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.

Stretch induces modifications in myocardial electrical and mechanical activity. Besides the effects of substances that block the stretch-activated channels, other substances could modulate the effects of stretch through different mechanisms that affect Ca 2ϩ handling by myocytes. Thirty-six Langendorff-perfused rabbit hearts were used to analyze the effects of the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943, propranolol, and the adenosine A 2 receptor antagonist SCH-58261 on the acceleration of ventricular fibrillation (VF) produced by acute myocardial stretching. VF recordings were obtained with two epicardial multiple electrodes before, during, and after local stretching in four experimental series: control (n ϭ 9), KB-R7943 (1 M, n ϭ 9), propranolol (1 M, n ϭ 9), and SCH-58261 (1 M, n ϭ 9). Both the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and propranolol induced a significant reduction (P Ͻ 0.001 and P Ͻ 0.05, respectively) in the dominant frequency increments produced by stretching with respect to the control and SCH-58261 series (control ϭ 49.9%, SCH-58261 ϭ 52.1%, KB-R7943 ϭ 9.5%, and propranolol ϭ 12.5%). The median of the activation intervals, the functional refractory period, and the wavelength of the activation process during VF decreased significantly under stretch in the control and SCH-58261 series, whereas no significant variations were observed in the propranolol and KB-R7943 series, with the exception of a slight but significant decrease in the median of the fibrillation intervals in the KB-R7943 series. KB-R7943 and propranolol induced a significant reduction in the activation maps complexity increment produced by stretch with respect to the control and SCH-58261 series. In conclusion, the electrophysiological effects responsible for stretch-induced VF acceleration in the rabbit heart are reduced by the Na ϩ /Ca 2ϩ exchanger blocker KB-R7943 and by propranolol but not by the adenosine A2 receptor antagonist SCH-58261. cardiac electrophysiology; mechanical stretch; Fourier analysis STRETCH induces the modulation of electrical and mechanical activity in myocytes. The modulation of electrical activity, also referred to as mechanoelectrical feedback (14,35), includes the depolarization of the resting potential (2,17,21,27,28,31,70), alterations of the shape and duration of action potentials (3,11,21,27,28,31,47,57,70), changes in refractoriness (4,7,9,11,27,36,47,48), and the induction of afterdepolarizations (16,18,34). These electrophysiological changes have been related to the generation of different types of cardiac arrhythmias (7, 9, 13-15, 24, 26, 35, 40, 47). The mechanical effects of stretch consist of an immediate and slow increase in force (45, 64), involving changes in myofilament Ca 2ϩ sensitivity, in the concentrations of intracellular Ca 2ϩ , and in the magnitude of Ca 2ϩ transients (1,3,29,33,58,69). These changes have been related to several mechanisms, including the actions of 1) endogenous angiotensin II (1, 46); 2) the Na ϩ /H ϩ exchanger (1, 3, 46, 66); 3) the Na ϩ /Ca 2ϩ exchanger (3,...

Training seems to increase the electrical stability of ventricular myocardium. As the electrophysiological modifications were exhibited in hearts not submitted to extrinsic nervous system or humoral influences, they are, at least in part, intrinsic modifications. These electrophysiological data also suggest that training could protect against reentrant ventricular arrhythmias.

The late inward Na(+) current inhibitor ranolazine attenuates the electrophysiological effects responsible for the acceleration and increase in complexity of ventricular fibrillation produced by myocardial stretch.

GS967 attenuates stretch-induced changes in cardiac electrophysiology.