Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart

Abstract

Right heart function is the main determinant of prognosis in pulmonary arterial hypertension (PAH). At present, no treatments are currently available that directly target the right ventricle, as we will demonstrate in this article.Meta-analysis of clinical trials in PAH revealed that current PAH medication seems to have limited cardiac-specific effects when analysed by the pump-function graph. Driven by the hypothesis that ''left'' and right heart failure might share important underlying pathophysiological mechanisms, we evaluated the clinical potential of left heart failure (LHF) therapies for PAH, based on currently available literature.As in LHF, the sympathetic nervous system and the renin-angiotension-aldosterone system are highly activated in PAH. From LHF we know that intervening in this process, e.g. by angiotensinconverting enzyme inhibition or b-blockade, is beneficial in the long run. Therefore, these medications could be also beneficial in PAH. Furthermore, the incidence of sudden cardiac death in PAH could be reduced by implantable cardioverter-defibrillators. Finally, pilot studies have demonstrated that interventricular dyssynchrony, present at end-stage PAH, responded favourably to cardiac resynchronisation therapy as well.In conclusion, therapies for LHF might be relevant for PAH. However, before they can be implemented in PAH management, safety and efficacy should be evaluated first in well-designed clinical trials.

Treatment of right heart failure on pulmonary arterial hypertension: is going left a step in the right direction?

“…Thus, there is room for innovative thinking. This is precisely what HANDOKO et al [2] have done in the current issue of the European Respiratory Review. Taking a refreshing physiological point of view, the authors acknowledge that advanced stage P(A)H symptomatology and prognosis is essentially determined by the state of the right ventricle, and that, contrary to prevailing belief, currently prescribed targeted therapies do not act on the right ventricle.…”

“…However, the measurements of pulmonary vascular pressures and flows during a standard right heart catheterisation do not provide an adequate evaluation of ventricular pump function [20]. HANDOKO et al [2] correctly reason that the adaptation of right ventricular function to after load is, in essence, systolic, or homeometric, with secondary heterometric changes occurring in cases of excess of peripheral demand for increased flow. A right heart that is adequately adapted to increased pulmonary artery pressures remains normal in size, with an increased contractility matching pulmonary arterial elastance, at least at rest [21].…”

“…Taking a refreshing physiological point of view, the authors acknowledge that advanced stage P(A)H symptomatology and prognosis is essentially determined by the state of the right ventricle, and that, contrary to prevailing belief, currently prescribed targeted therapies do not act on the right ventricle. As a result, HANDOKO et al [2] have come forward with proposals derived from the treatment of left heart failure, including cautious but decisive use of b-blocker therapies and, in selected cases, resynchronisation therapy. 50 years ago, WOOD [3] proposed the ''vasoconstrictive factor'' as the primum movens of severe pulmonary hypertension.…”

“…HANDOKO et al [2] present an elegant haemodynamic analysis showing inverse directional changes of stroke volume and pulmonary artery pressure in randomised controlled trials of targeted therapies in PAH, leaving little space for direct inotropic effects. As for the reversal of vasoproliferation, this is of course difficult to demonstrate in patients.…”

The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy

“…1,2 However, it is increasingly recognized that, in addition to the pulmonary vasculature, the right heart is a viable therapeutic target in the treatment of pulmonary hypertension. 3,4 We have recently shown, using a hypoxia model of pulmonary hypertension in rats, that GW0742, a ligand for peroxisome proliferator-activated receptor (PPAR) β/δ, 5 reduces right heart hypertrophy without influencing pulmonary vascular remodeling. 6 This was a somewhat unexpected finding, since we and others found GW0742 to relax pulmonary vessels 6 or vascular cells 7 and to inhibit lung cell proliferation in vitro.…”