Cardiovascular window of opportunity

Rogerio Lobo, Rebecca Thurston, Cynthisa Stuenkel and Rachel Wong kicked off the Wednesday morning session of IMS 2018 with a cardiovascular focussed symposium. Underlining themes of the presentations included the cardiovascular window of opportunity, vasomotor symptoms and their association with subclinical risk factors, as well as broader risk factors and prevention of cardiovascular disease (CVD) in women.

Below are the presentations in more detail:

Physiology and clinical data regarding the window of opportunity - Rogerio Lobo

For a long time Framingham data has shown that regardless of age or menopause, endogenous oestrogen is protective against CVD. By the same concept, women who have a late reproductive life also show increased cardio-protection.

These and other data speak to the protective effects of oestrogen, primarily through interactions with arteries. The direct protective effects of oestrogen occur through non-genomic and longer-term genomic pathways.

It was hypothesised that oestrogen could be used therapeutically for cardio-protective purposes. The first trials, Rogerio explained, were secondary; it was thought that if oestrogen is administered in established disease then surely this would lead to improvements. Alas, this was not the case.

Thomas Clarkson was the first to show in a monkey model that the protective effects of oestrogen is age-related: early initiation of oestrogen is protective, while late intervention is not.

What is the underlying mechanism behind this?

An atherosclerotic plaque has a lot of activity in mural wall. One of the effects of oral oestrogen is the induction of matrix metalloproteinases - these act by breaking down the plaque. The breakdown of the plaque can release an atheroma - with the potential to cause a myocardial infarction or stroke. Patients with disease are more likely to have an existing atherosclerotic plaque and therefore are at higher risk of CVD as a result of oestrogen action.

This is considered to be the 'window of opportunity approach' . In the Women's Health Initiative (WHI), those who initiated therapy closer to menopause did not have early harm and tended to have benefit; in these women there were statistically significant benefits in coronary heart disease and mortality.

Similarly, in the ELITE trial (using oral oestradiol 1 mg), women who were within 6 years of menopause had a significant attenuation of the increase in carotid intima-media thickness compared to placebo and women who initiated therapy 6 or more years after menopause, which is in line with the 'window' hypothesis. 

To conclude Rogerio's presentation, data demonstrate that the window hypothesis is operative, and women who initiate certain forms of HRT close to the onset of menopause benefit in terms of a protective effect on CVD.

Menopause and its Symptoms in the Development of Cardiovascular Disease in Women - Rebecca Thurston

Rebecca opened with a broad introduction regarding CVD and women's cardiovascular health. Rebecca explained that although CVD is the leading cause of death in both men and women globally, women do not tend to develop the disease until later in life - post-menopause

The menopause transition is accompanied by symptoms for most midlife women. Vasomotor symptoms (VMS; hot flushes, night sweats) are the hallmark symptoms of menopause, reported by over 70% of midlife women, with 30% experiencing severe VMS. Sleep problems are also prevalent.

Rebecca highlighted that while VMS has long been understood to be important for women's quality of life, there is increasing evidence that is also has an impact on physical health. Menopausal symptoms, particularly VMS and sleep problems have been linked to indicators of CVD.

The SWAN study is a multi-site longitudinal, epidemiologic study designed to examine the health of women during their middle years. The study annually assessed a whole range different effects, physical markers and symptoms. Critically, it showed that women with VMS had an increase adverse cardiovascular risk profile.

What is the mechanism behind this?

Sex hormones, inflammation, CVD risk factors and the autonomic nervous system were all analysed but currently, no mechanism has been identified. More research is required to fully understand the relationship between VMS and CVD.

Do we have new preventive strategies for optimising CV health in women? - Cynthia Stuenkel

Paralleling Rogerio's earlier presentation, Cynthia discussed the importance of the 'window of opportunity' when considering hormone therapy. Cynthia suggested, however, that the window for preventing CVD in women could be opened much wider to encompass the decades prior to menopause. 

Regarding this, Cynthia poised the question: how is risk evaluated? And more importantly, how is it perceived? According to the National Study of Physician Awareness to CVD Prevention Guidelines, perception of risk was the primary factor associated with compliance with CVD preventative recommendations.

Current experts recommend screening for CVD risks as early as age 20 to 25 years. Recognising adverse pregnancy outcomes as red flags portending future development of CVD is essential. Furthermore, autoimmune disorders and breast cancer therapies contribute to CVD and heart failure and as such should be considered risk factors.

How can risk assessment and reduction be improved?

Cynthia argued that it would be far more effective to move forward proactively with CVD preventive strategies immediately following these clinical occurrences.

When we talk about the window of opportunity, open it.

Interrelationships between blood vessel function, cognition and fracture risk - Rachel Wong

Rachel closed the session with her abstract that was especially selected for presentation. In her introduction she highlighted that oestrogen decline and ageing are known to contribute to arterial stiffness, resulting in poor blood perfusion in bones and in the brain, thereby increasing the risk of bone loss and cognitive impairment.

Results from her lab group showed that in the cohort, cerebrovascular stiffness is associated with poor cognition and increased osteoporotic and hip fracture risks. The latter might reflect the effect of systemic arterial stiffness on the diminished blood supply to bones. The association between poor cognition and future fracture risk warrants further investigation.