Atrial Excitation-Contraction Coupling, Calcium Signaling and Electro-Mechanical Alternans

PROJECT SUMMARY/ABSTRACT
In atrial myocytes excitation-contraction coupling (ECC) and Ca release from the sarcoplasmic reticulum (SR)
have unique features that result from the lack or the irregular organization of the transverse tubule membrane
system. Atrial myocytes have two types of SR, junctional (j-SR) and non-junctional (nj-SR). Ca release from j-
SR is controlled by Ca entry through voltage-gated L-type Ca channels (ICa,L) whereas release from nj-SR
occurs by subsequent propagating wave-like Ca-induced Ca release (CICR) driven by the newly identified 'fire-
diffuse-uptake-fire' (FDUF) mechanism. IP3 receptor-induced Ca release (IICR) contributes to ECC by
enhancing inotropy, but also leads to arrhythmogenic Ca release and alternans. Cardiac alternans has been
linked to cardiac arrhythmia, including atrial fibrillation. Alternans is defined as beat-to-beat alternations in
action potential (AP) duration (APD, electrical alternans), contraction strength and Ca transient (CaT)
amplitude, and thereby generates a dynamic arrhythmia substrate. Disturbances of the bi-directional coupling
of [Ca]i and membrane voltage (Vm) regulation ([Ca]i↔Vm coupling) are responsible for alternans occurrence.
Sex differences in cardiac structural and electrical properties have been linked to differences in arrhythmia
susceptibility and determine alternans inducibility. Focusing on the FDUF mechanism, the overall goals are to
establish a mechanistic model of atrial ECC, Ca release and atrial alternans and its sex-specific attributes at
cellular, cell pair and organ level.
Specific aim 1. Determine FDUF-dependent mechanisms of atrial alternans. We will determine the critical
role of the novel FDUF paradigm in atrial alternans, testing the hypotheses that 1) uncoupling of j-SR and nj-
SR Ca release promotes 'reverse' FDUF and triggers alternans; 2) the FDUF trigger signal (ICa,L, junctional
CaT) has Vm dependence, and that 3) SERCA dependent Ca uptake; 4) mitochondrial Ca buffering, energetics
and redox signaling and 5) IICR modulate FDUF and alternans.
Specific aim 2. Determine FDUF alternans mechanisms in cell pairs. Alternans is either Vm- or Ca-driven.
Vm-driven alternans is spatially homogeneous, while Ca-driven alternans can be spatially discordant where
over short distances regions alternate out-of-phase. Cell pairs define the elementary structural and functional
unit of cell-cell communication. We will test 1) the spatio-temporal organization of CaT and APD alternans in
cell pairs, 2) how during Ca-driven alternans the FDUF mechanism, SERCA, mitochondrial signaling and IICR
determine cell pair alternans; and 3) how Vm-driven alternans precipitates CaT alternans in adjacent cells.
Specific aim 3. Determine the spatio-temporal organization and mechanisms of Ca- and Vm-driven
tissue alternans. We will determine at organ level (perfused hearts, live animals) the mechanisms,
manifestations and spatio-temporal organization of 1) Ca-driven and 2) voltage-driven alternans, and test
pharmacological interventions to reduce pro-arrhythmic alternans risk.

Grant Number: 5R01HL164453-04
NIH Institute/Center: NIH
Principal Investigator: Kathrin Banach