Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is due to right ventricular (RV) failure. It is unclear whether RV dysfunction initiates at the organ level or the subcellular level or both. We hypothesized that chronic pressure overload-induced RV dysfunction begins at the organ level with preserved Frank-Starling mechanism in myocytes. To test this hypothesis, we induced PAH with Sugen + hypoxia (HySu) in mice and measured RV whole organ and subcellular functional changes by in vivo pressure-volume measurements and in vitro trabeculae length-tension measurements, respectively, at multiple time points for up to 56 days. We observed progressive changes in RV function at the organ level: in contrast to early PAH (14-day HySu), in late PAH (56-day HySu) ejection fraction and ventricular-vascular coupling were decreased. At the subcellular level, direct measurements of myofilament contraction showed that RV contractile force was similarly increased at any stage of PAH development. Moreover, cross-bridge kinetics were not changed and length dependence of force development (Frank-Starling relation) were not different from baseline in any PAH group. Histological examinations confirmed increased cardiomyocyte cross-sectional area and decreased von Willebrand factor expression in RVs with PAH. In summary, RV dysfunction developed at the organ level with preserved Frank-Starling mechanism in myofilaments, and these results provide novel insight into the development of RV dysfunction, which is critical to understanding the mechanisms of RV failure. NEW & NOTEWORTHY A multiscale investigation of pulmonary artery pressure overload in mice showed time-dependent organ-level right ventricular (RV) dysfunction with preserved Frank-Starling relations in myofilaments. Our findings provide novel insight into the development of RV dysfunction, which is critical to understanding mechanisms of RV failure.

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

“…While Hemnes et al (2008) didn’t report pulmonary artery compliance (CPA), it is well known that as PVR increases in PH, CPA decreases ( Lankhaar et al, 2006 , 2008 ; Saouti et al, 2009 ) and this loss of compliance is an important component of RV afterload ( Wang and Chesler, 2013 ). Given this lack of data, decreases in CPA in response to Bleo were chosen to match published experimental measurements of CPA in mice with other forms of PH ( Tewari et al, 2013 ; Liu et al, 2015 , 2017a ; Wang et al, 2018 ). RV mass was increased to match RV hypertrophy reported by Cowley et al (2017) in Bleo mice.…”

“…This approach has only been used to explore the RV in a limited number of studies. Myocyte maximum force generation has been found to be preserved or increased in some models of PH ( Fan et al, 1997 ; Walker et al, 2011 ; Wang et al, 2018 ), but decreased in others ( Versluis et al, 2004 ; Dai et al, 2006 ; Cowley et al, 2015 , 2017 ). In particular, in RVF secondary to LV failure and RVF due to bleomycin-induced pulmonary fibrosis ( Wang et al, 2010 ; Cowley et al, 2017 ), maximum myocyte force generation (Fmax) decreases.…”

CrossTalk opposing view: The mouse SuHx model is not a good model of pulmonary arterial hypertension

“…The same authors recently reported evidence of RV dysfunction with impaired preload‐independent contractility by modifying the Ciuclan procedure to continue hypoxia and weekly Sugen 5416 injections for 8 weeks (Wang et al . ). Unfortunately, even after extending the hypoxia and Sugen 5416 exposure of the Ciuclan model by 2.67 times, RV cardiac output was preserved and the authors noted that there was no evidence of RV failure (Wang et al .…”

“…Unfortunately, even after extending the hypoxia and Sugen 5416 exposure of the Ciuclan model by 2.67 times, RV cardiac output was preserved and the authors noted that there was no evidence of RV failure (Wang et al . ).…”

CrossTalk proposal: The mouse SuHx model is a good model of pulmonary arterial hypertension

“…; Wang et al . ). More importantly, studies further demonstrate that certain genetically modified mouse models show blunted responses to SuHx‐induced RV remodelling and dysfunction (Kapur et al .…”