Fast and furious: new ways to think about, study and treat cardiac arrhythmias

Heart rate is perhaps the most fundamental measurement in all of physiology. School children measure their pulse in biology class to see if it rises with exercise. The media sometimes report that a champion athlete has a very low resting heart rate or that a famous actor, politician or business tycoon has been hospitalized with an irregular heart beat. Along similar lines, an electrocardiogram (ECG) is perhaps the most common physiological test or monitor used in clinical medicine. From this ‘old’ test it is possible with some certainty to tell if the patient has acute ischaemia, a history of myocardial infarction, left ventricular hypertrophy, and a host of more subtle forms of cardiac disease. Additionally, a whole ‘industry’ has grown around the treatment of various forms of irregular heart beats (arrhythmias) that includes drugs, pacemakers, implantable defibrillators, and ablation of electrically vulnerable areas of the heart that generate arrhythmias. The ECG is also monitored acutely in ambulances, operating rooms and intensive care units in case there is a need to intervene in a patient who is unstable and cannot maintain their own cardiovascular and respiratory homeostasis. The industry noted above is also growing for several reasons. First, as the population ages and formerly acute diseases that were once fatal become survivable, more people end up with conditions like atrial fibrillation, the most common arrhythmia (Go, 2005). It is estimated that there is new onset of atrial fibrillation in several per cent of people per year over the age of 70. Second, as interventions permit myocardial infarction and congestive heart failure to be increasingly survivable, the survivors can have a host of heart rhythm problems including bouts of ventricular tachycardia and ventricular fibrillation. Third, there are rare and potentially lethal forms of arrhythmia associated with ‘channelopathies’ that strike the apparently young and healthy and as screening tests for these conditions emerge it may be possible to intervene and avert disaster (Tester & Ackerman, 2009). Finally, since the heart rhythm is an electrical event generated by various channels, the tools of the ‘new biology’ are leading investigators to look for genetic and molecular clues to what generates a normal heart rhythm and what goes wrong during various forms of arrhythmia. This search is occurring at levels of integration that range from large population and family-based genetic investigations to studies in model systems. In this issue of The Journal of Physiology, Zhao and colleagues (Zhao et al. 2009) in the Robinson laboratory at Columbia University report the results of an exploration of the role of hyperpolarization-activated cyclic nucleotidegated (HCN) pacemaker channels in spontaneously active myocyte culture. They used sophisticated overexpression of an engineered chimeric channel (HCN212) made from the HCN2 and HCN1 isoforms, as well as a native isoform, HCN2. HCN212 was developed several years ago (Wang et al. 2001) from the native isoforms HCN1 (which activates faster, producing an intrinsically faster pacemaker) and HCN2 (which has a better response to the adrenergic mediator cyclic AMP (cAMP)). The initial hope was that HCN212 channels would mate the two desirable sets of properties and make cardiac cells pace rapidly and respond well to β-adrenergic stimulation when needed. However, when HCN212 channels were overexpressed in vivo, they caused rapid pacemaking and periods of pacemaker failure, producing undesirable pauses in cardiac rhythm and paroxysmal ventricular tachycardias (Plotnikov et al. 2008). When Zhao et al. studied the effects of overexpression of HCN212 on pacemaking in newborn rat heart cells cultured together in a 2-dimensional monolayer, they found that it caused much more unstable ‘bursting rhythms’ compared to HCN2. The differences between HCN2 and HCN212 could not be attributed to differences in voltage dependence, current amplitude or the response to cAMP, all of which were similar for both. The turning-on (activation) and turning-off (deactivation) of HCN212 were faster than for HCN2. Computer simulations based on the basic properties of the channels suggested that HCN212 should pace faster, which it did, but failed to explain the differential reliability in pacemaker function. Then Zhao et al. studied the effects of differences in the time-dependent (kinetic) properties of the channels and their response to changes in frequency. They found that HCN2 current responds to faster rates by decreasing instantaneous current at the end of a firing train and increasing the lag to current turn-on. Both of these changes cause feedback slowing of pacemaker current as rate accelerates, tending to dampen rate increases but maintain more steady pacemaking activity. In contrast, HCN212 does not show this type of feedback behaviour, making it faster but less stable. The authors conclude that non-equilibrium behaviour and dynamic consequences of rate change are important determinants of pacemaking function that need to be considered in engineering pacemaker channels for biological pacemakers. Why are the observations in this paper, and the model used to make them, of potential interest from a ‘clinical perspective’? At some level, studies in isolated cardiomyocytes are a ‘long way’ from intact animals or humans and the many physiological systems that can influence heart rhythm. However, there are a number of ways the approach and findings are important. First, the approach described in the paper could be used to screen new pacemaker channel candidates for biological pacemaker engineering. Biological pacemakers are in rapid development, with the hope that they will eventually replace electrical pacemakers. Implanted electrical pacemakers, with their batteries that run out, wires that can break and surfaces that can get infected, have been a mainstay of therapy for patients with excessively slow and/or unreliable cardiac rhythms for many years (Kaszala et al. 2008). The hope is that the problems inherent to putting a foreign, breakable and complicated electrical device into the body can be avoided by using gene and/or cell therapy to create a more natural ‘biological pacemaker’ within a patient's own heart. Many approaches are being used, and a prime candidate for enhancing pacemaker function is to enhance the quantity and/or quality of ‘pacemaker channels’ in a region of the patient's heart, either by locally overexpressing them or by transferring cells carrying them (Marbán & Cho, 2008). The question, then, is what type of pacemaker channel to use? The heart naturally expresses three types of pacemaker channels, HCN1, 2 and 4, with HCN4 being the predominant intrinsic form (Stillitano et al. 2008). However, it is also possible to mix and match different components of pacemaker channels by making ‘chimeras’ like HCN212, attempting to improve on nature. The results of the Zhao study indicate how this can go wrong, and how relying on steady-state channel behaviour to predict pacemaking function may be insufficient, since subtle differences in non-equilibrium behaviour may make a big difference in pacemaker reliability. Second, while gene therapy approaches to treat common diseases still seem a long way away, successful gene therapy for chronic arrhythmias could in the long run be ‘cost-effective’ (Amit et al. 2008). Currently many patients with chronic arrhythmias spiral into multiple cycles of hospital admission and discharge when therapy is inadequate. They also undergo multiple invasive procedures and receive implantable devices that are resource intensive. With atrial fibrillation, stroke can be a personally and socially devastating (and costly) complication in an otherwise independent older person (Go, 2005). In this context, the model described might be used to test approaches to gene therapy and ultimately limit the need for invasive procedures and implantable devices. One might envision that pathways that influence the responses seen in Fig. 4 could be genetically manipulated in the cardiomyocyte model to see what impact they have on the rates generated during depolarization. Finally, the model used in the paper or some modification of it might also be used to better understand what goes wrong in various forms of inherited or acquired channelopathies. S. Nattel's work in this area is supported by Canadian Institutes of Health Research Awards (MOP 44365, MGP6957), by the European-North American Atrial Fibrillation Research Alliance (ENAFRA) Network Award from Fondation Leducq and by the Mathematics of Information Technology and Complex Systems (MITACS) Network of Centers of Excellence.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.