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 angiotensin-converting enzyme inhibition or β-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.

FIGURE 1.

Haemodynamic changes during the progression of pulmonary arterial hypertension (PAH). The continuous rise in pulmonary vascular resistance (PVR) during the progression of PAH is initially compensated by concentric remodelling of the right ventricle (RV). Right atrial pressure (P_ra) remains normal and there is a steep increase in mean pulmonary artery pressure (P̄_pa) as cardiac index (CI) at rest is preserved. In the next stage, the RV is not able to fully compensate for the further increase of PVR and starts to decompensate; eccentric RV remodelling is observed. There is a modest rise in P̄_pa as CI also starts to fall. At this stage P_ra remains at near normal levels. In the final stage of overt right heart failure there is a severe drop in CI, a steep rise in P_ra and, even though PVR still increases, P̄_pa drops due to the low output state. Changes in RV function fit to the different disease stages in PAH and explain the prognostic importance of CI and P_ra over P̄_pa. In systemic sclerosis associated-PAH (·-·-·-), the ability of the RV to adapt to the increasing PVR appears limited, therefore, the heart fails at lower PVR [7]. The aim of specific RV-therapies (- - - -) is to improve the ability of the heart to adapt to its afterload. Ref.: reference/normal value.

FIGURE 2.

Distinguishing cardiac-specific from pulmonary-specific effects in pulmonary hypertension (PAH) patients. a) Pressure curves of the right ventricle (RV) and the main pulmonary artery are shown. Maximal isovolumic pressure is estimated (P_iso) by sine wave fit [18]. b) Pressure–volume loops can be constructed from instantaneous pressure and volume measurements by use of conductance catheters. End-systolic elastance (E_es) is considered a load-independent measure of RV contractility and is measured from the slope of the connecting line between end-systolic pressure (P_es) and P_iso [19]. c) Increase in contractility. d) Decrease in pulmonary vascular resistance (PVR). An alternative approach for describing heart function is the pump-function graph [20]. Here, average RV pressure versus stroke volume (SV) at steady state are plotted (the working point) and by the same single-beat estimation (P̄_iso), a pump-function graph is constructed (–––––). The slope of the line from the origin through the working point is a measure for PVR divided by heart period (PVR/T) and, therefore, a measure for RV afterload. When RV contractility increases (c), this is observed in the pump-function graph by increased P̄_iso while SV_max remains unchanged; the new working point has moves to the upper right (#). When RV afterload is reduced (PVR/T decreases; d), the pump-function graph remains unchanged, while the new working point moves to the lower right (¶). P̄: mean pressure; P_pa: pulmonary artery pressure; P_RV: RV pressure curve.

FIGURE 3.

Meta-analysis of pulmonary arterial hypertension (PAH) trials by pump function. Each arrow shows the general absolute change in indexed stroke volume (ΔSV_i) and mean pulmonary artery pressure (ΔP̄_pa; as a surrogate measure for mean right ventricle pressure) per study group of all placebo controlled randomised clinical trials in PAH reporting serial haemodynamic measurements [33]. A decrease in SV_i was always accompanied by an increase in P̄_pa in the placebo group (red arrows), implying an increase in pulmonary vascular resistance (PVR) without relevant changes in cardiac contractility. For the intervention groups (blue arrows), an increase in SV_i was always accompanied by a decrease in P̄_pa, implying reduction in PVR without important changes in cardiac contractility. Therefore, current PAH medications predominantly have pulmonary vasodilating effects with only limited cardiac-specific effects.

FIGURE 4.

Schematic diagram showing as yet unexplored pathophysiological mechanisms in pulmonary arterial hypertension (PAH). RV: right ventricular; ETRAs: endothelin receptor antagonists; PDE-5: phosphodiesterase-5; CRT: cardiac resynchronisation therapy; SNS: sympathetic nervous system; RAAS: renin–angiotensin–aldosterone system; ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotension receptor blockers; MSNA: muscle sympathetic nervous activity; HRV: heart rate variability; βAR: cardiomyocyte β₁-adrenergic receptor; AT1R: cardiomyocyte angiotensin type 1 receptor; Aldo ant: aldosterone antagonist; RHF: right heart failure; ICD: implantable cardioverter defibrillator.