Tackling change: menopause as a cardiovascular disease risk factor and the path to health equity

1. Introduction

Prevention as a way to decrease cardiovascular disease morbidity and mortality has long been promoted. Cardiovascular societies and organizations have argued that an ounce of prevention is worth a pound of cure, producing significant reductions in cardiovascular disease mortality and prolonging lives.

Initiatives to decrease risk through nutrition, exercise, and healthy life choices have reaped benefits, but some cardiovascular risks are inescapable, particularly for women. For example, cardiovascular disease is a leading cause of mortality associated with pregnancy,¹ and while pregnancy is typically—but not universally—a choice, many of the cardiovascular risks of pregnancy are inescapable. Poverty increases cardiovascular disease morbidity and mortality,² and women are disproportionately impoverished. There are strong arguments that some of the risks faced by women are not biologically based and that entrenched sociological inequities have powerful roles in driving cardiovascular disease.³

One of the most significant risk factors for cardiovascular disease in women is unavoidable: menopause. Women who live beyond their reproductive phase experience menopause, whether it is following a gradual, decade-long disruption in ovarian function, or the abrupt loss of functional ovaries through oophorectomy or other events that cause a sudden loss of ovarian function. Despite the virtual certainty of menopause, the mechanisms by which menopause shapes cardiovascular risk remain largely unknown, presenting a substantial obstacle to the development of interventions that mitigate risk and improve women’s health.

2. Obstacles to health

Why is there such a significant knowledge gap with menopause? Surprisingly, the connection between menopause and cardiovascular health was unknown until a 1976 report from the Framingham study identified a connection.⁴ Interestingly, comments from a journal editor immediately following the study harshly and dismissively criticized the proposed link.

While the relationship between menopause and cardiovascular disease is confirmed, little headway in understanding the mechanisms beyond the decline of oestrogens has occurred. This embarrassing lack of progress derives in large part from under-investment in women’s health research: globally only 4% of research and development budgets are directed to women’s health issues, of which the vast majority goes to cancer and reproductive research. In North America, Canadian and US federal health funding agencies dedicate 7 and 11% of their budgets to women’s health, respectively. It is clear why our knowledge of women’s health generally—and cardiovascular health specifically—is indigent when systems generating information are starved for resources.

A second factor inhibiting advances in understanding the health effects of menopause has been the lack of an animal model for fundamental scientific research. Ovariectomized animals have traditionally been used to investigate physiological changes and pathological risks of menopause, but this model does not include the transitional phase of perimenopause, and it removes androgen-producing elements of the ovaries that remain intact after menopause. Lab animals like mice do not experience menopause, which precludes aging animals as a model.

Ground-breaking work by Dr Patricia Hoyer’s group at the University of Arizona led to the development of an animal model of menopause in which the injection of 4-vinylcyclohexene diepoxide (VCD) induces a gradual disruption in ovarian function that closely mimics the human condition.⁵ The ability to study the complex physiological changes of menopause in lab animals represents a significant advance in the ability to investigate not only the impact of menopause on cardiovascular disease but also a host of alterations that arise postmenopause.

3. Foundational research

The development of the physiologically relevant VCD model of menopause creates an unprecedented opportunity to advance our understanding of women’s heart health through fundamental research. The model has been used to investigate the impact of menopause on atherosclerosis,⁶ blood pressure regulation,⁷ and ischaemic injury,⁸ identifying molecular changes and mechanisms of increased cardiovascular disease risk.

One of the most powerful elements of the VCD-induced model of menopause is the ability to study perimenopause and its impact on health for the first time in animal models. We showed that cardiac myofilaments are dynamically affected during perimenopause,⁹ as is calcium removal by SERCA2a.¹⁰ These studies allowed the temporal characterization of molecular alterations in the cardiovascular system that occur in conjunction with perimenopausal changes in ovarian hormone synthesis.

The exploration of the chronological development of menopause is critical for the creation of rationally designed therapies that specifically target maladaptive changes in a time-sensitive manner. Clinical trials examining the effectiveness of oestrogen replacement therapy revealed that the timing of treatment onset was critical for maximum benefits, with interventions starting within 10 years of menopause being the most effective. We reported that the cardiac response to oestrogen receptor agonists varies across perimenopause,⁹ an effect that could explain discrepant findings concerning oestrogen replacement therapy and the role of timing. Our data on perimenopause suggest that the window of therapeutic opportunity might be earlier than the onset of menopause and that perimenopausal interventions should be considered to mitigate cardiovascular changes that underlie postmenopausal risk.

4. Path forward

The creation of an animal model of menopause that faithfully recapitulates the complex hormonal changes in a temporally relevant manner represents a critical step in understanding how menopause acts as a powerful risk factor for cardiovascular disease. This model also offers the opportunity to discover the molecular changes underlying risk and creates the opportunity to design mitigating interventions.

While basic science research is vital to understand the effects of menopause and improve women’s cardiovascular health, there remain significant obstacles on the path towards gender equity: social barriers, including the disproportionate number of girls and women who are impoverished, permit and promote poor health. Unequal access to care in the form of economic barriers and systematic discrimination cause women to receive less guideline-driven care. Finally, the underinvestment in research focused on women’s health perpetuates the knowledge gap that bolsters health inequality.

Some movement to erase gender-based health discrepancies have started, with global leading efforts by the Canadian Institutes of Health Research to ensure a greater inclusion of females in health research, and a plan by the US National Institutes of Health to invest $12 billion in new funding for women’s health research. True equity requires broader societal change, including in health, research, and academic organizations, and demands stable financial support. The payoff from these investments will be substantial: a 2024 report by the McKinsey Group estimates that closing the knowledge gap in women’s health will erase 75 million years of life lost due to poor health or early death each year and boost the global economy by $1 trillion annually, far outweighing the financial costs of equality.

Without these changes, unavoidable risk factors like menopause will continue to exert needless and negative impacts on women’s health, which costs us all.

Funding

W.G.P. is supported with a National Women’s Health Research Initiative award and a project grant from the Canadian Institutes of Health Research, as well as a Grant-in-Aid from the Heart and Stroke Foundation of Canada.

Data availability

There are no new data associated with this article.

References

Author

Biography: Glen Pyle is a professor of Molecular Cardiology and a member of IMPART at Dalhousie Medicine and the Women's Health Research Institute at BC Women's Hospital + Health Centre. He received his PhD in Physiology and Biophysics from the University of Tennessee Health Sciences Center and completed an American Heart Association fellowship at the University of Illinois at Chicago. His research team is focused on menopause, intimate partner violence, and women's heart health and has been funded by the Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and Natural Sciences and Engineering Research Council of Canada.

Author notes