Michel David

Systemic Free Radical Activation Is a Major Event Involved In Myocardial Oxidative Stress Related to Cardiopulmonary Bypass

Background Cardiopulmonary bypass (CPB) can induce deleterious effects that could be triggered in part by radical oxygen species; however, their involvement in the course of surgery has been elusive. The aim of this study was to evaluate the time course and origin of radical oxygen species release, myocardial or not, in patients undergoing coronary artery surgery involving CPB. Methods Blood samples were taken from periphery and coronary sinus of patients during CPB, and oxidative stress was evaluated by direct and indirect approaches. Direct detection of alkyl and alkoxyl radicals was assessed by electron spin resonance spectroscopy associated with the spin-trapping technique using &agr;-phenyl-N-tert-butylnitrone. Results The authors showed that the spin adduct concentration was not influenced by anesthesia and pre-CPB surgery. A rapid systemic increase of plasma spin adduct concentration occurred after starting CPB, and it stayed at a high concentration until the end of CPB. At the beginning of reperfusion period, radical oxygen species release was accelerated in the coronary sinus; however, it was not significant. A positive correlation was found between &agr;-phenyl-N-tert-butylnitrone adduct concentrations and (1) the duration of CPB and (2) concentration of postoperative creatine phosphokinase of muscle band (CPK MB). Plasma vitamin E and C, ascorbyl radical, uric acid, thiol, plasma antioxidant status, and thiobarbituric acid reacting substances were also measured but did not give relevant indications, except for uric acid, which seemed to be consumed by the heart during reperfusion. Conclusion The results indicate that a systemic production of free radicals occurs during CPB that may overwhelm the production related to reperfusion of the ischemic heart. This systemic oxidative stress is likely to participate in secondary myocardial damage.

Surgical outcome of traumatic rupture of the thoracic aorta

BACKGROUND The aim of this study was to point out the results of different techniques of spinal cord protection in surgically-treated patients with traumatic thoracic aorta (TTA). METHODS A multicentric study was carried out involving 182 patients with TTA. Four patients died before surgery. Two patients were operated on without any investigation and 2 had no aortic tear at thoracotomy. The remaining 174 patients had aortic isthmus disruption and were included in the study. The mean age was 32.3+/-14.29 years with 126 men (72.4%) and 48 women (27.6%). Road accidents were causal in 163 patients (93.66%); polytraumatism was frequent. A standard chest roentgenogram led to a diagnosis which was confirmed with aortography in 94.8% of cases. Surgical repair of visceral lesions was performed in 52 patients (29.9%) for traumatic spleen, liver, diaphragm, mesentery, and gut. These operations were done before or after aortic operation in 21.3% and 8.6% of cases, respectively. Thirty-three patients (19%) died and 9 (5.2%) had paraplegia. Sixty-nine patients had clamp and sew technique (group 1). Ninety-three patients had different types of extracorporeal circulation (group 2), and 12 patients had Gott shunt (group 3). No difference appeared between the 3 groups according to mortality and paraplegia. But the sex ratio, age, visceral lesions, craniocerebral lesions, the type of aortic repair, and cross-clamp time were discriminative. RESULTS The univariate analysis point out age, cross-clamp time, hemothorax, and anatomical type of aortic injury as the risk factors of death. This was confirmed by a multivariable test which retained age, cross-clamp time, and hemothorax as risk factors. When not diagnosed in time, TTA is serious and has a bad prognosis. In spite of a high mortality and morbidity, the surgical management has improved. Immediate operation and medullar protection are the stumbling block in this operation. CONCLUSIONS Operation can be delayed in some cases, but one must take care of hemodynamic instability. This calls for a repair of the serious associated lesions first, or of a quick performing of a thoracotomy for ruptured aorta. The question remains, is it better to protect the spinal cord with the lower aortic perfusion and avoid the simple cross-clamp? Clinical studies give few answers to this question, and the best answer has not yet been given, as we lack prospective studies in this field.

Hypoxaemia associated with an enlarged aortic root: a new syndrome?

Objective: To assess the mechanisms through which an enlarged aortic root may facilitate right to left shunting through a patent foramen ovale. Patients: 19 patients with the platypnoea-orthodeoxia syndrome (POS) were compared with 30 control patients without platypnoea. Interventions: Multiplane transoesophageal echocardiography. Main outcome measures: The aortic root diameter, atrial septal dimension behind the aortic root, and amplitude of the phasic oscillation of the septum were measured. Four groups of patients were compared: 12 platypnoeic patients with a dilated aortic root (POS-D), 7 platypnoeic patients with a normal aortic root (POS-N), 15 control patients with a dilated aortic root (CONT-D), and 15 control patients with a normal aortic root (CONT-N). Results: In POS-D and CONT-D patients, the apparent atrial septal dimension was 16.3 (2.7) mm and 17.4 (5.9) mm respectively, compared with 24.4 (5.2) mm in POS-N patients and 25 (4) mm in CONT-N (p < 0.005). Furthermore, the amplitude of septal oscillation was 14.7 (2.5) mm in the POS-D group versus 5.8 (2.4) mm in CONT-N (p < 0.001) compared with 23.3 (3) mm in seven patients with an atrial septal aneurysm (p <0.001). Conclusion: Patients with an enlarged aorta have an apparently smaller dimension and increased mobility of the atrial septum. These findings appear to result from compression by the aortic root and decreased septal tautness. Consequently, a “spinnaker effect” with the inferior vena caval flow may take place, opening the foramen ovale and leading to sustained right to left shunting.

Effects of Cyclosporin and Cremophor on Working Rat Heart and Incidence of Myocardial Lipid Peroxidation

Cyclosporin A (CsA) is widely used as the immunosuppressant of choice for preventing graft rejection. However, its clinical use is hampered by certain side effects, especially its nephrotoxicity and other cardiovascular side effects. CsA for intravenous infusion contains cremophor (Cre) and this vehicle has significant adverse effects on endothelial function and vascular muscle. The present study was aimed at investigating the direct effects of CsA and Cre on isolated and perfused rat hearts in the dosage that closely approximates the peak level achieved for the prevention of graft rejection in the rat. Transplantation is a clinical setting in which the myocardium may be exposed to transient ischemia. In this study, we have shown that the vehicle of CsA, namely Cre, has significant adverse effects on cardiac function. We observed a reduction in coronary flow and aortic output. Addition of CsA appeared to induce a further reduction of aortic flow. We have also shown that a significant increase of thiobarbituric acid reactive substances, considered as an index of lipid peroxidation, occurred in the reperfused heart in the presence of Cre+CsA. Our experimental study shows that Cre turned out to be toxic to myocardium by itself. In the heart, potential Cre-CsA interactions possibly potentiating CsA toxicity could not be excluded. The increase of lipid peroxidation in the heart perfused with CsA suggests that reactive oxygen species may be involved in the detrimental effects of this substance on the heart.

Atrial and vascular oxidative stress in patients with heart failure.

Heart failure is characterized by a great number of metabolic and histological defects, however, previous studies did not provide strong evidence of a correlation between the antioxidant status of myocardial tissue itself and cardiac function. The goal of our study was to assess, in patients with heart failure consecutive to dilated cardiomyopathy (DCM), alterations in norepinephrine (NE), lipid peroxidation (malonedialdehyde: MDA) and iron levels in different parts of the myocardium and aorta, in relation to functional parameters. Biopsied heart samples were obtained from 12 DCM patients and from 4 brain-dead organ donors (Controls). The left ventricular ejection fraction (LVEF) was reduced to 19.1±2.6% in DCM. For all patients, the distribution of NE in the atria, ventricles and vessels was different, but NE content in control hearts was systematically higher than in cardiomyopathy patients. MDA levels tended to be higher in the different samples from the DCM group in comparison with the values obtained in the C group; the values were significantly decreased (p<0.05) in endocardium and the aortic samples. In the right atrium there was a significant correlation between NE content and LVEF and between MDA and iron concentrations. These findings could give further insights into the relationship between iron metabolism disturbances and the severity of cardiovascular diseases.

Regional heterogeneity of decreased myocardial norepinephrine and increased lipid peroxidation levels in patients with end-stage failing heart secondary to dilated or ischemic cardiomyopathy.

BACKGROUND Regional alterations in norepinephrine (NE) and lipid peroxidation in the myocardium of patients with heart failure is not well known. This study was designed to investigate regional myocardial NE levels and lipid peroxidation index and their relationships with the functional parameters in two pathologic conditions: dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). METHODS Biopsied heart samples were obtained from 13 DCM and 10 ICM patients (orthotopic cardiac transplantation). Tissue NE was assayed by high-pressure liquid chromatography with electrochemical detection. Tissue lipid peroxidation (malondialdehyde, MDA) was evaluated by the thiobarbituric acid (TBA) reaction. RESULTS Non-failing hearts (controls, n = 4) were included in this study for comparison. Left ventricular dysfunction was present at rest with a mean left ventricular ejection fraction (LVEF) of 19.1 +/- 2.6% for DCM patients and 17.4 +/- 2.0% for ICM patients. The amount of NE in control hearts was significantly lower (p < 0.05) than in DCM or ICM hearts. For all patients, there were several differences in distribution of NE among the sub-divisions of the atria and ventricles studied. NE content was significantly higher in the right atria than in the left atria or ventricles. A significant correlation between LVEF and NE concentrations was observed in the left septum of ICM and DCM patients and in the left ventricle of the ICM group. In DCM and ICM patients, some parts of the left ventricle showed higher levels of lipid peroxides compared with controls. MDA levels in patients with DCM varied little from one region to another, whereas in ICM patients there was considerable variation. CONCLUSIONS This study is the first demonstration of a correlation between the values of pre-operative LVEF and cardiac NE concentrations in specific parts of the myocardium. This effect could not be generalized to the entire heart. The pattern of myocardial MDA distribution did not follow that of the NE distribution.

The influence of extracorporeal circulation on the susceptibility of erythrocytes to oxidative stress

Extracorporeal circulation (ECC), a necessary and integral part of cardiac surgery, can itself induce deleterious effects in patients. The pathogenesis of diffuse damage of several tissues is multifactorial. It is believed that circulation of blood extracorporeally through plastic tubes causes a whole body inflammatory response and a severe shear stress to blood cells. The aim of this study was to evaluate the level of oxidative stress and its deleterious effect on red blood cell (RBC) before (pre-ECC), immediately after (per-ECC) and 24 h after an ECC (24 h post-ECC). Several indicators of extracellular oxidative status were evaluated. The ascorbyl free radical (AFR) was directly measured in plasma using electron spin resonance (ESR) spectroscopy and expressed with respect to vitamin C levels in order to obtain a direct index of oxidative stress. Allophycocyanin assay was also used to investigate the plasma antioxidant status (PAS). Indirect parameters of antioxidant capacities of plasma such as vitamin E, thiol and uric acid levels were also quantified. RBC alterations were evaluated through potassium efflux and carbonyl levels after action of AAPH, a compound generating carbon centered free radicals. No changes in plasma uric acid and thiols levels were observed after ECC. However, vitamin E levels and PAS were decreased in per-ECC and 24 h post-ECC samples. Vitamin C levels were significantly lower in 24 h post-ECC and the AFR/ vitamin C ratio was increased. Differences in results had been noted when measurements took account of hemodilution. Increases of uric acid and thiols levels were observed after ECC. Vitamin E levels were not modified. However after hemodilution correction a significant decrease of vitamin C level was noted in 24 h post-ECC samples as compared to per-ECC sample. Whatever the way of measurement, vitamin C levels decreased suggesting the occurrence of ECC induced-oxidative stress. Concerning RBC, in the absence of AAPH, extracellular potassium remained unchanged between pre-, per- and 24 h post-ECC. AAPH induced a significant increase in extracellular potassium and carbonyls levels of RBC membranes, which was not modified by ECC. These results suggest the absence of alterations of RBC membrane during ECC despite the occurrence of disturbances in PAS. Such protection is of particular importance in a cell engaged in the transport of oxygen and suggests that RBC are equipped with mechanisms affording a protection against free radicals.

Fracture-embolization of duromedics valve prosthesis and microscopic uncommon lesions

We report a sudden leaflet fracture of a Duromedics mitral valve 6 years after implantation. The patient had cardiogenic shock and complained of asthenia, orthopnea, and tachycardia. Transesophageal echocardiography showed the lack of one leaflet of the prosthesis and regurgitation. An emergency mitral replacement was successfully performed. Angiographic computed tomography scan localized the sequestrum that embolized the common iliac arteries. Examination of the deficient prosthesis showed multiple lesions and, in particular, a subsurface lesion that may be characteristic of carbon pyrolytic valves.

Long term aortic stenosis on magnetic resonance imaging after direct repair for acute traumatic rupture of the thoracic aorta.

Thirty two patients underwent aortic repair for acute traumatic rupture of isthmus in our institution between 1978 and 1998. Twenty seven direct sutures were performed and ®ve vascular prostheses were implanted. Medullar protection was: cardiopulmonary bypass (5/32), Gotts shunt (4/32), left atria-femoral artery circulatory assistance (3/32), and 20 simple clamps. Hospital mortality was 9.38% (three patients). No paraplegia was observed, but there were four cases of regressive spinal cord injury (12%). Follow-up was 24/27 survivors (two subsequent deaths) with a mean time of follow-up of 9 ^ 4:8 years. The clinical aortic status was excellent in all the patients. Two-thirds of these patients have been checked by MRI; aortic reconstitution revealed: a normal thoracic aorta in 14 patients (Fig. 1), a stenosis on the direct suture line in three European Journal of Cardio-thoracic Surgery 19 (2001) 82±83