Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature

Abstract

Pulmonary hypertension (PH) is defined by elevated mean pulmonary artery pressure following the pathological remodelling of small pulmonary arteries. An increase in right ventricular (RV) afterload results in RV hypertrophy and RV failure. The pathophysiology of PH, and RV remodelling in particular, is not well understood, thus explaining, at least in part, why current PH therapies have a limited effect. Existing therapies mostly target the pulmonary circulation. Because the remodelled RV fails to support normal cardiac function, patients eventually succumb from RV failure. Developing novel therapies that directly target the function of the RV may therefore benefit patients with PH. In the past decade, several promising studies have investigated novel cardioprotective strategies in experimental models of PH. This review aims to comprehensively discuss and highlight these novel experimental approaches to confer, in the long-term, greater health benefit in patients with PH. AbbreviationsBMPR-2, bone morphogenetic protein receptor-2; EUK-134, superoxide dismutase and catalase mimetic; HDACs, histone deacetylases; HIF-1α, hypoxia inducible factor-1α; LV, left ventricle; miRs, micro-RNAs; NHE-1, sodium hydrogen exchanger-1; NRF2, nuclear respiratory factor-2; PASMCs, pulmonary arterial smooth muscle cells; PH, pulmonary hypertension; RV, right ventricular IntroductionPulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure ≥25 mm Hg at rest, as assessed with right heart catheterization Simonneau et al., 2013). It is a growing health burden in both developed and developing countries (Mocumbi et al., 2015). The global prevalence of PH is not known, due to a lack of global PH registries (Thienemann et al., 2014). In Europe, the prevalence of PH is calculated to range from 0.3 to 6%, and in particular, idiopathic PH affects approximately six individuals per million people (Humbert et al., 2006;Mocumbi et al., 2015). A similar prevalence has been reported in Australia for PH secondary to left ventricular heart disease (0.33 to 6.6% per million people) (Lam et al., 2009;Strange et al., 2012). The prevalence of PH on the African continent is not known (Mocumbi et al., 2015), and therefore, a multinational multicentre registry of PH was recently established in Africa to describe PH presentation, severity, management, causes and comorbidities (Thienemann et al., 2014). In South Africa, the Heart of Soweto cohort study captured 2505 cases with heart failure, of which one-third was diagnosed with right heart failure due to chronic lung disease (26%) and pulmonary artery hypertension (20%) (Sliwa et al., 2008;Stewart et al., 2011). This study demonstrated that the prevalence of PH may not be as rare as thought to be.PH develops in many clinical conditions, including human immune virus/acquired immune deficiency syndrome, sickle cell disease, systemic sclerosis, schistosomiasis, congenital heart disease and chronic obstructive pulmonary disease (Graham et al., 2010;Papamatheakis et al., 2014;Simonneau et al.,...

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“…In general, attenuation of mitochondrial-derived oxidative stress is a reasonable therapeutic concept to attenuate RV hypertrophy and transition to RV failure (for review, see Maarman et al, 2017).…”

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“…PH is defined as a mean pulmonary artery pressure ≥20 mmHg, when diagnosed with right heart catheterization 60,61 . Characteristic features include sustained vasoconstriction, vascular remodeling, and thrombosis formation 62 .…”

“…PH is defined as a mean pulmonary artery pressure ≥20 mmHg, when diagnosed with right heart catheterization. 60 , 61 Characteristic features include sustained vasoconstriction, vascular remodeling, and thrombosis formation. 62 Pathologic triggers are believed to prime cells in the pulmonary arterioles to excessive proliferation that leads to narrowing and obliteration of the vessel lumen, and thus, elevated pulmonary artery pressure.…”

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