Cardiac Alternans: Mechanisms and Clinical Utility in Arrhythmia Prevention

Figure 1. Schematic diagram of Ca2+ cycling includes the L‐type Ca2+ channel, the ryanodine receptor (RyR) channel, the phospholamban (PLB), the sarcoplasmic reticulum (SR) Ca2+ ATPase pump (SERCA2a), the Na+/Ca2+ exchanger (NCX), and the mitochondria. The effect of the SR Ca2+ content on a proposed model for cellular alternans is also demonstrated: the solid/dashed lines indicate the SR Ca2+ baseline ([Ca2+]SR‐base) and the SR Ca2+ content threshold ([Ca2+]SR‐th) at which Ca2+ release occurs, respectively. Calcium‐induced calcium release is manifested by an operational baseline of [Ca2+]SR in the diseased heart that is lower than the threshold to trigger spontaneous Ca2+ release in the normal heart. Inset: Representative traces of voltage (black) and intracellular calcium (purple) transients from a single cell along with the resultant mechanical contraction (red).

Figure 2. Representative examples of simultaneously measured (A) cytosolic Ca2+ (Fluo‐4, AM) and mitochondrial Ca2+ (x‐Rhod‐1, AM) alternans, and (B) cytosolic Ca2+ (Rhod‐2, AM) and sarcoplasmic Ca2+ (Fluo‐5N) alternans.

Figure 3. A, Examples of concordant calcium transients ([Ca2+]) and action potential (AP) alternans recorded in a left ventricular canine myocyte (at 0.8 seconds). Arrows indicate location of subthreshold early afterdepolarizations. L and S indicate Large/Long and Small/Short [Ca2+] AP, respectively. B, Superposition of intracellular Ca2+ concentration ([Ca2+]i) and APs from 2 consecutive beats during alternans. C, Left ordinate indicates the AP during alternans, while the right ordinate (in red) indicates open probability of state 1, PO 1 of the ryanodine receptor (RyR). The green area under the PO1V curve indicates the limits and the magnitude of the secondary RyR, while the same figure also indicates the timing of the peak of that secondary release with respect to the AP upstroke. D, Left ordinate presents the sum (black line) of the IC a,L (blue line) and INCX (red line), and the right ordinate the RyR state 1 open probability PO 1 (magenta line). The primary and secondary RyR releases are indicated by “↑” and an “*”, respectively.

Figure 4. Representative example of the effect of pacing during the absolute refractory period during alternans in a mouse myocyte. A, Stable alternans resulting from pacing at increasingly higher stimulation rates. B, Pacing during the absolute refractory period eliminates alternans. C, Upon termination of pacing, alternans resumes. D, Beat‐to‐beat action potential duration (APD) for each of the interventions (A through C).

Figure 5. Transition from concordant alternans to discordant alternans during 4 consecutive beats for unipolar, near‐field bipolar, and far‐field bipolar signals from left ventricular (LV) catheter in the failing heart model. Amplitudes are normalized with red corresponding to higher amplitudes and blue pointing to lower amplitudes. The representation demonstrates that the discordant alternans observed in both QRS and T waves are originating in the region of the heart spanned by leads LV5 to LV10 with similar spatiotemporal propagation effect on the neighboring leads.

Figure 6. A, Circumflex coronary artery occlusion induced repolarization alternans, preceding ventricular fibrillation (VF). Alternans voltage and Kscore estimated from body surface as well intracardiac right ventricular (RV), left ventricular (LV), and coronary sinus (CS) unipolar leads. The beginning of the occlusion is marked by a vertical line. B, One observes a significant increase of alternans voltage and Kscore, for several minutes, preceding the onset of VF in both surface and LVCS leads. Red line indicates alternans voltage and Kscore thresholds for the respective leads (N=17). VT/VF indicates ventricular tachycardia/ventricular fibrillation. * denotes presence of significant repolarization alternans, defined as at least 1 min of data with both alternans voltage and Kscore greater than their respective thresholds, in at least one lead, in a 5 min window before the event.

Figure 7. Example of the use of R‐wave triggered pacing during the absolute refractory period to suppress spontaneous repolarization alternans (RA) during acute ischemia. Alternans voltage (A) and Kscore (B) are plotted for intracardiac leads CS2CS7, CS2LV7, and CS2LV10. R‐wave triggered pacing (amplitude: +4 mA, pulse width: 10 ms, R‐wave coupling: 10 ms) is delivered from the right ventricular apex (RV12). a, spontaneous visible RA at baseline; (b) pacing delivered on every even beat results in RA suppression; (c) termination of pacing results in rising of the alternans voltage and Kscore to the baseline level. Transitions between interventions are indicated by dashed vertical lines, while red horizontal lines indicate the mean values of the alternans voltage and Kscore during each intervention. C, ECG morphology changes during the above‐described interventions. a, visible RA at baseline, (b) pacing decreases the RA level, (c) pacing is interrupted and RA becomes again visible. Panels show the median odd (red)/even (blue) beats of a 128‐beat sequence during each intervention.

Figure 8. Demonstration of the utility of pacing during the absolute refractory period to suppress spontaneous repolarization alternans (RA) during acute ischemia (N=7 animals). (A) Alternans voltage and Kscore for each animal at baseline during balloon occlusion, during triggered pacing and during baseline again after cessation of pacing. (B) Summary results for alternans voltage and Kscore across all animals, during the three interventions. At baseline, during balloon occlusion, markedly elevated levels of RA are observed. When triggered pacing is initiated, a significant decrease in alternans voltage and Kscore is observed. With cessation of pacing, the RA magnitude again returns to the elevated levels seen at baseline. CS indicates coronary sinus; LV, left ventricular; RV, right ventricular. *denotes statistical significance of p<0.05.