A Novel Strategy for the Management of Lung Congestion: Targeting TRPV4 Channel, the ‘Gate Keeper’ of Pulmonary Capillary Permeability

This article refers to ‘Targeting pulmonary capillary permeability to reduce lung congestion in heart failure: a randomized, controlled pilot trial’ by G.M. Stewart et al., published in this issue on pages 1641–1645. Lung congestion presents one of the hallmark features of heart failure, not only being a major determinant of type and severity of clinical manifestations but also driving prognosis by promoting pulmonary vascular dysfunction and right ventricular failure in addition to impairing gas exchange and pulmonary function.1, 2 Pathophysiology of lung congestion has been classically considered to result from passive fluid extravasation from lung capillaries towards the alveoli and interstitium due to pathologically elevated pulmonary venous pressure that surpasses the intravascular oncotic pressure, according to Starling's equation. Therefore, traditional therapeutic strategies aiming to tackle congestion focus on the reduction of pulmonary intravascular pressure, either through decreasing total intravascular volume with diuretics or through afterload reduction with vasodilators. However, the classic view of the pathogenesis of lung oedema has been challenged by a series of published studies showing that active endothelial signalling pathways possibly contribute to enhanced vascular permeability under conditions of increased pulmonary pressures, thereby promoting oedema formation.3, 4 A key molecule in this respect is the transient receptor potential vanilloid 4 (TRPV4), an endothelial transmembrane cation channel that becomes activated by pressure-induced mechanical stretch of the endothelium.5 Activation of TRPV4 allows intracellular influx of Ca2+, which in turn activates signalling pathways that result in cytoskeletal reorganization and disruption of inter-endothelial junctions, thereby increasing vascular permeability.6, 7 In ex-vivo models of hydrostatic stress-induced pulmonary oedema, both pharmacological blockade of TRPV4 and TRPV4 gene knockout have been shown to prevent development of lung oedema.6 Moreover, in experimental models of ischaemic chronic and acute heart failure, pre-treatment with an orally active TRPV4 blocker prevented the development of pulmonary oedema, while treatment with the same blocker resolved oedema already established in animals post-myocardial infarction.8 Importantly, TRPV4 channel did not appear to regulate endothelial permeability under conditions of normal pulmonary pressures. Therefore, TRPV4 would present a suitable candidate for pharmacologic modulation in pathophysiologic conditions associated with elevated pulmonary pressures, most notably heart failure, with a reasonable possibility that its modulation would not disrupt physiological endothelial processes. Indeed, a first-in-human study with GSK2798745, a novel orally active TRPV4 inhibitor, has reported the safety and tolerability of this intervention in healthy subjects and in a small group of New York Heart Association (NYHA) class II heart failure patients.9 Of interest, worsening of dyspnoea that could be theoretically caused by impediment of fluid transport back to the lung capillaries from the alveoli was not reported with TRPV4 inhibition compared to placebo. A significant step forward in the clinical research concerning this novel concept for the prevention and resolution of lung congestion has been made with the study by Stewart et al.10 published in the present issue of the Journal. In this pilot, double-blind, cross-over, placebo-controlled study, short-term treatment with GSK2798745 has resulted in a trend towards improvement of pulmonary gas exchange as assessed by lung diffusing capacity for carbon monoxide in symptomatic patients with chronic heart failure, suggestive of reduced lung congestion. At the same time, treatment with GSK2798745 was safe and well-tolerated by patients as compared to the placebo period, confirming earlier first-in-human studies. Although statistical significance was not reached, which might have been affected by the small sample size, the two different protocols used for assessment of lung diffusing capacity, or the inclusion of rather moderately symptomatic patients (NYHA class II/III: 55/45%) in whom a smaller treatment effect as regards reduction of lung congestion might be expected, this study is significant for three reasons. First, it confirms in clinical grounds the novel concept of the contribution of abnormal capillary permeability for the development of cardiogenic pulmonary oedema, which is not merely the result of passive backward transfer of elevated hydrostatic pressures. Importantly, abnormal permeability is mediated through TRPV4 channel-induced activation of intracellular endothelial signalling pathways. Second, it confirms safety of the orally administered novel TRVP4 inhibitor GSK2798745. With respect to the potential adverse event of interest of worsening dyspnoea, no such event was reported by any of the patients throughout the whole study duration. In addition, semiquantitative scoring of dyspnoea by a self-reported five-point Likert scale did not reveal any significant differences between active therapy and placebo periods. Third, this study provides encouraging preliminary results regarding the efficacy of the TRVP4 inhibitor GSK2798745 in improving lung congestion, even in patients with stable moderate symptoms treated with optimal contemporary heart failure medications including diuretics, beta-blockers and vasodilators (Table 1). As previously noted, lung congestion, both acute and residual chronic, is a driver of worse prognosis in heart failure patients, thereby presenting as a therapeutic target per se.11, 12 Diuretics are currently first-line symptomatic anti-congestive therapy. However, they are not spared from several unwanted side effects, most importantly hypovolaemia/hypotension, electrolyte abnormalities, worsening of renal function, and adverse neurohormonal activation, which in practice limit their use although residual congestion is frequently encountered.13 Therefore, there is an unmet need to tackle residual congestion through novel therapeutic strategies targeting the end-effector molecules of active pulmonary inter-endothelial fluid leakage that would be additive to standard heart failure pharmacotherapies (Figure 1). Indeed, further clinical research is needed to draw firmer conclusions as to the safety and potential efficacy of TRPV4 inhibition in congestive heart failure, in order to include larger patient populations, as well as patients from a wider clinical spectrum of congestive heart failure, from mildly to severely symptomatic advanced chronic heart failure and possibly hospitalized heart failure.14 Moreover, further measures for the assessment of resolution of congestion should be evaluated, including echocardiography and lung ultrasound as well as natriuretic peptides in adequately powered studies.15 Clearly, the study by Stewart et al.10 presents an important first step in the arena of clinical research for TRPV4 inhibitors in cardiogenic pulmonary congestion, showing promising results that justify stepped-up clinical investigation. Conflict of interest: none declared.