This 59-year-old man had ischemic cardiomyopathy and left ventricular ejection fraction (LVEF) of 20%. (A) Pacing at 109 beats/min; (B) action potential duration (APD) shows minimal oscillations over time. However, when 64 consecutive beats were superimposed, (C) action potential (AP) amplitude shows marked alternans, shown by the separation of even (blue line) and odd (red line) beats. (D) AP amplitude alternans (k-score = 10.4, absolute voltage of alternation [V_alt] = 175 µV) is depicted on this spectrum across beats, as peak magnitude at 0.5 cycles/beat. (E) T-wave alternans (TWA) is positive at this time (gray areas) in X, Y, and vector magnitude (Vm) leads, with low levels of bad beats and noise, and no confounding respiratory (Resp), heart rate (HR), or RR-interval alternans. FFT = fast-Fourier transform; MAP = monophasic action potential; RV = right ventricle.

Alternans predominates in AP phase II of left ventricular (LV) APs in this 59-year-old man with coronary artery disease and an LVEF of 21%. (A, B) Action potential duration (APD) does not oscillate during pacing. However, (C) marked AP amplitude alternans in phase II is seen (red/blue separation). (D) AP alternans occurs in phase II (arrows, k-score = 7.9, absolute voltage of alternation [V_alt] = 59 µV) but is undetectable in phase III (k-score = –0.38); AP duration variations were also minimal. (E) T-wave alternans (TWA) was positive at this time (arrows) in leads Y, Z, and Vm. Abbreviations as in Figure 1.

(A) No AP amplitude alternans in a 66-year-old male control patient with LVEF of 66% testing negative for TWA. AP alternans k-score = –1.1. (B) AP phase II alternans (arrow) (k-score = 6.3; absolute voltage of alternation [V_alt] = 72 µV) in a 72-year-old man with ischemic cardiomyopathy and LVEF of 26%. Red/blue lines indicate superimposed odd/even beats. Abbreviations as in Figure 1.

Conduction does not vary ("flat restitution") at 109 beats/min (i.e., diastolic interval [DI] 270 to 290 ms), measured as activation time (AT) from right ventricle apical (RVA) extrastimuli to a second monophasic action potential (MAP) site. This was true for (A) preserved restitution, where AT prolonged only for very short DI (<40 ms) in a 55-year-old man with LVEF of 35%; and (B) broad restitution, whereas AT prolonged for DI <120 ms in a 62-year-old man with LVEF of 31%. Both patients had coronary artery disease. CL = cycle length; RVOT = right ventricular outflow tract; other abbreviations as in Figure 1.

Modeled reduction in calcium uptake >70% (but not altered transient outward current [I_to] or sodium channel inactivation) causes AP and TWA at 109 beats/min. (A) Human left ventricle (LV) wedge dimensions (endocardium = orange; mid-myocardium = light green; epicardium = light blue). (B) Spectral AP alternans and TWA develop in the endocardium as sarcoplasmic reticulum calcium uptake current [I_up] reduces to 0.25 to 0.30 of baseline. (C) Mean change in endocardial phase II amplitude (middle left panel) and peak diastolic intracellular calcium ([Ca]i) (far right panel) computed at locations indicated by gray circles (far left and middle right panels). The number of alternating beats out of 64 is indicated. (D, top) Control endocardial AP and pseudo-electrocardiogram with bounding boxes, denoted by dashed lines, depicting AP phase II and T-wave data ranges. (D, bottom) AP phase II and T-wave alternans for I_up reduced by 74%; red lines = odd; blue lines = even; orange lines = control. Note similarity to clinical alternans (Figs. 1, 2, and 3B). T-wave locations used to compute TWA amplitude differences are denoted by *. Abbreviations as in Figure 1.

(A) Odd (solid lines) and even (dotted lines) beats for a single endocardial cell at steady state with sarcoplasmic reticulum calcium uptake current (I_up) reduced by 70%, showing alternans in action potential (AP), intracellular calcium ([Ca]_i), L-type calcium current (I_CaL), and sarcoplasmic reticulum calcium (CaSR). (B) APs superimposed (blue line = odd; red line = even) for (left) I_CaL, (middle) [Ca]_i, and (right) CaSR, clamped to the odd traces in (A). Clamping to even beats did not change the results.

Action potential (AP) amplitude alternans (k 1.47) prospectively predicted sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) or implantable cardioverter-defibrillator (ICD) therapy (in the validation sample) on Kaplan-Meier analysis (p = 0.04). Solid line = AP amplitude alternans; dashed line = no AP amplitude alternans.