Towards Improved Human In Vitro Models for Cardiac Arrhythmia: Disease Mechanisms, Treatment, and Models of Atrial Fibrillation

Figures

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  Figure 1. Epidemiology of AFib. Strong increase in prevalence, incidence, mortality, and disease burden from 1990 to 2019.

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  Figure 2. Risk factors for AFib. AFib, atrial fibrillation; GOF, gain-of-function mutation; LOF, loss-of-function mutation; KCNH2, gene encoding a subunit of the voltage-gated potassium channel Kv11; KCNK3, gene encoding TASK-1, a two-pore domain K+ channel with atrial-specific expression shown to be a major determinant of resting membrane potential in human atrial cardiomyocytes; GJA5, gene encoding for connexin 40; NPPA, gene encoding the precursor protein for atrial natriuretic peptide (ANP), a circulating hormone produced in the cardiac atria; BMI, body mass index; NA, not applicable; RR, relative risk; HR, hazard ratio; OR, odds ratio; CI, Confidence interval; RR, Relative Risk; HR, Hazard Ratio [2,5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28].

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  Figure 3. (A) Propagation of electrical signals within the heart. (B) Atrial and ventricular action potential in healthy cardiomyocytes. SAN = Sinoatrial node; AVN = Atrioventricular node; RA = Right atrium; LA = Left atrium; RV = Right ventricle; LV = Left ventricle; RMP = Resting membrane potential. The dashed line in A indicates electrical propagation.

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  Figure 4. Types of triggers for AFib. (A) Rapid firing ectopic foci, for example arise in the pulmonary vein. (B) Types of re-entry. Left: re-entrant circuit around an anatomical barrier. Depending on the size of the excitable gap (space between WF and WT), re-entry will be sustained or not. Middle: a leading circle with no excitable gap (WF anchors WT) forming a refractory area in its center due to continuous centripetal activation. The smallest circuit that can sustain re-entry. Right: spiral wave re-entrant rotor. At the singularity point (star), an excitable but not excited core is formed. (Depending on the curvature of the WF blue), the rotor will be maintained. Arrows indicate velocity. SAN = Sinoatrial node; AVN = Atrioventricular node; WF = Wavefront; WT = Wavetail; WL = Wavelength [3,49,50,51].

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  Figure 5. Overview of underlying disease mechanisms of AFib. Calcium disorders resultant from β-adrenergic (β-AR) stimulation, sarcoplasmic reticulum (SR) Ca2+ leaks, or atrial ischemia typically result in diastolic Ca2+ release from the SR, increasing cytosolic Ca2+ and activating the NCX exchanger which produces a transient-inward current causing a membrane depolarization (Delayed AP Duration, DAD—red line) [3,41,52]. In contrast, calcium disorders, such as low extracellular potassium (K+), allow L-type Ca2+ (ICa,L) channels to recover from the inactivation that occurs during the AP, generating an inward current and resulting in Early APDs (EADs—red line) [3]. Atrial tachycardia can also act as a substrate for EADs, caused by a reduced L-type Ca2+ channel (ICa,L) and the increase in inward-rectifier currents (IK1 and IKACh,C), overall reducing the APD [3,53,54]. Conduction disturbances, such as abnormal gap junctions or tissue fibrosis, and short APDs act as substrates for re-entry and rotors [2,55]. The triggers ultimately lead to AFib. With AFib progression, substrates might change, reinforcing the vulnerability of the substrate to maintain AFib (“AFib begets AFib,” looping red line…

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  Figure 6. (A) Effect of wavefront curvature on conduction velocity (CV) [57,60]. (B) Current-to-load mismatch where the source volume is smaller than the sink volume, leading to a block of the activation wavefront (purple lines). Arrows indicate direction of electrical propagation.