Risk factors such as
hypertension and diabetes are known to augment the activity and tissue expression of
angiotensin II (Ang II), the major effector
peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify
disease progression. Treatment with
antihypertensive agents may result in regression of
left ventricular hypertrophy, with different
drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with
angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and
angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and
stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12
amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell
protease,
chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS.