Alternans in atria: Mechanisms and clinical relevance

Abstract

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca²⁺ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria.

Keywords: Action potential; Alternans; Arrhythmias; Atria; Calcium signaling.

Fig. 1

AP and Ca²⁺ alternans occur simultaneously. (A) Simultaneously recorded APs and Ca²⁺ transients in current-clamped atrial myocytes. (B) Superimposed AP traces recorded during large (black) and small (gray) amplitude Ca²⁺ transients. Figure modified with permission from [17].

Fig. 2

Membrane potential determines calcium alternans through modulation of sarcoplasmic reticulum Ca²⁺ load and L-type Ca^{2 +} current. Two distinct AP-like voltage commands were generated from prerecorded atrial APs observed during Ca²⁺ alternans: AP_{CaT_Large} (observed during large systolic Ca²⁺ release) and AP_{CaT_Small} (observed during small CaTs). Morphology of these voltage commands is shown on the bottom of panel C. Sequences with only AP_{CaT_Large}, only AP_{CaT_Small} or alternating AP waveforms (as shown in B bottom) were applied to rabbit atrial myocytes. (A) (a) CaTs elicited in the same voltage-clamped atrial myocyte stimulated with different sequences of AP waveforms at various pacing frequencies. (b) Pacing with same- shape AP_{CaT_Small} waveforms (open circles) enhances degree of CaT alternans compared to AP_{CaT_Large} stimuli (black squares). CaT alternans ratio (AR, where 0 indicates conditions without alternans and 1 indicates a full skipping of Ca²⁺ release on every other beat) is further increased during alternans AP voltage clamp protocol (grey triangles). (B) Sarcoplasmic reticulum Ca²⁺ load ([Ca²⁺]_SR) measurements with Fluo-5N from the same voltage-clamped atrial myocyte exposed to three different AP clamp protocols (bottom). End-diastolic [Ca²⁺]_SR was higher during the same-shape AP_{CaT_Small} protocol compared to AP_{CaT_Large} and revealed [Ca²⁺]_SR alternans during the alternans AP clamp protocol. (C) Representative traces of L-type Ca²⁺ currents elicited with AP_{CaT_Large} and AP_{CaT_Small} voltage commands from the same atrial myocyte. Figure modified with permission from [52].

Fig. 3

Disturbances in intracellular Ca²⁺ cycling as a key mechanism for the development of alternans. (A) Ca²⁺ transient alternans recorded in voltage-clamped atrial myocytes under AP-clamp conditions when beat-to-beat V_m is kept constant. (B) Inhibition of cytosolic Ca²⁺ release by ryanodine abolishes AP alternans. APs and [Ca²⁺]_i recorded simultaneously from a current-clamped atrial myocyte. Panel B is from [17].

Fig. 4

Ca²⁺ signaling during excitation-contraction coupling in atrial myocytes. (A) Confocal images of a ventricular and an atrial myocyte from the same cat heart stained with the membrane-bound fluorescent dye Di-8-ANEPPS. The regular structures spaced in a sarcomeric pattern in the ventricular cell represent t-tubules. In contrast, the atrial myocyte is devoid of any t-tubular staining. (B) Ca²⁺ transient recorded in the confocal linescan mode. The scanned line was positioned perpendicular to the longitudinal axis of the cell (c). Electrical stimulation of the cell during acquisition of the linescan image triggered a ‘U’-shaped Ca²⁺ transient (b), indicating that [Ca²⁺]_i increased first at the periphery of the cell (a) before propagating towards the center of the myocyte. Panel d shows local Ca²⁺ transients measured in the subsarcolemmal space (ss) and the center of the cell (ct). The Figure is modified with permission from [72].

Fig. 5

Neighboring regions within an atrial myocyte can alternate out-of-phase. (A) Series of fluo-4 fluorescence images recorded under control conditions and during Ca²⁺ alternans. The images illustrate the rising phase of the Ca²⁺ transients marked by the arrows in (B). (B) Subcellular Ca²⁺ transients recorded from the regions marked by the boxes a–d (A). [Ca²⁺]_i images and subcellular Ca²⁺ transients reveal that the time of onset, the magnitude, and the phase of Ca²⁺ alternans exhibit large subcellular variations and that the upper and the lower half of the cell alternate out-of-phase. The Figure is modified with permission from [74].

Fig. 6

Atrial alternans precedes initiation of atrial fibrillation. Rate dependence of AP alternans in a 61-year-old male patient with paroxysmal atrial fibrillation. (A) No significant atrial AP alternans is observed at baseline pacing with cycle length (CL) of 500 ms. (B) At CL 300 ms, APD alternans is observed. (C) APD alternans were detectable and preceded AF initiation while pacing at CL 280 ms. V1, first ECG precordial lead; CSmid, middle coronary sinus; MAP, monophasic action potential. Figure is modified with permission from [98].