Taking the right ventricle to ‘task’ in pulmonary hypertension: role of TASK1/KCNK3 in RV dysfunction

This editorial refers to ‘Loss of KCNK3 is a hallmark of RV hypertrophy/dysfunction associated with pulmonary hypertension’ by M. Lambert et al., pp. 880–893. It has long been a truism in pulmonary arterial hypertension (PAH) that patients with similar hemodynamic abnormalities can have very different clinical presentations. One may have World Health organization (WHO) Class III or IV symptoms and another may be Class I, and this difference is largely determined by the right ventricle (RV) (see Figure 1). Numerous epidemiological studies have shown that the RV function is a critical determinant of the severity of functional impairment in PAH, as well as being one of the most powerful prognostic indicators for survival.1 Given the rather modest impact of currently available PAH therapies on functional capacity and survival, there is increasing interest in the development of novel therapeutic strategies to improve the ability of the RV to cope with pressure overload. The development of drugs to improve heart function as a treatment for heart failure is by no means a new concept. This has been a very successful strategy for the left ventricular (LV) dysfunction for over three decades, resulting in the introduction of highly effective therapies including beta blockers, renin-angiotensin system inhibitors and more recently combination therapy with neutral endopeptidase and angiotensin receptor inhibitors.2 Unfortunately, we are learning that the RV is very different from the LV and that these therapies do not appear to offer the same benefit for patients with RV failure.3 Mechanisms of maladaptive RV remodelling in pulmonary hypertension (PH). Schematic representation of cross-sectional images of hearts from two hypothetical PAH patients with similar hemodynamic abnormalities. The heart on the left shows adaptive RV remodelling with RV hypertrophy but no increase in the RV internal diameter. The heart on the right shows maladaptive RV remodelling, with a marked increase in RV chamber diameter, flattening of the septum and compression of the LV. Some of the major mechanisms that have been implicated in the transition from a compensated to decompensated RV in PAH are listed, including genetic factors, fibrosis, capillary loss, and ischaemia, inflammation and metabolic or mitochondrial remodelling. The PAH research community is only just beginning to focus on the underlying mechanisms responsible for adaptive and maladaptive RV remodelling in response to chronic pressure overload. This is an essential first step in the development of effective therapies specifically for RV failure, and these efforts have already led to the identification of several major determinants of RV decompensation in PAH including: mitochondrial and metabolic changes4; reduced angiogenesis and RV vascularization5; and inflammation and fibrosis6 (see Figure 1). Moreover, the intrinsic variability in the ability of individual PAH patients to adapt to chronic RV pressure overload, as highlighted earlier, points to a role for genetic determinants in adaptive and maladaptive RV remodelling. This is also supported by strain differences in the development of RV failure in rats in what is now considered to be a ‘gold standard’ model of severe PAH: inhibition of VEGFR2 by SU5416 (SU) together with a transient exposure to chronic hypoxia (CH).7 In the SU/CH model, Fischer rats exhibit high mortality at 6 weeks, whereas Sprague Dawley rats show excellent survival even beyond 12 weeks, despite very similar severity of haemodynamic changes.7 As in PAH patients, the difference in survival was closely associated with greater RV dysfunction and reduction in cardiac output in the Fischer rats.7 Interestingly, administration of cardiotrophin-1, a cytokine that induces physiological cardiomyocyte hypertrophy, restored adaptive remodelling in this model,8 providing proof-of-principle for RV targeted therapies for PAH. In this issue of Cardiovascular Research, Lambert et al.9 implicate KCNK3 (aka TASK1) in RV hypertrophy and dysfunction. This is particularly intriguing since this is one of almost a dozen genes that have been shown to be associated with hereditary (H) PAH, along with BMPR2 which is by far the most common.10 Interestingly, a recent report by some of the same authors of the present manuscript showed that HPAH patients harboring mutations in BMPR2 exhibited greater RV dysfunction, despite similar increases in afterload,11 suggesting that in addition to predisposing to lung vascular disease, this gene also has a role in adaptive RV remodelling. Now Lambert et al. report that KCNK3 plays a role in RV remodelling as well. They provide several lines of evidence to support this conclusion, including the observation that this K-channel is highly expressed in the RV of rodents and humans, is markedly down-regulated with RV hypertrophy, and that its pharmacological inhibition induces molecular and electrophysiological alterations in vitro that are similar to those seen in RV hypertrophy, while chronic inhibition in vivo selectively reduces RV function.9 Thus, loss-of-function mutations in at least two ‘PAH genes’ may not only cause lung vascular disease but may compromise the ability of the right heart to cope with the resulting increase in afterload. However, there are puzzling aspects to the KCNK3 story that deserve some reflection. For example, long-term in vivo inhibition of the KCNK3 channel resulted in a decrease in RV end-diastolic dimensions, whereas one would have expected this to be increased with RV dysfunction. Moreover, it would appear that inhibition of this K-channel also increased pulmonary arterial pressure, as evidenced by a decrease in PAAT on echocardiography. Thus, it is possible that the reduced RV function in response to the K-channel inhibitor was at least in part secondary to pressure overload. A direct role for KCNK3 is further challenged by the reported absence of structural or functional alterations in the RV in TASK-1 KO mice.12 To be certain, RV fibrosis and inflammation have not been carefully looked for in the KO model, so a more subtle RV phenotype cannot be excluded. Lambert et al. also showed that inhibition of KCNK3 led to an increase in action potential duration and thus providing a substrate for arrhythmogenesis. However, unlike LV dysfunction, ventricular arrhythmias are not a major problem in the management of PAH patients right heart failure; and syncope, when it occurs in advanced disease, is thought to have a mainly hemodynamic aetiology related to reduced cardiac output. Nonetheless, this report does address a very important problem: the critical role of the RV in determining the clinical course of patients with PAH and the potential contribution of mutations in genes linked to PAH, such as KCNK3, in the development of RV failure. Moreover, the implications of this work are not limited to PAH but may also apply to other more common forms of pulmonary hypertension (PH), including PH associated with left heart disease (WHO Group 2 PH), in particular heart failure with preserved ejection fraction (HFpEF).13,14 Not only is this condition as prevalent as the more classical heart failure associated with reduced LV function, but it carries a prognosis that is just as grave.13,15 And, as for PAH, symptoms and survival in HFpEF are again driven by RV dysfunction. Thus, insights into the mechanisms responsible for maladaptive remodelling of the RV in response to pressure overload may provide essential clues that will guide research into the development of effective RV-specific therapies that are urgently needed to treat right failure, regardless of its cause. This work was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR) to DJS. KRC is a recipient of Scholar Award from the CIHR Canadian Vascular Network. Conflict of interest: none declared.

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