A TRP to the emergency room: Understanding arrhythmia in the ageing heart

This editorial refers to ‘Arrhythmogenesis in the aged heart following ischaemia-reperfusion: role of transient receptor potential vanilloid 4’ by D. Peana et al., pp. 1126–1137. ‘Ageing like a fine wine’ is, unfortunately, an idiom that is not often used to describe to one’s cardiovascular health. Indeed, our likelihood of developing cardiovascular diseases increases as we age, and this includes an elevated risk of both atrial and ventricular arrhythmia.1,2 Faced with an ageing population, it is becoming more and more urgent that we unravel the mechanisms responsible for arrhythmia generation in older hearts. Higher prevalence and severity of ventricular arrhythmia in the aged are partly explained by increasing occurrence of ischaemic heart disease, and associated arrhythmias during myocardial infarction, but also cardiomyopathy and valvular disease.3 Higher arrhythmia risk is also believed to be in linked to structural remodelling of the ageing heart, as the ventricles develop hypertrophy and fibrosis.1,4 However, there is a growing appreciation that changes within cardiomyocytes themselves during ageing are pro-arrhythmic. The major players in cardiomyocyte Ca2+ homeostasis and electrophysiology are well described. The heartbeat is initiated as Na+ channel opening depolarizes the cell membrane, triggering Ca2+ entry through L-type channels, and subsequent Ca2+ release through ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This process is disrupted during ageing, as RyRs become leaky and expression of the SR Ca2+ ATPase is reduced, interfering with Ca2+ recycling into stores.5,6 Both alterations elevate resting Ca2+ concentration, and predispose cardiomyocytes to developing Ca2+ waves. These spontaneous Ca2+ release events, in turn, lead to the generation of delayed afterdepolarizations (and extrasystoles) as released Ca2+ is removed from the cell by the Na+–Ca2+ exchanger (NCX). This effect may be potentiated by higher NCX expression in older cardiomyocytes.5 Furthermore, greater NCX activity together with slower decay kinetics of L-type Ca2+ current and reduced transient outward current prolong the action potential during ageing,5,6 predisposing cells to early afterdepolarizations due to L-type channel re-opening. Reduction in cardiomyocyte t-tubule density during ageing may also provide a substrate for arrhythmia by favouring the generation of afterdepolarizations, re-entry, and alternans.7 Aside from the canonical Ca2+ handling proteins described above, the last years have shown that there are also other more minor players that may become significant in disease settings and during ageing. This list includes inositol 1,4,5-trisphosphate (IP3) receptors, proteins involved in store-operated Ca2+ release, mitochondrial Ca2+ transporters, and transient receptor potential (TRP) channels. This latter category of non-selective cation channels is particularly intriguing, as diverse TRP variants are expressed in cardiomyocytes, where they have been assigned a spectrum of roles spanning modulation of contractility, hypertrophy signalling, and mitochondrial function.8 Peana et al.9 provide exciting new insight into the role of one of these TRP isoforms, TRPV4, in the context of ischaemia and reperfusion in the aged heart. They observed that reperfusion arrhythmias were common in older mice, but that the incidence of these events was significantly reduced by treatment with the TRPV4 antagonist HC067047. Looking deeper into the underlying mechanisms with Langendorff heart experiments they found that, unlike in young animals, older mice exhibited susceptibility to membrane depolarization and Ca2+ over-activity during reperfusion. Again, these actions were inhibited by HC067047. Follow-up experiments with isolated cardiomyocytes illustrated similar HC067047-sensitive changes in Ca2+ homeostasis (larger Ca2+ transients, more frequent spontaneous Ca2+ release) when cells from aged hearts were exposed to osmotic stress. These data suggest that TRPV4, which is stretch-sensitive, is activated by the changing osmotic state during ischaemia/reperfusion. Specifically, pH is lowered and cellular metabolites accumulate during ischaemia, and reperfusion triggers hypo-osmotic stress as these levels return to baseline. Peana et al.9 propose that the resulting opening of TRPV4 channels and Ca2+ influx destabilizes cardiomyocyte electrophysiology by promoting Ca2+ overload and prolongation of the action potential. However, an accompanying depolarization of resting membrane potential is also expected to be pro-arrhythmic, as Na+ channel inactivation slows the upstroke of the action potential and conduction velocity, promoting re-entry. These data contribute to an emerging understanding of how molecular level changes, such as increased expression of TRPV4 in cardiomyocytes, favour arrhythmogenesis in the aged heart. However, as with ageing in general, cardiac ageing is a heterogeneous phenomenon, since individuals biologically age at different rates. The present data appear to support this paradigm, as the authors observed that only a sub-population of hearts and cardiomyocytes exhibited depolarization and Ca2+ over-activity during reperfusion. With an eye towards eventual patient therapy, how can we predict which individuals are at the greatest risk for such phenomena? Recent data have indicated that ageing, including cardiac ageing, can be predicted by employing a frailty index that assesses an individual’s overall health.4,10 Furthermore, frailty appears to be linked to the presence of key cytokines involved with the inflammatory response. The present data suggest that perhaps other factors such as TRP expression levels might also serve as biomarkers for cardiac frailty, ageing, and arrhythmia risk. Sex differences should also be considered. Although both male and female mice were employed in the study by Peana et al.,9 accumulating evidence indicates that ageing includes sex-dependent changes in cardiomyocyte Ca2+ handling.4 Addressing these differences between the sexes and between individuals has important implications for how we treat patients. For example, the use of Class IV anti-arrhythmic drugs, which inhibit L-type Ca2+ channels, might be expected to have detrimental effects in the subset of older patients for which channel expression is reduced. Similar concerns could be raised for other classes of drugs targeting Na+ or K+ channels, which may be altered in some older individuals but not others. New therapies aimed at inhibiting TRPV4 could be envisioned, but only for the sub-population of patients where this channel is upregulated. The current findings by Peana et al.9 indicate that some individuals suffering from ischaemic heart disease could be a key target group for this type of anti-arrhythmic intervention. Thus, an important take-home message is that, while we must strive to personalize cardiac medicine on an individual basis, this fine-tuning must take into account each individual’s biological age. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.