There's no RV in ReVerse...or is there?
Jeremy A. Mazurek, MD
University of Pennsylvania
Philadelphia, PA, USA
While there is an extensive literature dedicated to left ventricular (LV) reverse remodeling in heart failure (HF), with current staples of HF therapy proven to not only improve outcomes but also improve left heart structure and function, the same may not be true for the right ventricle (RV) in pulmonary arterial hypertension (PAH). A simple 'pubmed' search using the terms "LV reverse remodeling" produced 785 results, while a search of "RV reverse remodeling pulmonary hypertension" yielded only 52 items. So the question remains: In PAH, does the RV reverse remodel after the initiation of pulmonary hypertension (PH)-specific therapy?
PAH is a rare condition characterized by significant elevations in pulmonary artery pressure and pulmonary vascular resistance that results in high RV afterload leading to exercise intolerance, RV failure and ultimately, death. It is the RV adaptation to this increased load, and not pulmonary artery pressure elevation per se, that dictates clinical symptoms and outcomes.
Initial RV hypertrophy gives way to progressive RV remodeling and maladaptation, perpetuated by RV ischemia and a glycolytic shift in RV metabolism, eventually leading to RV failure . Thus, despite advances in PAH therapy over the last 2 decades, largely directed at the underlying pathobiology at the level of the pulmonary vasculature, morbidity and mortality remain quite high. And while prior study has shown dramatic improvements in RV structure and function in the subset of patients with PAH who have undergone bilateral lung transplantation, and in those with chronic thromboembolic PH who have undergone successful pulmonary thromboendarterectomy, the majority of patients with PAH are often on long-term, double and triple drug combination PH-therapy, whose effects on RV reverse remodeling are less definitive .
Data from the early days of sildenafil and bosentan show a reduction in RV mass, and improvements in RV:LV ratio and eccentricity index when sildenafil is added to bosentan therapy as compared to bosentan alone [3-5] This is matched by improvements in hemodynamic metrics including PVR and cardiac index (CI), as well as improvements in NT-proBNP levels. Interestingly, long-term epoprostenol therapy was not found to reverse RV dilatation and hypertrophy . Study of the effects of newer PH therapies on RV reverse remodeling is currently underway [7, 8].
As the effects of modern PH therapies on hemodynamic and imaging parameters of RV structure and function are further clarified, we are able to better risk stratify patients not simply based on baseline values, but rather on improvement in values or absolute values on serial assessment after exposure to PH-specific therapy. Nickel et al. found that while many traditional parameters were predictive of survival at baseline (including WHO functional class, CI, mixed-venous O2 saturation, and NT-proBNP), follow-up assessment of these parameters in response to therapy were more predictive of prognosis than baseline values [9) Similarly, serial RV ejection fraction (RVEF) in response to PH-specific therapy was superior to baseline RVEF in assessing patient outcome in PAH with a survival advantage of a follow-up RVEF > 35% vs. < 35%, independent of change in PVR [5, 10].
Recently, we reported on the prognostic value of follow-up tricuspid annular plane systolic excursion (TAPSE), an easily assessable and reproducible echocardiographic metric of RV function, in a PAH population . Previous reports showed the prognostic significance of baseline TAPSE in a PAH population with a nearly 4-fold increased risk of death in patients with reduced baseline TAPSE. That study, however, assessed TAPSE at one undefined time-point, and thus, it did not reflect the prognostic value of echo-derived RV function in response to PH-specific therapy .
In the recent report, we evaluated 70 patients with PAH with baseline and follow-up echocardiography after the initiation of PH therapy. We assessed the prognostic role of follow-up TAPSE and specifically a treatment TAPSE goal of ≥ 2cm, which is reflective of normal RV function. Overall, 66% of patients were on double or triple combination therapy at follow-up (median time to follow-up echocardiogram was 384 (201-753) days) with a significant improvement in TAPSE (1.6±0.5 cm vs. 2.0±0.4 cm; p< 0.0001), along with improvements in other echocardiographic and functional parameters at follow-up. Importantly, while baseline TAPSE stratified at 2 cm did not predict survival in this cohort, when we stratified by follow-up TAPSE ≥ 2cm there was a significant survival advantage in those with follow-up TAPSE ≥ 2cm as compared to those with follow-up TAPSE < 2 cm (log-rank p=0.004; HR 0.21, (95% CI 0.08-0.60)).
Furthermore, 28 of 37 patients (76%) with follow-up TAPSE ≥ 2cm had a TAPSE < 2 cm at baseline, with 19 of 37 (51%) having a baseline TAPSE ≤ 1.6 cm. This group, therefore, was representative of patients with significantly reduced TAPSE at baseline that improved to normal at follow-up after initiation of PH-specific therapy. Thus, we propose that follow-up TAPSE ≥ 2cm is both an achievable treatment target, as well as a powerful prognostic marker in patients with PAH.
This data supports the call from the 5th World Symposium on PH for "the need to identify clinically relevant treatment goals that correlate with long-term outcome" . It also highlights the role of echocardiography, which is noninvasive, relatively inexpensive and widely available in identifying the ability of the RV to indeed ReVerse remodel in the setting of PH-specific therapy. Further work in this area is needed with the development of more therapies, and specifically RV-targeted therapies, to ultimately provide even better outcomes for our patients stricken with this condition. ■
Disclosure Statement: The author has no conflicts of interest to disclose.
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