Heart-Brain Health: A Two-Way Street

For centuries, folklore from every corner of the globe has held that a person’s psychological state can affect their physical health, sometimes suddenly and fatally. Apocryphal tales of death from fright or heartbreak abound, from the biblical account of Ananias and Sapphira both keeling over lifeless after being accused of lying to the Holy Spirit to Romeo and Juliet’s Lord Montague recounting how his wife’s “grief of my son’s exile hath stopp’d her breath.”

The first modern scientist to explore this phenomenon was Walter Bradford Cannon, Class of 1900, who was chair of the Department of Physiology at HMS. He coined the term “fight or flight” in 1915 and in 1942 published a paper in American Anthropologist presenting reports of so-called voodoo death recounted by explorers in South America, Africa, Australia, New Zealand, and the Caribbean since the 1500s. Cannon reviewed several cases in which an apparently healthy, vibrant individual began to languish after being accused of misdeeds by a powerful tribal leader and died within one to four days. He also noted one incident in which a shaman came to the bedside of a young man named Rob and said, oops, it had all been a mistake. “The relief,” Cannon writes, “was almost instantaneous. That evening Rob was back at work, quite happy again, and in full possession of his physical strength.”

Cannon proposed, iconoclastically, that these incidents were not the work of dark magic as was supposed, but instead resulted from the “sympathetico-adrenal complex” constricting the blood vessels in response to “shocking emotional stress.” He pointed out that toward “the victim’s last gasp” one might find low blood pressure, rapid and thready pulse, and clammy skin — all associated with heart failure.

Linked in heath and illness

There’s no longer any doubt that Cannon was right: Our thoughts and emotions can affect our heart health, and what happens to the heart, likewise, can influence the health of the brain. Solid research now links PTSD, anxiety, depression, Parkinson’s disease, bipolar disorder, and schizophrenia to increased risk of cardiovascular disease (CVD), and studies associate CVD with impaired cognition, white-matter damage, cerebrovascular disease, and dementia. According to the Alzheimer’s Association, postmortem studies show that as many as eight in ten patients with Alzheimer’s also have heart problems.

These comorbidities don’t just make for an interesting pathology to untangle. The World Health Organization calls heart disease the number-one cause of death worldwide and depression the “single largest contributor to global disability.” In the United States alone, chronic diseases cost $37 trillion a year, or almost 20 percent of the nation’s GDP, in direct expenses and lost productivity. “Both mental health and heart disease make up a large share of that,” says Jill Goldstein, an HMS professor of psychiatry and medicine and founder and executive director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital. “And when they co-occur, the cost increases even further. These disorders are also major risk factors for Alzheimer’s disease and the aging brain,” adding, “So if we do not target them early to prevent what’s coming down the road for our aging population, they could tank our economy.”

You know you’re nervous when you get butterflies in your stomach, but is the brain making the butterflies or are they already there and then you perceive them?

Eighty years after Cannon first posited the existence of a brain-heart connection, the science remains in its infancy, largely because skepticism lingered for decades. In 1985 in the New England Journal of Medicine, then editor Marcia Angell, now a corresponding member of the faculty of the Department of Global Health and Social Medicine in the Blavatnik Institute at HMS, wrote an editorial noting that research had not shown a link between psychology and physiology though she acknowledged that “most Americans” believed in one. “She basically said, Wouldn’t it be great if this were true, but it’s not,” says Laura Kubzansky, a behavioral sciences professor at the Harvard T.H. Chan School of Public Health who has studied the link. “You can find arguments like this into the 2000s. Part of the reason is that historically it was hard to get research funded, which meant the studies weren’t very good. It’s still under-resourced compared with many topics.”

Terms like cardioneurology, neurocardiology, and psychocardiology all arose in the 1960s to describe aspects of this emerging interdisciplinary field, yet even today, no major medical body — not the U.S. Centers for Disease Control and Prevention, the National Institutes of Health, or the American Heart Association — lists psychological troubles as a risk factor for cardiovascular disease. The tide may be slowly turning, though; all three organizations at least address stress and other mental health disorders on their websites, and in 2021 the AHA issued a scientific statement, signed by Kubzansky and thirteen others, affirming that one’s mental state can play a role in heart health.

“For something to be elevated to the status of risk factor,” Kubzansky says, “there has to be a lot of evidence. In the past two decades the quality of evidence has become increasingly rigorous and convincing, and it’s getting harder to dismiss.”

The link also tends to get short shrift from clinicians, in part, says Goldstein, because medicine has grown up siloed by organ systems and separate diseases. “Although physicians specialize, given all the technological advances in certain fields,” she notes, “it is also important to look at commonalities among organ systems.”

Understanding shared causal pathways is an important first step. “The vagus nerve is probably the most-researched channel through which the heart and mind talk,” says Kubzansky.

The vagus nerve highway

Among the longest nerves in the human body, the vagus controls autonomic functions like breathing, heart rate, and blood pressure, as well as reflexes like coughing and survival behaviors like eating and drinking.

“The vagus nerve is a bidirectional information highway,” says molecular neuroscientist Stephen Liberles, a professor of cell biology in the Blavatnik Institute at HMS and a Howard Hughes Medical Institute Investigator. “

It has sensory neurons that take information from the body to the brain and motor neurons that go in the opposite direction.” Liberles explains that though we know “a dizzying array” of neurons innervate essentially every major organ in the body, for many neurons it’s unclear what initiates the communication between body and brain. “You know you’re nervous when you get butterflies in your stomach,” he says, “but is the brain making the butterflies or are they already there and then you perceive them? We have no idea what neurons in the circuit are firing or how they send signals deeper into the brain.”

Liberles studies neural populations in the vagus nerves of mice “with exquisite control” by introducing genes for light- sensitive proteins. “We can precisely measure the roles of particular neurons in physiology and behavior,” he says, “by activating or eliminating them and then observing the response.” When you trigger a specific neuron, does the animal become stressed? Does it eat more? Does its heart rate increase?

The catch, of course, is that scientists don’t always know for sure what a mouse is thinking or feeling, and they can’t do similar experiments on people because of the ethical issues around manipulating human genomes. But the electrical pathway isn’t the only connection. The immune, metabolic, vascular, and hormonal systems mediate interactions between the heart and brain, and there also has been a recent explosion of articles on the genetic traits shared by cardiometabolic diseases, depression, and CVD.

The influence of stress

“We know there are sex differences in the development of the brain and body, including the heart, beginning in fetal development,” says Goldstein. While fetal development is not deterministic, there are effects during this period that can set the stage for health across the life span, even though the effects can vary due to life experiences and exposures.”

Studies have shown that men and women have different stress reactions, too, which affect the brain and heart. In women, stress can increase lipid imbalance and platelet aggregation and decrease glucose regulation and the flow of blood to the heart, whereas men tend to experience greater spikes in blood pressure, heart rate, and adrenocorticotropic hormone, which controls the production of cortisol.

This is particularly concerning because 84 percent of U.S. residents who responded to a 2022 survey by the research organization ValuePenguin reported feeling stressed “weekly,” and in that same year, the American Psychological Association found that a third of its frazzled survey respondents considered their stress “overwhelming.”

Antonia Seligowski, an HMS assistant professor of psychology and director of Massachusetts General Hospital’s Neurocardiac Effects of Stress and Trauma Lab, says, “the research is clear that chronic, debilitating stress is more likely to bring about a heart condition.” PTSD, for example, is associated with a 27 percent increase in CVD events and cardiac-specific mortality, according to a meta-analysis reported in 2021 in JAMA Cardiology. “When we experience stress,” Seligowski explains, “our sympathetic nervous system triggers an immune response that releases cytokines in the blood, which inflame the arteries over time and promote the plaque that produces atherosclerosis, the main underlying cause of heart disease.”

A picture of those at risk

Stress may also be one reason for health inequities among various populations in the United States. While death rates from CVD have declined significantly in the past fifty years — from 1,034 to 327 per 100,000 people — numerous studies have shown that people of color have increased risk of heart problems and poorer outcomes once they do occur. “A lot of people are looking at why,” Kubzansky says. “Stress may be one reason, but there’s a paradox: Black people, for example, may seem to have more physical health difficulties, but they appear to have similar or lower rates of mental health problems than white people, even accounting for other social factors like income or education. So more data is definitely needed to better understand the role of stress in health disparities.”

Stress effects also differ by sex. Statistics from the National Center for PTSD show that twice as many women as men will have the disorder at some point in their lives. In part, says Seligowski, that’s because “women experience more interpersonal assault, which leads to PTSD more often than other types of experiences, like a car accident, for example.” Women are more inclined to report symptoms and seek treatment, too, which may contribute to their higher diagnosis rate.

The research is clear that chronic, debilitating stress is more likely to bring about a heart condition.

Nearly all cases of takotsubo cardiomyopathy, a weakening of the blood-pumping left ventricle in healthy individuals experiencing sudden stress, occur in women; in fact, research indicates that up to 5 percent of women suspected of having a heart attack actually have this disorder instead. Also known as broken heart syndrome, takotsubo was named after the ballooning left ventricle’s resemblance to a type of octopus trap used in Japan, where the malady was first described in 1990.

“There’s a greater propensity to develop takotsubo if there’s preexisting stress anxiety or underlying anxiety,” says Seligowski, who is working with a research group that found greater activity in the amygdala, a brain region involved in emotional processing, in patients with takotsubo. The disorder was initially implicated in the death of the actor Debbie Reynolds one day after her daughter, Carrie Fisher, died from cardiac arrest, though Reynolds’s official death certificate blames stroke. The jury is still out on Lady Montague.

Disposition may be key

Just like those butterflies in the stomach, the stress effect runs both ways.“An emerging area of research that we know much less about is how cardiac events can result in PTSD,” says Seligowski. But negative emotions are only part of the equation. In 2001, Kubzansky co-authored one of the first epidemiologic studies reporting that optimism is associated with a lowered risk of developing cardiovascular events, including angina, myocardial infarction, and death, adding these to a long list of other clinical outcomes that appear to be improved by an optimistic outlook, including cognitive decline, respiratory illnesses, infections, and even some cancers.

And Kubzansky and her colleagues learned the effect of having a positive outlook can be even stronger than the negative effect of pessimistic thinking, in part because it may help mitigate the stress response. “Optimistic individuals,” the study points out, “... may experience fewer stressors, or they may have more resources with which to deal with stress.”

From a clinical standpoint, why does this matter? “We spend a lot of time in medicine and public health looking at risk factors and deficits,” Kubzansky says, “but not nearly as much time looking at assets and resources. We can’t mitigate or remove all the environmental factors that can contribute to disease, but if we can identify a strength to add to the mix, it might improve overall health and reduce the disease burden rather than constantly trying to pick up the pieces after a disease has already developed or been set in motion.” A key point for patients is that optimism is 25 to 35 percent heritable, Kubzansky says. “That means there’s a lot of room to modify it.”

Educational and socioeconomic factors have been linked with higher optimism; while these may not be easily altered, studies have shown that regular physical activity, mindfulness, and an active social life can all help cultivate an optimistic outlook — and are within an individual’s power to change.

“These are correlations,” Kubzansky points out, “so it’s hard to say for sure whether they’re precursors to optimism or the results of it.” Greater social connectedness, for example, could promote optimism because problem-solving is easier when you’re not alone, she contends. Or maybe optimists are just more fun to be around, so they develop a larger social network. “Either way,” Kubzansky notes, “the qualities that correlate with optimism are worth striving for in themselves.”

The search for early warning signs

While interventions made later in life are helpful for preventing CVD, a life span perspective is absolutely critical, according to Goldstein. “There are naturalistic windows of opportunity for studying sex differences, specifically fetal development and puberty, and, in women, pregnancy and menopause,” she says. “During these windows, sex differences emerge as the body and brain are each differentially flooded with or depleted of gonadal hormones.”

Goldstein explains that these naturalistic windows can be used to understand the early origins of diseases that may occur later in life. “For example,” she says, “we know that there are developmental origins of disorders of the brain, like depression, and of the heart, like CVD. And we know that some of these early, even fatal, origins are shared between the brain and the heart.”

Understanding the shared roots, Goldstein says, “allows you to target one disorder, like depression, that onsets earlier than CVD in order to potentially help prevent the other,” adding that CVD typically occurs later than depression.

By studying fetal and early childhood antecedents and how major disorders occur at different periods across the life span, Goldstein maintains, “we can focus our therapeutics earlier and identify early resiliencies to either attenuate disability or prevent future disease.”

Which, of course, is the ultimate goal.

“Cardiologists and neurologists usually don’t see people until they’re either sick or almost sick,” Kubzansky says. “But that could start to change if clinicians look at health as a constellation and remember that mind and body are not separate. If you ignore what’s going on from a mental health perspective or ignore the heart health of patients with brain disorders, you’re going to miss a lot of opportunities to improve outcomes.”

Elizabeth Gehrman is a Boston-based writer.

Images: Michael Roy Kelly (painting); Gretchen Ertl (Liberles) John Soares (Seligowski)