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-δ-5-
steroid dehydrogenase, 3β- and
steroid δ-
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 of
mercury) 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
hypertension-related organ damage, this
drug may also reduce the cardiovascular risk in these patients beyond that expected by the reduction in systolic blood pressure alone.