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Normal and abnormal cardiac excitation: generation, propagation, and coupling to contraction

Final Report Summary - NORMACOR (Normal and abnormal cardiac excitation: generation, propagation, and coupling to contraction)

Cardiac arrhythmia is a major cause of morbidity and mortality in Europe and of growing socioeconomic concern. Recent data suggest that novel mechanisms such as HCN channels, mechanical effects on Ca handling and ion flux balances, and cellular heterogeneity may trigger and / or permit the sustenance of arrhythmias. The novelty of this projects approach was to focus on these potentially crucial, but ill-investigated, mechanisms by uniting eight leading labs from five EU countries who focus on individual arrhythmogenic aspects, in a bid to combine their expertise and shed light on how physiological or compensatory mechanisms may turn arrhythmogenic, and how this may be controlled or corrected.

Research on HCN-selective bradycardic drugs brought to the synthesis of new molecules with f-channel block properties, by modification of known HCN-blockers, or by de-novo design of a novel class of inhibitors. These molecules, which have been patented during the last year, represent an absolute innovation from several points of view. In fact, they might represent the basis for developing novel drugs acting on channels specifically expressed in different human tissues (e.g. neurons versus heart) Therefore, the high selectivity is a considerable step forward in the design and development of HCN-blockers as novel therapies for treating serious diseases (neuropathic pain, arrhythmias or tachycardia) and - at the same time - for reducing the risk of side effects. In this regard, some studies aimed at testing compounds' safety were already performed. From another but complementary point of view, they are powerful tools for preclinical investigations addressing the physiological and pathophysiological role of specific HCN isoforms in excitable cells.

The increasing awareness of the role of HCN in cardiac physiology, led to the hypothesis of its involvement in inherited heart rate disturbances and arrhythmias. A genetic screening of hHCN4 channel in cardiac patients was performed, leading to the identification of several new previously unidentified mutations of the HCN4 channel. Although a simple relation between the presence of a specific mutation and the arrhythmic state of the probands could not be proven, a novel link emerged for one mutaton possibly related to inappropriate sinus tachycardia syndrome.

A role for neuroendocrine system has been demonstrated for endothelin-1, which modulates the functional and molecular expression of the rapid component of the delayed rectifier potassium current in an atrial cell model. In parallel, alterations in ionic conductances of atrial myocytes from patients in sinus rhythm (SR) and in chronic atrial fibrillation (AF) have been demonstrated. Rabbit, dog, goat and sheep models of AF made available for the project added novel and intriguing information on the effects of pharmacological interventions in the remodelled AF cardiomyocyte.

Altogether, results are suggestive of a role of yet unidentified current components developing in AF, which render the cell largely insensitive to pharmacological strategies designed so far. As a consequence, the project addressed our attention to two major mechanisms turning out to be important but ill-investigated in atrial fibrillation (at variance with delayed rectifier potassium channels and calcium channels). In particular, new advancement was made on alterations in excitation contraction coupling mechanisms in atrial myocytes, both as a trigger and substrate for arrhythmia's development and recurrence.

In parallel with studies on the regulation of excitation contraction coupling mechanisms, the research focused on alterations in contractile atrial mechanisms. This issue is of utmost importance, since atrial stunning increase the thrombotic risk and predisposes to AF recurrence in cardioverted patients. The use of single myofibrils combined with miniaturised mechanical methods offers a significant improvement for the direct measurements of mechanical performance of normal and diseased cardiac muscle due to alteration of sarcomeric proteins. Though the myofibril, as a model for mechanical investigations, is superior in several ways to larger muscle preparations, to date only animal models had been used in cardiac muscle research at the single myofibril level. The project therefore established the feasibility of using single myofibrils from human cardiac samples for mechanical experiments and the sarcomeric mechanisms underlying active and passive force generation and relaxation. In the second part of the project, they applied this new technique demonstrating that significant differences exists in the passive and active characteristics of human atrial myofibrils prepared from surgical samples taken from patients in sinus rhythm (SR) and patients with chronic atrial fibrillation (cAF). Also, similar differences were observed in SR and AF atrial goat samples.

In silico predictions of drug effect on atrial action potential has been approached, by refining a mathematical model of the human atrial action potential developed in collaboration with partners. This part of the study has benefited from novel insight and experimental data input obtained from ion channels, in single cells, microfluidically structured cell cultures, native cardiac tissue sections, and three-dimensional (3D) reconstructions of histo-anatomically detailed cardiac tissue. In order to make the modelling tools developed easily sharable among partners, and with the wider academic community, a significant effort was dedicated at developing shared standards for cell model descriptions (CellML) and the encoding, curation, and presentation of atrial (and other) cell models at the CellML model repository which currently offers access to just under 400 individual cell models. they have also built and provided freely the first cell modelling environment in which CellML models can be used for in silico studies, and have contributed to the generation of the first freely available multi-cellular modelling environment suitable for CellML code Chaste:

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