Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Abstract

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes.Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Relevance of comorbidities on initial combination therapy in pulmonary arterial hypertension

“…Althought some discussion still persists on the opportunity of an initial combination therapy for those patients with cardiovascular risk factors (21), we observed that a not negligible proportion of patients with one comorbidity showed a considerable hemodynamic and clinical response to therapy, as 25% of patients had more than 51% reduction in PVR and up to 35% of patients achieved a low risk status. The importance of PVR reduction has been recently recognized by increasing evidence showing that a significant decrease in PVR is needed to induce RV reverse remodeling and functional recovery (14,(22)(23)(24)(25)(26)(27)(28). Patients with > 1 cardiovascular comorbidity showed a less important reduction in PVR associated with a higher proportion of RV dilation and severe tricuspid regurgitation compared with the others.…”

Commentary on: Echocardiography in Pulmonary Arterial Hypertension: Is It Time to Reconsider Its Prognostic Utility?

“…Initial combination therapy, including parenteral prostacyclins, is associated with a greater RHRR than with other treatment strategies and specifically, more than 50% of RHRR was obtained with >50% reduction in PVR [26]. All data verify that robust hemodynamic improvements can reverse pathologic remodeling of the right ventricle and restore RV function to normal in PAH [18], so if normal RV function were the goal of treatment during patients' follow-up, the prognosis could be better.…”

“…Right Heart Catheterization represents an accurate monitoring strategy and Cardiac Index is the first parameter associated to survival, reflecting indirectly RV function, already used in risk stratification assessment according to Guidelines. Interestingly, RV afterload reduction is not recommended to be the treatment goal, even though numerous studies suggest that greater RV afterload reduction leads to a profound reverse RV remodelling improving RV function and prognosis [18]. However, reaching threshold levels for pulmonary arterial pressure or vascular resistance seems to play pivotal role in interrupting the self-perpetuating injury of pulmonary vascular disease.…”

“…However, reaching threshold levels for pulmonary arterial pressure or vascular resistance seems to play pivotal role in interrupting the self-perpetuating injury of pulmonary vascular disease. Initial oral combination therapy especially using parenteral prostacyclin early after PAH diagnosis provides greater hemodynamic improvement with more robust reductions in mPAP and PVR, parameters proved to be related to adverse pulmonary arterial and right heart remodelling [18].…”

Let’s Talk about Sex: Sexual Health in Pulmonary Arterial Hypertension

“…With disease that may not be completely addressed by oral or inhaled therapies, parenteral therapy is warranted. Newer guidelines are driven primarily by patient risk stratification, and combination and escalation therapy is often recommended if low-risk status is not achieved ( 14 , 15 ). This approach may not account for a patient’s perspective or the impact of multiple therapies on HRQOL.…”