUND: Exercise electrocardiography (ECG) is frequently used as a diagnostic measure in patients with suspected coronary artery disease (CAD). However, it has low sensitivity for the detection of CAD. Magnetocardiography (MCG) has been proposed as an alternative tool to accurately diagnose CAD. OBJECTIVE: To date, a direct comparison of MCG to ECG has not been performed. This study sought to compare them for predicting the presence of significantly obstructive CAD. METHODS: The patients with chest pain or other symptoms suggestive of CAD were enrolled in the analysis. All the patients underwent a clinical evaluation, exercise ECG, MCG test, and coronary angiography (CA). CAD was defined as stenosis ≥70% in at least one major coronary artery on quantitative analysis of CA. RESULTS: We prospectively enrolled 202 consecutive patients who suggested CAD. The prevalence of CAD on CA was 39.1%. Sensitivity and accuracy for CAD diagnosis was higher for MCG compared with exercise ECG (sensitivities 68.4% and 40.5%, p <0.001, specificities 95.1% and 91.1%, p = 0.267, and accuracies 84.7% and 71.3%, p <0.001, respectively). There was no incremental diagnostic value of combined MCG and ECG to detect coronary artery disease (p = 0.357). CONCLUSIONS: For the patients with intermediate to high risk of CAD, MCG exercise test provides better diagnostic accuracy for the detection of relevant obstruction of the epicardial coronaries when directly compared to exercise ECG.

Magnetocardiography scoring system to predict the presence of obstructive coronary artery disease.

BACKGROUND: Magnetocardiography (MCG) has been proposed as a non-invasive and functional technique with high accuracy for diagnosis of myocardial ischemia. OBJECTIVE: This study sought to develop a novel scoring system of MCG for predicting the presence of significant obstructive coronary artery disease (CAD). METHODS: In a training set of 108 subjects, predictors of ≥70% stenosis in at least one major coronary vessel were prospectively identified from MCG variables. The final model was then retrospectively validated in a separate set of 45 subjects. RESULTS: In the multivariable logistic regression, among those in the training set, elevated scores were predictive of ≥70% stenosis in all subjects (OR: 40.85; 95% CI: 6.28-265.90; p < 0.001). In the validation set, the score had an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) for ≥70% stenosis. At an optimal cutoff, the score had 89% sensitivity, 77% specificity, 74% positive predictive value (PPV), 91% negative predictive value (NPV), and 82% accuracy for ≥70% stenosis. Partitioning the score into three levels of predicted risk, 91% of subjects could be identified or excluding CAD (81% PPV and 84% NPV). CONCLUSION: We described an MCG score with high accuracy for predicting the presence of anatomically significant CAD.

Pioglitazone, a peroxisome proliferator-activated receptor γ activator, suppresses coronary spasm.

OBJECTIVE: We examined whether a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, suppresses coronary spasm. BACKGROUND: Patients with coronary spastic angina (CSA) also have endothelial dysfunction and inflammation. Activation of PPAR-γ improves endothelial dysfunction and inflammation. PARTICIPANTS AND METHODS: The study participants included 73 consecutive CSA patients (47 men and 26 women, mean age 63.6±10.4 years) who were admitted to our institution with a suspicion of CSA because of episodes of chest discomfort occurring mostly at rest in whom coronary spasm was induced by an intracoronary acetylcholine injection and a repeat acetylcholine provocation injection was administered after 6 months of follow-up. Thirty-six of the patients were administered pioglitazone15-30 mg/day added on calcium channel blockers (CCBs) (pioglitazone group) and 37 were administered CCBs alone (control group). Clinical and laboratory data were also examined before and after 6 months of follow-up and the results between the two groups were compared. RESULTS: Coronary spasm was suppressed in 18/36 patients (50.0%) in the pioglitazone group (P<0.001) and 8/37 patients (21.6%) in the control group (P=0.008) after 6 months of treatment. Coronary spasm was thus significantly reduced in the pioglitazone group compared with the control group (P=0.011). The levels of total white blood cell count and high-sensitivity C-reactive protein decreased significantly (P<0.001 and P<0.001, respectively) in the pioglitazone group, whereas these levels did not differ in the control group (P=0.15 and 0.39, respectively) after the treatment. CONCLUSION: Pioglitazone added on CCBs significantly reduced coronary spasm compared with CCBs alone after 6 months of treatment. Pioglitazone may thus prove to be a novel therapy for coronary spasm.

Differences and interactions between risk factors for coronary spasm and atherosclerosis--smoking, aging, inflammation, and blood pressure.

Objective Coronary spasm as well as atherosclerosis plays an important role in the pathogenesis of coronary heart disease. However, the relationship between coronary spasm and atherosclerosis is not well known. The purpose of the present study was to examine the differences and interactions between risk factors for coronary spasm and atherosclerosis and thereby explore the pathogenesis of coronary spasm. Methods The study subjects consisted of 938 patients with chest discomfort (522 men and 416 women, mean age 65.2±11.0) who underwent intracoronary-acetylcholine provocation tests for coronary spasm. Coronary risk factors, including age, gender, body mass index, blood pressure, high-sensitivity C-reactive protein (hsCRP), white blood cells, glucose, lipid profiles, and other laboratory chemistries were examined. Results Four hundred and ninety-six patients (315 men and 181 women, mean age: 65.1±11.4) were diagnosed with coronary spastic angina (CSA), while the remaining 442 patients (207 men and 235 women, mean age: 65.3±10.7) were diagnosed with non-CSA. A multiple logistic regression analysis revealed men, smoking, hsCRP, and low diastolic blood pressure (DBP) to be predictors (p=0.001, p=0.009, p=0.034, and p=0.041, respectively) for CSA, while age, diabetes mellitus, low high-density lipoprotein-cholesterol, systolic blood pressure (SBP), uric acid and male gender were found to be predictors (p<0.001, p<0.001, p<0.001, p=0.002, p=0.006 and p=0.029, respectively) for atherosclerosis. Conclusion Predictors for coronary spasm were smoking, hsCRP and low DBP, whereas those for atherosclerosis were age, diabetes mellitus, high SBP, and uric acid in that order. These findings suggest that the pathogenesis of coronary spasm differs from that of atherosclerosis.

Alcohol flushing and positive ethanol patch test in patients with coronary spastic angina: possible role of aldehyde dehydrogenase 2 polymorphisms.

OBJECTIVE: Coronary spasm plays an important role in the pathogenesis of coronary heart disease (CHD) and angina pectoris caused by coronary spasm or coronary spastic angina (CSA) is prevalent in Japan. However, the precise mechanisms underlying coronary spasm are unclear. Alcohol intolerance is prevalent among East Asians, and we previously reported that coronary spasm could be induced by alcohol intake in CSA patients. We herein examined whether CSA is associated with alcohol intolerance in Japanese subjects. METHODS: The study subjects consisted of 80 CSA patients (57 men/ 23 women, mean age 62 ± 12) and 52 non-CSA patients (25 men/27 women, mean age 63 ± 10). The ethanol patch test (EPT) and questionnaire which evaluates flushing after ethanol intake, along with an examination of clinical features and laboratory chemistry data for CHD risk factors were done. Gender (male) and smoking were higher (p=0.007, and p=0.019, respectively) and plasma HDL cholesterol level was lower (p=0.035) in the CSA patients than in the non-CSA patients. Multivariable logistic regression analysis including age, EPT, smoking, and plasma HDL cholesterol level as independent variables revealed that positive EPT and smoking were significant predictors of CSA (p=0.011 and p=0.016, respectively). CONCLUSION: Positive EPT and alcohol flushing following alcohol intake, as well as smoking and plasma levels of HDL cholesterol, were significantly associated with CSA in Japanese patients. Therefore, alcohol ingestion as well as smoking is a significant risk factor for CSA in Japanese.

Coronary spastic angina is associated with insulin resistance - possible involvement of endothelial dysfunction.

OBJECTIVE: In this study, we examined whether coronary spastic angina (CSA) is associated with insulin resistance. BACKGROUND: There is increasing evidence that insulin resistance is associated with endothelial dysfunction. Patients with CSA show endothelial dysfunction. METHODS: The study participants include 111 CSA patients (81 men and 30 women, mean age 62±12 years) and 53 participants without CSA (24 men and 29 women, mean age 63±10 years), serving as the controls. The oral glucose tolerance test was performed, and anthropometric parameters, plasma glucose and insulin levels, lipid profiles, and other laboratory parameters were evaluated. RESULTS: Homeostasis model assessment of insulin resistance (HOMA-IR), Log HOMA-IR, the quantitative insulin sensitivity check index, the insulin sensitivity index, and insulin resistance 60-120 min after glucose load (log post-glucose-IR) were calculated as surrogate markers of insulin resistance. The number of men, the number of smokers, log post-glucose-IR, the insulin sensitivity index, and fasting plasma glucose levels were higher in CSA patients compared with controls (P=0.001, 0.001, 0.004, 0.012, and 0.013, respectively), whereas plasma high-density lipoprotein cholesterol levels were lower (P<0.001). CONCLUSION: Insulin resistance on glucose load (log post-glucose-IR), plasma high-density lipoprotein cholesterol levels, and smoking were significantly associated with CSA (r=0.225, P=0.004; r=-0.313, P<0.001; and r=0.258, P=0.001, respectively).

Suppression of primary aldosteronism and resistant hypertension by the peroxisome proliferator-activated receptor gamma agonist pioglitazone.

The peroxisome proliferator-activated receptor gamma (PPAR γ) agonists have been reported to have antiproliferative and tumor-suppressive effects. We report a case of 55-year-old man with primary aldosteronism (PA) whose hyperaldosteronism was suppressed with the PPAR γ agonist pioglitazone. He had drug-resistant hypertension, hypokalemia, and diabetes mellitus. The diagnosis of PA was confirmed by the oral sodium loading test (20.5 µg/d of urinary aldosterone) and Captopril challenge test (19.5 ng/dL of plasma aldosterone). Computed tomography imaging revealed no apparent adrenal mass. The result of the posture stimulation test was consistent with the diagnosis of idiopathic adrenal hyperplasia. On administration of pioglitazone (30 mg/d) and nifedipine (40 mg/d), hypertension and hypokalemia improved and plasma aldosterone decreased for more than 6 months. The sodium loading test done after 6 months of the administration revealed the near normal results (11.2 ng/dL of plasma aldosterone and 13.1 µg/d of urinary aldosterone). The findings indicated that pioglitazone suppressed PA.

Aerobic interval exercise training in the afternoon reduces attacks of coronary spastic angina in conjunction with improvement in endothelial function, oxidative stress, and inflammation.

BACKGROUND: Coronary spasm plays an important role in the pathogenesis of ischemic heart disease. Endothelial function is impaired in patients with coronary spasm. Exercise training has been shown to improve endothelial function. OBJECTIVE: We examined the effects of aerobic interval exercise training (AIT) on attacks in conjunction with endothelial function in patients with coronary spastic angina. PARTICIPANTS AND METHODS: The study participants were 26 patients with rest angina (19 men and 7 women, mean age 61.7±11.7 years) in whom coronary spasm was documented and no severe organic lesions were found. The numbers of attacks and of individuals with attacks were examined in conjunction with endothelial function, oxidative stress, inflammation, and insulin resistance before and after 3 successive days of AIT. RESULTS: The number of attacks/patient and the ratio of patients with attacks/5 days decreased [from 2 (1, 7) to 0 (0, 2), P<0.001, and from 23/26 (88.5%) to 10/26 (38.5%), P<0.001] in conjunction with the improvement in endothelial function assessed by improved flow-mediated dilatation (4.8±2.7 vs. 6.9±2.8%, P<0.001), plasma levels of diacron-reactive oxygen metabolites (363±58 vs. 349±61 U.CARR, P=0.001), interleukin-6[1.63 (1.33, 2.22) vs. 1.39 (1.09, 2.02) pg/ml, P=0.012], high-sensitivity C-reactive protein [0.087 (0.041, 0.136) vs. 0.063 (0.028, 0.085) mg/dl, P=0.028], and homeostasis model assessment-insulin resistance [1.79 (1.41, 2.39) vs. 1.54 (1.17, 1.79) mg/dl µU/ml, P=0.005] after AIT. CONCLUSION: AIT in the afternoon suppressed the attacks in conjunction with improvement in endothelial function, oxidative stress, inflammation, and insulin resistance in patients with coronary spastic angina.