FIS PI21/01984 SGLT2

PI21/01984

The research project is aligned with the priority lines of strategic actions related to health and contemplates improving the control of complications derived from highly prevalent diseases, progressing in research on cardiovascular diseases and transferring research results to the clinical practice. Currently, an increase in the prevalence of obesity, metabolic syndrome and its complications, including cardiac arrhythmias and sudden death, is expected. For this reason, it is of social interest to deepen a better understanding of the mechanisms involved in its development, as well as to provide new preventive and therapeutic options.

The metabolic syndrome, in which obesity, hypertension, glucose intolerance and dyslipidemia are present, affects an increasingly important sector of the general population and its relationship with the development of cardiovascular diseases and with the appearance of complications that reduce both the quality of life of these people and their life expectancy. In metabolic syndrome, the risk of sudden death and cardiac arrhythmias such as atrial fibrillation increases, and the mechanisms involved are still poorly understood. The origins of the arrhythmic activity must be sought in the changes of the active and passive properties of the cardiac tissues that produce alterations in the formation of the impulses and in their propagation. Such changes are generally caused by both compromised tissue integrity (eg increased fibrosis) and altered electrophysiological properties of cardiac tissue. The advances in the knowledge of these mechanisms and, as a consequence of this, the approach of therapeutic actions that allow to avoid their appearance, will offer clear benefits to the people affected.

GOALS

The research project that is presented aims to investigate both the effect that the alterations that define the metabolic syndrome have on the electrical properties of the heart, as well as their relationship with the processes of establishment, maintenance and cessation of atrial fibrillation, the most frequent sustained arrhythmia. in the general population, which is associated with increased mortality and serious complications such as systemic embolism or heart failure. Secondly, the project aims to analyze the possible beneficial effects of pharmacological inhibition of the type 2 sodium-glucose cotransporter on changes in cardiac electrical properties and on the propensity to develop arrhythmia.

METHODOLOGY

The experimental model used will develop the metabolic syndrome modifying the diet (high in fats and sugars) and the pro-arrhythmic modifications and their control through the prescribed treatment will be analyzed. In this case we will work with a group of NZW rabbits (n=25) that will be fed for 28 weeks with a diet high in fat and sugar. On the other hand, the control group (n=15) will be housed for the same period of time and will be fed with standard feed. In a subgroup of animals with metabolic syndrome, we will administer empagliflozin from week 28 (1.5 mg/kg/day). We will study the components of the metabolic syndrome for 32 weeks by recording blood pressure, electrocardiographic activity, weight, and analysis of various blood metabolites (glucose, cholesterol, and triglycerides, among others), also evaluating cardiac function and some of the electrophysiological characteristics of the heart in vivo. After 32 weeks, the atrial electrical properties will be studied in a Langendorff-type isolated heart model using epicardial optical mapping. Subsequently, we will induce atrial arrhythmias and atrial fibrillation, in addition to studying the dynamics, complexity, and characteristics of arrhythmic episodes. Biochemical analyzes will be carried out on the gene and protein expression of the main ionic channels that carry transmembrane ionic currents, the proteins of the intimate junctions and the degree of myocardial fibrosis will be quantified. Finally, mathematical models derived from our experimental data will be used to determine the possible arrhythmogenic mechanisms.

RESULTS

The results can help to establish the necessary scientific bases to guide and propose clinical studies aimed at avoiding the triggering of cardiac arrhythmias in various contexts. Appropriate control of the factors involved can prevent the appearance of atrial fibrillation in the general population. Progress in technologies used to investigate cardiac arrhythmias is also contemplated, including procedures for analysis, interpretation, and quantification of cardiac activation patterns during complex arrhythmias.

The dissemination of the results of the research is one of the lines of action of INCLIVA and the results of the project will be disseminated through the media available at the institute (press releases, website and social networks), with the purpose of to bring them closer to society and to sectors of the population with special interest in the project area. Participation in communication actions aimed at patients, patient associations and the general public in the context of research activities within the institute. On the other hand, the results of the project will be presented at scientific meetings in the area (both national and international), as well as in indexed journals with a high impact factor, preferably opting for open access publications whenever feasible and stating the grants. received for its development, in accordance with current regulations.

SGLT2,metabolic syndrome,cardiac arrhythmias,Langendorff-type isolated heart model,epicardial optical mapping

Cánvoves Femenía, Joaquin (UV)

Genovés Martínez, Patricia (IIS La Fe)

Research group GRELCA

Physiology departament

Faculty of Medicine and Odontology

Avenida Blasco Ibáñez, 15

46010- Valencia

Institute of Health Carlos III

Minister of Science and Innovation

European Commission

INCLIVA

Universitat de València

• AGE - Health Research Projects