RHOA/RHO-KINASE PATHWAY

RhoA/Rho-Kinase Pathway for Pulmonary Hypertension

Table of Contents

Introduction1

Discussion3

Disease Etiology5

Molecular triggers in PHT development6

RhoA/Rho-kinase pathway7

Conclusion11

References12

RhoA/Rho-Kinase Pathway for Pulmonary Hypertension

Introduction

Pulmonary hypertension (PHT) is a debilitating disease characterised by an increase in pulmonary arterial pressure and resistance. In early life, persistent pulmonary hypertension of the newborn (PPHN) occurs in approximately 1 per 1000 term or near-term live births in North America. PPHN usually presents within one to two days of birth, and frequently results from clinical syndromes associated with persistent hypoxaemia, including meconium aspiration and perinatal asphyxia (Hiroki, Shimokawa, Higashi et al. 2004, p. 537). Other conditions that may lead to PHT during the neonatal period and infancy include congenital diaphragmatic hernia and severe cases of chronic lung disease of prematurity. Persistent pulmonary hypertension of the newborn has an associated mortality of 10-20% and survivors have an high morbidity (40-50%) in the form of cognitive delays, cerebral palsy, hearing loss and frequent need for re-hospitalisation. The incidence of severe adverse outcomes from other forms of neonatal PHT is likely higher.

An increased propensity to PHT in the newborn period, compared to other stages of life, is predominantly related to two factors: (1) failure of the normal fall in pulmonary vascular resistance (PVR) required for a successful transition to postnatal life and (2) the rapid development and persistence of anatomical changes in the heart and pulmonary vasculature, known collectively as "vascular remodelling" (Hiroki, Shimokawa, Higashi et al. 2004, p. 537). Structural and functional consequences of remodelling include narrowing of the vessel lumen, exaggerated responses to vasoconstrictors, decreased relaxation and reduced responsiveness to vasodilators, all of which contribute to a "fixed" increase in PVR. Increased PVR affects the right heart by increasing right ventricular (RV) afterload, leading to right ventricular hypertrophy (RVH). Clinically, neonatal PHT presents with an elevated Fi02 requirement and mechanical ventilation may be insufficient to restore an adequate Pa02. If left untreated, right ventricular performance deteriorates, leading to cor pulmonale and eventual death.

The current gold-standard treatment for neonatal PHT is inhaled nitric oxide (iNO), which is approved for use in neonates above 35 weeks' gestational age by Health Canada and the United States Food and Drug Administration, and was the first therapy approved for treatment ofhypoxaemic respiratory failure following large clinical trials (Hiroki, Shimokawa, Higashi et al. 2004, p. 537).

Though iNO is used extensively in NICUs across developed nations, there are a number of serious drawbacks to its use, including non-responsiveness in up to 40% of patients. For those patients who responded initially, rebound PHT (upon attempted weaning from iNO) or non-sustained response is frequently observed. Rebound PHT is thought to be caused by a down-regulation of endogenous NO production and/or upregulated type 5 phosphodiesterase (PDE-V) expression following iNO treatment (Hiroki, Shimokawa, Higashi et al. 2004, p. 537).

Though most patients respond to iNO therapy in terms of improved systemic oxygenation and a decreased need for more invasive interventions, such as extracorporeal membrane oxygenation (ECMO), its use has not been associated with improvements in long term outcomes such as cerebral palsy, or ...