Atrial fibrillation (AF), the most common form of cardiac arrhythmia, is preceded by episodes of alternans in the atrium. These beat-to-beat alternations in action potential (AP) duration, contraction strength and Ca transient (CaT) amplitude form a dynamic AF substrate by creating temporal and spatial heterogeneity of electrical tissue properties and Ca signaling. Heart failure (HF) induced atrial remodeling changes the expression and regulation of key Ca handling proteins thereby promoting profound changes of excitation-contraction coupling (ECC) that further increase susceptibility to atrial arrhythmogenic Ca release and alternans. Due to the lack or paucity of a transverse tubular system atrial ECC reveals unique features that are strikingly different from ventricular myocytes and make atrial cells especially prone to develop alternans. The bidirectional coupling of membrane voltage (Vm) and [Ca]i regulation (Vm?[Ca]i coupling) creates complex feedback mechanisms that play a pivotal role for the generation of alternans. Therefore, the overall goal of this proposal is to establish an experimentally tested mechanistic model of atrial alternans and to establish a mechanistic link between atrial alternans, atrial remodeling in HF and AF at the cellular, multicellular and whole heart level.
Specific aim 1. Identify the cellular mechanisms of electrical (AP duration, APD) and CaT alternans in atrial myocytes. We will test the hypothesis that disturbances of atrial Ca signaling during ECC (sarcoplasmic reticulum (SR) Ca load hypothesis vs. refractoriness hypothesis) are the primary cause of alternans and through the regulation of Ca-dependent membrane conductances (voltage-gated L-type Ca, Na/Ca exchange, Ca-dependent chloride and small conductance Ca-activated K currents) Ca alternans determines electrical APD alternans and increase the propensity of proarrhythmic Ca release events.
Specific aim 2. Identify the HF remodeling attributes that enhance atrial alternans propensity. We will test the hypothesis that atrial Ca signaling proteins and pathways as well as the ECC mechanism undergo profound remodeling in HF that result in a higher propensity of atrial alternans. In a rabbit left-ventricular HF model we will further test how enhanced IP3 receptor-mediated Ca release, increased SR Ca leak and remodeled mitochondrial Cauptake facilitates the probability of atrial alternans.
Specific aim 3. Establish a mechanistic causation linking atrial alternans and AF. Tissue arrhythmia (AF) requires cell-to-cell communication, an arrhythmogenic focus (ectopic activity) and transient or permanent tissue inhomogeneity (conduction heterogeneity). In Langendorff perfused hearts (normal and HF) the spatio- temporal properties of tissue-wide APD and CaT alternans and the relationship to AF inducibility will be investigated by atrial bipolar electrograms, multielectrode surface mapping and Ca imaging. In cell pairs cell-to- cell communication mechanism underlying alternans will be investigated. Therapeutic strategies will be developed to curtail the increased risk of alternans and AF in HF.

Public Health Relevance

Cardiac alternans is a recognized risk factor for cardiac arrhythmia and sudden cardiac death, and precedes the onset of atrial fibrillation, the most common form of cardiac arrhythmia. This study seeks to determine in atrial myocytes the mechanism of alternans, and to identify the disturbances of intracellular calcium regulation in atria of the diseased heart (heart failure) where alternans and arrhythmia are more likely to occur. In normal and diseased atria the relationship between alternans and atrial fibrillation will be determined.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Shi, Yang
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Rush University Medical Center
Schools of Medicine
United States
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Kanaporis, Giedrius; Blatter, Lothar A (2017) AP and Ca2+ alternans: An inseparable couple. Channels (Austin) 11:368-369
Blatter, Lothar A (2017) The intricacies of atrial calcium cycling during excitation-contraction coupling. J Gen Physiol 149:857-865
Kanaporis, Giedrius; Blatter, Lothar A (2017) Membrane potential determines calcium alternans through modulation of SR Ca2+ load and L-type Ca2+ current. J Mol Cell Cardiol 105:49-58
Kanaporis, Giedrius; Blatter, Lothar A (2017) Alternans in atria: Mechanisms and clinical relevance. Medicina (Kaunas) 53:139-149
Kanaporis, Giedrius; Blatter, Lothar A (2016) Ca(2+)-activated chloride channel activity during Ca(2+) alternans in ventricular myocytes. Channels (Austin) 10:507-17
Kanaporis, Giedrius; Blatter, Lothar A (2016) Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes. J Physiol 594:699-714