Dobrev, D. | Search bioRxiv

bioRxiv2022

Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodeling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the proarrhythmic contributions of individual AF-induced alterations. Here, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca2+/calmodulin-dependent protein kinase II, CaMKII) involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signaling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis positions CaMKII as a key nodal master switch of the adaptive changes and the maladaptive proarrhythmic triggers at the cellular and tissue levels and establishes CaMKII inhibition as potential anti-AF strategy. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy. Significance statementDespite significant advancement in our understanding of pathological mechanisms and alterations underlying atrial fibrillation (AF), a highly prevalent clinical arrhythmia causing substantial health and socioeconomic burden, development of effective pharmacological therapeutics for AF remains an urgent unmet clinical need. We built a systems framework integrating key processes and their regulatory upstream signaling pathways that are involved in atrial electrophysiology and modified by AF. By simulating populations of single atrial cardiomyocyte models and heterogeneous tissues, our analysis demonstrated synergistic interactions between upstream signaling pathways that promote atrial arrhythmogenesis across spatial scales, added new insight into complex atrial arrhythmia mechanisms, and revealed adaptive and maladaptive alterations caused by AF, thus providing a powerful new tool for identifying innovative therapeutic approaches against AF.

physiology↗

bioRxiv2020

Major threats to a migratory raptor vary geographically along the eastern Mediterranean flyway

Millions of large soaring birds migrate from the Palaearctic to Africa every year, and follow distinct flyways around the Mediterranean Sea. While there is conservation concern for many long-distance migratory bird populations, the magnitude and geographic range of threats affecting birds along flyways are poorly known, which complicates efficient mitigation. We used an endangered soaring migrant, the Egyptian Vulture Neophron percnopterus, as an example species to assess important threats in 13 countries along the eastern Mediterranean flyway. We tracked 71 birds using satellite telemetry to quantify mortalities, surveyed 4198 km of powerlines to detect dead birds, conducted 910 interviews to quantify the prevalence of poison use, and assessed the magnitude of direct persecution by surveying markets and hunters. We lost 44 birds (50% in Europe and the Mediterranean Sea, 16% in the Middle East, and 34% in Africa), and mortality causes varied geographically. Inadvertent poisoning resulting from rural stakeholders targeting predators occurred along most of the flyway. On the breeding grounds in eastern Europe, poisoning and collision and electrocution continue to be major threats. Electrocution on small and poorly designed electricity pylons was most severe in Turkey, Ethiopia and Saudi Arabia, while direct persecution to meet market demands for belief-based use of vulture products appears to be the largest threat in Nigeria and Niger. Illegal direct persecution for leisure is a major threat in the Middle East and Egypt. Although our work cannot quantitatively estimate which of the identified threats has the greatest demographic impact on Egyptian Vultures, none of threats are species-specific and are therefore relevant for many other migratory birds. Our assessment highlights the key threats per country that range states need to address to meet their obligations under the Convention of Migratory Species to protect migratory birds.

zoology↗