Keiko Nakagawa

Vitamin E Deficiency in Variant Angina

BACKGROUND Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm. METHODS AND RESULTS Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma alpha-tocopherol levels as well as alpha-tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma gamma-tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels were not significantly different between group 1 patients with and those without a significant organic stenosis. In group 1, both alpha- and gamma-tocopherol levels were significantly elevated after a > or = 6-month angina-free period. The alpha-tocopherol levels in the LDL fraction were significantly lower in group 1 than in group 4. Plasma alpha-tocopherol levels were significantly correlated with those in the LDL fractions. In 6 patients of group 1 still having anginal attacks while receiving calcium channel blockers, the addition of vitamin E acetate (300 mg/d) significantly elevated plasma alpha-tocopherol levels and inhibited the occurrence of angina. CONCLUSIONS Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

Chronic Kidney Disease and CHADS2 Score Independently Predict Cardiovascular Events and Mortality in Patients With Nonvalvular Atrial Fibrillation

Chronic kidney disease is a risk factor for cardiovascular events, but how it relates to the prognosis associated with clinical risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (AF) is not well known. Estimated glomerular filtration rate (eGFR), score for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS(2)), and clinical outcomes of cardiovascular events were determined in 387 patients with nonvalvular AF (mean age 66 years, 289 men, mean follow-up 5.6 ± 3.2 years). Decreased eGFR (<60 ml/min/1.73 m(2)) combined with CHADS(2) score ≥2 was associated with higher all-cause (12.9% vs 1.4% per year, hazard ratio [HR] 6.9, p <0.001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, p <0.001) mortalities compared to preserved eGFR (≥60 ml/min/1.73 m(2)) combined with CHADS(2) score <2. This was also true for rates of cardiac events (cardiac death, nonfatal myocardial infarction, or hospitalization for worsening of heart failure, 10.4% vs 1.3% per year, HR 8.9, p <0.001), ischemic stroke (3.6% vs 0.2% per year, HR 11.0, p <0.001), and cardiovascular events (cardiac events and ischemic stroke, 13.6% vs 1.5% per year, HR 8.3, p <0.001). On multivariate analysis, CHADS(2) score ≥2, decreased eGFR, and male gender independently predicted all-cause mortality. In conclusion, combined eGFR and CHADS(2) score could be an independent powerful predictor of cardiovascular events and mortality in patients with nonvalvular AF. Long-term mortality, cardiac events, and stroke risk were >8 times higher when decreased eGFR (<60 ml/min/1.73 m(2)) was present with higher CHADS(2) score (≥2).

Alterations of autonomic nervous activity preceding nocturnal variant angina: Sympathetic augmentation with parasympathetic impairment ☆ ☆☆ ★

BACKGROUND Autonomic nervous discharge has been implicated in the pathogenesis of coronary artery spasm. METHODS Cardiac autonomic nervous activities were evaluated from the power of the low-frequency and the high-frequency spectral components of heart rate variability with Holter monitoring in 18 patients with nocturnal variant angina. Samples during the first 512 seconds of each 10-minute period from 60 minutes before to immediately before an anginal attack occurring during the night or at dawn (2:00 to 7:00 AM) were analyzed by fast Fourier transformation. RESULTS The R-R interval during the 10- to 0-minute period was significantly shorter than those during the other 10-minute periods. The coefficient of variance of the high-frequency component (0.15 to 0.40 Hz) (CVHF) from the 10- to 0-minute period was not significantly different from the other 10-minute periods. However, both the coefficient of variance of the low-frequency component (0.04 to 0.15 Hz) (CVLF) and the ratio of CVLF and CVHF (CVLF/CVHF) were significantly greater during the 10- to 0-minute period than those during the 30- to 20-minute period, respectively. A significant nighttime fluctuation in the spectral components of heart rate variability with a peak in the CVHF and a nadir in both the CVLF and CVLF/CVHF observed in the control group was blunted in the patients during the attack-free periods while they were medicated with calcium entry blockers. CONCLUSION Sympathovagal imbalance, sympathetic activation without parasympathetic augmentation, enhanced in the early morning may play an important role in the genesis of coronary artery spasm in patients with nocturnal variant angina.

Consumption of vitamin E in coronary circulation in patients with variant angina

OBJECTIVES The plasma status of vitamin E has been suggested to be linked to the activity of coronary artery spasm. This study was designed to determine whether vitamin E is actually consumed in the coronary circulation in patients with active variant angina having repetitive spasm-induced transient myocardial ischemia and reperfusion. METHODS Blood samples were obtained simultaneously from the aortic root, coronary sinus and right atrium in 12 patients with variant angina due to spasm of the left coronary artery, nine patients with stable effort angina and nine control subjects. Plasma vitamin E (alpha- and gamma-tocopherol) concentrations were determined by use of high-performance liquid chromatography and plasma lipid peroxides were measured as thiobarbituric acid-reactive substances (TBARS). RESULTS At baseline, both plasma alpha- (p < 0.01) and gamma- (p < 0.05) tocopherol levels were significantly lower in the coronary sinus (5.50 +/- 0.50 and 0.55 +/- 0.07 mg/l, mean +/- SEM) than in the aortic root (6.63 +/- 0.57 and 0.63 +/- 0.08 mg/l) and also in the right atrium (6.44 +/- 0.61 and 0.63 +/- 0.09 mg/l) in the variant angina group. The TBARS level was significantly (p < 0.05) higher in the coronary sinus than in the aortic in this group. In contrast, these levels were not significantly different between the samples from the coronary sinus and the aortic root or the right atrium in the control group and also in the stable effort angina group. The coronary sinus-aortic difference in plasma vitamin E levels in the variant angina group was not significantly altered after left coronary artery spasm induced by intracoronary injection of acetylcholine. Also, the plasma vitamin E levels in the aortic root, coronary sinus and right atrium all remained unchanged in the stable effort angina group after pacing-induced angina and in the control group after intracoronary administration of acetylcholine. CONCLUSIONS Transcardiac reduction in plasma vitamin E concentrations concomitant with lipid peroxide formation was demonstrated in patients with active variant angina, suggesting actual consumption of this major endogenous antioxidant. Oxidative stress and vitamin E exhaustion may be involved in the pathogenesis of coronary artery spasm.

Relation of left atrial blood stasis to clinical risk factors in atrial fibrillation

BACKGROUND The present study was conducted to investigate whether an accumulation of clinical risk factors for thromboembolism would correlate with severity of blood stasis in the left atrium (LA) and aortic atherosclerosis in patients with nonvalvular atrial fibrillation (NVAF). METHODS Risk levels of thromboembolism were assessed in 515 (mean age 67.5 years) NVAF patients using CHADS(2) score (an acronym for Congestive heart failure, Hypertension, Age >or=75, Diabetes mellitus, and prior Stroke or transient ischemic attack) to estimate the thromboembolic risk. Spontaneous echocardiographic contrast in the LA (LASEC), left atrial appendage (LAA) peak flow velocity, and severity of atherosclerosis in the descending aorta were determined with transesophageal echocardiography. RESULTS LASEC was significantly increased, and LAA flow velocity significantly decreased in correlation with an increase in the risk levels, as evaluated by CHADS(2) score (p<0.001). Severity of aortic atherosclerosis also increased in correlation with an increase in the risk levels (p<0.001). Even at the comparable risk level, patients with chronic atrial fibrillation (AF) (n=268) had higher LASEC (p<0.001) and lower LAA flow velocity (p<0.001) than those with paroxysmal AF (n= 52) who were in AF rhythm at the time of echocardiographic investigation. CONCLUSION Severity of blood stasis in the LA and aortic atherosclerosis correlates with an accumulation of clinical risk factors for thromboembolism in NVAF patients. Additionally, the severity of blood stasis in the LA was greater in chronic AF patients than in paroxysmal AF patients at the comparable risk level.

Exercise-induced U-wave alterations as a marker of well-developed and well-functioning collateral vessels in patients with effort angina.

OBJECTIVES We sought to determine whether exercise-induced U-wave alterations are observed in association with well-developed and well-functioning collateral vessels. BACKGROUND Although exercise-induced electrocardiographic (ECG) U-wave alterations including negative and prominent U waves have been established as a marker of significant or critical narrowing of a major coronary artery, the relation between this finding and the degree of collateral development has not yet been determined. METHODS Patients with stable effort angina were divided into two groups according to the presence (group A, n = 46) or absence (group B, n = 79) of exercise-induced either negative or prominent U waves in the precordial leads; the clinical profiles, coronary angiographic findings and also ischemic status during 60 s of coronary balloon occlusion were compared between the two groups. RESULTS The incidence of severe angina (CCS [Canadian Cardiovascular Society] class III or IV) was higher (p < 0.05) in group A (52%) than in group B (32%) patients. Good collateral vessels (Rentrop grade 2 or 3) into the perfusion territory of the culprit vessel were observed more frequently (p < 0.05) in group A (70%) than in group B (43%) patients. Coronary balloon angioplasty was carried out in 23 patients of group A and 40 patients of group B. Both ischemic ST changes (52% vs. 85%) and angina (57% vs. 80%) during balloon inflation were less (p < 0.05) frequently observed in group A than in group B. The incidence of no apparent myocardial ischemia with ST deviation or angina during the balloon inflation was higher (p < 0.05) in group A (39%) than in group B (10%) patients. In the prediction of the absence of myocardial ischemia during balloon inflation by the presence of exercise-induced U-wave alterations, the sensitivity was 69% (9/13) and the specificity was 72% (36/50) in the study patients. CONCLUSIONS Exercise-induced U-wave alterations are a marker for well-developed collateral circulation in patients with stable but severe effort angina. This finding is also highly predictive of the absence of myocardial ischemia during transient coronary balloon occlusion and possibly of low-risk for development of acute myocardial infarction or hemodynamic instability upon abrupt closure of the culprit coronary artery.

Lipoprotein(a) is a risk factor for occurrence of acute myocardial infarction in patients with coronary vasospasm

OBJECTIVES The purpose of this study is to determine whether lipoprotein(a) (Lp[a]) is an independent risk factor for coronary spasm and occurrence of acute myocardial infarction (AMI) in patients with coronary spasm. BACKGROUND Although elevated serum Lp(a) levels are known to be associated with coronary atherosclerosis and AMI, the association between the elevated level of this lipoprotein and coronary spasm remains to be elucidated. METHODS Serum Lp(a) levels were measured using a latex immunoassay in 77 patients with coronary spasm but without a significant (>75%) fixed coronary stenosis, including 16 with prior myocardial infarction (MI), in 177 patients with a fixed stenosis but without rest angina, including 114 with prior MI and in 81 control subjects without coronary artery disease. RESULTS The serum Lp(a) level in patients with coronary spasm (median; 17 mg/dl) was higher (p < 0.01) than in control subjects (12 mg/dl) but lower (p < 0.01) than in patients with a fixed stenosis (23 mg/dl). The incidence of subjects with higher (>25 mg/dl) serum Lp(a) levels was higher in patients with a fixed stenosis (46%, p < 0.01) but not in patients with coronary spasm (27%), compared with control subjects (21%). Among the patients with coronary spasm, the incidence of higher Lp(a) levels was higher in patients with than in those without a history of prior MI (56% vs. 21%, p < 0.05). The patients with higher Lp(a) levels had a higher incidence of prior MI than those without (41% vs. 13%, p < 0.05). The multivariate analysis confirmed that higher serum Lp(a) level is an independent determinant for prior MI in these patients (odds ratio, 4.19; 95%, confidence interval, 1.03 to 17.00). CONCLUSIONS Elevated serum level of Lp(a) was found to be associated with a history of prior MI in patients with coronary spasm, suggesting that Lp(a) may play an important role in the genesis of thrombotic coronary occlusion and the occurrence of AMI subsequent to coronary spasm.

Clinical and transesophageal echocardiographic variables for prediction of thromboembolic events in patients with nonvalvular atrial fibrillation at low-intermediate risk

BACKGROUND There is no clear consensus about antithrombotic treatment in atrial fibrillation (AF) patients at low-intermediate thromboembolic risk. Transesophageal echocardiography (TEE) is useful for prediction of thromboembolic events in AF. METHODS AND RESULTS Of 498 patients with nonvalvular AF, incidence of stroke, cardiac events, and mortality was investigated in 280 patients with CHADS(2) score 0 or 1 (mean age 64 years, mean follow-up 6.4 ± 3.1 years). Left atrial abnormality (low left atrial appendage flow, spontaneous echo contrast, or thrombi), complex aortic plaque (mobile, ulcerated, pedunculate, or thickness ≥ 4mm), or both were defined as TEE risk. The incidences of ischemic stroke, cardiovascular events, and death were higher in patients with TEE risk than in those without the risk (2.0%/year vs. 0.5%/year, p<0.05; 4.7%/year vs. 1.9%/year, p<0.01; and 4.7%/year vs. 2.0%/year, p<0.01, respectively). This was also true for patients with CHADS(2) score of 0 (1.7%/year vs. 0.3%/year, p<0.05; 4.1%/year vs. 1.6%/year, p<0.05; and 3.9%/year vs. 1.4%/year, p<0.01; respectively). On multivariate analysis, TEE risk predicted ischemic stroke, cardiovascular events, and mortality independently of clinical variables or CHADS(2) score. CONCLUSIONS TEE could be useful for further stratification of patients with nonvalvular AF stratified at low-intermediate risk (CHADS(2) score 0 or 1) and could indicate who should receive anticoagulation treatment.

High-density lipoprotein particles are large in patients with variant angina

OBJECTIVE Dyslipidemia in patients with coronary vasospasm may be characterized by low level of high-density lipoprotein (HDL)-cholesterol as well as apolipoprotein (apo) A-I but not high level of low-density lipoprotein-cholesterol. This study sought to examine the HDL particle size in patients with variant angina. METHODS The HDL particle size was examined by analyzing serum lipid levels in 38 patients with variant angina to compare with those of 40 control subjects and 30 normocholesterolemic patients with stable effort angina. Also, actual HDL size distribution was assessed by electrophoresis. RESULTS The HDL-cholesterol, apoA-I and apoA-II levels were all lower (P < 0.01 for each) in patients with variant angina and patients with stable effort angina as compared with control subjects. The apoA-II level was lower (P < 0.01) in patients with variant angina than in patients with stable effort angina. The apoA-I/apoA-II ratio was lower (P < 0.01) in patients with stable effort angina, but not in patients with variant angina as compared with control subjects. In contrast, the HDL-cholesterol/apoA-I ratio was higher in patients with variant angina than in control subjects (P < 0.01) and also patients with stable effort angina (P < 0.01). The slope of the regression line, comparing HDL-cholesterol and apoA-I levels, was greater in patients with variant angina than in control subjects (P < 0.05) and patients with stable effort angina (P < 0.05), suggesting an increase in larger HDL particles. Native polyacrylamide gel electrophoresis revealed that HDL particles in patients with variant angina were skewed towards larger sizes compared with control subjects (P < 0.01) and patients with stable effort angina (P < 0.01). The abnormal serum lipid values were normalized in the patients with variant angina after the medical treatment and inactivation of the coronary spasm. CONCLUSION High HDL-cholesterol/apoA-I levels associated with low serum HDL-cholesterol and apoA-I levels were characteristic in patients with variant angina, in whom HDL particles were large, cholesterol-rich and possibly malfunctioning.

Impact of persistent smoking on long-term outcomes in patients with nonvalvular atrial fibrillation

BACKGROUND Although smoking is a risk factor for cardiovascular diseases, little is known about the impact of smoking on long-term outcomes in patients with atrial fibrillation (AF). METHODS In 426 consecutive patients with nonvalvular AF (mean age, 66 years; 307 men; mean follow-up, 5.8±3.2 years), clinical variables including smoking status, CHADS2, and CHA2DS2-VASc score, incidences of cardiovascular events (stroke, myocardial infarction, or admission for heart failure), bleeding, and mortality were determined. RESULTS Incidences of intracranial bleeding (0.7% vs 0.1%/year, p<0.01), all-cause mortality (4.9% vs 2.6%/year, p<0.01), and death from stroke (0.8% vs 0.2%/year, p<0.05) were higher in patients with history of smoking than in those without it. Incidence of intracranial bleeding was significantly higher in persistent smokers than in non-persistent smokers (1.2% vs 0.2%/year, p<0.01). History of smoking predicted all-cause mortality [hazard ratio (HR), 2.7; 95% confidence interval (CI), 1.7-4.5; p<0.01] and death from stroke (HR 4.7; 95% CI 1.0-22.3; p<0.05) independent of age, antithrombotic treatment, CHADS2, and CHA2DS2-VASc score. Persistent smoking predicted intracranial bleeding (HR 4.4; 95% CI 1.1-17.6; p<0.05) independent of age and antithrombotic treatment. CONCLUSIONS Smoking status, independent of age, antithrombotic treatment, and clinical risk factors, predicted long-term adverse outcomes including bleeding events in patients with nonvalvular AF. There might be an obvious impact of persistent smoking on intracranial bleeding.