Emerging therapies for right ventricular dysfunction and failure

Abstract

Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited.Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular-and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA-and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.

Animal models of pulmonary hypertension: Getting to the heart of the problem

“…The lessons learned from animal models of PH are starting to bear fruit as emerging pharmacotherapies (reviewed elsewhere: Klinke et al, 2020), particularly those targeting RV metabolism, oxidative stress or inflammation, show success in pre-clinical and early clinical studies. Recent advances in small animal models of PH offer fresh potential to unravel the molecular mechanisms underlying the progression from adaptive remodelling to decompensation of RV function.…”

Off‐label use of PAH‐targeted medications approved for adults and their financial coverage by health insurances are vital for children with pulmonary hypertension

“…In severe disease, oral PAH medications should be further combined with parenteral prostacyclin analog (PCA) therapy (inhalation, intravenous infusion). 29,32,33 Besides their vasodilatory effects, some of the PAH-targeted drugs also have anti-proliferative and antiinflammatory effects, [34][35][36] aiming to prevent or at least slow down pulmonary vascular remodelling, which would lead to elevated pressure and resistance in the pulmonary circulation and right heart failure. 35 After the first PAH medications had become available for paediatric use (bosentan, sildenafil), the most common treatment strategy has been starting with monotherapy, followed by combination pharmacotherapy (usually a PDE5 inhibitor plus endothelin receptor antagonist).…”

“…In severe disease, oral PAH medications should be further combined with parenteral prostacyclin analog (PCA) therapy (inhalation, intravenous infusion) 29,32,33 . Besides their vasodilatory effects, some of the PAH‐targeted drugs also have anti‐proliferative and anti‐inflammatory effects, 34–36 aiming to prevent or at least slow down pulmonary vascular remodelling, which would lead to elevated pressure and resistance in the pulmonary circulation and right heart failure 35 …”

miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis

“…Pulmonary arterial hypertension (PAH) is an incurable disease resulting in the death of the patients due to right ventricular failure [ 1 , 2 ]; it is characterized by extracellular matrix (ECM) remodeling of the pulmonary arteries with increased collagen deposition, collagen cross-linkage, and elastic laminae breakdown. ECM remodeling frequently occurs during the early stage of PAH and plays a critical role in the pathogenesis of distal pulmonary vascular remodeling [ 3 , 4 , 5 ]. In addition, the ECM network plays a crucial role in cardiac homeostasis by providing structural support, facilitating force transmission, and transducing key signals to cardiomyocytes, vascular cells, and interstitial cells [ 6 ].…”