PPM 03-0322-190036

The most common abnormal heart rhythm in clinical practice, atrial fibrillation (AF), is associated with increased risk for stroke, heart failure, dementia and death. Both underlying etiologic risk factors and race/ethnicity determine susceptibility AF with the arrhythmia occurring more frequently in white than non-white populations. While reasons for this ethnic variability are unclear, studies have shown that both common and rare genetic variants increase susceptibility to AF in an individual in the presence of ethnic-specific risk factors. However, up to one-third of patients develop AF in the absence of underlying cardiac or systemic disease and studies of patients with “lone” or the early-onset (EO) form of the arrhythmia strongly support a genetic basis for AF. Despite recent advances in catheter-based therapy antiarrhythmic drugs (AADs) are still commonly used to treat symptomatic AF. However, membrane-active drugs are incompletely and unpredictably effective and can be associated with serious toxicities. The limited success of AADs is due, in part, to the heterogeneity of the underlying substrate, and failure to target therapy to the underlying mechanisms of AF in individual patients. Linkage analysis, candidate gene and next generation sequencing (NGS) have uncovered the underlying genetic mechanisms of AF in whites of European descent and identified novel therapeutic targets. However, the genetic basis of EOAF in non-white populations remains unclear. Specific Aim 1 will identify and phenotypically characterize Middle Eastern Arab probands and family members with EOAF and perform NGS to identify rare genetic variants associated with the arrhythmia. Genetic approaches have provided important insights into the underlying genetic mechanisms of EOAF but the translation of these discoveries to the bedside care of patients has been limited, in part, due to the challenges of adequately recapitulating human AF in cellular models. The ability to derive patient-specific atrial cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSC)-CMs holds great promise for modeling AF-linked mutations and developing cellular models of the arrhythmia that are genetically-matched to specific patients. Although human embryonic stem cells (hESCs) have generated atrial CMs for testing atrial-specific AADs such an approach has failed to elucidate the underlying cellular mechanisms of AF-linked mutations and model heritable AF. Specific Aim 2 will collect blood from Middle Eastern Arab probands with EOAF and unaffected family members to generate patient-specific atrial iPSC-CMs with the goal of elucidating the underlying cellular mechanisms of AF. We will determine the electrophysiologic (EP) phenotype of ion channel AF-linked mutations using patient-specific atrial iPSC-CMs and genetically correct the atrial iPSC-CMs using CRISPR-Cas9 system to definitively establish causality. We will then determine the EP phenotypes of these cell lines, assess novel mechanism-based therapies, and elucidate the underlying cellular mechanisms of EOAF. The overarching goals of this proposal are to harness the complementary skills of the multi-disciplinary team of investigators with expertise in clinical/cellular electrophysiology (EP), statistical genetics, biorepositories and stem cell technology. Our proposal is highly feasible, cost-efficient, and leverages the strengths and expertise of the Hamad Medical Corporation (HMC) network of hospitals; Qatar Biobank (QBB); Qatar and Hamad Bin Khalifa Universities; and the University of Illinois at Chicago (UIC). These studies will directly impact the care of Qatari patients with AF by: i) the generation of a candidate gene panel for EOAF in Middle Eastern Arabs; ii) developing a novel platform for modeling AF and drug discovery; iii) elucidating the underlying cellular mechanisms; and iv) identifying and assessing novel mechanism-based therapies for this common and morbid condition. Atrial iPSC-CMs will not only allow a more mechanism-based approach to the treatment of AF but will also enable a ‘path towards precision medicine’ with improved efficacy and reduced toxicities for individual Qatari patients with AF and reduced healthcare costs.