The promise of optogenetic arrhythmia termination

Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical routine. Although patients are often asymptomatic, the disease is associated with life-threatening complications, especially thromboembolism and stroke. Thus, arrhythmia termination to restore sinus rhythm and atrial contractility is the intuitive and first goal of every cardiologist. This is further supported by the famous term “AF begets AF” [1], meaning that the more AF episodes a patient has had in the past, the more likely is the next one due to structural and electrophysiological remodelling of the atria. Still, restoring and maintain sinus rhythm – so-called rhythm control – with electrical shocks and/or drugs has severe side effects, which explains why rate control – only preventing tachycardic AV conduction – was for a very long time as efficient as rhythm control. It is only with the recent success of pulmonary vein isolation that the paradigm of rhythm control also became superior in clinics. However, this procedure still requires preparation time, carries its own risks and has an overall 1–5-year efficiency of 60%–80%, leaving some patients with no efficient treatment option to restore sinus rhythm. Cardioversion on demand has been tested with implantable atrial defibrillators, but the required electrical energy was so high that patients did not tolerate the electrical shocks. Later and up to now, atrial tachypacing requiring only the energy of pacing was used to overpace the arrhythmia waves, but it is only effective for low frequencies in the range of atrial flutter. In principle, optogenetic stimulation could overcome these limitations and enable contactless and efficient termination of cardiac arrhythmia which could be performed pain-free. Light-sensitive ion channels and pumps can be expressed in mammalian excitable cells and used to control the membrane potential with light. Since its first applications in neuroscience, optogenetics has been extended to cardiac research. First, the feasibility of optical stimulation of the channelrhodopsin-2 (ChR2) expressing transgenic myocardium has been demonstrated, both in isolated cardiomyocytes and in the whole heart in vivo [2]. More recently, a cardiac-specific adeno-associated virus (AAV) carrying the ChR2 gene has been used as a vector to induce expression of ChR2 in mouse hearts, eventually enabling control of cardiac excitation in non-transgenic animals. The basic idea of applying optogenetics to terminate ventricular tachycardia has been achieved by three independent studies [3]. Notably, Bruegmann et al. [4] also predicted the applicability of optogenetics in a human heart using an in silico model. From these seminal studies, significant advantages have been recently demonstrated, including the possibility of optogenetic termination of AF in mice [5] and in rats even with implantable LEDs [6]. Despite the exciting potential of optogenetic applications, their use in clinical settings still faces significant challenges. Gene therapy involves three crucial elements: (i) the gene to be transferred, (ii) the tissue into which the gene will be introduced and (iii) the vehicle used for gene transfer into the target tissue. The safety of expressing ChR2 has been demonstrated in mammalian cardiomyocytes, but targeting cardiac tissue can be challenging. The low regenerative potential of the heart means that cardiac gene therapy must be performed on terminally differentiated cells – such as cardiomyocytes, which constitute only 20% of the total number of cells but 70%–80% of the cardiac mass. Although it is not essential for all cardiomyocytes to undergo transduction, the process still entails the genetic manipulation of a significant number of cells. Gene delivery vehicles can be categorized as non-viral or viral, each with its own advantages and drawbacks. Non-viral vectors have a favourable safety profile and low immunogenicity but suffer from low transfection efficiency and limited timespans of expression. Viral vectors, on the other hand, are quite efficient and represent the most promising option for in vivo human therapy with to date 17 gene therapies approved for clinical use. AAVs are the safest option for muscle tissue in humans due to the tropism of several subtypes allowing quite selective transduction of muscle cells. However, there are still unresolved issues related to their use. Pre-infections with natural AAVs and ultimately injection of AAVs generates neutralizing antibodies, which diminishes transduction efficiency and does not allow re-injection of AAVs. This is especially important because long-term persistence of ChR2 expression has to date only been demonstrated in the mouse heart [2], whereas data in rats is so far restricted to 6 weeks achieved only with strong immunosuppression. Recently, optogenetics has been demonstrated in one human patient to be efficient in restoring vision [7]. However, it is important to note that the eye has a blood–eye barrier and is thus immune-privileged. Thus, gene transfer – with genes taken from algae, bacteria and other priority pathogens – and channelrhodopsin expression pose major challenges to the immune system, and the safety has to be shown in more relevant animal models for a clear clinical perspective. The next true big step is the delivery of light in humans for optogenetic therapy. The device would require an integrated, multifunctional, biocompatible and elastic system that is custom formed to fit each patient's heart shape. It must account for minimally invasive access, motion artefacts, photon scattering/absorption and provide spatiotemporal resolution of physiological parameters for feedback control. Conformable devices that can wrap around the heart have been tested in animal models. However, implanting such devices in humans would have a significant impact, as patients with implanted devices occasionally require treatment for infections, coagulation and repairs – especially when the pericardium sack has to be opened. For these reasons, we believe that the first demonstration of transthoracic optogenetic cardioversion in rats by Pijnappels et al. in the current issue of the Journal of Internal Medicine [8] represents an important milestone in the field. Upscaling to the human heart could mean that illumination could be performed through the pericard and light devices fixed on the rib cage. The possibility that the pericardium sac would not have to be opened for implantation would probably reduce the infection risk. The herein reported light intensity of 25 mW/mm2 is still very high and in the range of the upper safety limits for therapeutic approaches. Thus, novel strategies based on sub-threshold optogenetics manipulation [9] could inspire new cardioversion protocols operating at low energy levels. In parallel, channelrhodopsin variants that are more light-sensitive and can be activated with red-shifted light are required. Very recently, a new variant ChRmine – which can be activated with red light (625 nm) and has much higher light-induced currents – allowed transthoracic optical pacing of mouse hearts [10]. However, in this case, strong desensitization has to be overcome for sustained depolarization, which is still the safest strategy for optogenetic arrhythmia termination without knowing the underlying arrhythmia substrate. This is desirable because it would provide a one-approach-suits-all treatment. Conceptualization; writing—original draft; writing—review and editing: Tobias Bruegmann and Leonardo Sacconi. The authors declare no conflict of interests.