An Ecosystem to Support Traditional Clinical Investigation
Lessons From Aging, Exercise, Blood Pressure, and Women
See related article, pp 1011–1020
In this edition of Hypertension, Nyberg et al1 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 known—the 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 al1 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 pre- and 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 al1 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 Know
First, 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 to the genetics of type II diabetes mellitus, rare variants might not explain much either.6 So, we know a lot, but there are gaps.
What We Do Not Know
In addition to the focus on vascular function, the Nyberg et al’s1 article starts with a succinct summary of some interesting facts about blood pressure in middle-aged women and a lot of what we do not know. The first is that something happens at menopause to accelerate the age-associated rise in blood pressure seen in women. This observation also highlights that blood pressure patterns in the population show marked sex and age differences and that blood pressure might be regulated differently in women and men.7 In young people, blood pressure is lower in women than men. However, something happens in middle age; by the seventh decade of life more women are hypertensive than men, and hypertension may be more difficult to treat in women than men.
Are these sex and age differences due to well-characteized differences in renal mechanisms that contribute to blood pressure regulation? Are they due to less vasoconstrictor tone in young women, but more vasoconstrictor tone in postmenopausal women?8 If it is mostly a matter of more vasoconstriction in postmenopausal women, is this because of a rise in sympathetic activity, a loss of vasodilator function, or more robust adrenergic constriction at the receptor smooth muscle interface? Is it all of the above, some of the above, mostly because of the loss of estrogen, an aging effect independent of estrogen, and interactions with vasoconstricting renal hormones? Are the positive effects seen for prostacyclin- and acetylcholine-mediated dilation in the leg circulation after training in the postmenopausal women seen for other dilator systems or agonists? Are they restricted to the legs or are systemic effects seen like the improved endothelial function seen in the arms of older men after a period of leg training? The list of questions goes on and on. So although Nyberg et al1 show that the resistance vessels of younger postmenopausal do in fact respond to exercise training, many questions remain about the integrative responses to exercise training that influence blood pressure in this demographic group. In addition, will older postmenopausal women respond similarly to younger postmenopausal women?
How and Who Will Answer These Questions?
The short answer to this question is that these research topics will be addressed like they always have been by teams of clinical investigators, integrative physiologists, and basic scientists working together in specialized research units designed to facilitate invasive studies with drug administration protocols and other short- and long-term interventions in normal volunteers and patients. However, this integrated approach is threatened by several factors. First, it is well accepted and has been known for many years that traditional MD clinical investigators may be a vanishing species.9 Second, the Clinical Research Center infrastructure that remains to support such scientists, their collaborators, and patients may also be vanishing. In the United States, this is due in large part to a collection of shortsighted policy decisions made at the National Institutes of Health.10 In the middle 2000s, roughly 80 specialized Clinical Research Centers were supported by National Institutes of Health, and if the current policy remains in place no such centers will be supported by the early 2020s. Although this clearly represents a US centric perspective, informal discussions with colleagues from around the world suggests that such infrastructure is under threat in many countries. However, a PubMed search could not find a comprehensive international report on this topic, and an international survey of such resources would, thus, seem both warranted and urgent.
So, here we are in the early 21st century with an aging population, a host of noncommunicable diseases, and reams of data ranging from epidemiology to medical records to gene sequencing and diminishing resources to connect the physiological, pathophysiological, and mechanistic dots that explain how complex disease phenotypes emerge in humans and what might be done about them. Consistent with these concerns, leading bioinformatics experts are now openly warning about the limited ability of electronic health records to capture and provide research grade phenotypic data.11
In conclusion, Nyberg et al1 show the ongoing power of deep phenotyping and mechanistic studies in human subjects. The novel observations related to blood pressure, vascular biology, menopause, and exercise training in women from this study also make the larger case for continued support of the people and infrastructure critical for such deep phenotyping studies in humans.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- © 2016 American Heart Association, Inc.
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