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Published On January 23, 2020

BASIC RESEARCH

Broken Hearted

An unusual syndrome connects grief and stress to cardiac damage. Discoveries about its physiology reveal a complex connection to the brain.

A broken heart may evoke images of fainting heroines, but “broken-heart syndrome” is a real—and dangerous—medical phenomenon. Every year an estimated 7,000 to 14,000 people in the United States are diagnosed with the condition, which damages the heart and can be triggered by tragedy. A growing body of research ties it to the way the brain manages stress.

Hikaru Sato, a physician at the Hiroshima City Hospital in Japan, was the first to document the physical aspects of the syndrome in the early 1990s. His patients experienced a combination of sudden, life threatening symptoms: chest pain, shortness of breath and increased levels of the cardiac enzymes that an injured heart produces. Sato assumed these people were having heart attacks, but their arteries weren’t blocked. Instead their hearts seemed stunned and changed shape, the bottom tip ballooning into what Sato likened to a Japanese octopus trap, or takotsubo.

Over the years, researchers dug into the cause of “takotsubo cardiomyopathy” and why some people are particularly susceptible to it. Most of those who develop the syndrome recover, but it can be lethal. The main culprit is severe psychological stress, such as a death in the family or a physical injury. But its precise physiological pathway remains unclear and there are no specific treatments.

“The susceptibility question is key,” says Ilan Wittstein, a cardiologist at Johns Hopkins Medicine. “Can anyone who is subjected to the right amount of stress get takotsubo? Or does it have to do with a stress response abnormality? Or a neurological defect?”

Takotsubo is often misdiagnosed because, as Sato originally observed, it closely resembles a heart attack. The heart suddenly weakens, triggering changes in muscle cells and coronary blood vessels that prevent the left ventricle—the heart’s main pumping chamber—from working properly. It is estimated that as many as 3% of presumed heart attacks in men and as many as 5% in women actually involve takotsubo syndrome. But Wittstein says he believes that these numbers are too low and don’t fully reflect the scope of the problem. “We are going to see more of it every year as physicians get better at detecting it.”

One promising theory about how the syndrome develops points toward a brain-heart connection. An April 2019 study published in the European Heart Journal showed, for the first time, that those who experienced takotsubo cardiomyopathy had reduced function in parts of their brains. In those patients, brain regions that are responsible for processing emotions and that regulate the autonomic nervous system—which controls heartbeat, breathing and digestion—didn’t communicate properly with each other. Both of those regions play a major role in managing stress, the researchers explained, and a decrease in communication between them might somehow make people more susceptible to developing takotsubo syndrome.

“A severe enough dose of emotional or physical stress can essentially overload the brain’s ability to control its response,” says Gregory Fricchione, director of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital who studies the effects of stress and psychiatric disorders on cardiac health. “Instead the heart is flooded with neurotransmitters by an unbridled sympathetic nervous system, effectively stunning it.” But, Fricchione adds, it’s still unclear whether affected patients had weak brain connectivity before the takotsubo episode or because of it.

This may also point to a role for psychiatric conditions that interfere with emotional regulation. In fact, patients with takotsubo syndrome appear to have a high prevalence of psychiatric and neurologic disorders. One 2015 study in The New England Journal of Medicine, for example, found that 42% of the patients with takotsubo had a psychiatric diagnosis and 27% had a history of chronic neurologic disorders.

“Psychological disorders may have a pathogenic role,” says Abhiram Prasad, a cardiologist at the Mayo Clinic who specializes in takotsubo. “People with depression, for example, have an exaggerated norepinephrine response to emotional stress. Norepinephrine and other catecholamines increase the rate and force of the heart’s contractions.”

Other parts of the picture are also coming into focus. One study published in late 2018 showed that patients with the syndrome had higher than usual numbers of inflammatory cells infiltrating their myocardium, the middle layer of the heart that allows it to contract and pump blood. Elevated levels of cytokines—a kind of protein that promotes an immune response—also pointed to an important role for inflammation.

Many researchers suggest that hormonal dysregulation is a key culprit. More than 90% of reported cases of takotsubo syndrome are in women ages 58 to 75, who may be more vulnerable because of reduced levels of estrogen after menopause. Studies in rats that had their ovaries removed showed that giving estrogen to the animals while they were under stress protected them to some degree from left-ventricle dysfunction that may be similar to takotsubo syndrome.

“We need to identify specific targets in order to treat this condition properly,” Prasad says. “We all experience stress, and we all respond differently. It’s figuring out what makes victims of takotsubo different, so that we can protect their hearts.”

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