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An Experimental Model of Diet-Induced Metabolic Syndrome in Rabbit: Methodological Considerations, Development, and Assessment

In recent years, obesity and metabolic syndrome (MetS) have become a growing problem for public health and clinical practice, given their increased ...

Universitat de València

Methionine has shown protective effects in experimental models of myocardial infarction and is highly reactive to oxidative compounds produced by polymorphonuclear leukocytes (PMN), which in turn have been associated with myocardial damage. We have investigated the effect of methionine administration on spontaneous leukocyte peroxidative activity in myocardial ischemia and reperfusion.

Flow cytometric analysis of peroxidative activity in granulocytes from coronary and peripheral blood in acute myocardial ischemia and reperfusion in dogs: protective effect of methionine.

We have studied the intrinsic modifications on myocardial automatism, conduction, and refractoriness produced by chronic exercise. Experiments were performed on isolated rabbit hearts. Trained animals were submitted to exercise on a treadmill. The parameters investigated were 1) R-R interval, noncorrected and corrected sinus node recovery time (SNRT) as automatism index; 2) sinoatrial conduction time; 3) Wenckebach cycle length (WCL) and retrograde WCL, as atrioventricular (A-V) and ventriculoatrial conduction index; and 4) effective and functional refractory periods of left ventricle, A-V node, and ventriculoatrial retrograde conduction system. Measurements were also performed on coronary flow, weight of the hearts, and thiobarbituric acid reagent substances and glutathione in myocardium, quadriceps femoris muscle, liver, and kidney, to analyze whether these substances related to oxidative stress were modified by training. The following parameters were larger (P < 0.05) in trained vs. untrained animals: R-R interval (365 +/- 49 vs. 286 +/- 60 ms), WCL (177 +/- 20 vs. 146 +/- 32 ms), and functional refractory period of the left ventricle (172 +/- 27 vs. 141 +/- 5 ms). Corrected SNRT was not different between groups despite the larger noncorrected SNRT obtained in trained animals. Thus training depresses sinus chronotropism, A-V nodal conduction, and increases ventricular refractoriness by intrinsic mechanisms, which do not involve changes in myocardial mass and/or coronary flow.

Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart.

To determine whether chronic physical training increases atrial and ventricular refractoriness in isolated rabbit heart.

Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart.

The aim of this study was to determine whether the changes in myocardial activation pattern resulting from acute stretching during ventricular fibrillation can be counteracted by administering a compound that blocks receptors sensitive to stretch. The study involved 16 isolated rabbit hearts, in which refractoriness and activation frequency during ventricular fibrillation were measured before, during and after localized acute stretching of the left ventricular free wall, either without (series A, n=8) or with (series B, n=8) the presence of streptomycin, 200 micromol. At baseline and during and after stretching, ventricular fibrillation was slower with streptomycin perfusion in series B than in series A (dominant frequency at baseline, 13+/-2 Hz vs. 16+/-2 Hz, respectively; P< .005; dominant frequency with stretching, 14+/-2 Hz vs. 19+/-3 Hz, respectively; P< .005). Streptomycin attenuated the electrophysiological changes produced by stretching and had a direct effect on refractoriness and activation frequency during ventricular fibrillation.

[Effect of streptomycin on stretch-induced change in myocardial activation during ventricular fibrillation].

An experimental model is used to analyze the characteristics of ventricular fibrillation in situations of variable complexity, establishing relationships among the data produced by different methods for analyzing the arrhythmia.

Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study.

Abnormal QT interval durations and dispersions have been associated with increased risk of ventricular arrhythmias. The present study examines the possible arrhythmogenic effect of inducing QT interval variations through local epicardial cooling and warming.

QT interval heterogeneities induced through local epicardial warming/cooling. An experimental study.

Metabolic syndrome (MetS) has become one of the main concerns for public health because of its link to cardiovascular disease. Murine models have been used to study the effect of MetS on the cardiovascular system, but they have limitations for studying cardiac electrophysiology. In contrast, the rabbit cardiac electrophysiology is similar to human, but a detailed characterization of the different components of MetS in this animal is still needed. Our objective was to develop and characterize a diet-induced experimental model of MetS that allows the study of cardiovascular remodeling and arrhythmogenesis. Male NZW rabbits were assigned to control (n = 15) or MetS group (n = 16), fed during 28 weeks with high-fat, high-sucrose diet. We measured weight, morphological characteristics, blood pressure, glycaemia, standard plasma biochemistry and the metabolomic profile at weeks 14 and 28. Liver histological changes were evaluated using hematoxylin-eosin staining. A mixed model ANOVA or unpaired t-test were used for statistical analysis (P<0.05). Weight, abdominal contour, body mass index, systolic, diastolic and mean arterial pressure increased in the MetS group at weeks 14 and 28. Glucose, triglycerides, LDL, GOT-AST, GOT/GPT, bilirubin and bile acid increased, whereas HDL decreased in the MetS group at weeks 14 and 28. We found a 40% increase in hepatocyte area and lipid vacuoles infiltration in the liver from MetS rabbits. Metabolomic analysis revealed differences in metabolites related to fatty acids, energetic metabolism and microbiota, compounds linked with cardiovascular disease. Administration of high-fat and high-sucrose diet during 28 weeks induced obesity, glucose intolerance, hypertension, non-alcoholic hepatic steatosis and metabolic alterations, thus reproducing the main clinical manifestations of the metabolic syndrome in humans. This experimental model should provide a valuable tool for studies into the mechanisms of cardiovascular problems related to MetS, with special relevance in the study of cardiovascular remodeling, arrhythmias and SCD.

Article	Year
Flow cytometric analysis of peroxidative activity in granulocytes from coronary and peripheral blood in acute myocardial ischemia and reperfusion in dogs: protective effect of methionine. Cytometry\| PubMed ID: 10486526	1999
Intrinsic changes on automatism, conduction, and refractoriness by exercise in isolated rabbit heart. Journal of applied physiology (Bethesda, Md. : 1985)\| PubMed ID: 11744664	2002
Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart. Acta physiologica (Oxford, England)\| PubMed ID: 18346209	2008
[Effect of streptomycin on stretch-induced change in myocardial activation during ventricular fibrillation]. Revista espanola de cardiologia\| PubMed ID: 18364190	2008
Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study. Revista espanola de cardiologia (English ed.)\| PubMed ID: 24775451	2013
QT interval heterogeneities induced through local epicardial warming/cooling. An experimental study. Revista espanola de cardiologia (English ed.)\| PubMed ID: 25432709	2014
Development and characterization of an experimental model of diet-induced metabolic syndrome in rabbit. PloS one\| PubMed ID: 28542544	2017

Luis Such

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