INTRODUCTION: Pulmonary Hypertension (PH) as an etiologically heterogeneous disease group is accompanied by increased right ventricular (RV) afterloads resulting in adaptive or maladaptive right ventricular remodeling. The maladaptive RV remodeling has a very poor prognosis. Thus, sensitive biomarkers for the early diagnosis of PAH are important to control the disease progression by appropriate medication. The purpose of the current study was to investigate whether the parameter of ventricular-arterial coupling (VAC) derived by MRI, was a more sensitive index to reflect the histopathological changes of the lung tissue in the first group of PH (pulmonary arterial hypertension: PAH) than the conventionally used RV functional indices.

Methods: Three experimental groups of Sprague Dawley rats were included in the study: controls (n=6), animals with severe PAH (n=4; induced by a single-dose subcutaneous injection of 60 mg/kg Monocrotaline (MCT) dissolved in 300 µl NaCl 0.9%) and with moderate PAH (n=6; induced by the same medication as the severely diseased group and an additional oral application of 15 mg/kg Macitentan from day 14 to 28. 5D phase-contrast magnetic resonance imaging (MRI, center-out stack-of-stars sequence) was performed between day 26 and 28 after MCT injection on all groups by the use of a 9.4 Tesla Bruker BioSpec USR 94/20 small animal imaging system.  Right after MRI measurement, the 5D data were analyzed and 4D stacks of cine images were reconstructed from them. The 4D-cine series of RV were segmented manually to calculate end systolic volume (ESV), end diastolic volume (EDV), VAC as EDV/ESV ratio, ejection fraction (EF) and stroke volume (SV). In addition, the tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography to determine the disease severity. Finally, histology of the lungs was performed and assessed by using an established pulmonary sum-score system. All experiments were conducted in accordance with the ethical guidelines.

Results: In a k-independent-samples Kruskal-Wallis H-Test, the MRI parameters of VAC, EF, SV, EDV, and ESV could differentiate between all the different experimental groups (P<0.05). However, when correlating the parameters with the results of histology by linear correlation analysis, the strongest correlation coefficient value was obtained for VAC compared to all investigated parameters (VAC: r=-0.95 vs. EF: r= -0.91, SV: -0.66, EDV: 0.76, ESV: 0.89). Likewise, similar results were calculated for the correlation with TAPSE (VAC: r = 0.85, EF: r = 0.81, SV: r = 0.55, EDV: r= 0.61, and ESV: r = 0.77).

Conclusion: When revisiting the native VAC equation defined by the ratio of the ventricular elastance (Ees) and arterial elastance (Ea), a simplified equation can be derived and presented as the ratio of EDV to ESV:

[EDV/ESV] = [E_es/E_a] +1

It could be observed that ESV enlarged on-average by 39% faster than EDV (213 vs. 153 ml respectively) during the disease progression; emphasizing on the fact that the ratio of EDV/ESV could reflect the extent of RV pressure afterload. In addition, EDV/ESV reflected the pulmonary histopathological changes more strongly than EF, SV, EDV, and ESV, suggesting its suitability for the prediction of the disease severity and its objective prognosis in individual cases.