Joël de Leiris

Mediterranean diet and the French paradox: Two distinct biogeographic concepts for one consolidated scientific theory on the role of nutrition in coronary heart disease

Time for primary review 26 days. Scientists and physicians have long been debating the Mediterranean-style diet and the French paradox for coronary heart disease (CHD). However, folksy they sound, these two biogeographic concepts can still be very useful to explain unexpected or controversial medical and scientific data, such as the low mortality rate from CHD in Mediterranean Southern Europe and in France as compared with other European countries. Understanding these concepts may help improve our ability to treat and prevent CHD. Most of the present confusion probably comes from the consistent underestimation by physicians and scientists of the role of nutrition in CHD. This article is not aimed at giving a comprehensive review of these two complex notions, which have to be analyzed in a broad geographic, climatic, agricultural, historical and socioeconomic context. We will only provide a superficial overview, in relation to the epidemiology of CHD. Finally, we will try to introduce the two concepts as a fundamental premise of a new scientific theory on the role of nutrition in CHD, a theory that remains to be fully formulated. ### 2.1 Definition The definition of the Mediterranean-style diet varies according to the particular Mediterranean area that is considered. For instance, the Greek version of the Mediterranean diet is dominated by the consumption of olive oil and by a high consumption of vegetables and fruits [1]. Since antioxidants are common in these foods, an antioxidant action may provide a plausible explanation for the apparent benefits of that diet [1]. According to another version, however, the Mediterranean diet is a non-strict vegetarian diet rich in oleic acid, omega-3 fatty acids, fiber, vitamins of the B group and various antioxidants, but low in saturated and polyunsaturated fat [2]. With that wider definition, the expected benefits for the prevention of CHD go far … * Corresponding author. Laboratoire du Stress Cardiovasculaire et Pathologies Associees, UFR de Medecine et Pharmacie, Domaine de la Merci, 38706 La Tronche, Grenoble, France. Tel.: +33-4-7663-7471; fax: +33-4-7663-7152

Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure

Chronic heart failure (CHF) seems to be associated with increased oxidative stress. However, the hypothesis that antioxidant nutrients may contribute to the clinical severity of the disease has never been investigated.

Effects of sustained low-flow ischemia on myocardial function and calcium-regulating proteins in adult and senescent rat hearts

OBJECTIVE Both aging and myocardial ischemia are associated with alterations of calcium-regulating proteins. We investigated the effects of graded levels of low-flow ischemia on myocardial function and on SR Ca(2+)-ATPase (SERCA2), Na(+)-Ca2+ exchanger (NCX) and ryanodine receptor (RyR2), at mRNA and protein levels in both adult and senescent myocardium. METHODS Isolated hearts from 4 and 24 month old (mo) rats were retrogradely perfused during 180 min at 100% (100% CF, n = 11 and n = 11 respectively. 30% (30% CF, n = 10 and n = 12) or 15% (15% CF, n = 13 and n = 8) of their initial coronary flow, and active tension and coronary resistance (in % of their baseline value) were recorded. After 180 min of perfusion. NCX, RyR2 and SERCA2 mRNAs (in % of age-matched 100% CF group value) and protein levels were quantitated in the left ventricles by slot blot and Western blot analysis, respectively. RESULTS In 24 mo hearts, low-flow ischemia induced a greater fall in active tension (-65 +/- 7% vs. -40 +/- 4% in 4 mo 30% CF, p, 0.01 and -82 +/- 2% vs. -60 +/- 5% in 4 mo 15% CF groups, p < 0.05 after 15 min of ischemia) and a greater increase in coronary resistance (+357 +/- 44% vs. +196 +/- 39% in 4 mo 30% CF, p < 0.05 and +807 +/- 158% vs. +292 +/- 61% in 4 mo 15% CF groups, p < 0.001 after 15 min of ischemia). An increased accumulation of SERCA2 (+36% and NCX (+46%) transcripts, but not RyR2, already occurred in 24 mo 30% CF group while the 3 transcripts accumulated in 24 mo 15% CF group. In 4 mo rats SERCA2 (+26%), NCX (+35%) and RyR2 (+81%) mRNA levels only increased in the 15% CF group. Corresponding calcium-regulating protein levels were unaltered whatever the degree of flow reduction in both 4 mo and 24 mo hearts. CONCLUSION Low-flow ischemia does not induce calcium-regulating protein loss in both adult and senescent hearts. The increase in mRNAs coding for calcium-handling proteins and the impairment of myocardial function which occur at a lesser degree of coronary flow reduction in senescent hearts, indicate a higher vulnerability to low-flow ischemia during aging.

Heme oxygenase-1 related carbon monoxide production and ventricular fibrillation in isolated ischemic/reperfused mouse myocardium

Heme oxygenase‐1 (HO‐1)‐dependent carbon monoxide (CO) production related to reperfusion‐induced ventricular fibrillation (VF) was studied in HO‐1 wild‐type (+/+), heterozygous (+/−), and homozygous (−/−) isolated ischemic/reperfused mouse heart. In HO‐1 homozygous myocardium, under aerobic conditions, HO‐1 enzyme activity, HO‐1 mRNA, and protein expression were not detected in comparison with aerobically perfused wild‐type and heterozygous myocardium. In wild‐type, HO‐1 hetero‐ and homozygous hearts subjected to 20 min ischemia followed by 2 h of reperfusion, the expression of HO‐1 mRNA, protein, and HO‐1 enzyme activity was detected in various degrees. A reduction in the expression of HO‐1 mRNA, protein, and enzyme activity in fibrillated wild‐type and heterozygous myocardium was observed. In reperfused/nonfibrillated wild‐type and heterozygous hearts, a reduction in HO‐1 mRNA, protein expression, and HO‐1 enzyme activity was not observed, indicating that changes in HO‐1 mRNA, protein, and enzyme activity could be related to the development of VF. These changes were reflected in the HO‐1‐related endogenous CO production measured by gas chromatography. In HO‐1 knockout ischemic/reperfused myocardium, all hearts showed VF, and no detection in HO‐1 mRNA, protein, and enzyme activity was observed. Thus, interventions that are able to increase endogenous CO may prevent the development of VF.

Effect of dietary antioxidant trace element supply on cardiac tolerance to ischmia—reperfusion in the rat

Over a 10-week period, female Wistar rats received a diet containing various levels of four trace elements (Zn, Cu, Mn, Se), co-factors of antioxidant enzymes (superoxide dismutase SOD, glutathione peroxidase GPx), in order to examine the influence of supplementation or deficiency of these elements (i) on tissue antioxidant enzyme defence systems, and (ii) on the susceptibility of the myocardium to ischemia-reperfusion injury. At the end of the dietary treatment, hearts were perfused at constant flow (11 ml/min) before being subjected to 15 min of total global normothermic ischemia, followed by reperfusion. The effects of the various diets (deficient, standard or supplemented) were estimated by studying functional recovery of various cardiac parameters (left ventricular developed pressure LVDP, dP/dtmax, heart rate x LVDP) as well as ultrastructural tissue characteristics. Furthermore, SOD and GPx activities were measured before ischemia and at the end of the reperfusion period. Results suggest that: (a) the activity of antioxidant enzymes increased or decreased significantly when diet was respectively supplemented with, or deficient in, trace elements, but was not further modified by an ischemia-reperfusion episode: (b) the recovery of cardiac function during reperfusion, and ventricular myocardial ultrastructure were significantly improved under the influence of trace element supplementation when compared to both standard and deficient groups. These results illustrate the protective effect of trace elements which are co-factors of antioxidant enzymes in limiting ischemia-reperfusion induced injury, and suggest a possible use in the field of anti-ischemic therapy.

Effects of selenium deficiency on the response of cardiac tissue to ischemia and reperfusion

Over a 10-week period, female Wistar rats received a diet containing a low level of selenium, cofactor of the antioxidant enzyme glutathione peroxidase (GPx) in order to examine the influence of deficiency of this trace element (i) on tissue antioxidant enzyme defence systems, and (ii) on the susceptibility of the myocardium to ischemia-reperfusion injury. At the end of the dietary treatment, hearts were perfused at constant flow (11 ml/min) before being subjected to 15 min of global normothermic ischemia, followed by 30 min of reperfusion. The effects of selenium deficiency were estimated by studying functional recovery of various cardiac parameters (left ventricular developed pressure LVDevP, heart rate HR, and the product HR x LVDevP), as well as ultrastructural tissue characteristics. Furthermore, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured at the end of the reperfusion period. Results suggest that: (a) the activity of GPx is decreased by selenium deficiency while SOD activity remains unchanged, (b) the recovery of cardiac function and myocardial ventricular ultrastructure during reperfusion are altered in the selenium-deficient group compared to controls. These results illustrate the crucial role that selenium, the co-factor of one of the major antioxidant enzymes of the myocardium, plays in determining the vulnerability of the heart to ischemia and reperfusion.

Effect of Antioxidant Trace Elements on the Response of Cardiac Tissue to Oxidative Stressa

Abstract: It is now well established that several trace elements, because of their involvement in the catalytic activity and spatial conformation of antioxidant enzymes, may contribute to the prevention of oxidative stress such as occurs upon reperfusion of ischemic tissue. The aim of this paper is (1) to review the role of these trace elements (Cu, Mn, Se, and Zn) in antioxidant cellular defenses in the course of post‐ischemic reperfusion of cardiac tissue, (2) to provide experimental data suggesting that variations in trace element dietary intake may modulate the vulnerability of cardiac tissue to ischemia‐reperfusion, and (3) to discuss in more detail the effect of Mn ions, which seem to play a special protective role against reperfusion injury. Some results obtained from experiments in animal models of myocardial reperfusion have shown that the dietary intake of such trace elements can modulate cardiac activity of antioxidant enzymes and, consequently, the degree of reperfusion damage. In addition, experimental data on the protective effects of an acute treatment with Mn are presented. Finally, experimental evidence on the protective role of salen‐Mn complexes, which exhibit catalytic SOD‐ and CAT‐like activities against reperfusion injury, are described. These complexes should be of considerable interest in clinical conditions.

Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status

Ageing is associated with an increase in myocardial susceptibility to ischemia and a decrease in post-ischemic recovery of function. In the present study, we have examined the effects of ageing on (i) myocardial ischemic contracture, (ii) the reperfusion syndrome and lipid peroxidation upon reperfusion, and (iii) the activity of enzymes involved in reactive oxygen species elimination. Hearts from male Wistar rats aged 4 (adults), 16 (old) or 24 months (senescent) were subjected to 20-min zero flow ischemia and 30-min reperfusion ex vivo. Cardiac activity of superoxide dismutase, catalase, and glutathione peroxidase, as well as cardiac content of thiobarbituric acid reactants were assessed in frozen heart samples. The effects of ageing on ischemic contracture of the sarcomeres were assessed on electromicrographs of tissues taken at the end of ischemia. In our experimental conditions, ischemic contracture of the sarcomeres increased progressively during ageing. In contrast, the severity of the reperfusion syndrome increased between 4 and 16 months of age, and then decreased up to 24 months of age. We propose that the peak of susceptibility of the myocardium to reperfusion observed during moderate ageing might be related to a decrease in the ability of cardiomyocytes to dismutate hydrogen peroxide as suggested by the observed decrease in catalase activity. Finally, the better resistance to the reperfusion syndrome exhibited by senescent rats compared to old rats might be due to a natural selection of a subpopulation of rats which is particularly resistant to oxidative stress.

Protective effect of dietary n-3 polyunsaturated fatty acids on myocardial resistance to ischemia-reperfusion injury in rats

Dietary n-3 polyunsaturated fatty acids (PUFA) reduce coronary heart disease (CHD) complications, such as chronic arrhythmia and sudden cardiac death. Improved myocardial resistance to ischemia-reperfusion injury results in smaller myocardial infarction, which is a major factor in the occurrence of CHD complications. We hypothesized that a specific dietary fatty acid profile (low in saturated and n-6 PUFA but high in plant and marine n-3 PUFA) may improve myocardial resistance to ischemia-reperfusion injury and reduce infarct size. To test this assumption, we used a well-defined rat model of myocardial infarction. Based on our results, in comparison to a diet that is high in either saturated or n-6 PUFA but poor in plant and marine n-3 PUFA, a diet that is low in saturated fats and n-6 PUFA but rich in plant and marine n-3 PUFA results in smaller myocardial infarct size (P < .01). The effects of the 3 diets were also examined by analyzing the fatty acid composition of plasma, erythrocyte cell membranes, and the phospholipids of myocardial mitochondria. The results show a great accumulation of n-3 PUFA and a parallel decrease in arachidonic acid, the main n-6 PUFA, in plasma, cell membranes, and cardiac mitochondria (P < .0001). We conclude that improved myocardial resistance to ischemia-reperfusion may be one of the critical factors explaining the protective effects of dietary n-3 PUFA against CHD complications in humans. In addition to increasing n-3 PUFA intake, an optimal dietary pattern aimed at reducing cardiovascular mortality should include a reduction of the intake of both saturated and n-6 PUFA.

Free radicals in reperfusion-induced arrhythmias: Study with EUK 8, a novel nonprotein catalytic antioxidant

Oxyradicals have been implicated as a possible cause of postischemic reperfusion arrhythmias (RA). However, the ability of enzymatic scavengers such as superoxide dismutase and/or catalase to reduce RA remains controversial. The purpose of the present work was to determine whether a nonprotein catalytic antioxidant, EUK 8, may limit RA in isolated heart preparations. The catalytic dismutation of H2O2 by EUK 8 was demonstrated using a Clark electrode. EUK 8s ability to scavenge oxyradicals was studied in vitro by electron spin resonance (ESR) in presence of superoxide-anion generating system. ESR concentration-effect curves obtained led us to use EUK 8 at 50 mumol/l in isolated heart preparations. Isolated rat hearts were submitted to 10 min regional ischemia induced by left coronary artery ligation. Reperfusion was achieved by releasing the coronary ligation, and the incidence and duration of early ventricular arrhythmias were then investigated. In the treated-group, EUK 8 was added to the perfusion fluid (50 mumol/l) 90 s before reperfusion. Our results show that EUK 8 significantly reduced the severity of RA as assessed by the arrhythmia score measurement (control: 3.46 +/- 0.21 vs. EUK 8: 2.73 +/- 0.27, p < .05). In conclusion, EUK 8 is able to limit RA in our experimental model. This effect might be related to the catalytic antioxidant properties of this complex.