Monitoring and modulating cardiac bioelectricity: from Einthoven to end-user

Abstract

In 2024, we celebrate the 100th anniversary of Willem Einthoven receiving the Nobel Prize for his discovery of the mechanism of the electrocardiogram (ECG). Building on Einthoven's legacy, electrocardiography allows the monitoring of cardiac bioelectricity through solutions to the so-called forward and inverse problems. These solutions link local cardiac electrical signals with the morphology of the ECG, offering a reversible connection between the heart's electrical activity and its representation on the body surface. Inspired by Einthoven's work, researchers have explored the transition from monitoring to modulation of bioelectrical activity in the heart for the development of new anti-arrhythmic strategies, e.g. via optogenetics. In this review, we demonstrate the lasting influence that Einthoven has on our understanding of cardiac electrophysiology in general, and the diagnosis and treatment of cardiac arrhythmias in particular.

Keywords: Einthoven; Electrocardiography; Forward problem; Inverse problem; Mechanism of arrhythmia; Nobel Prize; Optogenetics; Reentry.

Graphical Abstract

Figure 1

Electrogram recordings by A.D. Waller and W. Einthoven. (A) Glass capillary galvanometer measurement by A.D. Waller (white is Hg; black is H₂SO₄). (B) Glass capillary galvanometer measurement by W. Einthoven [flipped compared with (A)]. (C) Mathematical post hoc processing of the measurement in (B) showing correct relative inflection peaks. (D) String galvanometer measurement validating the mathematical post hoc processing. Edited from Einthoven et al. and Waller.

Figure 2

The forward and inverse problem of monitoring bioelectrical activity. The forward problem needs the solid angle theory to transfer the cardiac electrical activity into an ECG. The inverse problem needs the body’s surface potential as an intermediate step to calculate the cardiac electrical activity from a measured ECG signal. Parts edited from van der Waal et al., Meijborg et al. and Holland and Arnsdorf.

Figure 3

From Einthoven to end-user. The inverse problem makes use of the ECG to interpret monitored heart rhythms and find appropriate arrhythmia modulating interventions suited for the end-user. While the conventional modulating treatments have shortcomings, optogenetics can overcome each one of them.

Figure 4

Optogenetics for high spatiotemporal control of bioelectricity. Cardiomyocytes are equipped with light-activated ion channels or pumps by transduction with viral vectors. The light-gated ion channels are opened when exposed to excitatory light, resulting in either depolarization (blue line) or repolarization (red line) of the optogenetically modified cells.

Figure 5

Study of optogenetic spiral wave termination mechanisms in cardiomyocyte cultures by optical voltage mapping. (A) Control wells showing rotor initiation and persistence. (B) Global illumination leads to rotor termination by elevating the membrane potential in the whole cell layer. (C) Regional illumination can direct the spiral core to an edge of the well, causing termination of reentry. (D) local illumination can drag the spiral core slowly towards an edge of the well resulting in arrhythmia termination.

Figure 6

Study of optogenetic spiral wave termination mechanisms in Langendorff-perfused hearts by optical voltage mapping. (A) Control heart (rat) showing rotor persistence in the ventricles, together with an associated electrogram. (B) Global illumination for 1 s elevates the membrane potential in the whole rat ventricle and thereby terminates the rotor. (C) Regional 500 ms illumination of the apex of the rat ventricles results in rotor termination due to critical mass reduction or Purkinje interference. (D) Limiting the rotation area of a spiral wave by local 1 s illumination can end reentry in mice.