Sex differences and the brain-heart connection
Author: Emilie Théberge, MSc. Medical Genetics, Clinical Research Coordinator (University of British Columbia/Vancouver General Hospital) Editors: Romina Garcia de leon & Shayda Swann (Blog Co-coordinators)
Published: December 30th, 2022
Note: *Biological sex (ie. female, male) is not the same as gender (ie. woman, man, nonbinary, Two-Spirit, etc.), which is a social construct and identity. Throughout this blog post, the cited literature assumes cisgender biological sex-gender, wherein women = cisgender females and men = cisgender males. The extent to which conclusions of sex differences cited in this post apply to trans- and non-binary/individuals with other gender identities is understudied and required. Read more here.
Stress is a part of the human experience: It need not control us, nor define us, but it is inevitable.
When, though, does stress overwhelm to the point where it tips the body’s scale into a disease state — mental and/or chronic illness — with an accelerating feedback loop? When the stressor is unlikely to be going away anytime soon, how do we adapt, find hope, and help others see hope when they do not see a way out?
A large-scale wildfire may cause short-term (“acute”) stress if one is nearby, but it has a defined endpoint when it is put out and is no longer a threat. But, there can be long-term (“chronic”) consequences to one’s lungs from inhaling too much smoke; to the local ecosystem, charred to a crisp; or the ability for people to live on the land in its wake, with entire lives uprooted, sometimes lost, needing to start anew somewhere else. This wildfire metaphor may be translated to the acute effects and chronic mental and physiological adaptations caused by events like the COVID-19 pandemic or the loss of a close loved one. Rather than the scale of the event or how many people it affects, more important is the subjective impact the stressful event has had on you. Everyone has different thresholds of stress tolerance based on their prior experiences — and what we’re starting to learn — some biological (genetic) susceptibility to how their bodies manifest this stress, too.
Reality is complicated and intersectional; people of different genders, ages, economic status, races, ethnicities, and nationalities may cite different causes of stress and types of coping, and their bodies will adapt differently to these stressors. People who experience pregnancy and/or menopause have different “normals” throughout their adulthood as the hormones fluctuate drastically during and between these major events, and this affects their body’s ability to deal with stressors.
Despite being half of the world’s population, I am shocked at how little research in the psychiatric and neuroscience space studies sex differences* or even allows sex differences to be uncovered by chance in the experimental design. Around 1 in 4 Canadians were estimated to have depression in 2021 — and across borders, depression rates are consistently reported twice as high in women (20%) than in men (10%). How much of this is attributed to biological sex differences — how are we wired differently? Do the physical manifestations of mental stress and depression differ between the sexes? For my thesis, I decided to explore these ideas.
The recently published “immunometabolic theory of depression” piqued my interest. So much of the depression literature focuses on dysfunction within the brain, ignoring the context of its link to the cardiovascular and metabolic system from which it feeds. Recent genetics literature on depression has pointed towards genes and molecular pathways that implicate the immune system, specifically chronic-low-grade inflammation, as a key driver of depression. The brain controls the perception of stress and the heart reacts to it, and chronic low-grade inflammation is a result of this system staying “on” too long after the perceived threat has passed.
Depression is systemic, a whole-body concern. This means it can affect more organs: for example, those of our cardiovascular system. Through prior and current clinical research experience working with patients with heart disease — from whom I’ve heard many stories first-hand of mental stress or trauma that these patients speculate is related to their onset of heart disease — I have developed a keen interest in exploring these connections. Heart disease does not manifest itself suddenly overnight; chest pain (angina) to the point of a heart attack (myocardial infarction) comes from a complex interaction of metabolic and immune factors building up over time from imbalances in the body (ie. from stress). This can manifest in ways such as plaque in the large blood vessels in coronary artery disease, and/or dysfunction of our smallest blood vessels such as in microvascular dysfunction. Traditional risk factors like high cholesterol, diabetes, high blood pressure, smoking, and obesity have well-characterized relationships to the risk of heart disease, but have different effects between men and women.
My curiosity about the brain-heart relationship led me to want to learn how to analyze “big data” in biobanks: huge datasets that sample entire populations to study relationships between variables that may not be visible in smaller cohorts of, say, 100 or 200 people. In my thesis, I studied a sample of over 16,000 people from the Canadian Longitudinal Study on Aging (CLSA) cohort of 50,000 people, and I found sex differences in the genetic and cardiometabolic risk factors associated with depression. Women with a history of clinical depression were at higher odds of having comorbid histories of heart disease, diabetes, hypothyroidism (which results in slower metabolism), and/or a higher “polygenic risk score” for depression (a single lifetime-risk genetic score predicted from thousands of genetic variants with small individual effects summed together). Men with depression, on the other hand, did not show significant relationships with those conditions compared to men without depression — for them, high blood pressure was significant, while high genetic risk was not, in the overall model. Of note, younger age and lower annual income were the two factors contributing the most to my statistical models for both sexes. This highlights that there is an important social aspect, and potential biological associations, with regard to pre-menopausal women’s bodies compared to post-menopausal, which warrants further study with more sex-specific variables.
I hope that you, reader, are feeling empowered and more curious about this brain-heart connection, and that this thesis commentary has helped you think about depression and sex differences differently. Depression is not just in the head: it’s a whole-body dysfunction to cope with stress that can happen to anybody, and its effects can be reversed when balance is found again. In consultation with your primary health care provider, you can make a habit of checking on your body regularly, through actions like checking your cholesterol, blood sugar, and thyroid levels in blood tests, monitoring your blood pressure, and seeking support for your mental health as you may for your physical health. They are interconnected, and gradual mental and physical decline in our youth have the potential to snowball into earlier life-threatening heart disease. It is imperative that we, in this post-COVID era, talk about individual and collective actions we can take to treat depression in our friend groups, families, and workplaces, thinking about long-term solutions over quick fixes.