SUMMARY
Right ventricular (RV) dysfunction and the inability of the RV contractility to keep up with increased afterload, or
ventricular-arterial (V-A) uncoupling, in pulmonary hypertension (PH) are strongly related to poor outcomes in
PH. Several preclinical studies, including ours, demonstrate multi-fold increases in RV free wall (RVFW)
contractile forces that occur as a crucial adaptive mechanism. Yet, as RV continues to remodel the relative
increase in contractility is less compared to the increase in afterload causing V-A uncoupling. RV wall contractility
depends on the ability of the muscle to generate active forces to deform the free wall and an optimal myo-
architecture helicity to translate the generated force to the desired RV ejection. However, increased wall stiffness
or changes in helicity requires generation of more contractile forces which may become limited, hampering RV’s
adaptation and function. Indeed, several studies have demonstrated that patients with PH have increased RV
stiffness which independently predicts worse outcomes. However, how changes in RVFW architecture, stiffness
and contractility progress and relate to RV’s transition to maladaptation remain unknown. In addition, as RV
remodeling is primarily triggered by increases in RV afterload, the role of resistive vs. pulsatile components of
afterload in RV maladaptation remains unclear. Understanding the biomechanical basis of the transition from
adaptive to maladaptive RV to identify at-risk patients remains an unmet need in PH. We hypothesize that
passive remodeling in the RVFW competes against contractile adaptation, and coalescing passive (stiffness)
and active (contractility) remodeling of the RV into stiffness-to-contractility ratio (SCR), which depends on distinct
contributions of resistive and pulsatile afterload, enables early identification of RV’s transition to V-A uncoupling
before RV’s dysfunction is evident in global markers. We will test this hypothesis via the following aims:
1. Determine mechanisms underlying elevations in SCR and resulting V-A uncoupling. We will separate the
independent contribution of passive and active tissue-level biomechanical characteristics to organ-level function.
2. Develop and validate tools to non-invasively estimate SCR in predicting V-A uncoupling. We will develop and
use an integrated echocardiography-deep learning tool to non-invasively assess the independent role of early
increases in SCR in predicting V-A uncoupling. 3. Identify the contributions of PVR and PAC in increasing SCR.
We will separate the contributions of increases in distal resistance versus reductions in PA compliance to RV
afterload and increases in SCR. 4. Determine the role of RV passive and active remodeling events and SCR in
functional outcomes and clinical events in patients. We will determine relationships between SCR, V-A coupling,
and clinical events in retrospective human patients. Our studies will establish a novel RVFW-level prognostic
marker, delineate its biomechanical basis, and develop non-invasive tools to estimate it. Our results will assist
with identifying PH patients at risk early in the disease to study therapeutic strategies to maintain and improve
RV function in PH.
