Vascular Stiffening in Pulmonary Hypertension: Cause or Consequence? (2013 Grover Conference Series)

Abstract

Recent studies have indicated that systemic arterial stiffening is a precursor to hypertension and that hypertension, in turn, can perpetuate arterial stiffening. Pulmonary artery (PA) stiffening is also well documented to occur in pulmonary hypertension (PH), and there is evidence that pulmonary vascular stiffness (PVS) may be a better predictor of outcome than pulmonary vascular resistance (PVR). We have hypothesized that the decreased flow-damping function of elastic PAs in PH likely initiates and/or perpetuates dysfunction of pulmonary microvasculature. Recent studies have shown that large-vessel stiffening increases flow pulsatility in the distal pulmonary vasculature, leading to endothelial dysfunction within a proinflammatory, vasoconstricting, and profibrogenic environment. The intricate role of stiffening-stimulated high pulsatile flow in endothelial cell dysfunction includes stepwise molecular events underlying PA hypertrophy, inflammation, endothelial-mesenchymal transition, and fibrosis. In addition to contributing to microenvironmental alterations of the distal vasculature, disordered proximal-distal PA coupling likely also plays a role in increasing ventricular afterload, ultimately causing right ventricle (RV) dysfunction and death. Current therapeutic treatments do not provide a realistic approach to destiffening arteries and, thus, to potentially abrogating the effects of high pulsatile flow on the distal pulmonary vasculature or the increased work imposed by stiffening on the RV. Scrutinizing the effect of PA stiffening on high pulsatile flow-induced cellular and molecular changes, and vice versa, might lead to important new therapeutic options that abrogate PA remodeling and PH development. With a clear understanding that PA stiffening may contribute to the progression of PH to an irreversible state by contributing to chronic microvascular damage in lungs, future studies should be aimed first at defining the underlying mechanisms leading to PA stiffening and then at improved treatment approaches based on these findings.Keywords: pulmonary hypertension, arterial stiffening, wave reflection, smooth muscle cell, endothelial cell, inflammation, right ventricle, treatment. Arterial stiffening is increasingly recognized as a risk factor of cardiovascular events as well as a guide for pharmacological treatment of cardiovascular diseases. Yet its exact role in the development and progression of cardiovascular diseases such as hypertension remains elusive. A recent study, however, presented convincing data supporting the possibility of a cause-effect relationship between arterial stiffness and systemic hypertension: higher levels of arterial stiffness and central pressures preceded and were associated with an increased risk of hypertension, but hypertension did not cause arterial stiffness. 1This work demonstrated that increased vascular stiffness could be a precursor to hypertension. A key implication from these observations is that arterial stiffness, when used as a measure of cardiovascula...

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