Investigating the Direction of Causation in Frailty and Cardiovascular Disease

It remains the case that a great deal of aging research these days is purely observational, which is, I think, unfortunate. This is an age in which more than mere observation of aging might be achieved; the first interventions likely to reliably slow or reverse aspects of aging are making their way out of the laboratory and into clinical development. There should be a lesser emphasis in the research community on watching what happens to a population of older individuals who lack effective treatments for aging, and a correspondingly greater emphasis on getting those treatments built and into the clinic.

Given this, does it really matter how frailty and cardiovascular disease interact? Would the world be changed by knowing, in detail, the exact relationship between the two? Both of these conditions will be banished in the wealthier half of the world fifty years from now, defeated and controlled by forms of regenerative medicine that are periodically applied to remove the root causes of these conditions. That will be achieved by focusing on those causes, ignoring the detailed end-stage mechanisms and relationships of the conditions that result.

Aging as it exists today will be a curio of the past given a further fifty years of development after that point. How much scientific work today goes towards considering how exactly different patient populations experienced the now extinct condition smallpox in the absence of effective treatments? How valuable was that sort of research during the years in which the first meaningful treatments were deployed? I'd say that, at that time, observational lines of research added very little to progress in defeating smallpox - and the situation will be much the same for aging.

In older adults both cardiovascular disease (CVD) and frailty are highly prevalent. Novel and advanced cardiovascular therapeutic treatments have improved life expectancy and consequently led to an increasing number of older adults suffering from chronic CVD. This presents an enormous clinical and public health burden. Frailty describes a state of vulnerability due to an age-related decline in many physiological systems and is associated with a considerably increased risk of falling, disability, hospitalisation, and mortality. According to cross-sectional data, CVD appears to be positively associated with frailty in community-dwelling older adults. However, cross-sectional studies do not clarify if CVD leads to frailty or if frailty precedes the development of CVD.

From a pathophysiological point of view, both directions are plausible. For example, exercise related symptoms in patients with CVD could lead to physical inactivity making them more likely to become frail. Additionally, comorbidities, as well as physical and cognitive decline are common in older adults with CVD. This could lead to a loss of homeostatic capability to withstand stressors and increase the risk of frailty. Yet, one could also argue that physical inactivity and its sequelae (e.g. obesity) due to frailty is a risk factor for development of CVD. Also, frailty is associated with a chronic state of low-grade inflammation which could trigger CVD.

The present study studied the bidirectional effect of CVD on frailty among community-dwelling older adults. First, we observed cross-sectional associations between CVD and frailty. Patients with CVD, especially those with peripheral arterial disease and heart failure, were more likely to be frail. Longitudinally, mainly HF was associated with incident frailty. These patients were at least twice as likely to become frail, which puts these patients at an equal or even higher risk of incident frailty than subjects with chronic lung disease, arthritis, or diabetes. Analyses studying the reverse association revealed that in this older population, frailty does not precede development of CVD during three years of follow-up.



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