Therapeutic Challenges and Emerging Treatment Targets for Pulmonary Hypertension in Left Heart Disease

Abstract

Pulmonary hypertension (PH) attributable to left heart disease (LHD) is believed to be the most common form of PH and is strongly associated with increased mortality and morbidity in this patient population. Specific therapies for PH‐LHD have not yet been identified and the use of pulmonary artery hypertension‐targeted therapies in PH‐LHD are not recommended. Endothelin receptor antagonists, phosphodiesterase‐5 inhibitors, guanylate cyclase stimulators, and prostacyclins have all been studied in PH‐LHD with conflicting results. Understanding the mechanisms underlying PH‐LHD could potentially provide novel therapeutic targets. Fibrosis, oxidative stress, and metabolic syndrome have been proposed as pathophysiological components of PH‐LHD. Genetic associations have also been identified, offering additional mechanisms with biological plausibility. This review summarizes the evidence and challenges for treatment of PH‐LHD and focuses on underlying mechanisms on the horizon that could develop into potential therapeutic targets for this disease.

Prospects of mitochondrial transplantation in clinical medicine: Aspirations and challenges

“…Right ventricular mass and wall thickness were also restored in the group that received mitochondria. This study may help with establishing mitochondrial transplantation as a therapy for pulmonary hypertension secondary to structural heart defects (Lteif, Ataya et al 2021). It can be inferred from this work that mitochondrial transplantation not only reverses pulmonary hypertension but may also help restore ventricular function induced by a left-to-right shunt.…”

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

“…In response to diverse stimuli, mostly from ECs, it can contract or relax, modifying the lumen diameter of blood vessels and altering vascular resistance. Normally, ECs produce prostacyclin, a potent platelet aggregation inhibitor and vasodilator [ 5 ]. However, the low expression of its cognate receptor was noted in PASMCs isolated from patients with IPAH compared to that in normal controls, indicative of a potential reduction in active prostacyclin signaling.…”

“…Nevertheless, mortality among intermediate- and high-risk PAH patients remains high, highlighting the need for better disease management [ 4 ]. Novel treatment options are to be proposed based on a deeper understanding of PAH pathogenesis [ 5 , 6 , 7 ]. Here, we focus on the activin/inhibin family of molecules, which have recently gained traction as promising therapeutic targets for PAH.…”

Pulmonary Hypertension in Patients With Heart Failure With Mid-Range Ejection Fraction

“…Apart from the treatment of the underlying left heart pathology (i.e., HFmrEF) there is currently intense research investigating novel treatments targeting the pulmonary vasculature directly (5,94). Approaches currently under study for patients with PH in the context of HF include among others the β3 adrenergic receptor agonist mirabegron, the antifibrotic agent PBI 40-50, the rho kinase inhibitor fasudil, the calcium sensitizer levosimendan, oral sodium nitrite, and catheter-based pulmonary artery denervation (5,94). It is likely that only certain pulmonary vascular phenotypes with PH in HFmrEF or HFpEF will derive benefit from such an approach.…”