Temporal relationship between ECG and single cardiomyocyte action potential. (A) The waves and intervals of a normal ECG. (B) Schematic representation of a ventricular action potential and its major underlying ionic currents. The downward arrow indicates influx; the upward arrow, efflux.

Schematic illustration of intracellular Ca²⁺ cycling and associated second messenger pathways in cardiomyocytes (figure modified from ref. 84). AC, adenylyl cyclase; α, G protein subunit α; α-receptor, α-adrenergic receptor; β, G protein subunit β; β-receptor, β-adrenergic receptor; γ, G protein subunit γ; LTCC, L-type Ca²⁺ channel; CAMKII, Ca²⁺-calmodulin kinase II; I-1, inhibitor 1; NCX, Na⁺/Ca²⁺ exchanger; P, phosphate group; PLC, phospholipase C; PLN, phospholamban; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; SERCA2a, SR Ca²⁺-ATPase isoform 2a; T-tubule, transverse tubule.

Proposed scheme of events leading to transmembrane ionic imbalances during myocardial ischemia. Net intracellular Na⁺ gain due to a mismatch of Na⁺ influx and efflux will cause net cellular K⁺ loss, extracellular K⁺ accumulation, and an increase in intracellular Ca²⁺ due to activation of the Na⁺/Ca²⁺ exchanger operating in the reverse mode. Cellular Ca²⁺ overload will cause triggered arrhythmias by the mechanisms illustrated in Figure 3. Lysophosphatidylcholine is a product of diacyl phospholipid catabolism generated by the enzyme phospholipase A2 during ischemia. Question marks indicate that the pathway/mechanism is hypothetical. [ATP]_i, intracellular concentration of adenosine triphosphate; Cx43, connexin-43; [H⁺]_i, intracellular proton concentration; I_K, delayed rectifier K⁺ current; I_K,ATP, ATP-sensitive potassium current; I_K1, inward rectifier K⁺ current; I_Na, fast Na⁺ current; Na/H, sodium-hydrogen exchanger; [K⁺]_o, extracellular K⁺ concentration; TTX, tetrodotoxin (a specific blocker of the fast sodium current).

Factors contributing to arrhythmogenesis in hearts with heterogeneous sympathetic innervation. Myocardial injury (e.g., myocardial infarction) or chronic hypercholesterolemia (51) will cause a spatially uneven increase in sympathetic nerve density in the heart, resulting in regional variations in release and, consequently, variations in tissue levels of sympathetic neurotransmitters. Chronic, nonuniform elevations of neurotransmitters, through alterations in the expression of L-type Ca²⁺ channels and K⁺ channels, create spatial dispersion of action potential duration. Action potential prolongation and augmented Ca²⁺ influx through L-type Ca²⁺ channels combine to increase the susceptibility to EAD- and/or DAD-triggered activity in hyperinnervated regions. If the triggered beat propagates throughout the rest of the heart, the preexisting spatial dispersion of action potential duration and, thus, myocardial refractoriness facilitate the initiation of tachyarrhythmias. Locally elevated levels of neuropeptide Y and norepinephrine may increase coronary artery tone, thereby critically reducing the coronary perfusion reserve under conditions of increased oxygen demand (e.g., physical and/or emotional stress) and causing regional ischemia, which contributes to the development of an arrhythmia.

Proposed scheme of events leading to DADs and triggered tachyarrhythmia. (A) Congenital (e.g., ankyrin-B mutation) and/or acquired factors (e.g., ischemia, hypertrophy, increased sympathetic tone) will cause a diastolic Ca²⁺ leak through RyR2, resulting in localized and transient increases in [Ca²⁺]_i in cardiomyocytes. (B) Representative series of images showing changes in [Ca²⁺]_i during a Ca²⁺ wave in a single cardiomyocyte loaded with a Ca²⁺-sensitive fluorescent dye. Images were obtained at 117-ms intervals. Focally elevated Ca²⁺ (ii) diffuses to adjacent junctional SR, where it initiates more Ca²⁺ release events, resulting in a propagating Ca²⁺ wave (iii–viii). Reproduced with permission from Biophysical Journal (85). (C) The Ca²⁺ wave, through activation of Ca²⁺-sensitive inward currents, will depolarize the cardiomyocyte (DAD). In cardiomyocytes, the inward I_Na/Ca is the major candidate for the transient inward current underlying DADs, although the role of the Ca²⁺-activated Cl^– current [I_Cl(Ca)] and a Ca²⁺-sensitive nonspecific cation current [I_NS(Ca)] cannot be excluded. If of sufficient magnitude, the DAD will depolarize the cardiomyocyte above threshold resulting in a single or repetitive premature heartbeat (red arrows), which can trigger an arrhythmia. Downregulation of the inward rectifier potassium current (I_K1), upregulation of I_Na/Ca, or a slight increase in intercellular electrical resistance can promote the generation of DAD-triggered action potentials. S, stimulus. Modified with permission from Circulation Research (26) and Nature (12).