Introduction
A major determining factor on outcomes in patients with pulmonary arterial hypertension (PAH) is right ventricular (RV) function.1 During the progression of PAH, many of the molecular mechanisms that drive transition from compensated RV hypertrophy (RVH) to dilatation and failure remain enigmatic. Recently, animal modelling of RVH and RV failure in PAH has revealed a substantial downregulation of mitochondrial oxidative metabolism in favour of glycolysis. The molecular mechanisms controlling this metabolic shift in the RV are unclear,2 but, in part, may involve alterations of potassium channel function.3–5 Importantly, in rodents with experimental PAH6 7 or chronic RV overload,8 RVH, RV electrical remodelling and RV dysfunction can be normalised with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase which in turn activates pyruvate dehydrogenase (PDH) to favour oxidative metabolism. These findings suggest that alterations in mitochondrial function, metabolism and energy substrate utilisation are keys to understanding the progression to RV failure. Observational human data through positron emission tomography corroborate these findings by revealing increased uptake of glucose in PAH-dependent RV dysfunction.9 10 However, data are sparse regarding the efficacy and safety profile of DCA in humans, and it is currently not an US Food and Drug Administration (FDA)-approved medication. Alternatively, ranolazine, which is currently approved for chronic stable angina,11 12 also activates PDH13–15 and has been shown to inhibit fatty acid oxidation, myocardial late sodium currents and sodium-dependent calcium overload, as previously reviewed.16 Recently, in a rodent model of RVH, ranolazine was reported to successfully reverse metabolic dysfunction and improve cardiac output and exercise capacity.15 17 A number of small single-centred studies on the use of ranolazine in pulmonary hypertension (PH) have recently been completed. A study reported 12 patients with PAH (six ranolazine and six placebo) were given the drug acutely and followed for 12 weeks in a safety study of ranolazine in acute vasoreactivity and found it to be safe without impact on haemodynamics (NCT01757808).18 Another study looking at 10 patients with 8 completing follow-up in an open-label ranolazine study in PAH patients with angina or angina equivalent showed symptomatic and functional improvement at 3 months (NCT01174173).19 A third small study looking at the effect of ranolazine in 10 patients with PH and diastolic LV dysfunction and follow-up in 6 months has not yet published results (NCT02133352). Thus, ranolazine may have therapeutic potential in RV dysfunction and PH, and could be readily ‘repurposed’ as an already FDA-approved medication.
Ranolazine is a racemic mixture and chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole. In the USA, ranolazine is available for oral administration as film-coated, extended-release tablets containing 500 or 1000 mg of active ingredient. Ranolazine has antianginal and anti-ischaemic effects that do not depend on reductions in heart rate or blood pressure.