Targeting vagal activity could improve breast cancer survival

ATLANTA – Vagal activity predicts survival in patients with metastatic or recurrent breast cancer, a study showed.

The findings are intriguing, given that vagal activity is modifiable, according to Dr. David Spiegel, Willson Professor of Psychiatry and Behavioral Sciences and director of the center on stress and health at Stanford (Calif.) University.

The study, conducted by Dr. Spiegel and his colleagues, is one of several that together are beginning to elucidate the connections among sleep, stress, and vagal tone, and the effects these factors have on cancer outcomes. For example, in one earlier study of metastatic breast cancer patients, the group demonstrated that good sleep efficiency predicted longer survival (Sleep. 2014 May 1;37[5]:837-42).

“There’s something about sleep that we think has an effect on disease progression,” Dr. Spiegel said at the annual meeting of the American Psychiatric Association.

In another study, the team showed that breast cancer patients who slept better at night had better vagal tone the following morning.

“We all kind of know that a problem that has been keeping you from getting to sleep or worrying you a lot the night before suddenly seems more soluble in the morning after you’ve had a good night’s sleep. You’re better able to self-soothe in the morning,” he said, noting the importance of this evidence that “sleep improves vagal tone.”

Heart rate variability is a good measure of vagal tone, vagal activity, and the ability to self-soothe, he explained, noting that heart rate variability also predicts longer survival with cardiac disease; it seems to reduce the risk of fatal arrhythmias, and also predicts recovery from myocardial infarction.

Others have suggested that it might have an effect on cancer, and there seems to be a link between vagal activity and inflammatory processes, Dr. Spiegel said.

“There is reason to think that poor heart rate variability might be associated with cancer progression as well, and that’s what we wanted to study in a group of metastatic cancer patients,” he said.

Dr. Spiegel and his colleagues measured high-frequency heart rate variability (HF-HRV), which appears to be the best measure of parasympathetic tone, has been associated with longer survival in humans and animals, and is related to immune system functioning.

“We hypothesized that higher heart rate variability would predict longer survival in patients with MRBC [metastatic or recurrent breast cancer],” he said.

In 87 patients with metastases to bone, skin, or viscera who underwent a variety of stress measures, including a 5-minute resting baseline electrocardiogram, 43 had higher HF-HRV, and 44 had lower HF-HRV. Higher baseline HF-HRV did, indeed, predict significantly longer survival (hazard ratio, 0.75).

“The main hypothesis was confirmed – that patients with better vagal tone, higher high-frequency heart rate variability had significantly longer survival over the ensuing 7 years, compared with the patients who had poorer heart rate variability, poorer vagal tone,” he said (Psychosom Med. 2015;77[4]:346-55).

Visceral metastasis status and baseline heart rate both were related to HF-HRV and survival, and the combination of HF-HRV and heart rate further improved survival prediction (HR, 0.64), he noted.

“This is basically coactivation of higher parasympathetic and lower sympathetic activity related to longer survival,” he explained.

Reconstructive surgery, the presence of visceral metastases, and sleep efficiency each were found to be associated with heart rate variability; thus several analyses were conducted “to try to disentangle these relationships and determine what the major variables were that predicted survival,” Dr. Spiegel said.

“It turns out that heart rate variability and visceral metastases were significantly related, and heart rate variability did not predict survival,” he said, explaining that those with visceral metastases (and therefore, cancer with a much poorer prognosis) died sooner, but heart rate variability didn’t make much of a difference. “Where we saw the heart rate variability effect was among those with better prognosis.”

A combination measure of high heart rate variability (“a pretty pure measure of vagal activity, not sympathetic activity”) and low heart rate (“more driven by the sympathetic adrenal-medullary system”) is an even stronger predictor of overall survival, he said.

This suggests that autonomic nervous system variables play a strong role in predicting overall cancer survival, Dr. Spiegel said, noting that depression was not a confounder.

“This is important, because we have, in other studies, found that depression is associated with lower heart rate variability, as you might expect,” he said. In fact, depression has been found to predict shorter survival in cancer patients over a period of 10 years. In an earlier study, cancer patients with worsening depression in the first year died sooner than those with depression that improved during the first year (J Clin Oncol. 2011;29[4]:413-20).

“The median survival difference was about 2 years, so this is not a trivial difference in overall survival,” he said, stressing that the finding is based on more chronic and severe depression.

Other studies have demonstrated relationships between circadian rhythm disruption and cancer survival. In one such study involving patients with metastatic colorectal cancer, circadian rhythm/rest activity cycle (more activity during the day, more rest at night) was associated with better quality of life and predicted survival.

“This has been shown now in several cancers, and it’s clear that a combination of higher activity and better sleep predict longer survival with different kinds of cancers,” Dr. Spiegel said, explaining that a hallmark of a healthy hypothalamic-pituitary-adrenal axis is good diurnal variation of cortisol with high levels in the morning and declining levels throughout the day.

Women with metastatic breast cancer and poorer survival tended to have flat or increasing levels of cortisol throughout the day, he said, adding that the same was true in a study of patients with lung cancer, and that there is evidence that those among them with flatter, more abnormal cortisol patterns throughout the day also have shorter survival.

Animal studies suggest that cortisol might directly suppress the activity of tumor suppressor genes, he explained, noting that there is also increasing evidence of autonomic dysregulation effects on inflammatory processes associated with tumor growth.

“Some basic research on this in animal models shows that if you block adrenergic arousal, you can block the growth of blood vessels from tumors. This has led some people to look at the use of antiadrenergic drugs like the beta-blocker propranolol, and it turned out – to everyone’s surprise – that breast cancer patients who happened to be on beta-blockers for hypertension actually lived longer than those who didn’t,” he said.

This adds to the growing evidence that dysregulation in the sympathetic and parasympathetic systems have effects on survival, he said.

A look at another factor related to sleep disruption – bedtime misalignment – showed that patients who adhere to their preferred sleep pattern, and who are therefore sleeping better, had a difference in disease-free interval; those whose bedtime was misaligned had a shorter time between diagnosis and disease recurrence (Chronobiol Int. 2014 Mar 31[2]214-21).

“Disease-free interval is a very strong predictor of ultimate overall survival, so there seems to be another relationship here between circadian disruption and disease progression in breast cancer,” Dr. Spiegel said.

Taken together, these findings demonstrate a strong association between vagal activity and survival in patients with metastatic or recurrent breast cancer, extending the known predictive window of HF-HRV beyond palliative care to cancer, Dr. Spiegel said.

“Vagal activity can be altered through behavioral, pharmacological, and surgical interventions and thus may be a promising target for increasing survival in patients with metastatic cancer,” he said.

Dr. Spiegel’s studies were funded by the National Cancer Institute and the National Institute on Aging.

[email protected]

ATLANTA – Vagal activity predicts survival in patients with metastatic or recurrent breast cancer, a study showed.

The findings are intriguing, given that vagal activity is modifiable, according to Dr. David Spiegel, Willson Professor of Psychiatry and Behavioral Sciences and director of the center on stress and health at Stanford (Calif.) University.

The study, conducted by Dr. Spiegel and his colleagues, is one of several that together are beginning to elucidate the connections among sleep, stress, and vagal tone, and the effects these factors have on cancer outcomes. For example, in one earlier study of metastatic breast cancer patients, the group demonstrated that good sleep efficiency predicted longer survival (Sleep. 2014 May 1;37[5]:837-42).

“There’s something about sleep that we think has an effect on disease progression,” Dr. Spiegel said at the annual meeting of the American Psychiatric Association.

In another study, the team showed that breast cancer patients who slept better at night had better vagal tone the following morning.

“We all kind of know that a problem that has been keeping you from getting to sleep or worrying you a lot the night before suddenly seems more soluble in the morning after you’ve had a good night’s sleep. You’re better able to self-soothe in the morning,” he said, noting the importance of this evidence that “sleep improves vagal tone.”

Heart rate variability is a good measure of vagal tone, vagal activity, and the ability to self-soothe, he explained, noting that heart rate variability also predicts longer survival with cardiac disease; it seems to reduce the risk of fatal arrhythmias, and also predicts recovery from myocardial infarction.

Others have suggested that it might have an effect on cancer, and there seems to be a link between vagal activity and inflammatory processes, Dr. Spiegel said.

“There is reason to think that poor heart rate variability might be associated with cancer progression as well, and that’s what we wanted to study in a group of metastatic cancer patients,” he said.

Dr. Spiegel and his colleagues measured high-frequency heart rate variability (HF-HRV), which appears to be the best measure of parasympathetic tone, has been associated with longer survival in humans and animals, and is related to immune system functioning.

“We hypothesized that higher heart rate variability would predict longer survival in patients with MRBC [metastatic or recurrent breast cancer],” he said.

In 87 patients with metastases to bone, skin, or viscera who underwent a variety of stress measures, including a 5-minute resting baseline electrocardiogram, 43 had higher HF-HRV, and 44 had lower HF-HRV. Higher baseline HF-HRV did, indeed, predict significantly longer survival (hazard ratio, 0.75).

“The main hypothesis was confirmed – that patients with better vagal tone, higher high-frequency heart rate variability had significantly longer survival over the ensuing 7 years, compared with the patients who had poorer heart rate variability, poorer vagal tone,” he said (Psychosom Med. 2015;77[4]:346-55).

Visceral metastasis status and baseline heart rate both were related to HF-HRV and survival, and the combination of HF-HRV and heart rate further improved survival prediction (HR, 0.64), he noted.

“This is basically coactivation of higher parasympathetic and lower sympathetic activity related to longer survival,” he explained.

Reconstructive surgery, the presence of visceral metastases, and sleep efficiency each were found to be associated with heart rate variability; thus several analyses were conducted “to try to disentangle these relationships and determine what the major variables were that predicted survival,” Dr. Spiegel said.

“It turns out that heart rate variability and visceral metastases were significantly related, and heart rate variability did not predict survival,” he said, explaining that those with visceral metastases (and therefore, cancer with a much poorer prognosis) died sooner, but heart rate variability didn’t make much of a difference. “Where we saw the heart rate variability effect was among those with better prognosis.”

A combination measure of high heart rate variability (“a pretty pure measure of vagal activity, not sympathetic activity”) and low heart rate (“more driven by the sympathetic adrenal-medullary system”) is an even stronger predictor of overall survival, he said.

This suggests that autonomic nervous system variables play a strong role in predicting overall cancer survival, Dr. Spiegel said, noting that depression was not a confounder.

“This is important, because we have, in other studies, found that depression is associated with lower heart rate variability, as you might expect,” he said. In fact, depression has been found to predict shorter survival in cancer patients over a period of 10 years. In an earlier study, cancer patients with worsening depression in the first year died sooner than those with depression that improved during the first year (J Clin Oncol. 2011;29[4]:413-20).

“The median survival difference was about 2 years, so this is not a trivial difference in overall survival,” he said, stressing that the finding is based on more chronic and severe depression.

Other studies have demonstrated relationships between circadian rhythm disruption and cancer survival. In one such study involving patients with metastatic colorectal cancer, circadian rhythm/rest activity cycle (more activity during the day, more rest at night) was associated with better quality of life and predicted survival.

“This has been shown now in several cancers, and it’s clear that a combination of higher activity and better sleep predict longer survival with different kinds of cancers,” Dr. Spiegel said, explaining that a hallmark of a healthy hypothalamic-pituitary-adrenal axis is good diurnal variation of cortisol with high levels in the morning and declining levels throughout the day.

Women with metastatic breast cancer and poorer survival tended to have flat or increasing levels of cortisol throughout the day, he said, adding that the same was true in a study of patients with lung cancer, and that there is evidence that those among them with flatter, more abnormal cortisol patterns throughout the day also have shorter survival.

Animal studies suggest that cortisol might directly suppress the activity of tumor suppressor genes, he explained, noting that there is also increasing evidence of autonomic dysregulation effects on inflammatory processes associated with tumor growth.

“Some basic research on this in animal models shows that if you block adrenergic arousal, you can block the growth of blood vessels from tumors. This has led some people to look at the use of antiadrenergic drugs like the beta-blocker propranolol, and it turned out – to everyone’s surprise – that breast cancer patients who happened to be on beta-blockers for hypertension actually lived longer than those who didn’t,” he said.

This adds to the growing evidence that dysregulation in the sympathetic and parasympathetic systems have effects on survival, he said.

A look at another factor related to sleep disruption – bedtime misalignment – showed that patients who adhere to their preferred sleep pattern, and who are therefore sleeping better, had a difference in disease-free interval; those whose bedtime was misaligned had a shorter time between diagnosis and disease recurrence (Chronobiol Int. 2014 Mar 31[2]214-21).

“Disease-free interval is a very strong predictor of ultimate overall survival, so there seems to be another relationship here between circadian disruption and disease progression in breast cancer,” Dr. Spiegel said.

Taken together, these findings demonstrate a strong association between vagal activity and survival in patients with metastatic or recurrent breast cancer, extending the known predictive window of HF-HRV beyond palliative care to cancer, Dr. Spiegel said.

“Vagal activity can be altered through behavioral, pharmacological, and surgical interventions and thus may be a promising target for increasing survival in patients with metastatic cancer,” he said.

Dr. Spiegel’s studies were funded by the National Cancer Institute and the National Institute on Aging.

[email protected]

ATLANTA – Vagal activity predicts survival in patients with metastatic or recurrent breast cancer, a study showed.

The findings are intriguing, given that vagal activity is modifiable, according to Dr. David Spiegel, Willson Professor of Psychiatry and Behavioral Sciences and director of the center on stress and health at Stanford (Calif.) University.

The study, conducted by Dr. Spiegel and his colleagues, is one of several that together are beginning to elucidate the connections among sleep, stress, and vagal tone, and the effects these factors have on cancer outcomes. For example, in one earlier study of metastatic breast cancer patients, the group demonstrated that good sleep efficiency predicted longer survival (Sleep. 2014 May 1;37[5]:837-42).

“There’s something about sleep that we think has an effect on disease progression,” Dr. Spiegel said at the annual meeting of the American Psychiatric Association.

In another study, the team showed that breast cancer patients who slept better at night had better vagal tone the following morning.

“We all kind of know that a problem that has been keeping you from getting to sleep or worrying you a lot the night before suddenly seems more soluble in the morning after you’ve had a good night’s sleep. You’re better able to self-soothe in the morning,” he said, noting the importance of this evidence that “sleep improves vagal tone.”

Heart rate variability is a good measure of vagal tone, vagal activity, and the ability to self-soothe, he explained, noting that heart rate variability also predicts longer survival with cardiac disease; it seems to reduce the risk of fatal arrhythmias, and also predicts recovery from myocardial infarction.

Others have suggested that it might have an effect on cancer, and there seems to be a link between vagal activity and inflammatory processes, Dr. Spiegel said.

“There is reason to think that poor heart rate variability might be associated with cancer progression as well, and that’s what we wanted to study in a group of metastatic cancer patients,” he said.

Dr. Spiegel and his colleagues measured high-frequency heart rate variability (HF-HRV), which appears to be the best measure of parasympathetic tone, has been associated with longer survival in humans and animals, and is related to immune system functioning.

“We hypothesized that higher heart rate variability would predict longer survival in patients with MRBC [metastatic or recurrent breast cancer],” he said.

In 87 patients with metastases to bone, skin, or viscera who underwent a variety of stress measures, including a 5-minute resting baseline electrocardiogram, 43 had higher HF-HRV, and 44 had lower HF-HRV. Higher baseline HF-HRV did, indeed, predict significantly longer survival (hazard ratio, 0.75).

“The main hypothesis was confirmed – that patients with better vagal tone, higher high-frequency heart rate variability had significantly longer survival over the ensuing 7 years, compared with the patients who had poorer heart rate variability, poorer vagal tone,” he said (Psychosom Med. 2015;77[4]:346-55).

Visceral metastasis status and baseline heart rate both were related to HF-HRV and survival, and the combination of HF-HRV and heart rate further improved survival prediction (HR, 0.64), he noted.

“This is basically coactivation of higher parasympathetic and lower sympathetic activity related to longer survival,” he explained.

Reconstructive surgery, the presence of visceral metastases, and sleep efficiency each were found to be associated with heart rate variability; thus several analyses were conducted “to try to disentangle these relationships and determine what the major variables were that predicted survival,” Dr. Spiegel said.

“It turns out that heart rate variability and visceral metastases were significantly related, and heart rate variability did not predict survival,” he said, explaining that those with visceral metastases (and therefore, cancer with a much poorer prognosis) died sooner, but heart rate variability didn’t make much of a difference. “Where we saw the heart rate variability effect was among those with better prognosis.”

A combination measure of high heart rate variability (“a pretty pure measure of vagal activity, not sympathetic activity”) and low heart rate (“more driven by the sympathetic adrenal-medullary system”) is an even stronger predictor of overall survival, he said.

This suggests that autonomic nervous system variables play a strong role in predicting overall cancer survival, Dr. Spiegel said, noting that depression was not a confounder.

“This is important, because we have, in other studies, found that depression is associated with lower heart rate variability, as you might expect,” he said. In fact, depression has been found to predict shorter survival in cancer patients over a period of 10 years. In an earlier study, cancer patients with worsening depression in the first year died sooner than those with depression that improved during the first year (J Clin Oncol. 2011;29[4]:413-20).

“The median survival difference was about 2 years, so this is not a trivial difference in overall survival,” he said, stressing that the finding is based on more chronic and severe depression.

Other studies have demonstrated relationships between circadian rhythm disruption and cancer survival. In one such study involving patients with metastatic colorectal cancer, circadian rhythm/rest activity cycle (more activity during the day, more rest at night) was associated with better quality of life and predicted survival.

“This has been shown now in several cancers, and it’s clear that a combination of higher activity and better sleep predict longer survival with different kinds of cancers,” Dr. Spiegel said, explaining that a hallmark of a healthy hypothalamic-pituitary-adrenal axis is good diurnal variation of cortisol with high levels in the morning and declining levels throughout the day.

Women with metastatic breast cancer and poorer survival tended to have flat or increasing levels of cortisol throughout the day, he said, adding that the same was true in a study of patients with lung cancer, and that there is evidence that those among them with flatter, more abnormal cortisol patterns throughout the day also have shorter survival.

Animal studies suggest that cortisol might directly suppress the activity of tumor suppressor genes, he explained, noting that there is also increasing evidence of autonomic dysregulation effects on inflammatory processes associated with tumor growth.

“Some basic research on this in animal models shows that if you block adrenergic arousal, you can block the growth of blood vessels from tumors. This has led some people to look at the use of antiadrenergic drugs like the beta-blocker propranolol, and it turned out – to everyone’s surprise – that breast cancer patients who happened to be on beta-blockers for hypertension actually lived longer than those who didn’t,” he said.

This adds to the growing evidence that dysregulation in the sympathetic and parasympathetic systems have effects on survival, he said.

A look at another factor related to sleep disruption – bedtime misalignment – showed that patients who adhere to their preferred sleep pattern, and who are therefore sleeping better, had a difference in disease-free interval; those whose bedtime was misaligned had a shorter time between diagnosis and disease recurrence (Chronobiol Int. 2014 Mar 31[2]214-21).

“Disease-free interval is a very strong predictor of ultimate overall survival, so there seems to be another relationship here between circadian disruption and disease progression in breast cancer,” Dr. Spiegel said.

Taken together, these findings demonstrate a strong association between vagal activity and survival in patients with metastatic or recurrent breast cancer, extending the known predictive window of HF-HRV beyond palliative care to cancer, Dr. Spiegel said.

“Vagal activity can be altered through behavioral, pharmacological, and surgical interventions and thus may be a promising target for increasing survival in patients with metastatic cancer,” he said.

Dr. Spiegel’s studies were funded by the National Cancer Institute and the National Institute on Aging.

[email protected]