Raised Cortisol Levels Later in the Day May Predict Cardiovascular Deaths

A slower decline in salivary cortisol measurements throughout the day appear to be associated with an increased risk in cardiovascular-related death, based on an analysis of diurnal samples from more than 4,000 individuals.

"This is the first study to show that diurnal patterns in cortisol release across the day are predictive of subsequent cardiovascular-related mortality in men and women. Our findings suggest that slope in cortisol is related to cardiovascular-related mortality, comprising a raised late-evening level of cortisol rather than a depressed morning level," wrote Meena Kumari, Ph.D., and her colleagues at the department of epidemiology and public health at University College London.

However, the data don’t suggest any significant association between cortisol slope and noncardiovascular-related mortality. Likewise, no association was apparent for the cortisol awakening response (CAR).

Many studies have investigated a possible association between cortisol levels and cardiovascular disease, using serum or plasma cortisol as a biomarker for stress. However, the results so far have been equivocal. The authors noted that the diurnal rhythm in cortisol release is likely to be a contributing factor to inconsistencies between studies (J. Clin. Endocrinol. Metab. 2011 Feb. 23 [doi:10.1210/jc.2010-2137]).

The general cortisol pattern is characterized by a relatively high cortisol level at waking that is followed by a peak in cortisol at 30 minutes after waking, followed by a decline across the day reaching the bottom of the trough at midnight.

In this study, the researchers analyzed sequential salivary samples taken from waking to bedtime in individuals from phase 7 (2002-2004) of the Whitehall II study, which was initially recruited during 1985-1988 (phase 1) from 20 London-based civil service departments.

Diurnal cortisol patterns could be determined from six saliva samples obtained over the course of a normal weekday: at waking, 30 minutes later, 2.5 hours later, 8 hours later, 12 hours later, and at bedtime. Data from the Whitehall study II also include measurement of conventional risk factors and a follow-up of overall, cardiovascular, and noncardiovascular deaths based on comprehensive medical records.

In all, 6,941 individuals participated in phase 7 with a mean age of 61 years. Saliva sample collection was initiated part way through phase 7.

Mortality follow-up was available through the National Health Services Central Register until Jan. 31, 2010; the mean duration of follow-up for phase 7 was 6.1 years.

Stress on the day of cortisol sampling was measured by questions on whether the participant had experienced a stressful event and, if yes, how stressful this was.

Z scores were created for the CAR, slope, waking cortisol, and cortisol measures at bedtime. Cox proportional hazards models were used to determine the hazard ratio (HR) using the four standardized cortisol measures as linear terms.

The final number of cortisol samples for analysis was 24,121 from 4,047 participants with cortisol measures available. The average CAR was 7.31. The average diurnal slope estimated from the hierarchical linear model was –0.1288 nmol/L per h.

Individuals who subsequently died were more likely to be obese, report more fatigue, smoke, and have raised glucose levels in phase 7 than were those who survived. Of the main causes of death, the increased risk of mortality was from an increased risk of cardiovascular death rather than death from to cancer, which had an HR of 1.17.

In all, there were 32 cardiovascular deaths. The average CARs in participants who died, compared with those who survived, were 8.35 and 7.31 after researchers adjusted for age, sex, waking time, time since waking, and social position. The concomitant diurnal slope values were –0.1143 vs. –0.1290, which was a significant difference.

No CAR association was seen for cardiovascular or noncardiovascular mortality, although a linear association was observed with mortality attributed to cardiovascular disease for slope in cortisol across the day.

However, a flatter slope in cortisol patterns across the day can happen because of low waking values or high evening values of cortisol. The researchers then examined the association of cardiovascular and noncardiovascular events with waking cortisol and cortisol measured at bedtime to assess which accounted for flatter cortisol slope patterns.

They found that waking cortisol levels were unrelated to subsequent mortality. "The failure of waking cortisol to predict deaths argues against a role for the HPA [hypothalamic-pituitary-adrenal] axis in mediating the association of fatigue with mortality," the investigators noted.

However, cortisol measures at bedtime were predictive of cardiovascular-related mortality; the hazard ratio for each standard deviation increase in z score was 1.98, "suggesting that constantly elevated rather stable low cortisol level across the day accounted for the increased death risk," the researchers noted.

"The causes of flat slopes in cortisol or raised evening levels are unknown. It is unclear whether a flatter slope in cortisol is due to stress-related elevations, resulting from a stressful day, long-term changes in circadian regulation as a result of chronic stress, or impaired central negative feedback sensitivity of the HPA axis (particularly to melanocorticoid receptors) as recently described in obesity."

In addition, obesity was independently predictive of both cardiovascular and noncardiovascular mortality (HR, 2.10 and 1.72 respectively) based on analyses of bedtime cortisol. Fatigue was also predictive of both cardiovascular and noncardiovascular deaths (HR, 2.37 and 1.72 respectively), in analyses of bedtime cortisol. Interestingly, self-reported stress on day of cortisol sampling also was independently associated with cardiovascular deaths (HR, 3.45).

"Our findings are novel in that they suggest a cause-specific association with cardiovascular mortality in a nonclinical population. The pathway by which this association occurs remains unclear, but further follow-up of our participants with cumulated numbers of deaths will allow examination of these issues in greater detail," wrote Dr. Kumari and her coinvestigators.

The authors reported that they have nothing to disclose.

A slower decline in salivary cortisol measurements throughout the day appear to be associated with an increased risk in cardiovascular-related death, based on an analysis of diurnal samples from more than 4,000 individuals.

"This is the first study to show that diurnal patterns in cortisol release across the day are predictive of subsequent cardiovascular-related mortality in men and women. Our findings suggest that slope in cortisol is related to cardiovascular-related mortality, comprising a raised late-evening level of cortisol rather than a depressed morning level," wrote Meena Kumari, Ph.D., and her colleagues at the department of epidemiology and public health at University College London.

However, the data don’t suggest any significant association between cortisol slope and noncardiovascular-related mortality. Likewise, no association was apparent for the cortisol awakening response (CAR).

Many studies have investigated a possible association between cortisol levels and cardiovascular disease, using serum or plasma cortisol as a biomarker for stress. However, the results so far have been equivocal. The authors noted that the diurnal rhythm in cortisol release is likely to be a contributing factor to inconsistencies between studies (J. Clin. Endocrinol. Metab. 2011 Feb. 23 [doi:10.1210/jc.2010-2137]).

The general cortisol pattern is characterized by a relatively high cortisol level at waking that is followed by a peak in cortisol at 30 minutes after waking, followed by a decline across the day reaching the bottom of the trough at midnight.

In this study, the researchers analyzed sequential salivary samples taken from waking to bedtime in individuals from phase 7 (2002-2004) of the Whitehall II study, which was initially recruited during 1985-1988 (phase 1) from 20 London-based civil service departments.

Diurnal cortisol patterns could be determined from six saliva samples obtained over the course of a normal weekday: at waking, 30 minutes later, 2.5 hours later, 8 hours later, 12 hours later, and at bedtime. Data from the Whitehall study II also include measurement of conventional risk factors and a follow-up of overall, cardiovascular, and noncardiovascular deaths based on comprehensive medical records.

In all, 6,941 individuals participated in phase 7 with a mean age of 61 years. Saliva sample collection was initiated part way through phase 7.

Mortality follow-up was available through the National Health Services Central Register until Jan. 31, 2010; the mean duration of follow-up for phase 7 was 6.1 years.

Stress on the day of cortisol sampling was measured by questions on whether the participant had experienced a stressful event and, if yes, how stressful this was.

Z scores were created for the CAR, slope, waking cortisol, and cortisol measures at bedtime. Cox proportional hazards models were used to determine the hazard ratio (HR) using the four standardized cortisol measures as linear terms.

The final number of cortisol samples for analysis was 24,121 from 4,047 participants with cortisol measures available. The average CAR was 7.31. The average diurnal slope estimated from the hierarchical linear model was –0.1288 nmol/L per h.

Individuals who subsequently died were more likely to be obese, report more fatigue, smoke, and have raised glucose levels in phase 7 than were those who survived. Of the main causes of death, the increased risk of mortality was from an increased risk of cardiovascular death rather than death from to cancer, which had an HR of 1.17.

In all, there were 32 cardiovascular deaths. The average CARs in participants who died, compared with those who survived, were 8.35 and 7.31 after researchers adjusted for age, sex, waking time, time since waking, and social position. The concomitant diurnal slope values were –0.1143 vs. –0.1290, which was a significant difference.

No CAR association was seen for cardiovascular or noncardiovascular mortality, although a linear association was observed with mortality attributed to cardiovascular disease for slope in cortisol across the day.

However, a flatter slope in cortisol patterns across the day can happen because of low waking values or high evening values of cortisol. The researchers then examined the association of cardiovascular and noncardiovascular events with waking cortisol and cortisol measured at bedtime to assess which accounted for flatter cortisol slope patterns.

They found that waking cortisol levels were unrelated to subsequent mortality. "The failure of waking cortisol to predict deaths argues against a role for the HPA [hypothalamic-pituitary-adrenal] axis in mediating the association of fatigue with mortality," the investigators noted.

However, cortisol measures at bedtime were predictive of cardiovascular-related mortality; the hazard ratio for each standard deviation increase in z score was 1.98, "suggesting that constantly elevated rather stable low cortisol level across the day accounted for the increased death risk," the researchers noted.

"The causes of flat slopes in cortisol or raised evening levels are unknown. It is unclear whether a flatter slope in cortisol is due to stress-related elevations, resulting from a stressful day, long-term changes in circadian regulation as a result of chronic stress, or impaired central negative feedback sensitivity of the HPA axis (particularly to melanocorticoid receptors) as recently described in obesity."

In addition, obesity was independently predictive of both cardiovascular and noncardiovascular mortality (HR, 2.10 and 1.72 respectively) based on analyses of bedtime cortisol. Fatigue was also predictive of both cardiovascular and noncardiovascular deaths (HR, 2.37 and 1.72 respectively), in analyses of bedtime cortisol. Interestingly, self-reported stress on day of cortisol sampling also was independently associated with cardiovascular deaths (HR, 3.45).

"Our findings are novel in that they suggest a cause-specific association with cardiovascular mortality in a nonclinical population. The pathway by which this association occurs remains unclear, but further follow-up of our participants with cumulated numbers of deaths will allow examination of these issues in greater detail," wrote Dr. Kumari and her coinvestigators.

The authors reported that they have nothing to disclose.

A slower decline in salivary cortisol measurements throughout the day appear to be associated with an increased risk in cardiovascular-related death, based on an analysis of diurnal samples from more than 4,000 individuals.

"This is the first study to show that diurnal patterns in cortisol release across the day are predictive of subsequent cardiovascular-related mortality in men and women. Our findings suggest that slope in cortisol is related to cardiovascular-related mortality, comprising a raised late-evening level of cortisol rather than a depressed morning level," wrote Meena Kumari, Ph.D., and her colleagues at the department of epidemiology and public health at University College London.

However, the data don’t suggest any significant association between cortisol slope and noncardiovascular-related mortality. Likewise, no association was apparent for the cortisol awakening response (CAR).

Many studies have investigated a possible association between cortisol levels and cardiovascular disease, using serum or plasma cortisol as a biomarker for stress. However, the results so far have been equivocal. The authors noted that the diurnal rhythm in cortisol release is likely to be a contributing factor to inconsistencies between studies (J. Clin. Endocrinol. Metab. 2011 Feb. 23 [doi:10.1210/jc.2010-2137]).

The general cortisol pattern is characterized by a relatively high cortisol level at waking that is followed by a peak in cortisol at 30 minutes after waking, followed by a decline across the day reaching the bottom of the trough at midnight.

In this study, the researchers analyzed sequential salivary samples taken from waking to bedtime in individuals from phase 7 (2002-2004) of the Whitehall II study, which was initially recruited during 1985-1988 (phase 1) from 20 London-based civil service departments.

Diurnal cortisol patterns could be determined from six saliva samples obtained over the course of a normal weekday: at waking, 30 minutes later, 2.5 hours later, 8 hours later, 12 hours later, and at bedtime. Data from the Whitehall study II also include measurement of conventional risk factors and a follow-up of overall, cardiovascular, and noncardiovascular deaths based on comprehensive medical records.

In all, 6,941 individuals participated in phase 7 with a mean age of 61 years. Saliva sample collection was initiated part way through phase 7.

Mortality follow-up was available through the National Health Services Central Register until Jan. 31, 2010; the mean duration of follow-up for phase 7 was 6.1 years.

Stress on the day of cortisol sampling was measured by questions on whether the participant had experienced a stressful event and, if yes, how stressful this was.

Z scores were created for the CAR, slope, waking cortisol, and cortisol measures at bedtime. Cox proportional hazards models were used to determine the hazard ratio (HR) using the four standardized cortisol measures as linear terms.

The final number of cortisol samples for analysis was 24,121 from 4,047 participants with cortisol measures available. The average CAR was 7.31. The average diurnal slope estimated from the hierarchical linear model was –0.1288 nmol/L per h.

Individuals who subsequently died were more likely to be obese, report more fatigue, smoke, and have raised glucose levels in phase 7 than were those who survived. Of the main causes of death, the increased risk of mortality was from an increased risk of cardiovascular death rather than death from to cancer, which had an HR of 1.17.

In all, there were 32 cardiovascular deaths. The average CARs in participants who died, compared with those who survived, were 8.35 and 7.31 after researchers adjusted for age, sex, waking time, time since waking, and social position. The concomitant diurnal slope values were –0.1143 vs. –0.1290, which was a significant difference.

No CAR association was seen for cardiovascular or noncardiovascular mortality, although a linear association was observed with mortality attributed to cardiovascular disease for slope in cortisol across the day.

However, a flatter slope in cortisol patterns across the day can happen because of low waking values or high evening values of cortisol. The researchers then examined the association of cardiovascular and noncardiovascular events with waking cortisol and cortisol measured at bedtime to assess which accounted for flatter cortisol slope patterns.

They found that waking cortisol levels were unrelated to subsequent mortality. "The failure of waking cortisol to predict deaths argues against a role for the HPA [hypothalamic-pituitary-adrenal] axis in mediating the association of fatigue with mortality," the investigators noted.

However, cortisol measures at bedtime were predictive of cardiovascular-related mortality; the hazard ratio for each standard deviation increase in z score was 1.98, "suggesting that constantly elevated rather stable low cortisol level across the day accounted for the increased death risk," the researchers noted.

"The causes of flat slopes in cortisol or raised evening levels are unknown. It is unclear whether a flatter slope in cortisol is due to stress-related elevations, resulting from a stressful day, long-term changes in circadian regulation as a result of chronic stress, or impaired central negative feedback sensitivity of the HPA axis (particularly to melanocorticoid receptors) as recently described in obesity."

In addition, obesity was independently predictive of both cardiovascular and noncardiovascular mortality (HR, 2.10 and 1.72 respectively) based on analyses of bedtime cortisol. Fatigue was also predictive of both cardiovascular and noncardiovascular deaths (HR, 2.37 and 1.72 respectively), in analyses of bedtime cortisol. Interestingly, self-reported stress on day of cortisol sampling also was independently associated with cardiovascular deaths (HR, 3.45).

"Our findings are novel in that they suggest a cause-specific association with cardiovascular mortality in a nonclinical population. The pathway by which this association occurs remains unclear, but further follow-up of our participants with cumulated numbers of deaths will allow examination of these issues in greater detail," wrote Dr. Kumari and her coinvestigators.

The authors reported that they have nothing to disclose.