Alterations in cardiovascular function in an experimental model of lung fibrosis and pulmonary hypertension

New Findings

We have evaluated changes in cardiovascular physiology using echo in an experimental model of lung fibrosis. Remarkably, we report changes in cardiovascular function as early as day 7, concomitant with evidence of vascular remodeling. We also report that isolated pulmonary arteries were hyper‐contractile to a thromboxane A2 agonist. These findings are significant since the development of pulmonary hypertension is one of the most significant predictors of mortality in patients with lung fibrosis where there are no available therapies and a lack of animal models.

Abstract

Group III Pulmonary hypertension is observed in patients chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) or Idiopathic Pulmonary Fibrosis (IPF). Pulmonary Hypertension (PH) develops as a result of extensive pulmonary vascular remodeling and resultant changes in vascular tone that can lead to right ventricle hypertrophy. This eventually leads to right heart failure which is the leading indicator of mortality in patients with IPF. Treatments for Group III PH are not available, in part due to a lack of viable animal models. Here we have evaluated the cardiovascular changes in a model of lung fibrosis and PH. Data obtained from this study indicated that structural alterations in the right heart such as right ventricle wall hypertrophy occurred as early as day 21, where similar increases in right ventricle chamber size were seen between days 21–28. These structural changes correlated with decreases in the systolic function of the right ventricle and right ventricular cardiac output, which also occurred between the same time points. Characterization of pulmonary artery dynamics also highlighted that PH may be occurring as early as day 21 indicated by reductions in the velocity time integral; however, PH onsets at least from day 28 indicated by the significant reduction in pulmonary acceleration time values. In addition, we report hyperactivity of BLM‐exposed pulmonary arteries to a thromboxane A2 receptor (Tbxa2r) agonist. Interestingly, although Tbxa2r expression levels did not change in the lung, altered expression was seen in the heart.

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