An Ecosystem to Support Traditional Clinical Investigation

Abstract

I n this edition of Hypertension, Nyberg et al 1 from the University of Copenhagen report that both prostacyclin-and acetylcholine-induced vasodilation are blunted in the legs of young (mean age, 54 years) postmenopausal women and subsequently improved by endurance exercise training. At first glance, this is a terrific piece of mechanistic physiology and high resolution or deep phenotyping combined with an exercise training intervention in humans. It also begins to fill an important gap in our understanding of sex differences, aging, exercise, and resistance vessel physiology and pharmacology in humans that has relevance to blood pressure regulation and hypertension.As humans, age there is a generalized decline in endothelial-mediated vasodilator function. In older men, exercise training can limit the decline in resistance vessel vasodilator function with aging.2 In older women, much less is knownthe effects of exercise training on resistance vessel function have been studied minimally, and the studies on larger arteries suggest that endothelial function in older women may be less trainable than men.3 There is also speculation that the loss of estrogen at menopause contributes to potential sex differences in blood vessel trainability.In this context, the key finding of Nyberg et al 1 is that the resistance vessel vasodilator responses to both prostacyclin and acetylcholine are improved by training in a relatively young group of postmenopausal women. By contrast, training had minimal effects in a group of slightly younger (mean age, 50 versus 54 years) premenopausal women clearly suggesting a role for estrogen. Consistent with the differential effects of exercise training on vasodilator function in the preand postmenopausal women, blood pressure was only lowered by exercise training in the postmenopausal group. These findings close important gaps in our knowledge about aging, menopause, sex differences, and blood pressure. That such important knowledge gaps were filled using small-N clinical investigation coupled with invasive techniques, and a lifestyle intervention show the ongoing power of these classical approaches to clinical research. The findings of Nyberg et al 1 also highlight many key elements of what we know and do not know about blood pressure in humans because they age, especially older postmenopausal women. What We KnowFirst, we know that in many, but not in all population, blood pressure tends to rise with aging. 4 Second, elevated blood pressure is a risk factor for all forms of cardiovascular disease, renal failure, and cognitive decline. Third, keeping fit, avoiding obesity, and eating a healthy diet limits the risk of hypertension in most but not all people, and mild hypertension is less problematic in fit middle-aged people (especially men) in comparison to individuals with multiple risk factors. 5 Fourth, there is no obvious genetic explanation for most of these findings. The common disease common variant hypothesis has underperformed, and if the genetics of hypertension are at all parallel t...