Targeting calcium buffering: a promising way to manage atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Even though we’ve made progress in understanding the molecular mechanisms behind AF, treating it remains challenging.

A recent study presented new data showing that targeting intracellular calcium buffering mechanisms might be a promising way to manage AF. It has been known that altered intracellular calcium handling plays a significant role in AF, but the specifics of how calcium buffering works in this context were still unclear.

To elucidate how impaired calcium buffering contributes to arrhythmogenesis in persistent atrial fibrillation (persAF), researchers examined calcium buffering in atrial myocytes from patients with persAF and compared them to cells from patients with normal sinus rhythm. They also used human atrial subtype iPSC-CMs and mouse heart models to replicate these conditions in the lab.

The researchers used a combination of techniques, including simultaneous patch clamp and calcium imaging, Langendorff experiments, optical action potential acquisition, and automated patch clamp (Syncropatch 384, functional screening for atrial iPSC-CM specificity), among others.

The study shows that:

  • Atrial myocytes from persAF patients exhibited decreased cytosolic calcium buffering capacity due to lower levels of calcium-binding proteins, particularly cardiac troponin C (cTnC).
  • Knockdown of cTnC in iPSC-CMs led to reduced calcium buffering, mimicking the conditions in persAF. These cells showed a higher tendency for increased spontaneous calcium release events and developed action potential alternans, a precursor to arrhythmias.
  • In mouse models, reducing calcium buffering increased vulnerability to tachypacing-induced atrial arrhythmias, underscoring the direct link between impaired calcium buffering and arrhythmogenesis.

Overall, the study concludes that diminished expression of cTnC and other myofilament proteins significantly impairs cytosolic calcium buffering in persAF, promoting arrhythmogenic calcium waves and increasing the risk of atrial arrhythmias.

This suggests that if we can modulate calcium buffering, either through drugs or genetic interventions, we might improve treatment outcomes for AF patients. For example, drugs like levosimendan or omecamtiv mecarbil, known for their calcium-sensitizing properties, and supplements like taurine and β-alanine could be valuable additions to the current treatment options for AF.

Find the full article here: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.066577

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