This Is Your Heart on Stress

The Heart–Brain Connection, Multisystem Research, and Neurobiological Resilience

BY MICHAEL TABASKO, THE NIH CATALYST

Sage advice from doctor to patient warns of unmanaged stress. The famed INTERHEART study published in 2004 linked increased incidence of heart attacks to psychosocial stress factors in thousands of study participants (Lancet 364:953-962, 2004). More recently, researchers have found the attributable risk of stress on the heart to be particularly potent, on par with smoking, hypertension, and diabetes (Circ Cardiovasc Imaging 13:e010931, 2020).

But precisely how does stress—intangible and omnipresent—infiltrate our very fabric, and how can we stop it? Ahmed Tawakol proposed some answers at the 2023 Stephen E. Straus Distinguished Lecture in the Science of Complementary Therapies, Dec. 6, sponsored by NCCIH.

Tawakol is director of Nuclear Cardiology and co-director of the Cardiovascular Imaging Research Center at Massachusetts General Hospital and associate professor of Medicine at Harvard Medical School (Boston).

He and his collaborators take a whole-person approach to research and have pioneered imaging techniques that exquisitely show how stress manifests across multiple organs. “One of the keys to pursuing multisystem research is to make sure your team has broad expertise,” said Tawakol, a cardiologist who leans on guidance from collaborators including neurologists, psychologists, hematologists, and brain-imaging experts.

Leveraging those relationships, Tawakol’s team was the first to associate stress-associated brain activity in humans to cardiovascular disease events, such as heart attacks and strokes, and is testing how lifestyle interventions can be powerful treatment tools.

The enigmatic amygdala

For an external stressor—such as noise, danger, or the dreaded public speaking event—to trigger stress in the body, it first needs to be registered as a threat. That’s brokered primarily in the amygdala, our brain’s main emotion-processing center.

Using positron emission tomography in combination with computed tomography (PET/CT), Tawakol found that people experiencing stressors such as financial insecurity or chronic unhealthy noise exposure, or who had chronic anxiety disorders or depression, had heightened amygdalar activity. The degree to which this stress-related brain activity was elevated in turn strongly predicted the risk for and even the timing of subsequent cardiovascular disease events, even after adjusting for other risk factors.

Probing a pathway previously found in mice, Tawakol then used PET/CT to show that stressed individuals also had elevated immune activity in the bone marrow which correlated with increased arterial inflammation and plaque formation (Lancet 389:834-845, 2017).

“This supports a model that stress, through activation in the amygdala, stimulates the bone marrow [via sympathetic nerves], which increases arterial inflammation and leads to cardiovascular events,” said Tawakol, who cited several studies confirming this pathway, including one with former NHLBI Lasker Clinical Research Scholar Nehal Mehta (JACC Cardiovasc Imaging 13:465-477, 2020).

The neuroimmune arterial axis

Importantly, “amygdalar activity” is calculated as a ratio of activity in the amygdala relative to counter-regulatory signals from the prefrontal cortex (PFC), which placates an active amygdala. “It’s all about balance,” said Tawakol. In other words, if the PFC deems the amygdala has gone rogue, the PFC can send signals to calm it and mute the inflammatory cascade. Those with a healthy balance between the amygdala and PFC are considered neurobiologically resilient because stress activity is lower despite being exposed to stressors.

Conversely, Tawakol presented evidence where people who had routine amygdalar activity, but lower PFC regulation, still had an elevated risk of cardiovascular disease compared with their counterparts with effective cortical regulation (Circulation 146:A14065, 2022). This regulatory balancing act may have impacts beyond the heart, too. Brain scans have shown an association between amygdalar activity and survival from head and neck cancers (PLoS One 18:e0279235, 2023).

In another study that Tawakol suggested may hint at a future area of research, scientists demonstrated in a mouse model that sympathetic neural connections from the amygdala terminated near atherosclerotic plaques. When those circuits were interrupted, the plaque sizes reduced, showing how the peripheral nervous system may interact directly with diseased arteries (Nature 605:152–159, 2022).

Stress can also affect us acutely. Tawakol pointed to a surge in recorded heart attacks after earthquakes, political elections, and consequential World Cup soccer matches (N Engl J Med 358:475-483, 2008).

Fostering neurobiological resilience

Ready to de-stress? Mounting evidence is showing just how well lifestyle interventions work. Tai chi may thicken the cortical region of the brain and improve regulatory connectivity between the amygdala and PFC (Front Med (Lausanne) 2023; DOI:10.3389/fmed.2023.1210170). Structured breathing exercises appear very effective in calming the amygdala (J Neurosci 36:12448-12467, 2016).

Sleep turns out to be extremely important, especially for people genetically predisposed to stress-associated conditions like anxiety and depression. Tawakol found that these individuals were twice as likely to develop cardiovascular disease when sleep deprived compared with people with lower genetic risk (Circulation 148:A16298, 2023).

Exercise has long-term impact. “Its benefits are not transient; it changes the wiring of your brain,” said Tawakol, whose imaging studies have shown that exercise works, in part, by enhancing cortical control of the stress systems. Because of those direct effects on the brain, it was particularly effective in people with pre-existing depression. Getting beyond the recommended 150-300 minutes of moderate exercise per week in individuals with depression was associated with even greater cardioprotective benefits (Circulation 144:A13203, 2021).

Stress-reduction techniques are showing great promise, too. Stress reduction combined with exercise in a cardiac rehabilitation group was 50% more effective in reducing future cardiac events than standard rehabilitation alone (Circulation 133:1341-1350, 2016). What’s more is that emerging evidence suggests that uncontrolled stress might even lower survival from cancer and increase the risk of blood clots. “We are currently doing two studies testing stress reduction through a mindfulness intervention to see if it results in changes in the brain,” said Tawakol.

More studies are in the pipeline to uncover the mechanics behind exactly how lifestyle interventions build a stress-resistant brain and have downstream effects on bone-marrow activity and arterial inflammation. Demonstrating causation could further inform precision medicine approaches and help physicians tailor stress-fighting interventions for their patients.

Offering parting advice, Tawakol acknowledged that fitting lifestyle interventions into a busy life is no easy task. Nevertheless, he coaches his patients on just how detrimental stress is to their health and how powerful lifestyle interventions can be. “I would really try to combine techniques and prioritize the ones that work well within your life,” he said.

Stephen Straus’ Legacy and Multisystem Research at NCCIH

Stephen Straus was the first director of NCCIH. “Straus championed efforts to establish the efficacy and safety of complementary and integrative health practices while upholding NIH’s rigorous scientific standards,” said NCCIH Director Helene M. Langevin in her opening remarks welcoming Ahmed Tawakol to this year’s Stephen E. Straus Distinguished Lecture.

Multisystem research, whole-person health, and lifestyle interventions to help ameliorate the effects of chronic stress are also being explored at NCCIH. Intramural researchers there are particularly focused on the role of the brain in perceiving, modifying, and managing pain.

Some of those integrative investigators are doing work at the NIH Pain Research Center (PRC), a multidisciplinary initiative bringing together scientists from 11 NIH institutes and centers. PRC researchers are working to identify specific pain mechanisms, determine the efficacy of nonopioid treatments, and predict individual patient response to therapies and outcomes. For example, Lead Scientific Officer Eleni Frangos runs a collaborative study with NHLBI scientists Swee Lay Thein, Matthew Hsieh, and Deepika Darbari of Children’s National Hospital (Washington, D.C.) that looks at the brains and pain responses of sickle-cell patients after they receive a bone-marrow transplant or gene therapy. Some patients continue to experience pain after receiving curative therapy. To find out why, the PRC team uses functional magnetic resonance imaging to examine how pain-related brain activity and the connectivity between various brain regions differs between sickle-cell patients who have undergone one of those procedures and healthy individuals.