Cardiac arrhythmias lead to abnormalities in the rate or rhythm of the heartbeats, which result in a beating rate that is too quick, too slow, or irregular. The different cardiac arrhythmias are responsible for substantial worldwide morbidity and mortality and consequentially in significant burden on the health care systems. For example, atrial fibrillation (AF), the most common arrhythmia type, is associated with a doubling in all-cause mortality, a five-fold increase in stroke (being responsible for 30% of all stroke cases), and often with the development of progressive heart failure.
Major hurdles in studying and developing better treatments for cardiac arrhythmias, such as AF, have been the lack of suitable human cardiac tissue models and specifically those reflecting patient/disease-specific functional and structural abnormalities and the inability to perform targeted, high-resolution, functional, and reversible perturbations of the system.
To address these challenges, we aimed to combine advances in genetics, human induced pluripotent stem cells (hiPSCs) and genome-editing (CRISPR) technologies, development biology-inspired differentiating systems yielding specific heart cell subtypes, novel tissue engineering strategies, state-of-the-art electrophysiology methodologies, and emerging concepts from the fields of optogenetics and chemogenetics.
To achieve the overall goal of the project, our first aim was to establish efficient differentiation protocols from hiPSCs to derive specific cardiac cell subtypes, primarily focusing on atrial cells. We next aimed to combine advances in clinical genetics, hiPSC, and genome editing (CRISPR) technologies to develop and study patient/disease-specific hiPSC models of familial AF. Since arrhythmias in AF are re-entrant and therefore cannot be modelled at the cellular level, the second aim focused on establishing novel cardiac tissue models to study arrhythmia mechanisms and therapies, initially simple 2D models and later by using advanced tissue-engineering concepts to establish complex 3D atrial tissue models of AF.
Our third and fourth aims involved integrating optogenetic and chemogenetic tools into these tissue models and eventually into animal models. Optogenetics involves the expression, by gene therapy means, of light sensitive proteins (ion channels) in different electrically-active tissues, while chemogenetics involves introduction of engineered proteins (ligand-specific engineered receptors) into the targeted cells, whose function can be controlled externally by specific pharmacology. Using these approaches, we aimed to provide mechanistic insights and to develop novel anti-arrhythmic therapies for arrhythmias like AF.
By completing the aforementioned goals of the project, the deliverables went beyond the state-of-the-art by providing novel experimental platforms to study cardiac electrophysiology at the single-cell and tissue levels. This can eventually to lead to a paradigm shift in the way human cardiac arrhythmias can studied and treated.
