Carole Richard

Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential

Diabetes has emerged as a major threat to worldwide health. The exact mechanisms underlying the disease are unknown; however, there is growing evidence that the excess generation of reactive oxygen species (ROS) associated with hyperglycemia, causes oxidative stress in a variety of tissues. In this context, various natural compounds with pleiotropic actions like α-lipoic acid (LA) are of interest, especially in metabolic diseases such as diabetes. LA, either as a dietary supplement or a therapeutic agent, modulates redox potential because of its ability to match the redox status between different subcellular compartments as well as extracellularly. Both the oxidized (disulfide) and reduced (di-thiol: dihydro-lipoic acid, DHLA) forms of LA show antioxidant properties. LA exerts antioxidant effects in biological systems through ROS quenching but also via an action on transition metal chelation. Dietary supplementation with LA has been successfully employed in a variety of in vivo models of disease associated with an imbalance of redox status: diabetes and cardiovascular diseases. The complex and intimate association between increased oxidative stress and increased inflammation in related disorders such as diabetes, makes it difficult to establish the temporal sequence of the relationship.

Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases.

In the past few years, a growing interest has been given to the possible antioxidant functions of a natural acid, synthesized in human tissues: alpha-lipoic acid (ALA). Both the oxidized (disulfide) and reduced (dithiol: dihydrolipoic acid, DHLA) forms of ALA show antioxidant properties. ALA administered in the diet accumulates in tissues, and a substantial part is converted to DHLA via a lipoamide dehydrogenase. Commercial ALA is usually a racemic mixture of the R and S forms. Chemical studies have indicated that ALA scavenges hydroxyl radicals, hypochlorous acid, and singlet oxygen. ALA exerts antioxidant effects in biological systems not only through direct ROS quenching but also via transition metal chelation. ALA has been shown to possess a number of beneficial effects both in the prevention and treatment of diabetes in experimental conditions. ALA presents beneficial effects in the management of symptomatic diabetic neuropathy and has been used in this context in Germany for more than 30 years. In cardiovascular disease, dietary supplementation with ALA has been successfully employed in a variety of in vivo models: ischemia-reperfusion, heart failure, and hypertension. More mechanistic and human in vivo studies are needed to determine whether optimizing the dietary intake of ALA can help to decrease cardiovascular diseases. A more complete understanding of cellular biochemical events that influence oxidative damage is required to guide future therapeutic advances.

The free oxygen radicals test (FORT) to assess circulating oxidative stress in patients with acute myocardial infarction.

BACKGROUND AND AIM Reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases including cardiovascular diseases. Several methods have been developed for the direct or indirect measurement of oxygen free radical and its by-products. The current study was designed to validate the new free oxygen radicals test (FORT) and to investigate the potential relationships between ROS and clinical or biological factors in male patients with acute myocardial infarction (AMI). METHODS We analysed FORT values in samples from 66 patients with AMI. RESULTS FORT values ranged from 324 to 1198 FORT units, with a median value of 581 (494-754) FORT units. In univariate analysis, FORT values were positively related only to LVEF <40% (p=0.005), levels of CRP (r=0.438, p<0.001) and peak CK (r=0.274, p=0.028). Multiple linear regression analysis showed that CRP (p=0.023), LVEF <40% (p<0.001) and the presence of diabetes (p=0.039) were independent predictors of serum FORT values. This statistical model can explain 45% of the variance in FORT values (R(2)=0.45). CONCLUSIONS The FORT is a simple tool to assess circulating ROS in routine clinical practice. Oxidative conditions such as inflammation and diabetes are the major determinants of FORT values in patients with AMI.

Effects of angiotensin-1 converting enzyme inhibition on oxidative stress and bradykinin receptor expression during doxorubicin-induced cardiomyopathy in rats.

To evaluate the mechanisms and the impact of the angiotensin-converting enzyme inhibitor perindopril (P) in a model of doxorubicin (D)-induced cardiotoxicity, male Wistar rats received D (1 mg/kg/d, IP for 10 days), P (2 mg/kg/d by gavage from day 1 to day 18), D (for 10 days) + P (for 18 days) or saline. D decreased systolic blood pressure and body and heart weights. Left ventricular diastolic diameter was increased by D (P < 0.01), but it was not attenuated by P. D decreased plasma vitamin C (P < 0.05) and increased the ascorbyl radical/vitamin C ratio (P < 0.01). This ratio was attenuated by P. No difference was found among groups in cardiac troponin I, brain natriuretic peptide concentrations, and tissue oxidative stress (OS). Myocardial MCP-1 expression was higher in the D group. Cardiac kinin receptor (B1R and B2R) expression was not affected by D, yet binding sites for B2R and B1R were increased in D+P and P groups, respectively (P < 0.05). In conclusion, D induced cardiac functional alterations, inflammation and plasma OS whereas tissue OS, and cardiac kinin receptors expression were not modified. P did not improve cardiac performance, but it modulated kinin receptor expression and enhanced antioxidant defense.

General oxidative stress during doxorubicin-induced cardiotoxicity in rats: Absence of cardioprotection and low antioxidant efficiency of alpha-lipoic acid

To evaluate the effects of alpha-lipoic acid (AL) in a model of doxorubicin (DOX)-induced cardiotoxicity, male Wistar rats were treated with DOX (1 mg/kg/d; 10 d) in combination or not with AL (50 mg/kg/d; 15 d). Plasma oxidative stress was determined by hydroperoxides (ROOH) and the ascorbyl radical/ascorbate ratio. One and two months later, the functional parameters of the hearts were determined in vivo by catheterization and cardiac oxidative stress was assessed by malonedialdehyde (MDA) and O₂*⁻ (dihydroethidium fluorescence) content in tissue. After two months, body weight was higher in the DOX-AL group than in DOX (+16%), but this was due to ascites. Histological liver alterations were observed in both the DOX and DOX-AL groups. Plasma ROOH concentrations decreased after 10 days of AL treatment, but were greater in both the DOX and DOX-AL groups. After two months, a decrease in the cardiac contractility index (-27% and -29%, respectively) and cardiac hypertrophy were observed in DOX and DOX-AL. These dysfunctions were associated with 1) a reduction in plasma ascorbate levels and an increase in the ascorbyl/ascorbate ratio and 2) an increase MDA and O₂*⁻ content in cardiac tissue. In conclusion, a cumulative dose of 10 mg/kg doxorubicin induced functional alterations in the heart associated with plasma and cardiac oxidative stress. The co-administration of the antioxidant compound AL had no beneficial effects in this situation.

Frequency and Predictors of Stroke After Acute Myocardial Infarction Specific Aspects of In-Hospital and Postdischarge Events

Background and Purpose— Stroke is a serious complication after acute myocardial infarction (AMI) and is closely associated with decreased survival. This study aimed to investigate the frequency, characteristics, and factors associated with in-hospital and postdischarge stroke in patients with AMI. Methods— Eight thousand four hundred eighty-five consecutive patients admitted to a cardiology intensive care unit for AMI, between January 2001 and July 2010. Stroke/transient ischemic attack were collected during 1-year follow-up. Results— One hundred twenty-three in-hospital strokes were recorded: 65 (52.8%) occurred on the first day after admission for AMI, and 108 (87%) within the first 5 days. One hundred six patients (86.2%-incidence rate 1.25%) experienced in-hospital ischemic stroke, and 14 patients (11.4%-incidence rate 0.16%) were diagnosed with an in-hospital hemorrhagic stroke. In-hospital ischemic stroke subtypes according to the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification showed that only 2 types of stroke were identified more frequently. As expected, the leading subtype of in-hospital ischemic stroke was cardioembolic stroke (n=64, 60%), the second was stroke of undetermined pathogenesis (n=38, 36%). After multivariable backward regression analysis, female sex, previous transient ischemic attack (TIA)/stroke, new-onset atrial fibrillation, left ventricular ejection fraction (odds ratio per point of left ventricular ejection fraction), and C-reactive protein were independently associated with in-hospital ischemic stroke. When antiplatelet and anticoagulation therapy within the first 48 hours was introduced into the multivariable model, we found that implementing these treatments (≥1) was an independent protective factor of in-hospital stroke. In-hospital hemorrhagic stroke was dramatically increased (5-fold) when thrombolysis was prescribed as the reperfusion treatment. However, the different parenteral anticoagulants were not predictors of risk in univariable analysis. Finally, only 45 postdischarge strokes were recorded. Postdischarge stroke subtypes showed a more heterogeneous distribution of mechanisms. The annual rate of stroke post-AMI remained stable throughout the 10-year study period. Conclusions— The present study describes specific predictors of in-hospital and postdischarge stroke in patients with AMI. It showed a marked increase in the risk of death, both during hospitalization and in the year after AMI. After hospital discharge, stroke remains a rare event and is mostly associated with high cardiovascular risk.

Dual Diagnostic Role of 123I-MIBG Scintigraphy in Inverted-Takotsubo Pattern Cardiomyopathy.

We highlight the dual role of I-MIBG scintigraphy in inverted-Takotsubo pattern cardiomyopathy, the diagnosis of which is sometimes challenging: Firstly, I-MIBG scintigraphy can show myocardial sympathetic dysfunction (low I-MIBG uptake) in the hypokinetic basal segments, sparing the left ventricle apex. It is helpful in the imaging diagnosis of inverted-Takotsubo pattern cardiomyopathy and confirms that acute dysfunction of myocardial sympathetic nerve endings occurs with this cardiomyopathy. Secondly, I-MIBG scintigraphy is an accurate imaging examination to detect and localize pheochromocytoma; it can help in the search for an endogenous cause of this adrenergic stress-related cardiomyopathy.

Clinical predictors of successful thrombectomy with the Export® aspiration catheter in the acute phase of myocardial infarction. Data from the RICO survey working group

BACKGROUND Thrombus aspiration is applicable in a large majority of patients with acute myocardial infarction (AMI) and results in better reperfusion and clinical outcomes compared with percutaneous coronary intervention alone. Some aspiration procedures are, however, ineffective. To date, few clinical data are available on the predictors of successful thrombectomy in the acute phase of myocardial infarction. AIMS To determine the baseline clinical and angiographic characteristics associated with successful thrombectomy. METHODS Consecutive patients with ST elevation myocardial infarction with a baseline TIMI flow of 0 or 1, who underwent thrombus aspiration and primary or rescue angioplasty, were included. The main criterion for evaluation was an effective or ineffective aspiration defined, respectively, by the presence or absence of atherothrombotic material in the aspirate samples. RESULTS Among the 180 patients included, material was collected in 155 patients (86%). Patients with the presence of material were younger (61 vs 74 years, P=0.015), less frequently hypertensive (41% vs 68%, P=0.023) and had a lower systolic blood pressure at admission (135 vs 148 mmHg, P=0.031). No difference was observed between the two groups for angiographic parameters except for visible thrombus (61% vs 28%, P=0.005) and calcification (37% vs 60%, P=0.048). In multivariable analysis, the ability to remove the clot was affected by: age greater than 70 years (odds ratio 0.18, 95% confidence interval 0.06-0.51; P=0.001), admission systolic blood pressure (0.97, 0.95-0.99; P=0.003) and thrombus seen on angiography (4.54, 1.54-13.45, P=0.006). CONCLUSION The present study showed that manual thrombus aspiration is effective in most, but not all, patients. Further studies are needed to develop more efficient aspiration techniques and other aspiration devices to improve the results of such procedures.

0062: Clinical effectiveness of the systematic use of the GRACE scoring system for ischaemic outcomes and bleeding complications in the management of NSTEMI

Objectives We assessed the interest of systematically using the GRACE scoring system (in addition to clinical assessment) for in-hospital outcomes and bleeding complications in the management of NSTEMI compared with clinical assessments alone. Methods Multicentre, randomized study that included 572 consecutive NSTEMI patients, randomized 1:1, into group A: clinical stratification alone and group B: clinical+ GRACE score stratification. Main Outcome Measures In-hospital outcomes and bleeding complications. Results There was no significant difference between the two groups for baseline data or for in-hospital MACE. In multivariate analysis, only a GRACE >140 (OR: 3.5, 95% CI: 1.8-6.6, p 140, and these patients were significantly older, and were more likely to have a history of diabetes, stroke and renal failure, together with symptoms of heart failure. After multivariate analysis, the independent predictors of a lack of compliance with guideline delays were a GRACE score >140 (OR: 9.2; CI: 4.2-20.3, p Conclusions In a real-world setting of patients admitted with NSTEMI, the systematic use of the GRACE scoring system at admission in the PCI centre does not improve in-hospital outcomes and bleeding complications.

0294: Symptomatic AF but no silent AF is associated with an increased occurrence of ventricular arrhythmias after acute myocardial infarction

Objectives The aims of our study were to assess ventricular tachycardia or fibrillation (VT or VF) occurrence after AMI and to analyse the relationship with either symptomatic or silent AF occurrence. Background Silent or symptomatic AF are known to be common after AMI and to impair patients prognosis. But the reasons of this worse prognosis remain discussed. Methods 849 consecutive AMI were prospectively analyzed by continuous ECG monitoring (CEM) during the first 48 hours after admission. All AF, VT or VF episodes were confirm by standard ECG and sytematically reviewed by two investigators. The population was studied into three groups: No AF, Silent AF, and symptomatic AF after AMI. Results Forty five patients (5%) developed symptomatic AF and one hundred and thirty five developed silent AF (15.9%). Compared with the no AF group, patients with AF were markedly older 80 (67-85) and 81(71-88) vs. 62 (53-75) years; with p Conclusion Symptomatic AF is very common after AMI and impacts patient’s outcome with more frequent episodes of VT or VF and higher inhospital mortality (17.8%). Our large prospective study suggests that VT or VF occurrence associated with symptomatic AF could be linked with the higher mortality in this population.