Background:
Diagnosis of pulmonary hypertension (PH) in patients with left heart disease (LHD) is commonly late in the disease, as right heart catheterization is not routinely performed in LHD patients due to its inherent adverse effects. As such, non-invasive techniques to detect and monitor PH-LHD are an unmet clinical need. Yet, biomarkers of heart failure such as brain natriuretic peptide are neither specific nor sensitive for the presence or absence of PH or increased RV afterload, and standard echocardiography allows to estimate the systolic pulmonary artery (PA) pressure only if a tricuspid regurgitant jet can be recorded. Recently, PA stiffening has emerged as an important diagnostic and prognostic parameter in PH. Using a translational bench-to-bedside approach based on non-invasive echocardiography, we aimed to develop a non-invasive stiffness index to estimate PA stiffness as a diagnostic parameter in PH due to LHD.

Methods:
A rat model of congestive heart failure secondary to aortic banding (AoB) was used to induce PH-LHD and PA stiffening. PA radial strain and stroke volume were determined by 2D transthoracic echocardiography. From these, an echocardiographic stiffness index (Echo SI) was derived as a ratio of stroke volume to radial strain, and correlated to invasively measured pulmonary hemodynamics and ex vivo measured "true" PA stiffness. Next, the developed Echo SI was validated in a prospective cohort of seventeen LHD patients with or without PH prior to heart transplantation. Echo SI in patients was measured by 2D transesophageal echocardiography, and again compared to "true" PA stiffness measured ex vivo in intraoperatively collected PA specimens.

Results:
The rat AoB model was characterized by progressive development of congestive heart failure with PH-LHD and PA stiffening. Echocardiography derived PA strain and Echo SI correlated closely with invasive pulmonary hemodynamics and ex vivo measured "true" PA stiffness. As compared to right PA radial strain which detected "true" PA stiffness in PH-LHD patients with 72% sensitivity and 71% specificity, Echo SI performed superior with 87% sensitivity and 77% specificity.

Conclusion:
From echocardiographic analyses in a rodent model of PH-LHD, we derived a PA stiffness index, Echo SI, that was first validated by hemodynamic and biomechanic data in rodents, and subsequently in a prospective study in LHD patients. Echo SI allows for non-invasive assessment of PA stiffness in patients or animal models with LHD. As such, Echo SI may improve the clinical diagnosis and longitudinal monitoring of PH-LHD, and facilitate translation of biomechanic and pathomechanistic insights from preclinical studies to patient care.

This research was supported by the DZHK (German Centre for Cardiovascular Research), BMBF (German Ministry of Education and Research) and DSHF (Deutsche Stiftung für Herzforschung).