Mathematical Modeling to Investigate Antiarrhythmic Drug Side Effects: Rate-Dependence Role in Ionic Currents and Action Potentials Shape in the O’Hara Model

Sudden cardiac death due to ventricular arrhythmia is one of the leading causes of mortality in the world. In the last decades, it has proven that anti-arrhythmic drugs, which prolong the refractory period by means of prolongation of the cardiac action potential duration (APD), play a good role in preventing of relevant human arrhythmias. However, it has long been observed that the “class III antiarrhythmic effect” diminish at faster heart rates and that this phenomenon represent a big weakness, since it is the precise situation when arrhythmias are most prone to occur. It is well known that mathematical modeling is a useful tool for investigating cardiac cell behavior. In the last 60 years, a multitude of cardiac models has been created; from the pioneering work of Hodgkin and Huxley (1952), who first described the ionic currents of the squid giant axon quantitatively, mathematical modeling has made great strides. The O’Hara model, that I employed in this research work, is one of the modern computational models of ventricular myocyte, a new generation began in 1991 with ventricular cell model by Noble et al. Successful of these models is that you can generate novel predictions, suggest experiments and provide a quantitative understanding of underlying mechanism. Obviously, the drawback is that they remain simple models, they don’t represent the real system. The overall goal of this research is to give an additional tool, through mathematical modeling, to understand the behavior of the main ionic currents involved during the action potential (AP), especially underlining the differences between slower and faster heart rates. In particular to evaluate the rate-dependence role on the action potential duration, to implement a new method for interpreting ionic currents behavior after a perturbation effect and to verify the validity of the work proposed by Antonio Zaza using an injected current as a perturbing effect.

Design, preparazione e studio applicativo di nuovi metallopolimeri luminescenti a base di complessi ciclometallati di Ir(III)

The research project of my experimental thesis deals with the design, synthesis and characterization of a new series of luminescent metallapolymers to be exploited for their peculiar photophysical and opto-electronic properties. To this end, our design strategy consisted in the incorporation of brightly luminescent and colour tuneable Ir(III) cyclometalated complexes with general formula [Ir(C^N)2(N^N)]+, where C^N represents various phenyl piridine based cyclometalating ligands and N^N is an aromatic chelating N-heterocyle, into methyl methacrylate (MMA) based copolymers. Whereas the choice of the cyclometalating ligands was driven by the possibility to obtain different emission colours, the design of the N^N ligands was aimed to obtain a molecule capable of providing the chelate coordination to the metal centre and, at the same time, of being susceptible to polymerisation reactions. To fulfil these requirements, a new molecule (abbreviated as L) consisting in an alkylated 2-pyrydyl tetrazole structure equipped with a styryl unit was designed and successfully prepared. The preparation of the target cationic metallapolymers was accomplished by the complexation of the preformed MMA-L copolymers with different amounts of an appropriate Ir(III) dimeric precursor [(Ir(C^N)2Cl)2]. The investigation of the photophysical features of the new hybrid compounds in the solid state at r.t. suggested how these metallapolymers displayed brightly intense phosphorescent emissions, whose colour was found to span from blue to yellow according to the nature of the cyclometalating ligands. In all cases, the emissive performances were superior to those displayed by the corresponding mononuclear “model” complexes. These promising results pave the way for the application of this new class of metallapolymers as Luminescent Solar Concentrators for the photovoltaic technology and/or to solid state lighting.