Reduction in GLP-1 secretory capacity may be a novel independent risk factor of coronary artery stenosis.

Multiple factors regulate glucagon-like peptide-1 (GLP-1) secretion, but a group of apparently healthy subjects showed blunted responses of GLP-1 secretion in our previous study. In this study, we examined whether the reduction in GLP-1 secretory capacity is associated with increased extent of coronary artery stenosis in non-diabetic patients. Non-diabetic patients who were admitted for coronary angiography without a history of coronary interventions were enrolled. Coronary artery stenosis was quantified by Gensini score (GS), and GS ≥ 10 was used as an outcome variable based on its predictive value for cardiovascular events. The patients (mean age, 66.5 ± 8.8 years; 71% males, n = 173) underwent oral 75 g-glucose tolerant tests for determination of glucose, insulin and active GLP-1 levels. The area under the curve of plasma active GLP-1 (AUC-GLP-1) was determined as an index of GLP-1 secretory capacity. AUC-GLP-1 was not correlated with fasting glucose, AUC-glucose, serum lipids or indices of insulin sensitivity. In multivariate logistic regression analysis for GS ≥ 10, AUC-GLP-1 < median, age and hypertension were selected as explanatory variables, though fasting GLP-1 level was not selected. The findings suggest that reduction in GLP-1 secretory capacity is a novel independent risk factor of coronary stenosis.

Homocysteic Acid in Blood Can Detect Mild Cognitive Impairment: A Preliminary Study.

BACKGROUND: In the treatment of Alzheimer's disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-ß (Aß) biomarkers in predicting brain Aß burden at an individual level. However, it is as yet unproven that accumulation of Aß necessarily leads to the development of AD. OBJECTIVE: Homocysteic acid (HCA) is useful as an early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. METHODS: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients' plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. RESULTS: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116µM was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. CONCLUSION: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD.

Screening of primary aldosteronism by clinical features and daily laboratory tests: combination of urine pH, sex, and serum K.

OBJECTIVE: To develop and validate a scoring system for selection of patients who should proceed to endocrinologic examinations of primary aldosteronism in newly diagnosed hypertensive patients. METHODS: A multivariate logistic regression analysis for primary aldosteronism was undertaken by use of seven possible primary aldosteronism markers, age less than 40 years, female sex, moderate-to-severe hypertension, hypokalemia, serum Na minus Cl at least 40 mmol/l, serum uric acid 237.92 µmol/l or less (4.0 mg/dl), and urine pH (U-pH) at least 7.0, in consecutive outpatients newly diagnosed with hypertension. The diagnostic criteria of primary aldosteronism were plasma aldosterone concentration-to-plasma renin activity ratio [ARR, (ng/dl)/(ng/ml per h)] at least 20 and at least one positive result in four types of challenge tests. RESULTS: Of 130 patients, 24 were diagnosed with primary aldosteronism. The area under the receiver operating characteristic curve (AUC) for a logistic model incorporating all possible primary aldosteronism markers was 0.73 [95% confidence interval (CI): 0.61-0.85]. Removing high U-pH, female sex, and hypokalemia from the full model decreased the AUC by 0.059, 0.035, and 0.011, respectively. We devised pH of urine, female sex, low serum K (PFK) score, in which one point each was assigned to high U-pH, female sex, and hypokalemia. The prevalences of primary aldosteronism in patients with 0, 1, 2, and 3 points were 11, 14, 42, and 60%, respectively. In external validation datasets (n = 106), AUC of PFK score was significantly higher than that of hypokalemia alone (0.73, 95% CI: 0.63-0.83 vs. 0.53, 95% CI: 0.44-0.63, P < 0.01). CONCLUSION: PFK score may be a better parameter than hypokalemia alone for identifying patients with a high probability of having primary aldosteronism.

Targeting therapy for homocysteic acid in the blood represents a potential recovery treatment for cognition in Alzheimer's disease patients.

At present, we have no reliable means of recovering cognitive impairment in Alzheimer's disease (AD) patients. We hypothesized that homocysteic acid (HA) in the blood might represent one such pathogen that could be excreted into the urine. Since DHA is known to reduce circulating levels of homocysteine, and since exercise attenuates this effect, it follows that supplementation of the diet with DHA, along with increased levels of physical activity, may help to reduce cognitive impairment in AD patients. Our hypothesis was proven to be correct because memory problems in 3xTg- AD mice (a model for AD in which animals develop amyloid pathology), and in a mouse model of familial AD, were recovered following treatment with an anti-HA antibody and not by amyloid treatment. Interestingly, 3xTg-AD mice with amyloid pathology showed increased levels of HA level. This could perhaps be explained by the fact that amyloid precursor protein and/or presenilin increases calcium influx, which could then increase levels of superoxide and consequently increase levels of HA from homocysteine or methionine. Our hypothesis is also partially supported by an open clinical trial of certain dietary supplements that has shown impressive results. Also there are other treatments hypothesis which would be possible for the effective therapies, such as ribonucleoprotein therapy, a ß-secretase inhibitor treatment and the metabolic enhancement treatment.

Does a Reduction in the Glomerular Filtration Rate Increase the Overall Severity of Coronary Artery Stenosis?

OBJECTIVE: Chronic kidney disease is a risk factor of coronary events, however, its impact on coronary artery stenosis has not yet been clarified with the use of a large database. We examined the association between a reduced glomerular filtration rate (GFR) and the overall severity of coronary stenosis. METHODS: We enrolled 1,150 patients [mean age, 68±12 (SD) years; 66.6% men] who consecutively underwent coronary angiography for suspected stable angina pectoris. The overall severity of stenosis in the coronary arteries was assessed by the Gensini score (GS), and its logarithmic values (log-GS) were used for statistical analyses since the GS does not follow a normal distribution. RESULTS: The log-GS was significantly larger in men than in women (2.5±1.5 vs. 1.9±1.7), while the estimated GFR (eGFR) and comorbidities were comparable between both sexes. A multivariate regression analysis indicated that age, smoking, eGFR, HDL-cholesterol and HbA1c were independent explanatory variables of the log-GS in men, although the eGFR explained only 1.2% of the log-GS variation. In women, the eGFR was not included in the significant explanatory variables shown by the multivariate analysis. However, the sex difference in the regression for the eGFR-log-GS relationship was not statistically significant. CONCLUSION: A reduced eGFR is a significant, but minor, determinant of the overall severity of coronary artery stenosis in men and potentially women.

Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients.

Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-ß increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD.

Treatment of Alzheimer's disease with anti-homocysteic acid antibody in 3xTg-AD male mice.

Alzheimer's disease (AD) is an age-associated progressive neurodegenerative disorder with dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that homocysteic acid (HA) may be one of the pathological biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal amyloid-beta (Abeta) peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathological 3xTg-AD mice exhibited higher levels of HA in the hippocampus than did age-matched nontransgenic mice, suggesting that HA accumulation may precede both Abeta and tau pathologies. We then fed 3-month-old 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to increase the HA levels in the brain. Concomitantly, mice received either saline or anti-HA antibody intraventricularly via a guide cannula every 3 days during the course of the B6-deficient diet. We found that mice that received anti-HA antibody significantly resisted cognitive impairment induced by vitamin B6 deficiency and that AD-related pathological changes in their brains was attenuated compared with the saline-injected control group. A similar neuroprotective effect was observed in 12-month-old 3xTg-AD mice that received anti-HA antibody injections while receiving the regular diet. We conclude that increased brain HA triggers memory impairment and that this condition deteriorates with amyloid and leads to subsequent neurodegeneration in mouse models of AD.

Prolonged stress will induce Alzheimer's disease in elderly people by increased release of homocysteic acid.

Recently, many papers have reported the physiological functions of amyloid beta and amyloid precursor protein (APP). In particular, one of its functions is of importance for synaptic plasticity. Extracellular amyloid beta may suppress synaptic plasticity or inhibit long-term potentiation (LTP) from outside the cell. LTP is now considered the molecular basis of memory. Amyloid beta may induce the inhibition or loss of memory. We propose that suppression of LTP by amyloid beta induces a kind of physiological forgetfulness. On the other hand, homocysteic acid (HA) which is released from astrocytes under stress conditions accumulates the amyloid beta into neuronal cell, which consequently induces the inhibition of amyloid beta physiological function and induces strong LTP. We propose that HA induces strong unforgetful memory under stress condition such as PTSD and emotional depression. The situation is different in the elderly people. Prolonged stress in the elderly people may induce neurodegenerative diseases such as Alzheimer's disease. We observed that in the presence of excess methionine, HA induced alpha-synuclein protein in cultured cells, suggesting a hypermethylation model in vivo. Usually hypermethylation is observed in the ageing process. We have shown that HA promotes the accumulation of amyloid beta in cells, and that the production of alpha-synuclein, which induces the aggregation of amyloid beta, impairing the cell function. LTP is inhibited by deficient cellular function, which means that memories cannot be formed. In fact, there is confusion of memories in the early stages of Alzheimer's disease. Finally, the aggregated alpha-synuclein induces tau pathology, which induces cell death, leading to Alzheimer's pathology. In conclusion, we propose that HA induces Alzheimer's pathology in the elderly people because of prolonged stress.

Homocysteic acid induces intraneuronal accumulation of neurotoxic Abeta42: implications for the pathogenesis of Alzheimer's disease.

The causes of neuronal dysfunction and degeneration in Alzheimer's disease (AD) are not fully understood, but increased production of neurotoxic forms of amyloid beta-peptide-42 (Abeta42) seems of major importance. Large extracellular deposits of aggregated Abeta42 (plaques) is a diagnostic feature of AD, but Abeta42 may be particularly cytotoxic when it accumulates inside neurons. The factors that may promote the intracellular accumulation of Abeta42 in AD are unknown, but recent findings suggest that individuals with elevated homocysteine levels are at increased risk for AD. We show that homocysteic acid (HA), an oxidized metabolite of homocysteine, induces intraneuronal accumulation of a Abeta42 that is associated with cytotoxicity. The neurotoxicity of HA can be attenuated by an inhibitor of gamma-secretase, the enzyme activity that generates Abeta42, suggesting a key role for intracellular Abeta42 accumulation in the neurotoxic action of HA. Concentrations of HA in cerebrospinal fluid (CSF) were similar in AD and control subjects. CSF homocysteine levels were elevated significantly in AD patients, however, and homocysteine exacerbated HA-induced neurotoxicity, suggesting a role for HA in the pathogenic action of elevated homocysteine levels in AD. These findings suggest that the intracellular accumulation of Abeta42 plays a role in the neurotoxic action of HA, and suggest a potential therapeutic benefit of agents that modify the production and neurotoxic actions of HA and homocysteine.

Prognostic value of the Tei index combining systolic and diastolic myocardial performance in patients with acute myocardial infarction treated by successful primary angioplasty.

Cardiac systolic (left ventricular ejection fraction) and diastolic (mitral inflow velocity pattern and/or mitral deceleration time) function were reported as predictors of clinical outcome or left ventricular remodeling in patients with acute myocardial infarction (AMI). Recently, a new index (Doppler-derived index combining systolic and diastolic myocardial performance; Tei index) for combined systolic and diastolic ventricular function has been reported to be a useful and convenient method for evaluation of global ventricular function. We therefore investigated the usefulness of the Tei index by echocardiography for evaluation of infarct size and clinical outcome in patients with AMI treated by successful primary angioplasty. We analyzed 10 age-matched control subjects and 43 consecutive patients with first AMI treated by successful primary angioplasty. The Tei index of the AMI patients was significantly greater than that of the control subjects (0.630 +/- 0.106 vs 0.375 +/- 0.036, P << 0.0001). Also, the Tei index showed a significant positive correlation with peak creatine kinase values and (99m)Tc-tetrofosmin scores. Moreover, multiple logistic regression analysis showed that the Tei index >>0.70 ( P = 0.0313, odds ratio = 14.14) was the only significant explanatory factor for cardiac death or developed congestive heart failure. The Tei index combining systolic and diastolic myocardial performance reflects infarct size and might be a predictor of clinical outcome in patients with AMI treated by successful primary angioplasty.

Comparison of three-year clinical outcome of the multi-link stent with the Palmaz-Schatz stent in Japanese patients with coronary artery disease: a case control study.

Results of trials using the ACS Multi-Link (ML) stent, one of the new generation stents, were similar to or slightly better than those of trials using the Palmaz-Schatz (PS) stent. The purpose of this study was to compare long-term (3-year) clinical outcomes of patients with coronary artery disease treated with the ML stent to those treated with the PS stent. The present study consisted of 52 patients who underwent successful coronary ML stent implantation (ML group) and 52 matched control patients who underwent successful coronary PS stent implantation (PS group) from October 1997 to September 1999. During follow-up periods, cardiac events occurred in 11 patients (21%) in the ML group and 14 patients (27%) in the PS group, respectively (p = NS). Angiographic restenosis rates of American College of Cardiology/American Heart Association (ACC/AHA) lesion type A or B1 were 8.3% in both groups, and ACC/AHA lesion type B2 or C were 39.3% in the ML group and 35.7% in the PS group, respectively (p = NS). In addition, angiographic restenosis rates of ACC/AHA lesion type A or B1 were significantly lower than those of lesion type B2 or C in both groups. The results of the present study suggest that 6-month angiographic and 3-year clinical outcomes in patients with coronary artery disease treated by coronary stenting with the ML stent were comparable to those with the PS stent.

Coronary stent implantation in patients with a single coronary artery--a report of 3 cases.

An isolated single coronary artery is a rare congenital anomaly and a cause of cardiac ischemia, congestive heart failure, and sudden cardiac death. Reported here are 3 cases of single coronary artery with acute myocardial infarction in which coronary stenting was performed. Also reported are the coronary blood flow patterns of the right coronary artery arising from the single left coronary artery.

Clinical and angiographic results after MULTI-LINK stent implantation and their relation to aggregation of risk factors: two-year follow-up.

Results of trials using the ACS MULTI-LINK (ML) stent, one of the new generation stents, were similar to or slightly better than those of trials using the Palmaz-Shatz stent. The purpose of this study was to evaluate relatively long-term (2 years) clinical outcomes of patients with coronary artery disease treated with the ML stent and to determine independent factors correlated with target lesion revascularization and cardiac events. The present study consisted of 82 consecutive patients who had undergone successful coronary ML stent implantation from January 1997 to December 1999. During the follow-up period, cardiac events occurred in 16 (19.5%) patients. All patients underwent follow-up angiography and 12 (14.6%) of the 82 patients underwent target lesion revascularization. Multiple logistic regression analysis showed that aggregation of risk factors (> or = 3 risk factors) (p = 0.0274, odds ratio=5.14) and percent diameter stenosis >20% (p = 0.0395, OR = 4.586) were the significant explanatory factors of target lesion revascularization. In addition, aggregation of risk factors (> or = 3 risk factors) exhibited a tendency to correlate with cardiac events (p = 0.0528) on multiple logistic regression analysis. The results of the present study suggest that target lesion revascularization after coronary ML stent implantation was influenced by aggregation of major coronary risk factors and residual percent diameter stenosis and that long-term clinical outcome is influenced by the aggregation of risk factors.

Long-term follow-up after coronary stent implantation in patients with coronary artery disease.

Prospective randomized trials of coronary stenting in patients with coronary artery disease have shown a reduced incidence of cardiac events. However, little is known of the late outcome of patients treated with coronary stenting. The purpose of this study was to evaluate the relatively long-term clinical outcomes (3 to 6 years) of patients treated with successful coronary stenting. The long-term clinical outcome was studied in 101 consecutive patients (78 males and 23 females) who had undergone successful coronary stent implantation for coronary artery disease in our hospital from October 1994 to September 1997. During a follow-up period of 48.9+/-9.5 months (range, 6-73 months), cardiac events were documented in 37 patients. The rate of survival free of cardiac events was 67% at 3 years. Multiple logistic regression analysis showed that ACC/AHA lesion type and residual percent diameter stenosis greater than 20% after stenting were the significant explanatory factors of adverse cardiac events. Long-term clinical outcome in patients with coronary artery disease treated with successful coronary stenting was influenced by the ACC/AHA lesion type of stented lesion and residual percent diameter stenosis after stent implantation.

Blockade of angiotensin II type 1 receptors suppressed free radical production and preserved coronary endothelial function in the rabbit heart after myocardial infarction.

The hypothesis that blockade of angiotensin II type 1 (AT1) receptors after myocardial infarction prevents coronary endothelial vasomotor dysfunction by suppressing oxygen free radical production was examined. Rabbits underwent coronary ligation or a sham operation with or without infusion of valsartan, an AT 1 receptor blocker. Two weeks after the operation, the heart was isolated from each rabbit and perfused with buffer in the Langendorff mode, and coronary flow responses to acetylcholine and sodium nitroprusside were assessed. The ratio of heart weight to body weight and the lipid peroxide level in the myocardium were increased by 30 and 50%, respectively, 2 weeks after infarction. The coronary flow response to acetylcholine (10(-8) to 10(-5) M) was reduced by 50% in the hearts with infarction compared with the sham controls, although coronary flow responses to sodium nitroprusside were similar. The coronary flow response to acetylcholine in the hearts with infarction was restored by concurrent infusion of N -2-mercaptopropionyl-glycine, a free radical scavenger. Valsartan (10 mg/kg/d) infused after infarction prevented both ventricular remodeling and elevation of the tissue lipid peroxide level and preserved coronary flow response to acetylcholine. In conclusion, long-term AT1 receptor blockade after infarction protects the coronary arteries from endothelial vasomotor dysfunction through suppression of free radical production.