More about plasma renin and cardiovascular mortality.

Renin, the renal pressor substance, was discovered and described by Tigerstedt and Bergman in classic experiments published in 1898. It was not, however, until 1934 that Goldblatt identified the relevance of renin by showing that renal secretion of renin caused sustained renovascular hypertension in dogs. Others subsequently demonstrated that renin itself is not the pressor element, but rather is the rate-limiting component of the newly defined renin–angiotensin–aldosterone control system (RAAS). This RAAS has since become recognized as a key regulator of blood pressure control and a participating factor in its pathological consequences. In the past half century, the role of the RAAS in the pathophysiology of hypertension and as a basis for antihypertensive drug development was established. Plasma renin has also been associated with cardiovascular morbidity and mortality in hypertensive patients (Figure 1). Tomaschitz et al. have now extended that finding to patients in whom plasma renin was measured while taking antihypertensive drugs. Tomaschitz et al. measured the plasma renin concentration (PRC) using a sensitive automated immunoreactive chemiluminscence method that is comparable with the more traditional enzyme kinetic radioimmunoassay renin activity (PRA) assay. An exception is that very high PRC values (PRA .40 ng/mL/h; PRC .300 pg/ mL) are proportionally higher because they deplete plasma angiotensinogen, the renin substrate, in vivo, resulting in a reactive increase in renal renin secretion. Thus, at high levels, the PRA assay continues to reflect the in vivo rate of angiotensin formation. Tomaschitz et al. examined the 10 year mortality experience of 3316 Caucasian men and women referred to a single hospital for coronary angiography (the LURIC group). At baseline, participants were free of serious non-cardiovascular disease (CVD), had normal liver function, and, except for the 30% with ‘acute coronary syndrome’ (ACS), were in stable condition. Interval history is unavailable. Subjects were mostly males (70%) with an average age of 63 years. Stratification by ascending PRC quartiles revealed that at baseline PRC correlated with plasma angiotensin II, plasma aldosterone, C-reactive protein, uncontrolled hypertension, and heart failure. The principle finding was that, independent of traditional risk factors and antihypertensive drug therapy, a one standard deviation increase in PRC predicted 23% higher CVD mortality—mostly heart failure or sudden cardiac death. However, addition of PRC did not significantly improve prediction of CVD mortality beyond that provided by conventional risk factors. This prospective cohort study raises questions and generates fresh hypotheses. The authors accurately present this as a prospective cohort study of patients referred for coronary angiogiography. Not surprisingly, the population studied had a high degree of coronary artery disease. However, to better understand the issue in question—the relationship of renin to CVD mortality—it is important to note that nearly 90% were taking antihypertensive medications and so were most probably hypertensive patients. Measurements of renin have different meanings in normotensive and hypertensive individuals. In both cases volume contraction and/or falling blood pressure causes a reactive increase in plasma renin levels thereby increasing angiotensin II to increase arterial vasoconstriction; this response maintains an adequate blood pressure to ensure appropriate levels of tissue perfusion—a priori this is both an appropriate and beneficial response. At the same time, in normal circumstances, rising blood pressure suppresses renin secretion, leading to suppressed plasma renin levels. Renin becomes pathological whenever it fails to fall appropriately in response to the rising blood pressure. This suggests that in normal circumstances renin ought not to be associated with CVD. In fact no relationship of PRA levels to CVD was found in cohort studies of general populations. In contrast, plasma renin levels bear a continuous relationship to CVD in hypertensive patients, and those with the highest plasma renin levels have been shown to have a markedly increased CVD