Adducin and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 2: Clinical Studies

Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial
hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological
complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we
furnished data from rodents and human cells demonstrating two hypertension-triggering mechanisms—variants of adducin
and elevated concentrations of endogenous ouabain (within a particular range)—and their selective inhibition by the
drug rostafuroxin. Here, we have investigated the relationship between variants of genes encoding enzymes for ouabain
synthesis [LSS (lanosterol synthase) and HSD3B1 (hydroxy-d-5-steroid dehydrogenase, 3b- and steroid d-isomerase 1)],
ouabain transport {MDR1/ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1]}, and adducin activity
[ADD1 (adducin 1) and ADD3], and the responses to antihypertensive medications.We determined the presence of these
variants in newly recruited, never-treated patients. The genetic profile defined by these variants predicted the antihypertensive
effect of rostafuroxin (a mean placebo-corrected systolic blood pressure fall of 14 millimeters ofmercury)
but not that of losartan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive effect was twice
that of antihypertensive drugs recently tested in phase 2 clinical trials. One-quarter of patients with primary hypertension
display these variants of adducin or concentrations of endogenous ouabain and would be expected to respond
to therapy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin also underlie hypertensionrelated
organ damage, this drug may also reduce the cardiovascular risk in these patients beyond that expected by
the reduction in systolic blood pressure alone.