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Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.

BackgroundRight ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta‐analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease.Methods and ResultsMedline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat‐models, inducing pressure load by hypoxia, Sugen‐hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta‐analysis revealed increased Hedges’ g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochondrial respiratory capacity and fatty acid uptake varied considerably between studies, yet there was a model effect in carbohydrate respiratory capacity in MCT‐rats.ConclusionsThis systematic review and meta‐analysis on metabolic remodeling in the pressure‐loaded RV showed a consistent increase in glucose uptake and glycolysis, strongly suggest a downregulation of beta‐oxidation, and showed divergent and model‐specific changes regarding fatty acid uptake and oxidative metabolism. To translate metabolic results from animal models to human disease, more extensive characterization, including function, and uniformity in methodology and studied variables, will be required.

809 Hedges' g (95% CI) 0.2 (-1.0-1.5) Study Regurgitation models (n=135): P=0.737, I2=90.6% ) COMBINED (n=280): P=0.005, I2=86.7% 0 -7,5 7,5 Hedges' g (95% CI) 4.Study Regurgitation models (n=109): P<0.001, I2=61.0% Shunt models (n=81): P<0.001, I2=88.2% Ruzicka 1993, 7d (n=16) Ruzicka 1993, 28d (n=16) Szabó 2006, 90d (n=18) Bartelds 2011, 30d (n=11) Borgdorff 2012, 28d (n=20) COMBINED (n=190): P<0.001, I2=84.8%

For indexing cardiac measures in small animal models, tibia length (TL) is a recommended surrogate for body weight (BW) that aims to avoid biases because of disease-induced BW changes. However, we question if indexing by TL is mathematically correct. This study aimed to investigate the relation between TL and BW, heart weight, ventricular weights, and left ventricular diameter to optimize the current common practice of indexing cardiac parameters in small animal models. In 29 healthy Wistar rats (age 5–34 wk) and 116 healthy Black 6 mice (age 3–17 wk), BW appeared to scale nonlinearly to TL1 but linearly to TL3. Formulas for indexing cardiac weights were derived. To illustrate the effects of indexing, cardiac weights between the 50% with highest BW and the 50% with lowest BW were compared. The nonindexed cardiac weights differed significantly between groups, as could be expected ( P < 0.001). However, after indexing by TL1, indexed cardiac weights remained significantly different between groups ( P < 0.001). With the derived formulas for indexing, indexed cardiac weights were similar between groups. In healthy rats and mice, BW and heart weights scale linearly to TL3. This indicates that not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept in which cardiac parameters should not all be indexed to the same measure but one-dimensional measures to BW1/3 or TL1, two-dimensional measures to BW2/3 or TL2, and three-dimensional measures to BW or TL3. NEW & NOTEWORTHY In healthy rats and mice, body weight (BW) scales linearly to tibia length (TL) to the power of three (TL3). This indicates that for indexing cardiac parameters, not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept of dimensionally consistent indexing. This concept is proposed to be widely applied in small animal experiments.

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Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre- to post-puberty. 3-weeks old rat pups (n=57, 30-45g) were subjected to PAB or sham surgery. Animals were sacrificed either before or after puberty (4 and 8 weeks post-surgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 weeks, whereas females did not. After 8 weeks, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 weeks in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared to males (p=0.055). Histology showed significantly less RV myocardial fibrosis in female compared to male PAB rats 8 weeks after surgery. Myosin heavy chain 7/6 ratio switch and calcineurin signaling were less pronounced in female PAB rats, compared to males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure, compared to males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones.