Stress-related brain activity links depression and anxiety to higher heart disease risk

Recent medical research indicates that the heightened risk of heart disease observed in patients with depression or anxiety may stem from specific biological pathways involving the brain and immune system. A new analysis suggests that stress-related neural activity, combined with inflammation and nervous system imbalances, acts as a primary driver connecting mental health conditions to cardiovascular problems. The study, published in Circulation: Cardiovascular Imaging, provides evidence that addressing mental health could be an essential component of heart disease prevention.

Medical professionals have recognized a connection between psychiatric conditions and heart disease for some time. Previous observations established a statistical link, yet questions remained regarding whether this association existed independently of lifestyle factors such as smoking or poor diet. The biological mechanisms translating emotional distress into physical cardiovascular damage also lacked a complete explanation.

The authors aimed to determine if depression and anxiety contribute to heart risks through direct physiological changes rather than solely through behavioral choices. They sought to understand if suffering from both conditions simultaneously creates a greater danger than having a single diagnosis. The team also investigated whether treating these conditions as a continuum of stress could offer new insights into how emotions impact physical health.

“For years, depression and anxiety have been linked to heart disease, but the why has remained unclear. Some clinicians viewed mental health as a comorbidity, others as a marker of unhealthy behaviors, and others as a direct biological risk factor, but the mechanisms were debated,” said study author Shady Abohashem, cardiovascular investigator and head of Cardiac PET/CT Imaging Trials at Cardiovascular Imaging Research Center of Massachusetts General Hospital, and instructor at Harvard Medical School.

“What motivated us was a clear gap: stress-related brain activity has been shown to link anxiety and stress to cardiovascular disease, yet its role in depression was largely unexplored, despite depression being one of the strongest predictors of heart events. We also wanted to reflect clinical reality, depression and anxiety often occur together, yet most studies examine them in isolation. Our goal was to understand whether shared brain-autonomic-immune pathways help explain cardiovascular risk across this mental health spectrum.”

For their study, the researchers utilized data from the Mass General Brigham Biobank. This large repository contains genetic and health information from patients within the hospital system. The final analysis included 85,551 individuals between the ages of 18 and over, tracked over a period from 2010 to 2020.

The team categorized participants based on their mental health diagnoses at the time of enrollment. They identified groups with depression alone, anxiety alone, and those with concurrent diagnoses of both conditions. A control group consisted of individuals with neither diagnosis.

Researchers monitored these participants for Major Adverse Cardiovascular Events, commonly abbreviated as MACE. This category includes severe incidents such as heart attacks, strokes, heart failure, and the need for procedures to open blocked arteries. The team tracked these outcomes over a median follow-up period of approximately three and a half years.

A subset of the participants provided data for more specific biological investigations. To measure brain activity, the investigators analyzed brain scans from 1,123 individuals. These scans utilized 18F-fluorodeoxyglucose positron emission tomography, or PET/CT imaging.

This imaging technique allowed the researchers to observe metabolic activity in the amygdala. The amygdala is a region of the brain involved in processing fear and stress. The researchers compared activity in the amygdala to activity in the prefrontal cortex to calculate a ratio of stress-related neural activity.

The researchers also examined markers of the autonomic nervous system. This system controls involuntary bodily functions like heart rate and digestion. The researchers analyzed electrocardiograms from 7,862 participants to measure heart rate variability.

Heart rate variability refers to the fluctuation in time intervals between heartbeats. A lower variability typically indicates that the body is in a persistent state of stress or “fight or flight” mode. Higher variability generally suggests a healthier, more adaptable nervous system.

Finally, the team assessed chronic inflammation levels. They reviewed blood test results for C-reactive protein in 12,906 participants. Elevated levels of this protein serve as a standard marker for systemic inflammation in the body.

The analysis revealed that individuals with depression faced a significantly higher risk of cardiovascular events compared to those without the condition. Specifically, a diagnosis of depression was associated with a 24 percent increase in the risk of experiencing a major adverse cardiac event. This association persisted even after the researchers adjusted for traditional risk factors.

The statistical models accounted for variables such as age, sex, high blood pressure, diabetes, and cholesterol levels. They also controlled for lifestyle factors including smoking, alcohol consumption, body mass index, and exercise habits. Socioeconomic status was also included in the adjustment to ensure the findings were not driven by financial disparities.

The risk was even more pronounced for individuals diagnosed with both anxiety and depression. Participants with this comorbidity faced a 35 percent higher risk of cardiovascular events compared to the control group. This finding suggests that the co-occurrence of these conditions amplifies the burden on the heart.

The biological sub-studies provided evidence for how this damage occurs. Participants with depression or anxiety displayed heightened activity in the amygdala relative to the cortex. This specific pattern of brain activity is a hallmark of chronic stress processing.

These same individuals also exhibited reduced heart rate variability. This suggests their autonomic nervous systems were dysregulated and stuck in a state of heightened sympathetic arousal. Additionally, they showed elevated levels of C-reactive protein, indicating chronic inflammation.

Statistical mediation analysis linked these biological markers directly to the heart outcomes. The researchers found that the path from depression to heart disease flows partially through these three specific channels. The heightened brain activity appears to trigger the autonomic and immune responses that ultimately damage the cardiovascular system.

“Two things stood out,” Abohashem told PsyPost. “First, the strength and consistency of the biological signal, from the brain to the autonomic nervous system to inflammation, was striking. This wasn’t a single pathway but a coordinated stress response that helped explain cardiovascular risk.”

“Second, the amplified risk among people with both depression and anxiety was notable. It reinforces the idea that these conditions exist on a continuum, and that cumulative psychological stress may translate into cumulative biological risk.”

Abohashem noted that these results provide a clearer biological picture of how emotional distress physically affects the body. “The key takeaway is that mental health is biologically connected to heart health, not just emotionally or behaviorally,” he explained. “People with depression or anxiety had a meaningfully higher risk of heart attack, stroke, or related events, and that risk was even higher when both conditions were present.”

“Importantly, these differences aren’t trivial. The magnitude of risk we observed is comparable to other established cardiovascular risk factors, and it persisted even after accounting for lifestyle, socioeconomic factors, and traditional heart disease risks. Practically, this means that taking mental health seriously is also taking cardiovascular prevention seriously.”

However, the study is observational, meaning it identifies patterns but cannot definitively prove that mental health conditions cause heart disease. The reliance on medical billing codes for diagnoses introduces a potential margin of error regarding patient classification. Additionally, the participants were drawn from a hospital system biobank, which implies they may have had more health concerns than the general population.

“This study does not suggest that depression or anxiety directly ’cause’ heart disease in a simple way, nor that treating mental health alone will automatically prevent heart attacks,” Abohashem noted. “Our findings are observational.”

“What we show is that measurable biological stress pathways partially explain the association, which opens the door to integrated prevention strategies, but it doesn’t replace the need for prospective trials. Another important caveat is that brain imaging was available in a subset of participants, so while the biological signals are robust, they should be interpreted in that context.”

Future investigations will need to test whether treating depression or anxiety directly improves cardiovascular outcomes. Clinical trials could evaluate if stress-reduction therapies or anti-inflammatory treatments can break the link between the brain and the heart. The researchers hope this work leads to a more integrated model of prevention that treats the brain and heart as an interconnected system.

“Our long-term goal is to move from association to action,” Abohashem told PsyPost. “That means studying whether targeting stress-related brain activity and inflammation, through behavioral interventions, lifestyle changes, medications, or digital tools, can reduce cardiovascular risk.”

“We’re also interested in earlier prevention: identifying people at risk before heart disease develops, and understanding whether changes in brain or autonomic signals can serve as early warning markers or treatment targets. Ultimately, we hope this work helps shift prevention toward a more integrated brain–heart model.”

“One broader message is that integrated care isn’t optional, it’s necessary,” the researcher added. “Mental and cardiovascular health have traditionally lived in separate silos, but biology doesn’t respect those boundaries.”

“This study adds to a growing body of evidence showing that the brain, immune system, and heart are deeply interconnected. Recognizing that connection gives us an opportunity, not just to treat disease, but to rethink prevention in a more holistic and humane way.”

The study, “Depression and Anxiety Associate With Adverse Cardiovascular Events via Neural, Autonomic, and Inflammatory Pathways,” was authored by Shady Abohashem, Iqra Qamar, Simran S. Grewal, Giovanni Civieri, Sabeeh Islam, Wesam Aldosoky, Sandeep Bollepalli, Rachel P. Rosovsky, Antonia V. Seligowski, Lisa M. Shin, Antonis A. Armoundas, Michael T. Osborne, and Ahmed Tawakol.