A good night’s rest does more than just give you beauty sleep. New research suggests your sleep patterns could be linked to serious underlying health issues.
Adults suffering from chronic insomnia for at least a decade face significantly higher risks of developing conditions like heart disease, diabetes, and depression, according to the results.
However, the news isn’t all bad—the study also found that adults who make up for lost sleep on the weekends by taking naps are not at an increased risk for these underlying health problems.
More Than Half of Americans Exhibit Problematic Sleep Habits
The study, published in Psychosomatic Medicine, analyzed data from the Midlife in the United States (MIDUS), a national sample of continental U.S. residents between 25 and 74 years of age. The dataset included information on the sleep habits and chronic health conditions of approximately 3,700 individuals collected from 2004 to 2006 and from 2013 to 2017.
Four distinct sleep patterns were identified:
Good sleepers: People with “optimal sleep health across all dimensions”
Insomnia sleepers: People suffering from clinical insomnia, including short sleep duration, high daytime exhaustion, and difficulty falling asleep
Weekend catch-up sleepers: Those who may have irregular or shorter sleep during the week but longer sleep times on weekends or non-work days
Nappers: Those who typically slept well but took frequent daytime naps
More than half of the participants were either insomnia sleepers or nappers, both of which are considered sub-optimal sleep patterns.
The data revealed that people with chronic insomnia were 72-188 percent more likely to develop cardiovascular disease, diabetes, depression, and frailty compared to good sleepers. Overall, being an insomnia sleeper increased a person’s risk of a chronic condition by 28-81 percent.
The study found that “being a napper at any timepoint” was related to increased risks for diabetes, cancer and frailty
The researchers also noted that those with lower education and those who were unemployed were more likely to be insomnia sleepers, while older adults and retirees were more likely to be nappers.
Sleep Patterns Proven Difficult to Change
The study also found that sleep patterns tend to be remarkably resistant to change.
Overall, 77 percent of participants remained in the same sleep pattern, or “phenotype,” over the study period. More specifically, 90 percent of insomnia sleepers and 97 percent of nappers maintained those same habits throughout the study. Those categorized as weekend catch-up sleepers were more likely to transition into being nappers.
“These results may suggest that it is very difficult to change our sleep habits because sleep health is embedded into our overall lifestyle,” Soomi Lee, associate professor of human development and family studies at Penn State and the lead researcher, said in a press release. “It may also suggest that people still don’t know about the importance of their sleep and about sleep health behaviors.”
Despite the apparent rigidity of sleep patterns, education and consistent practice can help facilitate positive changes over time, according to Mr. Lee.
Objectives This study aims to examine the associations of daily step count with all-cause mortality and incident cardiovascular disease (CVD) by sedentary time levels and to determine if the minimal and optimal number of daily steps is modified by high sedentary time.
Methods Using data from the UK Biobank, this was a prospective dose–response analysis of total daily steps across low (<10.5 hours/day) and high (≥10.5 hours/day) sedentary time (as defined by the inflection point of the adjusted absolute risk of sedentary time with the two outcomes). Mortality and incident CVD was ascertained through 31 October 2021.
Results Among 72 174 participants (age=61.1±7.8 years), 1633 deaths and 6190 CVD events occurred over 6.9 (±0.8) years of follow-up. Compared with the referent 2200 steps/day (5th percentile), the optimal dose (nadir of the curve) for all-cause mortality ranged between 9000 and 10 500 steps/day for high (HR (95% CI)=0.61 (0.51 to 0.73)) and low (0.69 (0.52 to 0.92)) sedentary time. For incident CVD, there was a subtle gradient of association by sedentary time level with the lowest risk observed at approximately 9700 steps/day for high (0.79 (0.72 to 0.86)) and low (0.71 (0.61 to 0.83)) sedentary time. The minimal dose (steps/day associated with 50% of the optimal dose) of daily steps was between 4000 and 4500 steps/day across sedentary time groups for all-cause mortality and incident CVD.
Conclusions Any amount of daily steps above the referent 2200 steps/day was associated with lower mortality and incident CVD risk, for low and high sedentary time. Accruing 9000–10 500 steps/day was associated with the lowest mortality risk independent of sedentary time. For a roughly equivalent number of steps/day, the risk of incident CVD was lower for low sedentary time compared with high sedentary time.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Evidence has prompted healthcare professionals to prescribe increasing daily steps as an important intervention to reduce mortality and morbidity.
High sedentary time is associated with increased risk for mortality and morbidity.
Evidence is lacking on whether sedentary time modifies modifying effects of sedentary time on the optimal and minimal dose-response of daily steps associated with all-cause mortality and incident cardiovascular disease.
WHAT THIS STUDY ADDS
There was no effect modification by sedentary time levels on the dose–response association of daily steps.
The lowest mortality risk was observed between 9000 and 10 500 steps/day independent of sedentary time.
There was about a 10% lower cardiovascular disease risk for an equivalent number of daily steps for low sedentary time compared with high sedentary time.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings provide tangible targets that can be implemented in future daily step count and sedentary time-based interventions.
Our findings may inform the development of the first steps-based recommendations and future public health physical activity and sedentary time guidelines.
Introduction
Greater daily steps have established protective effects on health, and its potential benefits have been associated with lower mortality and cardiovascular disease (CVD).1–3 Recent studies have found as few as 4000 to 10000 steps are associated with lower mortality and morbidity with potentially continuing risk reductions for higher daily steps.1 2 4 5 In contrast, high amounts of sedentary time are associated with higher mortality and morbidity risk.6–9 Previous meta-analyses reported a 30%–50% increase in all-cause mortality and CVD from high levels of sedentary time (eg, >10–14 hours/day).6 7 Daily steps and sedentary time affect similar risk factors that contribute to the development of CVD and higher mortality risk, such as obesity, blood pressure and cholesterol.10 11 However, the current evidence on daily stepping comes from studies that did not consider whether (and to what extent) the association with mortality and incident CVD was modified or attenuated by levels of sedentary time.
Studies examining joint associations and effect modification have reported physical activity may offset or attenuate the higher risk of all-cause mortality12–15 and CVD16–18 associated with sedentary time. A meta-analysis of self-reported sedentary time and physical activity suggested that 60–75 min/day of moderate-to-vigorous physical activity (MVPA) lowered the detrimental associations of high sedentary time,19 while data from the 45 and Up Study showed high sedentary time was only associated with higher mortality risk in those not attaining the minimum threshold of current recommendations (at least 150 MVPA min/week).18 A harmonised meta-analysis of hip worn accelerometerdevices suggested that 30–40 min/day of MVPA attenuated the all-cause mortality risk attributed to sedentary time.20 Collectively, this body of evidence estimated time in intensity-specific physical activity needed to offset or substantially attenuate high levels of predominantly self-reported sedentary time. For many individuals, it may be challenging to recall time or estimate intensity to determine whether they are sufficiently active in relation to minute-based and intensity-based targets. Stepping-based information may provide a more tangible physical activity prescription that is easier to act on.
No study to date has examined if high sedentary time modifies the dose-response of daily steps with all-cause mortality and incident CVD. Such information can be used to advise the general public, inform guidelines and improve clinical intervention targets. Importantly, with the proliferation of wearable devices, steps-based and sedentary time-based health information could be streamlined through consumer wearables, making it easier to self-monitor levels, set goals and potentially improve physical activity promotion.21 22
We aimed to determine if sedentary time modified the optimal and minimal daily steps associated with all-cause mortality and incident CVD risk. We pursued these aims by examining the detailed dose response of daily steps across high and low sedentary time levels in a large cohort of UK adults using wrist-worn accelerometers.
Methods
Study participants
Participants were included from the UK Biobank Study, a prospective cohort of 502 629 participants between 40 and 69 years. All participants were enrolled between 2006 and 2010 and provided informed written consent. Participants completed physical examinations by trained staff and touchscreen questionnaires. We excluded participants with diagnosed CVD or cancer (ascertained through self-report, hospital admission and cancer registry records) prior to accelerometry measurement, missing covariate data or an event within the first 12 months from the accelerometry measurement (online supplemental figure 1).
From 2013 to 2015, 103 684 participants were mailed and wore an Axivity AX3 accelerometer (Newcastle upon Tyne, UK) on their dominant wrist for 24 hours/day for 7 days to measure physical activity. Prior to being mailed, the AX3 accelerometers were initialised to collect data with a sampling frequency of 100 Hz and a dynamic range between±8 g. Participants returned the devices by mail and the data were calibrated and non-wear periods were identified according to standard procedures.23 24 Monitoring days were considered valid if wear time was greater than 16 hours. In this study, participants were required to have at least three valid monitoring days, with at least one of those days being a weekend day, and have worn the monitor during sleep periods. Physical activity type was classified with a validated accelerometer-based activity machine learning scheme covering sedentary behaviour, small utilitarian movements, walking and running,25 26 consistent with previously published studies.3 5 27 We calculated steps during periods of ambulation using a tuned signal peak detection method28 29 used in previous studies3 5 and in validation studies shown to have a step detection accuracy of 89%29 and a total steps mean absolute percent error of 10%28 and a mean bias of 9%.30 A complete description of the step detection and internal validation is provided in online supplemental text 1. Primary exposures were daily time spent sedentary (based on absolute risk curves categorised as: low <10.5 hours/day and high ≥10.5 hours/day), and daily step counts.
Mortality and cardiovascular disease ascertainment
Participants were followed up to 30 September 2021 (England and Wales) or 31 October 2021 (Scotland), with deaths obtained through linkage with the NHS Digital of England and Wales or the NHS Central Register and National Records of Scotland. Inpatient hospitalisation data (England: 30 September 2021; Scotland: 31 July 2021; Wales 28 February 2018) were provided by either the Hospital Episode Statistics for England, the Patient Episode Database for Wales or the Scottish Morbidity Record for Scotland. CVD was defined as diseases of the circulatory system, excluding hypertension, diseases of arteries and lymphatic system. Online supplemental table 1 describes in detail CVD ascertainment methods.
Covariates
Our selection of covariates was based on previous daily stepping and sedentary time literature (online supplemental figure 2) and included age, sex, ethnicity, education, smoking status, alcohol consumption, fruit and vegetable consumption (servings per day), parental history of CVD and cancer, medication use (cholesterol, insulin and hypertension) and accelerometer-measured sleep time (hours/day). In sensitivity analyses, we included clinical factors that may be potential mediators: waist circumference, glycated haemoglobin A1C, high-density and low-density lipoprotein, diastolic and systolic blood pressure, and triglycerides. Complete covariate definitions are provided in online supplemental table 2.
Analyses
We calculated the adjusted dose–response absolute risk for all-cause mortality and incident CVD per 10 000 person-years, and crude risk percent (categorical). We used Cox proportional hazards regression models to estimate HR with 95% CIs for all-cause mortality. Fine-Gray subdistribution method was used for incident CVD analyses with non-cardiovascular deaths treated as a competing risk. In both sets of analyses, we used restricted cubic splines with knots at the 10th, 50th and 90th percentile to model the dose–response associations. No violations in any of the assumptions of Cox proportional hazard model were observed. Specifically, we checked for assumptions of Cox proportional hazard model including Schoenfeld residual, independence of survival times for individuals, linearity of covariates, continuous survival time, multicollinearity and independence of censoring date, and no violations were observed. Effect modification was tested by fitting an interaction term between sedentary time and daily steps. We examined the dose response for the optimal (nadir of the curve) and minimal (defined as 50% of the optimal dose5 27; ((1−opimal dose HR)/2) number of steps for high and low sedentary time. In all analyses, we set the reference data point to be the 5th percentile of daily steps among all participants (eg, 2200 steps).
We calculated E-values for the optimal and minimal daily steps to estimate the plausibility of bias from unmeasured confounding.31 To assess the robustness of our findings, we performed additional joint association analyses with 2200 daily steps (congruent with stratified analysis) and high sedentary time as the reference. In sensitivity analyses, we adjusted for clinical factors (see covariate section above) that could be considered mediators of the association between the exposures and outcomes. We further performed an analysis with alternate sedentary time groupings with the highest quartile (≥11.5 hours/day) categorised high sedentary time and the lowest three quartiles as low sedentary time. We also conducted sensitivity analyses to examine reverse causation bias by excluding underweight participants (body mass index <18.5 kg/m2), participants reporting self-rated fair or poor health, or participants with an event within the first 2 years of follow-up.32 33 We also assessed incident CVD risk using cause-specific analysis to provide estimates of direct effects.34 35 In addition, we assessed age subgroup differences for participants <60 years old and ≥60 years old using an interaction term for age in our incident CVD analysis.
We performed all analyses using R statistical software. We reported this study as per the Strengthening the Reporting of Observational Studies in Epidemiology guideline and the Checklist for statistical Assessment of Medical Papers.36
Patient and public involvement
No patients or members of the public were involved in the planning, design, data collection, analysis or interpretation of results for this study.
Equity, diversity and inclusion statement
Our study sample representative of all participants who participated in the UK Biobank study with valid accelerometer data, reflecting the demographic, geographical and socioeconomic diversity of the participants.
Results
Our analytical sample for mortality included 72 174 participants (average age (SD)= 61.1 (7.8) years; 57.9% female) followed up for an average of 6.9±0.8 years with 1633 deaths. Our incident CVD analysis sample included 71 441 participants with 6190 events. Median (IQR) total steps and sedentary time were 6222 (4102–9225) steps/day and 10.6 (9.7–11.6) hours/day, respectively. Participants wore the accelerometers for an average of 22.8 hours/day. Participant characteristics by sedentary time are provided in table 1. Participants classified as having high sedentary time (53.8% of the total sample) were more likely to be current smokers, use cholesterol and hypertension medication, and have higher central adiposity (waist circumference) compared with their low sedentary time counterparts. Within the high and low sedentary time levels, median daily steps were 4829 (3329, 6834) and 8362 (5883, 11 792), respectively.
The sex-adjusted and age-adjusted sedentary time dose–response absolute risk for all-cause mortality and incident CVD is shown in figure 1. We used the dose–response results to categorise participants as having high or low sedentary, reflective of when risk became pronounced. Using the difference between adjacent absolute risk estimates in 30 min increments, we found risk became more pronounced for both all-cause mortality and incident CVD at 10.5 hours/day of sedentary time.
Age-adjusted and sex-adjusted sedentary time dose–response absolute risk for all-cause mortality, and cardiovascular disease incidence. Shaded area represents 95% CI. Red circle indicates delineation between high and low sedentary time
Online supplemental table 3 and figure 2 present the crude risk and the multivariable-adjusted dose response of all-cause mortality and incident CVD associated steps/day by sedentary time level, respectively. Within the high sedentary time level (≥10.5 hours/day), accumulating <4000 steps/day (tertile 1) was associated with a crude mortality risk of 5.41% (95% CI 5.32% to 5.50%), whereas accumulating >8000 steps/day (tertile 3) was associated with a 3.05% (95% CI 2.96% to 3.13%) crude risk. The corresponding crude risk for participants within the low sedentary time level (<10.5 hours/day) was 3.74% (95% CI 3.62% to 3.86%) and 2.27% (95% CI 2.24% to 2.30%).
Adjusted absolute risk for all-cause mortality and cardiovascular disease incidence. Adjusted for age, sex, ethnicity, education, smoking status, alcohol consumption, diet, parental history of CVD and cancer, medication use (cholesterol, insulin and hypertension), sleep duration. Shaded area represents 95% CI. CVD, cardiovascular disease.
All-cause mortality
Among participants with high sedentary time, we observed the nadir of the curve at 9000 steps/day corresponding to an HR (95%CI) of 0.61 (0.51 to 0.73), compared with the referent 2200 steps/day (figure 3; effect modification p=0.756). The minimal dose was at 4100 steps/day with an HR of 0.80 (0.74 to 0.87). Among participants with low sedentary time, we observed an attenuation in the magnitude of the steps/day dose–response association with the nadir of the curve at 10 300 steps/day (0.69 (0.52 to 0.92)). We observed the minimal dose at 4400 steps/day with a corresponding HR of 0.84 (0.74 to 0.97). In our joint dose–response analysis (online supplemental figure 3), we observed consistent nadir and minimal dose values between the two sedentary time levels. The mortality risk was similar (eg, HR difference ≤0.03 units) between high and low sedentary time levels at 6000 steps/day and continued to be similar up to 9500 steps/day.
Stratified dose–response association of all-cause mortality and steps by sedentary time. Adjusted for age, sex, ethnicity, education, smoking status, alcohol consumption, diet, parental history of CVD and cancer, medication use (cholesterol, insulin and hypertension) and sleep duration. Shaded area represents 95% CI. Square=minimum dose (ED50); circle=optimum dose (nadir of curve). CVD, cardiovascular disease.
Incident cardiovascular disease
In the dose–response association between steps/day and incident CVD, we observed lower risk for the low sedentary time group, for an equivalent steps/day, compared with the high sedentary time group (figure 4; effect modification p=0.725). The HR differences between the two groups increased up to the nadir of both curves. The minimal dose was at 4300 steps/day for both high and low sedentary time with corresponding HR’s of 0.90 (95% CI 0.86 to 0.94) and 0.86 (95% CI 0.80 to 0.92). For high sedentary time, the optimal dose (nadir) was at 9700 steps/day with an HR of 0.79 (95% CI 0.72 to 0.86). In comparison, among participants with low sedentary time, we observed a similar optimal dose (9800 steps/day), with a lower corresponding HR of 0.71 (95% CI 0.61 to 0.83). In our joint dose–response analysis (online supplemental figure 4), the lower risk for an equivalent steps/day for low sedentary time compared with high sedentary time was consistent with our main analysis when steps/day exceeded 3700.
Stratified dose–response association of cardiovascular disease incidence and steps by sedentary time. Adjusted for age, sex, ethnicity, education, smoking status, alcohol consumption, diet, parental history of CVD and cancer, medication use (cholesterol, insulin and hypertension) and sleep duration. Shaded area represents 95% CI. Square=minimum dose (ED50); circle=optimum dose (nadir of curve). CVD, cardiovascular disease.
Additional and sensitivity analyses
When adjusting for waist circumference, glycated haemoglobin A1C, high-density and low-density lipoprotein, blood pressure and triglycerides, the association patterns remained consistent, although the magnitude was attenuated for high sedentary time and all-cause mortality (online supplemental figure 5). Exclusion of participants who had fair or poor self-rated health, were underweight or had an event within the first 2 years of follow-up showed generally consistent associations as our main analysis (online supplemental figure 6). For example, in the high sedentary time group 8700 steps/day was associated with the lowest all-cause mortality risk, and among the low sedentary time group the lowest risk was observed at 11 000 steps/day. Alternate sedentary time grouping with the highest quartile (≥11.5 hours/day; high sedentary time) and lowest three quartiles (low sedentary time) showed a consistent dose–response association pattern for incident CVD, and a higher magnitude of association for low sedentary time with all-cause mortality (online supplemental figures 7 and 8). Our E-values suggest a moderate degree of unmeasured confounding would be required to reduce our observed associations for mortality and incident CVD. For example, the minimal steps/day dose E-value ranged from 1.67 (1.21) to 1.81 (1.56) for all-cause mortality and 1.46 (1.32) to 1.60 (1.39) for incident CVD (online supplemental table 4). Cause-specific hazard analysis for incident CVD risk was similar to Fine-Gray subdistribution hazard analysis. For example, in cause-specific analysis the optimal dose was approximately 9600 steps/day for high sedentary time, and 9800 steps/day for low sedentary time (online supplemental figure 9). Subgroup analysis by age showed no association between steps and incident CVD risk among young participants (<60 years old) with low sedentary time. However, among young participants with high sedentary time, there was an inverse association with no upper limit for daily steps and lower incident CVD risk. Among older participants (≥60 years old), we observed lower risk for both low and high sedentary time, with lowest risk observed among older participants with low sedentary time (eg.<10.5 hours/day) at an equal number of daily steps. For older adults with high sedentary time, the lowest risk was observed at approximately 8500 steps/day (online supplemental figure 10; effect modification p=0.153).
Discussion
Our study adds new evidence to the literature by examining the dose–response association of daily steps with mortality and incident CVD risk in high and low sedentary time groups. For all-cause mortality, the optimal dose occurred between 9000 and 10 500 steps/day across sedentary time groups. Within the high sedentary time group we observed lower risk compared with the low sedentary time group at an equivalent number of daily steps. We found a lower incident CVD risk for an equivalent number of daily steps within the low sedentary time group compared with the high sedentary time group. There was consistency in the optimal and minimal steps/day association with incident CVD risk between the two groups at just under 10 000 steps/day and 4500 steps/day, respectively.
All-cause mortality
Previous prospective studies examining daily steps did not consider the potential effects of differing sedentary time levels on the association with health risks.1 37 Given the established dynamic between physical activity and sedentary time,17 18 such an exclusion may lead to overestimation of effect estimates and underestimation of the minimal and optimal steps/day dose response. Studies and meta-analyses assessing daily steps and all-cause mortality, which did not consider sedentary time, showed a curvilinear dose response that suggested between 6000 and 10 000 steps/day was associated with lower all-cause mortality.1–4 38 Our analyses expands on previous research and examines the influence of sedentary time on the daily stepping dose-response association. Between 6000 and 10 500 steps/day, we found mortality risk was about 10% lower for an equivalent number of steps in the high sedentary time group compared with the low sedentary time group. Our findings emphasise the importance of increasing daily steps particularly among adults who are highly sedentary. In the high sedentary time group, the stronger association could be attributable to the more pronounced impact of daily step accumulation in individuals who are at a higher risk of mortality from the adverse effects of sedentary time. Among the high sedentary time group, being sufficiently active through daily step accumulation may ameliorate downstream effects of sedentary time, lowering the risk of developing comorbidities and subsequently leading to lower mortality risk.39 40 If confirmed in future studies, our dose–response findings may help to improve health messaging and goal setting for the most at-risk individuals in the population.
Incident cardiovascular disease
We observed lower incident CVD risk for an equivalent number of daily steps for low sedentary time compared with high sedentary time, although with overlapping 95% CIs. This graded association pattern may be due to the separate contributions of sedentary time and daily steps (eg, physical activity) to cardiovascular health, leading to an additive effect on CVD risk. Our cause-specific hazards dose–response analysis, which provides a direct effect estimation, was comparable to our Fine-Gray subdistribution hazards analysis that provides an estimation of the direct and indirect effect estimation.34 Studies have demonstrated prolonged sedentary time contributes to increased inflammation, oxidative stress and induces adverse effects on cardiovascular autonomic nervous system function.41–43 In contrast, higher daily steps can lead to cardioprotective adaptations.44–46 We did not find evidence that daily steps could compensate for excess sitting time. This contrasts prior studies that have found MVPA can lower the risk of high sedentary time to be comparable to low sedentary time.17 18 47 The majority of daily steps occur at a light intensity1 3 and may explain in part the disparate findings between our study and MVPA intensity focused studies. Taken together, this suggests an important role of physical activity intensity to reduce the risks of sedentary time for CVD prevention.
Among the high sedentary time group, we found a 10%–21% lower CVD risk when daily step accumulation was between 4000 and 10 000 steps/day. The magnitude in the dose–response association we observed for steps/day with CVD risk was attenuated in comparison with two prior meta-analyses that did not account for differing levels of sedentary time.37 48 In addition, a prior meta-analysis37 of eight cohorts found there was no association between daily steps and lower incident CVD risk among participants <60 years old. Our results extend on this prior finding to provide nuanced information on the influence of sedentary time. Indeed, among adults <60 years old with low sedentary time (<10.5 hours/day), we did not find an association between daily steps and incident CVD risk. However, among adults <60 years old with high sedentary time, we observed an inverse linear association. This finding further highlights the potential health-benefits of increasing daily steps to mitigate CVD risk among highly sedentary adults. The absence of an association among adults <60 years old with low sedentary time could be due to the latency period for CVD to progress towards clinical endpoints of hospitalisations and death compared with their counterparts who have high sedentary time and are at a higher risk of cardiovascular events earlier in adulthood. Collectively, our results underscore the importance for a combination of decreasing sedentary time and increasing daily steps to improve cardiovascular health.
Implications
Our findings provide new insights regarding the dose response of daily steps, sedentary time, mortality and CVD risk. Overall, between 9000 and 10 500 steps/day was the optimum dose to lower mortality and CVD risk across sedentary time groups. Our prospective results provide relevant findings that can be used to augment public health messaging and inform the first generation of stepping-based and device-based physical activity and sedentary guidelines. Daily stepping targets are a simple metric clinicians and allied health providers can use to monitor and promote physical activity to their patients. Collectively, our findings may have important implications to help improve the efficacy of future trials and the precision of intervention treatments among individuals with varying physical activity and sedentary time levels.
Our results indicate sedentary time did not significantly modify the dose-response association of daily steps. We also found the amount of physical activity (eg, steps/day) needed to lower the risk of mortality and incident CVD may be lower than previously suggested using self-reported data.43 This is explained, in part, by differences between self-report and wearables-based measures. Self-reported physical activity is prone to over-reporting due to a combination of social desirability and recall bias,49 50 and being limited to measuring blocks of time where an individual may not be active throughout the duration. Wearables provide a continuous objective measure of movement that is not susceptible to the limitations of self-reported physical activity.
Strengths and limitations
To our knowledge, the current study is among the first aimed to determine the optimal and minimal number of daily steps to lower mortality and incident CVD risk across sedentary time levels. The large sample size and long follow-up allowed us to reduce the risk of reverse causation bias by removing participants with an event in the first 2 years of follow-up, prevalence of major disease, self-rated fair or poor health and who were underweight. Due to the observational design, we cannot rule out the presence of residual and unmeasured confounding. However, E-values indicate for the minimal dose an unmeasured confounder would need to have a moderate association, between 1.46 and 1.81, with the exposures and outcome for the observed relationships to be null. Covariate assessments occurred at a single timepoint and covariates were not treated as time varying.51 There was a median lag of 5.5 years between the UK Biobank baseline when covariate measurements were taken and the accelerometry study, although covariates were generally stable over time except for medication.52 53 Steps and sedentary time were obtained in a single time point, which can lead to regression dilution bias.54 Nevertheless, there was consistent daily steps in participants with repeated measurement 4 years later (n=3400; Kendall’s W=0.74). The UK Biobank had a low response rate and this may contribute to selection bias.55 Previous work, however, has shown that the poor representativeness of the UK Biobank sample to the UK population does not materially influence associations with mortality or disease risk.56
Conclusions
In our population-based cohort study of over 70 000 individuals, we did not find an effect modification by sedentary time levels on the dose–response association of daily steps. We found accruing between 9000 and 10 500 steps/day optimally lowered the risk of mortality and incident CVD independent of sedentary time. The minimal threshold associated with substantially lower mortality and CVD risk was between 4000 and 4500 steps/day. We found a lower incident CVD risk for an equivalent number of steps in the low sedentary time group compared with the high sedentary time group. These findings provide tangible targets that can be easily implemented in future steps-based and sedentary time-based interventions, and can inform the first generation of device-based guidelines.
The growing prevalence of genetic testing among healthcare professionals, researchers, and consumers has led to the discovery of incidental genetic abnormalities linked to cardiovascular diseases. However, the AHA warns that not all identified single gene variants necessarily indicate risk factors. To address this issue, a new scientific statement provides a framework for healthcare professionals to accurately assess genetic variants, communicate results with patients and their families, and establish robust multidisciplinary teams for tailored care when necessary.
A new American Heart Association scientific statement helps interpret incidentally found gene variants that may be associated with cardiovascular disease risk.
As healthcare professionals, researchers, and consumers increasingly use genetic testing, they are uncovering incidental genetic abnormalities, or variants, that are associated with cardiovascular diseases.
The AHA statement writing committee cautions that incidentally identified single gene variants may or may not be risk factors for disease, so it is important to interpret them correctly and cautiously.
The new scientific statement offers a framework to support healthcare professionals in appropriately assessing individual genetic variants, communicating findings with patients and families, and, when needed, how to create a strong multidisciplinary team for individualized care.
Increasing use of genetic testing means people may discover they have a gene variant associated with some types of cardiovascular disease (CVD). A new scientific statement, published today (March 27, 2023) in the American Heart Association (AHA) journal Circulation: Genomic and Precision Medicine, aims to help individuals and healthcare professionals understand what to do when a variant is discovered.
An American Heart Association scientific statement is an expert analysis of current research and may inform future guidelines. The new statement, “Interpreting Incidentally Identified Variants in Genes Associated with Heritable Cardiovascular Disease,” suggests the next steps to determine whether a variant truly carries a health risk, provides support to healthcare professionals on how to communicate with people and their families, and suggests the appropriate follow-up actions to care for people with variants deemed higher risk for CVD.
Variants associated with cardiovascular disease risk are often found “incidentally” when people undergo genetic testing for non-cardiac reasons, including screening or diagnosis of other diseases. These unexpected genetic variants may also be discovered with genetic testing through direct-to-consumer DNA testing kits.
Pretest genetic counseling is strongly encouraged to prepare patients for the possibility of incidental findings, how and whether findings will be communicated, and potential implications for themselves and family members.
“The scope and use of genetic testing have expanded greatly in the past decade with the increasing ease and reduced cost of DNA sequencing,” said Andrew P. Landstrom, M.D., Ph.D., FAHA, chair of the scientific statement writing committee and associate professor of pediatrics and cell biology at Duke University School of Medicine in Durham, North Carolina. “Where we would once look for genetic changes in a handful of genes, we can now sequence every gene and, potentially, the whole genome, allowing us to make genetic diagnoses that would have been impossible in the past. However, with increased genetic testing comes more surprises, including finding unexpected variants in genes that might be associated with cardiovascular disease.
“If we interpret these incidental variants incorrectly, it may lead to inappropriate care, either by suggesting patients have a risk of cardiac disease when they do not, or by not providing care to those with increased risk for a serious condition.”
This statement is the first to focus on inherited monogenic, or single-gene, diseases for CVD that can be passed on within families, such as hypertrophic cardiomyopathy or long QT syndrome. There are currently 42 clinically treatable, secondary variant genes that increase the risk of sickness or death from sudden cardiac death, heart failure and other types of cardiovascular disease, according to the American College of Medical Genetics and Genomics. Genetic variants that cause long QT syndrome cause the heart to electrically reset slower than normal after each contraction, which may cause electrical instability of the heart and may lead to fainting, arrhythmias or even sudden death.
Once an incidental genetic variant for CVD is found, the statement authors suggest a framework for interpreting the variant and determining whether it is classified as benign, uncertain, or pathogenic (disease-causing):
Healthcare professionals should only relay information to patients about incidentally identified variants if they are among the cardiovascular disease genes already known to be associated with CVD and if patients agreed during pretest genetic counseling to be informed about incidental findings.
Incidentally identified variants in genes with an uncertain association with CVD should not be reported.
If the discovered variant may increase the risk of CVD, a family history and medical evaluation by an expert health care professional are suggested, preferably a specialist working with or within a multidisciplinary team to address in the disease in question. The goal of this evaluation is to determine whether the individual has evidence of the disease, such as symptoms or relevant test results, or if there are any warning signs in the family history.
The genetic variant itself should be re-evaluated periodically by an expert or expert team to ensure whether the CVD link remains accurate. As knowledge about a variant evolves over time, its link to disease may be reclassified.
Finally, the medical evaluation and genetic re-evaluation should guide next steps, which may vary from dismissing the incidental variant as not likely to cause CVD to starting medical interventions. This may also involve periodic re-evaluation with appropriate tests (echocardiogram, blood tests, etc.) and possibly screening other family members for the variant.
“The list of incidental variants related to cardiovascular disease continues to evolve. This statement provides a foundation of care that may help people with a CVD-related genetic variant and their health care professionals take the next step in determining the individual and familial risk that a variant may or may not carry,” Landstrom said. “It’s also important to consult with genetics specialists to custom-tailor an evaluation and treatment plan to both the individual and the genetic variant in order to ensure the highest level of care possible.”
Less sitting and more frequent aerobic activities such as brisk walking may lower your risk of cancer.
Being sedentary for prolonged period of the day is becoming increasingly prevalent worldwide, yet many studies have shown that it increases the risk of cancer, cardiovascular disease, and overall mortality.
Sedentary lifestyles are becoming more prevalent globally due to the proliferation of electronics, and the increase in remote occupations. Many studies have shown that sedentary behavior is closely associated with increased risk and survival rate of six cancer types, diabetes and cardiovascular disease, and overall mortality.
A sedentary lifestyle refers to sitting or lying down for six or more hours a day (except sleeping), lack of obvious physical movement in daily life, and therefore, low energy consumption. According to an article published by Harvard Medical School, an estimated 67 percent of older adults sit for more than eight hours a day, while only 28 to 34 percent of those aged 65 to 74 are physically active.
Sitting for Long Periods Increases Risk of Cardiovascular Disease and Death
A sedentary lifestyle increases the risk of diabetes, depression, cardiovascular disease, and overall mortality rate. In 2022, JAMA Cardiology published a study involving a large cohort, analyzing the results of sedentary duration against overall mortality rate and major cardiovascular diseases. Of the 105,677 participants, 58.6 percent were female, average age 50.4 years, with average sitting time of 4 hours per day, and a median follow-up time of 11.1 years.
The study found that participants in the group that sat for 8 hours or more a day, compared to those who sat less than 4 hours per day, had an increased overall mortality rate (20 percent), and an increased risk of major cardiovascular disease (21 percent). The more sedentary/lower activity group also had significantly increased rates of diabetes, depression, physical disorders, and chronic diseases.
Another retrospective study involving more than 1 million people found that adults who sit for more than 9 hours a day have a significantly higher risk of death.
However, the authors of the paper also mentioned that those who engaged in about 60 to 75 minutes of daily moderate to vigorous physical activity did not have an increased risk of death even after sitting for more than 8 hours a day.
Sitting for Long Periods of Time Increases Cancer Risk
Sitting still for long periods is also a risk factor for cancer. Many studies have shown that sedentary behavior is associated with an increased risk of various cancer types. In 2022, the European Journal of Epidemiology published an umbrella review in which researchers included 14 meta-analyses from 77 original studies, covering 17 different cancer sites and including more than 200,000 cancer cases. Studies also found that sedentary behavior significantly increases the risk of six types of cancers as follows:
Breast—8 percent.
Colon—25 percent.
Prostate—8 percent.
Rectal—7 percent.
Endometrial—29 percent.
Ovarian cancer—29 percent.
Moreover, sedentary behavior can also lead to a decrease in the survival rate of cancer patients. Among colorectal cancer patients, sedentary behavior after diagnosis increases their specific risk of death by 61 percent.
Aerobic Exercise Reduces Risk of 9 Cancer Types
Evidence from the World Cancer Research Fund International shows that physical activity can reduce the risk of colon, breast, and endometrial cancer and can also help maintain a healthy body weight. In the United States, nearly half of adults do not get enough aerobic exercise, and 77 percent of high school students do not get sufficient physical exercise.
In August a cohort study published in the BMJ’s sister journal, British Journal of Sports Medicine, analyzed the relationship between cardiorespiratory fitness (CRF) and the risk of cancer in different parts of the body. The study included 1,078,000 young men who had been followed for an average of 33 years. Researchers divided CRF levels into three categories: high, moderate, and low.
CRF usually refers to a person’s ability to perform aerobic exercise, that is, the ability of the heart to pump blood and the lungs to inhale oxygen. The entire body needs oxygen to burn the energy stored in the body and turn it into heat energy, which is used by organs and muscles that need heat energy to move. Aerobic exercise includes brisk walking, rope skipping, running, swimming, and cycling, amongst others.
The study found that higher CRF was linearly related to lower risk of nine cancer types:
Head and neck—19 percent.
Esophageal—39 percent.
Stomach—21 percent.
Pancreatic—12 percent.
Liver—40 percent.
Colon—18 percent.
Rectal—5 percent.
Kidney—20 percent.
Lung—42 percent.
However, the study also found that people with higher levels of CRF had a 7 percent increased risk of prostate cancer and a 31 percent increased risk of skin cancer compared with people with low CRF levels.
Frequency of Activities Most Important
Koichiro Oka, a professor at the School of Sports Science at Waseda University in Japan, believes that prolonged sitting is a “silent killer.” He said that in general, calf muscles are continuously employed to maintain posture while standing, and thigh muscles are exercised when walking. This muscle contraction associated with physical activity stimulates metabolic functions related to blood sugar and triglycerides (neutral fat). On the other hand, lower body muscles contract less when sitting or lying down than when standing or walking. Therefore, sitting for prolonged periods will reduce metabolic function, lead to increased blood sugar and triglyceride concentrations, and result in various diseases.
Due to the COVID-19 pandemic, many people have more sedentary behaviors than ever before. Mr. Oka believes that to prevent the negative effects of prolonged sitting on the body, it is the frequency rather than the intensity of physical activity that is more important. He suggested that you try not to sit for more than 8 hours a day and get up from your seat every 20 to 30 minutes to practice some light activities, including light squatting, standing up from your seat, standing on tiptoes, or making yourself a cup of coffee. He also notes that health conditions such as back and neck pain and emotional states improve by reducing sedentary behavior by about an hour per day.
For people who spend a lot of time watching TV at home, he recommends getting up every 30 minutes and moving around as much as possible, not using the remote control when switching TV channels, completing some household chores (such as cleaning or washing dishes) as well as and standing up and walking around or stretching the body during commercials. All of these light activities in daily life are essential to maintain and improve physical and mental health.
Question Does enteric coating on aspirin reduce effectiveness or increase safety in patients with cardiovascular disease?
Findings In this post hoc secondary analysis of 10 678 participants with atherosclerotic cardiovascular disease from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness (death, hospitalization for myocardial infarction, or hospitalization for stroke) or safety (major bleeding) end points between enteric-coated aspirin and uncoated aspirin among participants, regardless of which dose of aspirin they were assigned.
Meaning These findings suggested that enteric coating on aspirin is not associated with changes in the effectiveness or safety of aspirin for secondary prevention of cardiovascular events, allowing patients to determine the aspirin formulation.
Abstract
Importance Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations.
Objective To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes.
Design, Setting, and Participants This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023.
Intervention ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months.
Main Outcomes and Measures The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population.
Results Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07).
Conclusions and Relevance In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population.
Introduction
Aspirin has been one of the most widely used medications since its introduction in the 1890s.1 Its irreversible inhibition of both cyclooxygenase 1 synthase reducing production of the eicosanoid thromboxane A2 needed for platelet aggregation makes it ideal for prevention of ischemic cardiovascular events, such as myocardial infarction (MI), stroke, and transient ischemic attack1–3 but at the price of substantial adverse effects, including gastrointestinal (GI) tract bleeding, intracranial hemorrhage (ICH), and generalized bleeding.4 Enteric coating of aspirin delays the breakdown of the tablet until it is in the higher pH of the duodenum and has been shown to reduce gastric erosion5 but has not been shown to reduce gastrointestinal bleeding.6–9 Historically among clinicians and advanced practice providers such as nurse practitioners and physician assistants, it has been recommended for patients to use enteric-coated aspirin over the plain pressed uncoated formulations to minimize GI tract ulceration and bleeding,10 but to our knowledge, no study has shown that the enteric-coated formulation is safer than uncoated aspirin.
The association of enteric-coated aspirin with secondary prevention of cardiovascular disease is controversial. Several studies have proposed that the enteric coating reduces the bioavailability of aspirin due to reduced dissolution and absorption.2,11–14 In 2021, the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness) trial evaluated the safety and effectiveness of high-dose (325 mg) vs low-dose (81 mg) daily aspirin in 15 076 patients with established atherosclerotic cardiovascular disease (ASCVD).15 The results of the trial showed no statistical significance between high- and low-dose aspirin on the primary composite end points of all-cause death, hospitalization for MI, or hospitalization for stroke, as well as no significant difference in major bleeding between the 2 doses of aspirin.15 The present post hoc secondary analysis of the ADAPTABLE trial was designed to provide insight into the effectiveness and safety of enteric-coated aspirin compared with uncoated aspirin among patients with ASCVD.
Discussion
In this post hoc secondary analysis of ADAPTABLE, a large multicenter, pragmatic, randomized clinical trial, we evaluated the association of aspirin formulation (enteric-coated vs uncoated aspirin) with the effectiveness and safety of aspirin in secondary prevention of ASCVD. The results of this analysis did not show any difference in the effectiveness or safety outcomes analyzed by formulation of aspirin consumed regardless of the dose of aspirin participants were randomly assigned. While prior pharmacodynamic studies2,18 have found that enteric coating impedes the temporal dissolution of the aspirin in the small intestine and limits overall drug absorption, the results of the present study suggest no clear differences in clinical outcomes and should promote further discussion about the appropriate formulation and dose for individual patients.
Due to reduced aspirin bioavailability and the possibility of limited cardiovascular protection, the value of enteric-coated aspirin has been called into question during the last few decades. Cox et al18 reported on a 2-week patient volunteer study comparing the bioavailability of aspirin and inhibition of thromboxane A2 between enteric-coated aspirin and uncoated aspirin. They found that 100% of patients using uncoated aspirin showed higher than 95% thromboxane A2 inhibition compared with 87% of patients receiving enteric-coated aspirin (P < .001). A similar study by Grosser et al10 with 400 patients showed that 83% of patients who took a single-dose of enteric-coated aspirin (325 mg) had greater than 60% reduction in cyclooxygenase activity in 8 hours compared with 100% of patients who took a single dose of uncoated aspirin (325 mg). A sensitivity analysis in the present study using enteric coating and aspirin as time dependent variables also showed that the enteric coating did not modify the outcome response to aspirin dose over time. While it is not known what level of aspirin-induced platelet inhibition is needed to decrease cardiovascular events, this finding implies that enteric coating did not limit the effectiveness of aspirin in providing cardiovascular protection in this patient population.
Acid-reducing medications, such as proton pump inhibitors and histamine type 2 receptor antagonists, used to buffer aspirin within the stomach, have been shown to affect dissolution of the enteric formulations of aspirin by altering the pH, composition, and ionic strength in the stomach.19 The effect on the ability of enteric-coated aspirin to inhibit platelet aggregation has been mixed, with 1 study20 showing no effect with lansoprazole and another study21 showing reduced platelet aggregation when pantoprazole was given with enteric-coated aspirin. Although the pharmacodynamics suggest that enteric-coated aspirin may be less effective than uncoated aspirin, there are no studies, to our knowledge, addressing the question of whether combining ARM with enteric-coated aspirin will result in more adverse clinical outcomes. In the present analysis, we found that the primary efficacy end point of death from any cause, hospitalization for MI, or hospitalization for stroke had similar cumulative incidences reported across 26.2 months in both the enteric-coated aspirin and uncoated aspirin cohorts, regardless of whether patients were also taking ARM.
In terms of the safety profile, enteric coating has been postulated to have better protection against GI tract bleeding and other major bleeding events.22 A double-blind placebo-controlled crossover trial by Hawthorne et al23 showed that enteric coating virtually eliminated gastric mucosa toxic effects compared with nonenteric coating at both high and low doses of aspirin, with similar inhibition of prostaglandin synthesis. Since then, a follow-up study has shown that while this may be true with short-term use, long-term administration of both enteric-coated aspirin or uncoated aspirin causes gastric complications and the development of erosion.24 A meta-analysis demonstrated less-than-convincing effects of GI tract protection with enteric-coated aspirin.25 However, the point estimate for major bleeding with enteric-coated aspirin in the present study showed an 18% relative risk reduction, although the 95% CI was wide, so that a reduction in bleeding with enteric-coated aspirin cannot be reliably excluded. Similar to the lack of an association of enteric coating with the efficacy of aspirin, no significant difference in safety outcomes was observed with enteric-coated aspirin compared with uncoated aspirin in this analysis. We found that more participants randomly assigned to receive the lower dose aspirin (81 mg) took enteric-coated aspirin, while more participants randomly assigned to receive the 325-mg dose used uncoated aspirin. As these data were based on data at randomization and not on the actual drug taken throughout the study, there is no discernable reason for this difference. The rationale behind this finding could be that more patients were given low-dose aspirin because of the perception that low-dose aspirin is less irritating to the GI tract than high-dose aspirin.
When major bleeding was evaluated within formulation cohorts, there was no association with aspirin dose among participants using uncoated aspirin and a small but significant association among patients using enteric-coated aspirin at 325 mg compared with 81 mg. The lack of bleeding difference in the participants using uncoated aspirin may account for the apparent lack of difference in major bleeding seen in the overall ADAPTABLE trial. The results of the present study for the enteric-coated aspirin cohort differed from those of other trials in which no difference in major bleeding was noted; however, in those trials, formulation of aspirin used was not mentioned.26,27
It has been proposed that the coadministration of ARM with enteric-coated aspirin would decrease the frequency of bleeding. However, we were unable to demonstrate a clinical interaction between ARM and the presence of enteric coating associated with either major bleeding or GI tract bleeding in this analysis.
Conclusions
In this post hoc secondary analysis of data from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness or safety end points between enteric-coated aspirin and uncoated aspirin among participants with established ASCVD although a reduction in bleeding with enteric-coated aspirin cannot be reliably excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve ischemic and bleeding outcomes among patients with ASCVD
According to Elizabeth Arias, a researcher for the Centers for Disease Control and Prevention (CDC), the COVID-19 pandemic impacted the U.S. life expectancy. “[It will take] some time before we’re back where we were in 2019,” she said.
The Daytona Beach News-Journal reported that according to CDC numbers, life expectancy for the entire U.S. was 77 years in 2020. However, this dropped to 76.4 years by 2021 – in time for the introduction of the COVID-19 injections that year.
One study by the Cedars-Sinai Medical Center in California found that heart attack deaths climbed for all age groups during 2020 and 2021. But the biggest jump in heart attack deaths was seen in the group aged 25 to 44 at 29 percent.
COVID-19 injections shorten men’s lives by 24 years
The CDC’s own data also disclosed the true dangers of the vaccines. According to the Daily Expose, men injected with the mRNA COVID-19 vaccines could see as much as 24 years taken off their lifespan as a result.
The public health agency’s all-cause mortality data shows that each dose of the COVID-19 vaccine a person got raised their mortality rate by seven percent in 2022, compared to 2021. In other words, people injected with five doses were 35 percent more likely to die in 2022 than in 2021.
The Expose compared the COVID-19 vaccines to “slow-acting genetic poison” based on this data, given the fact that people do not appear to be recovering from the damage caused by earlier vaccines when it comes to excess mortality. It ultimately warned that a person injected with five doses would be 350 percent more likely to pass away in 2031, and a shocking 700 percent more likely to die in 2041 than an unvaccinated person.
Dr. Robert Califf, commissioner of the Food and Drug Administration (FDA), acknowledged this reduced life expectancy. “We are facing extraordinary headwinds in our public health with a major decline in life expectancy,” he wrote on X. “The major decline [of life expectancy] in the U.S. is not just a trend; I’d describe it as catastrophic.”
Not surprisingly, Califf stopped short of pinning the blame on the COVID-19 vaccines. Many of those who dare to suggest that the injections are responsible for excess deaths find themselves being censored.
In one instance, whistleblower Barry Young from New Zealand shared data from the country’s health agency that pointed to a strong link between the COVID-19 injections and excess mortality. According to the data he shared, the vaccines killed more than 10 million around the world.
But this revelation came with a steep price, as Young was arrested and now faces prison time. Nevertheless, the whistleblower said he shared the data as it blew his mind. He also wanted experts to analyze it and make people aware of what is happening.
Jackie Robinson was the first Black person to play Major League Baseball, making his debut in the spring of 1947 with the Brooklyn Dodgers at 28 years of age. Wearing number 42, Robinson broke the color barrier in America’s cherished pastime sport. Robinson would go on to win the league’s Most Valuable Player award only 2 years later, leading in batting average and stolen bases. In addition to playing professional baseball, Jackie Robinson was a champion for civil rights and a pioneer in human dignity, consistently persevering through challenges of racial discrimination both on and off the field. Whereas these memories are the often-remembered tales of Robinson and his associated fame, examining untold stories, including his place of birth and his post-baseball cardiometabolic health, may help us more deeply understand ongoing modern-day atherosclerotic cardiovascular disease (ASCVD) inequities, as well as opportunities to develop prevention strategies.
Robinson was born to a family of sharecroppers in Cairo, GA. He experienced a challenging youth in a single-parent household; his mother, Mallie, cared for him and his 4 siblings. Robinson’s hometown of Cairo, a rural town with a diverse ethnic composition, includes a considerable prevalence of Black (46%), White (33%), and Hispanic (18%) people. The rural and southern sections of the United States are disproportionately affected by disparities that adversely affect cardiovascular health; there is a large difference in the age-adjusted ASCVD mortality rate (43 per 10 000) in rural compared with metropolitan areas,[1] whereas the South has the highest burden of disability-adjusted life-years due to ASCVD.[2] Furthermore, racism is an often-overlooked contributor to the persistent gaps in cardiovascular health. Of concern, a plaque honoring Jackie Robinson in Cairo was recently vandalized in a series of incidents across Georgia that appear to have been racially motivated. Robinson’s birthplace thus symbolizes the current challenging landscape for ASCVD prevention in the United States, particularly in rural and southern areas of the country, where not all individuals have equitable access to medical care, affordable therapies, and a local environment that promotes cardiovascular health.
Despite being an all-star professional athlete and Major League Baseball’s Most Valuable Player, Jackie Robinson’s end of career and post-baseball life were affected by adverse cardiometabolic health and mental stress. In 1952, at 33 years of age, he was diagnosed with type 2 diabetes (T2D), and it was noted that his weight would regularly fluctuate throughout his career. Shortly after his rookie season, Robinson and friends celebrated on a trip through the southern United States, during which it was claimed that he gained 25 pounds due to poor dietary habits. He would also regularly travel back to support his home state of Georgia. On one occasion, he returned to Albany, GA, with a suitcase of money to bail out Albany State University students who had been arrested during a peaceful protest after not being allowed to sit at a lunch counter to order food.
Such accounts allude to the fact that Robinson was playing baseball with prediabetes and the burden of mental stress, 2 early and upstream risk factors for ASCVD, and that even professional athletes can benefit substantially from routine preventive care. Whereas Jackie Robinson did have access to medical care, many of his risk factors were largely untreated until the end of his career, when he started to experience complications of T2D, including progressive loss of vision, while playing baseball. Related to Robinson’s case is the fact that Black adults are 60% more likely to be diagnosed with T2D and have a much higher case fatality rate (39% versus 19%) compared with White adults.[3] Therefore, continued efforts are necessary in T2D prevention and care to reduce disease burden in Black communities.
The biology of adversity underlying the potential link between Robinson’s mental stress and poor cardiometabolic outcomes may have included behavioral (eg, food availability), system-level (eg, racism and risk factor screening), and physiological (eg, accelerated subclinical atherosclerosis) pathways.[4] Overall, the social determinants of health related to Jackie Robinson’s hometown in the rural South and the mental stress burden of battling racial tensions throughout his career should not be overlooked in the interpretation of his cardiometabolic risk across his life span.
A significant ASCVD risk factor burden, including T2D and obesity, would unfortunately contribute to Robinson’s early passing in 1972 at 53 years of age due to sudden cardiac death. T2D is a strong risk factor for sudden cardiac death; it is an important contributor to ischemic heart disease, which contributes to up to 80% of all sudden cardiac deaths. The comprehensive management of ASCVD risk factors among those with T2D is critical to the prevention of sudden cardiac death.[5] Robinson’s death could have been delayed, even prevented, with appropriate approaches to lifestyle and pharmacotherapies, in addition to resilience strategies geared toward mitigating mental stress and racial discrimination.
In today’s medicine and sports era, athletes have more often been open to acknowledging their health concerns to help affect the general public in places such as Cairo. However, previous stories related to cardiovascular health went unnoticed or remained largely untold, as in the case of Jackie Robinson. The untold Jackie Robinson story specifically illustrates that no person is immune to the development of ASCVD risk factors and their sequelae but also demonstrates the potential benefits of comprehensive prevention. Jackie Robinson’s story sheds light on the pathophysiology of atherogenesis, as well as the ticking-clock hypothesis of long-term cardiometabolic risk.
Jackie Robinson helped to equalize the playing field for athletes of all backgrounds to participate on the main stage of Major League Baseball, and he was a vocal civil rights advocate. Robinson’s well-known story is important to share; however, Robinson’s untold story of premature ASCVD may be just as important, as it emphasizes that the preventive cardiology playing field continues to be inequitable throughout communities across the United States. As stated by native Atlantan Dr Martin Luther King Jr, “What affects one of us affects all of us.” We hope that reviewing Jackie Robinson’s largely untold social and medical history can help to inspire a new field of dreams in the quest of reducing preventable ASCVD burden and mortality for all.
Posttraumatic stress disorder (PTSD) is characterized by a persistent maladaptive reaction after exposure to severe psychological trauma. Traumatic events that may precipitate PTSD include violent personal assaults, natural and human-made disasters, and exposure to military combat or warfare. There is a growing body of evidence for associations of PTSD with major risk factors for cardiovascular disease (CVD), such as hypertension and diabetes, as well as with major CVD outcomes, such as myocardial infarction and heart failure. However, it is unclear whether these associations are causal or confounded. Furthermore, the biological and behavioral mechanisms underlying these associations are poorly understood. Here, the available evidence on the association of PTSD with CVD from population, basic, and genomic research as well as from clinical and translational research are reviewed, seeking to identify major research gaps, barriers, and opportunities in knowledge acquisition and technology as well as research tools to support and accelerate critical research for near-term and longer-term translational research directions. Large-scale, well-designed prospective studies, capturing diverse and high-risk populations, are warranted that include uniform phenotyping of PTSD as well as broad assessment of biological and behavioral risk factors and CVD outcomes. Available evidence from functional brain imaging studies demonstrates that PTSD pathophysiology includes changes in specific anatomical brain regions and circuits, and studies of immune system function in individuals with PTSD suggest its association with enhanced immune inflammatory activity. However, establishment of animal models and human tissue biobanks is also warranted to elucidate the potential causal connection of PTSD-induced brain changes and/or inflammation with CVD pathophysiology. Emerging large-scale genome-wide association studies of PTSD will provide an opportunity to conduct mendelian randomization studies that test hypotheses regarding the presence, magnitude, and direction of causal associations between PTSD and CVD outcomes. By identifying research gaps in epidemiology and genomics, animal, and human translational research, opportunities to better justify and design future interventional trials are highlighted that may test whether treatment of PTSD or underlying neurobiological or immune dysregulation may improve or prevent CVD risk or outcomes.
Epidemiologic studies on the relationship between avocado intake and long‐term cardiovascular disease (CVD) risk are lacking.
Methods and Results
This study included 68 786 women from the NHS (Nurses’ Health Study) and 41 701 men from the HPFS (Health Professionals Follow‐up Study; 1986–2016) who were free of cancer, coronary heart disease, and stroke at baseline. Diet was assessed using validated food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios and 95% CIs. A total of 14 274 incident cases of CVD (9185 coronary heart disease events and 5290 strokes) were documented over 30 years of follow‐up. After adjusting for lifestyle and other dietary factors, compared with nonconsumers, those with analysis‐specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled hazard ratio, 0.84; 95% CI, 0.75–0.95) and a 21% lower risk of coronary heart disease (pooled hazard ratio, 0.79; 95% CI, 0.68–0.91). No significant associations were observed for stroke. Per each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80 (95% CI, 0.71–0.91). Replacing half a serving/day of margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with a 16% to 22% lower risk of CVD.
Conclusions
Higher avocado intake was associated with lower risk of CVD and coronary heart disease in 2 large prospective cohorts of US men and women. The replacement of certain fat‐containing foods with avocado could lead to lower risk of CVD.
Nonstandard Abbreviations and Acronyms
FFQ
food frequency questionnaire
HPFS
Health Professionals Follow‐up Study
MUFA
monounsaturated fatty acid
NHS
Nurses’ Health Study
PREDIMED
Prevencion con Dieta Mediterranea (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet)
SFA
saturated fatty acid
TC
total cholesterol
Clinical Perspective
What Is New?
Clinical trials have studied avocado‐induced changes in the cardiovascular risk factors; however, these studies have been limited to intermediate risk factors as end points.
In 2 large US cohorts of men and women, higher intake of avocado (≥2 servings/week) was associated with lower risk of cardiovascular disease and coronary heart disease.
The replacement of margarine, butter, egg, yogurt, cheese, or processed meats with avocado was also associated with a lower risk of cardiovascular disease.
What Are the Clinical Implications?
Our findings support the existing evidence on the intake of plant‐based healthy fats and their positive impact on diet quality and their role in cardiovascular disease prevention in the general population.
Cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke, is the leading cause of death in the United States.1 However, CVD can be largely prevented by a healthy lifestyle including a healthy diet.2, 3 The American Heart Association/American College of Cardiology recommends a heart‐healthy diet limited to 5% to 6% of calories from saturated fatty acid (SFA) and underscores the replacement of SFA and trans‐fat with monounsaturated fats (MUFA) and polyunsaturated fats,4 for the prevention of CVD.
Avocados are a nutrient‐dense fruit, containing dietary fiber, potassium, magnesium, MUFA, and polyunsaturated fatty acids, as well as phytonutrients and bioactive compounds, which have been independently associated with cardiovascular health.5, 6, 7 The most commonly consumed variety in the United States (Hass avocado) contains ≈13 g of oleic acid in a medium‐sized fruit (136 g), comparable to the amount of oleic acid in 1.5oz (42 g) of almonds or 2 tablespoons (26 g) of olive oil.5 Specifically, half an avocado provides up to 20% of the daily recommended fiber, 10% of potassium, 5% of magnesium, and 15% of folate, as well as 7.5 g of MUFA and 1.5 g of polyunsaturated fatty acid.5, 8 As such, avocados can be a nutrient‐dense component of a healthful dietary pattern. National population data have indicated that after accounting for lifestyle and sociodemographic factors including socioeconomic status, avocado consumers tend to have higher high‐density lipoprotein (HDL) cholesterol levels; a lower risk of metabolic syndrome; and lower weight, body mass index (BMI), and waist circumference, compared with avocado nonconsumers.6
Although avocado‐induced changes in the CVD risk profile of individuals have been investigated, clinical trials are limited to intermediate risk factors as end points.9, 10, 11, 12, 13, 14, 15, 16, 17 These studies have involved a varied daily dose of avocado (0.5–2 avocados) and primarily evaluated serum lipids. Compared with low‐fat, cholesterol‐lowering diets, avocado‐containing diets showed unchanged HDL cholesterol levels, while triglyceride, low‐density lipoprotein (LDL) cholesterol, and total cholesterol (TC) levels were comparable or reduced.9, 10, 11, 12, 13, 14, 17 However, these trials used avocados as a source of MUFA in dietary interventions that replaced macronutrients to determine the impact of dietary fat intake on serum lipids.
A recently published systematic review and meta‐analysis18 encourages the examination of avocado intake in well‐conducted prospective observational studies to examine the association between avocado consumption and clinical CVD end points. In this study, we aimed to examine the association between avocado consumption with total CVD, CHD, and stroke, in 2 large US prospective cohort studies, the NHS (Nurses’ Health Study) and the HPFS (Health Professionals Follow‐up Study). We also conducted substitution analyses to estimate the risk of total CVD, CHD, and stroke when different fat‐containing food sources were replaced by avocado.
Methods
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Study Design and Population
The HPFS19 is an ongoing prospective cohort study established in 1986 consisting of 51 529 US male health professionals aged 40 to 75 years from all 50 US states. The NHS20 is a prospective cohort study that began in 1976 and consists of 121 700 registered female nurses aged 30 to 55 years from 11 US states. Participants from both cohorts responded to validated questionnaires inquiring about lifestyle, medical history, and other health information at baseline and every 2 years thereafter to update personal information on lifestyle behaviors, risk factors, and diagnoses of chronic diseases.20, 21 A detailed description of the 2 cohorts has been previously reported.22 Baseline for both cohorts was 1986, when avocado consumption was first included as part of the food frequency questionnaires (FFQs) and detailed information about diet and lifestyle was assessed with subsequent biennial questionnaires.
We excluded men and women who had a baseline history of heart disease, stroke, or cancer because the diagnoses of these conditions might have changed diet. We also excluded participants with missing information on avocado intake, and those who were out of the predefined limits of energy intake levels (<800 or >4200 kcal/day for men and <500 or >3500 kcal/day for women). After exclusions, a total of 62 225 women and 41 701 men remained for analysis. The protocol was approved by the institutional review board of Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health. All participants gave informed consent.
Ascertainment of CVD
The primary outcome measure was incident cases of total CVD defined as the composite of fatal CHD and nonfatal myocardial infarction and fatal and nonfatal stroke. Secondary outcomes included incident cases of: total CHD, defined as fatal CHD and nonfatal myocardial infarction; and total stroke, defined as fatal and nonfatal ischemic, hemorrhagic, and unknown subtypes of stroke. When a participant reported an incident event on each biennial questionnaire, permission was requested to examine medical records, reviewed by study investigators blinded to the participant’s risk factor status. For each event, the month and year of diagnosis was recorded as the diagnosis date. Nonfatal events were confirmed through review of medical records. Myocardial infarction was defined according to the World Health Organization criteria and cardiac‐specific troponin or other cardiac enzyme levels.23 When medical records were unavailable, interviews or letters confirmed CHD events that were designated as “probable.” Strokes were confirmed if data in the medical records fulfilled the National Survey of Stroke criteria requiring evidence of a neurological deficit with sudden or rapid onset that persisted for >24 hours or until death.24 Strokes were classified as ischemic stroke (thrombotic or embolic occlusion of a cerebral artery), hemorrhagic stroke (subarachnoid and intraparenchymal hemorrhage), or stroke of probable or unknown subtype (subtype data not available). Death ascertainment was performed by searching the National Death Index,25 by family members’ response to follow‐up questionnaires, or by reports from participants’ professional organizations. We requested access to medical records, autopsy reports, and death certificates to confirm all suspected deaths caused by myocardial infarction. Fatal myocardial infarction was confirmed by medical records or autopsy reports. Death certificates alone were not considered sufficient to confirm myocardial infarction as the cause of death unless family members or medical records indicated that the participant was diagnosed with coronary artery disease before death but after admission into the study. We included all confirmed and probable cases in our report because results were similar after probable cases were excluded. Follow‐up for deaths was >98% complete.
Assessment of Avocado Consumption
Dietary intake was assessed using a validated semiquantitative FFQ with over 130 items administered every 4 years. The reproducibility and validity of these FFQs have been described in detail elsewhere.26, 27 Participants were asked how often, on average, they consumed each food of a standard portion size in the past year. The frequency responses ranged from never or less than once per month to ≥6 times per day. Avocado intake was calculated from 1 questionnaire item that specifically asked about avocado amount and frequency. Avocado intake was collapsed into 4 categories: (1) never or less than once per month, (2) 1 to 3 times per month, (3) once per week; and (4) ≥2 times per week. We also analyzed avocado intake as a continuous variable by including half a serving of avocado (one‐fourth of an avocado), which is equivalent to 40 g, in the multivariable models. Total margarine was calculated on the basis of the reported frequency of stick, tub, or soft margarine and the amount of margarine added from baking and frying at home. Butter intake was also calculated on the basis of the frequency that butter was added to foods and used for frying, sautéing, and baking. Olive oil intake was calculated from the frequency of consumption of 3 questionnaire items (olive oil salad dressing; olive oil added to food or bread; and olive oil used for baking and frying at home). Other plant oils (eg, corn, safflower, soybean, canola) amounts were estimated from the participant’s reported oil brand and type of fat used for cooking at home, including frying, sautéing, baking, and salad dressing. Intakes of dairy, mayonnaise, eggs, yogurt, cheese, processed meats, and nuts, and nutrients were calculated on the basis of the US Department of Agriculture and Harvard University Food Composition Database28 and our biochemical analyses.
Assessment of Covariates
Baseline history of hypertension, hypercholesterolemia, and type 2 diabetes were determined by self‐report of a physician diagnosis. Updated biennial information on lifestyle and CVD risk factors was assessed including age, body weight, smoking status, physical activity, aspirin and other medication use, multivitamin use, menopausal status, postmenopausal hormone therapy and oral contraceptives use, and newly diagnosed chronic disease (self‐reported physician diagnosed). Height was ascertained for women in 1976 and for men in 1986. Height and body weight were used to calculate BMI (kg/m2). Alcohol intake was updated on the FFQs every 4 years. Demographic information was also collected via mailed questionnaires, in 1986 for men and in 1992 for women. This included the participants’ ancestry (“Your ancestry: Southern European/Mediterranean; Scandinavian; Other Caucasian; African‐American; Hispanic; Asian; Native‐American; Other”). Since the data on race and ethnicity in our cohorts were collected more than 30 years ago, they are not consistent with the current standard classifications.
Statistical Analysis
Person‐years of follow‐up for each participant were calculated from the return of the baseline questionnaire to the date of diagnosis of CVD, death, or end of follow‐up (June 30, 2016, for the NHS, and January 31, 2016, for HPFS), whichever came first. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs of developing CVD according to avocado intake. Model 1 was adjusted for age. Multivariable model 2 was adjusted for age; race (White or other [Black, American‐Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander]), ancestry (Southern European/Mediterranean, other Caucasian/Scandinavian, other); alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–14.9, and ≥15.0 g/day); smoking status (never, former, current smoker [1–14 cigarettes per day, 15–24 cigarettes per day, or ≥25 cigarettes per day]); physical activity (<3.0, 3.0–8.9, 9.0–17.9, 18.0–26.9, ≥27.0 metabolic equivalents–h/week); family history of diabetes (yes, no); family history of myocardial infarction (yes, no); family history of cancer (yes, no); baseline diabetes (yes, no); baseline hypertension or antihypertensive medication use (yes, no); baseline hypercholesterolemia or cholesterol‐lowering medication use (yes, no); multivitamin use (yes, no); aspirin use (yes, no); postmenopausal status and menopausal hormone use (premenopausal, postmenopausal [no, past, or current hormone use]; women only); total energy intake (kcal/day); and BMI (kg/m2, continuous). Multivariable model 3 was additionally adjusted for trans‐fat and quintiles of red and processed meat, fruits and vegetables other than avocado, nuts, soda (caloric and low or noncaloric), whole grains, eggs, tortilla (whole and chips; tertiles in NHS), breads, and cheese intakes. Race was dichotomized for the statistical analysis since >90% of our population is White and having multiple categories would affect the degrees of freedom of the model.
Spearman correlations were used to assess the correlation between avocado and other types of fats.
We used the simple update approach for dietary variables, including the covariates, wherein the most recently reported diet is assessed against incident disease by the end of the subsequent interval (eg, whether intake reported in 1988 was associated with CVD in 1992). Thereby, the information closest to the time of the event was used in the primary analyses. This analysis took into account a substantial increase in avocado intake among our cohort participants over the past 3 decades. With the exception of fixed covariates, which includes family history of disease, baseline medical conditions, and race, ethnicity, and ancestry, we used the same method to update the rest of the covariates. This method considered changes in covariate lifestyle behaviors at follow‐up (biennially, every 4 years for alcohol), applied to smoking status, alcohol intake, physical activity, multivitamin and aspirin use, and postmenopausal status and menopausal hormone use. Because participants may alter dietary patterns after the diagnosis of major illness, we stopped updating dietary variables when participants reported a diagnosis of coronary artery bypass, angina, or cancer, although follow‐up continued until CVD end point occurrence, death, or the end of the study period.29 Missing values during follow‐up were replaced by using the carry‐forward method.
Prespecified subgroup analyses were performed according to baseline age (<60 compared with ≥60 years), BMI (<25 compared with ≥25 kg/m2), family history of myocardial infarction (yes compared with no), ancestry (Southern European/Mediterranean, and other Caucasian compared with other [including Hispanic]), and above and below the median for each of the following: alternative healthy eating index score, total fruit intake, total vegetable intake, green vegetable intake, and lettuce intake. Significance was assessed by the Wald test on cross‐product terms on the basis of avocado intake and the stratification variables. The proportion of participants with Hispanic ancestry in the study population is low, which precluded us from looking specifically into this subgroup that may have a higher intake of avocados.
We also estimated the risk of total CVD when substituting half a serving of avocado (40 g, one‐fourth of an avocado) for the equivalent amount (40 g) of other types of fat‐containing foods: margarine, butter, mayonnaise (regular and light), eggs, yogurt (plain, sweetened, and artificially sweetened), cheese (cottage or ricotta, cream, and all other cheeses including hard—regular and low‐fat or light), processed meats (beef or pork hot dogs, bacon, salami, bologna, sausages, kielbasa, other similar deli‐type processed sandwich meats), olive oil, other plant oils (corn, safflower, soybean, and canola oils), nuts (peanuts, walnuts, and other nuts), and dairy foods (milk, cheese, yogurt) with total CVD by including both variables in the same multivariable model previously described and mutually adjusted for other types of fat‐containing food sources. These foods were considered since avocado could often be used as an alternative in the same manner (ie, ingredient, spread, dressing, topping). We used the difference between regression coefficients and in variances and covariances to derive the HRs and 95% CIs of the substitution analyses.
Sensitivity analyses were conducted to test the robustness of the results. First, to test whether the results were affected by selectively stopping updating diet, diet was continuously updated until the end of follow‐up. Second, models were mutually adjusted for other types of fat‐containing food sources (ie, margarine, butter, mayonnaise, eggs, yogurt, cheese, processed meats, olive oil, other plant oils, dairy foods). Third, sensitivity analyses excluding BMI from the models were conducted. Fourth, to test whether the results were altered by socioeconomic status, models were adjusted for median household income and education. Fifth, instead of using the simple update approach of diet, the average of the 2 most recent measures of diet were used. Finally, in place of the simple update method, the cumulative average of all the FFQs that asked about avocado intake was used. For this particular research question, we considered the simple update approach as the most suitable method since avocado intake in the cohorts was almost negligible during the first few FFQs. Bonferroni corrections to account for multiple testing were conducted at α=0.025 (alpha corrected for 2 secondary outcomes) and α=0.005 (alpha corrected for 11 tests in the substitution analyses).
Tests for linear trend were conducted by assigning the median value to each category of intake and modeling this value as a continuous variable. HRs from multivariate models in each cohort were pooled by using a fixed‐effect inverse‐variance meta‐analysis. Proportional hazards assumptions were assessed, and no variables violated the assumption. All P values were 2‐sided, and an α level of <0.05 was considered statistically significant. Data were analyzed with the SAS package, version 9.4 (SAS Institute, Cary, NC).
Results
During 30 years of follow‐up (median follow‐up duration was 13.3 and 14.2 years for men and women, respectively), there were a total of 14 274 total CVD cases documented, 6661 in the HPFS and 7613 in the NHS. Mean intake of avocado increased from an average of 17.2 g/week (0.2 servings/week) in 1986 to 32.3 g/week (0.4 servings/week) in 2014 for HPFS, and from 9.2 g/day (0.1 servings/week) in 1986 to 16.3 g/week (0.2 servings/week) in 2010 for NHS, while the intake of margarine, mayonnaise, dairy foods, and other plant oils decreased (Table S1). The Spearman correlations between avocado and other fat‐containing foods are presented in Table S2. Characteristics of participants according to frequency of avocado intake at baseline 1986 are shown in Table 1. Men and women with a higher intake of avocado also tended to have a higher total energy intake and better diet quality, characterized by a higher intake of fruits and vegetables, whole grains, nuts, dairy products such as yogurt and cheese, and alternative healthy eating index score. The mean intake of avocado in the highest baseline category (≥2 servings/day) was about 40 g/day (Table 1).John Wiley & Sons, Ltd
Values are mean±SD or %, and are standardized to the age distribution of the study population. HPFS, n=41 701; NHS, n=68 786. AHEI indicates alternative healthy index; BMI, body mass index; and MET, metabolic equivalent task.
*Baseline is 1986.
†Includes sweetened and artificially sweetened soda.
‡Includes plain, sweetened, and artificially sweetened yogurt.
After adjusting for major diet and lifestyle factors, compared with nonconsumers, those with an analysis‐specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled HR, 0.84; 95% CI, 0.75–0.95; P trend=0.0007) (Table 2). When BMI was excluded from the models, the results were unchanged (pooled HR, 0.84; 95% CI, 0.75–0.95; P trend=0.0005) (Table S3). When the models for avocado were mutually adjusted for other types of fat‐containing food sources, the pooled HR for CVD was 0.89 (95% CI, 0.80–0.98; P trend=0.02) (Table S4). Per each half a serving/day (one‐fourth avocado) increase in avocado intake, the pooled HR for CVD was 0.80 (95% CI, 0.71 to 0.91; P trend=0.0007). Comparing extreme categories of avocado intake after adjusting for potential confounders, the pooled HRs were 0.79 (95% CI, 0.68–0.91; P trend<0.001) for CHD and 0.94 (95% CI, 0.78–1.14; P trend=0.78) for stroke (Table 2). The pooled estimate for the overall HR of ischemic stroke was 0.93 (95% CI, 0.69–1.25; P trend=0.62) per each half a serving/day increase in avocado consumption (Table S5).John Wiley & Sons, Ltd
HR (95% CI)
Never or <1 per month
1–3 per month
1 per week
≥2 per week
P value for trend
HR (95% CI) forhalf serving (one‐fourth avocado) increase in avocado Intake per day
Model 2 was adjusted for: age (years); race (Whiteor other [Black, American‐Indian or Alaskan Native, Asian, Native Hawaiian or Other Pacific Islander]); ancestry (Southern European/Mediterranean, other Caucasian/Scandinavian, other); alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–14.9, and ≥15.0 g/day); smoking status (never, former, current smoker [1–14 cigarettes per day, 15–24 cigarettes per day; or ≥25 cigarettes per day]); physical activity (<3.0, 3.0–8.9, 9.0–17.9, 18.0–26.9, ≥27.0 metabolic equivalent task–h/week); family history of diabetes (yes, no); family history of myocardial infarction (yes, no); family history of cancer (yes, no); baseline diabetes (yes, no); baseline hypertension or antihypertensive medication use (yes, no); baseline hypercholesterolemia or cholesterol‐lowering medication use (yes, no); multivitamin use (yes, no); aspirin use (yes, no); in women, postmenopausal status and menopausal hormone use (premenopausal, postmenopausal [no, past, or current hormone use]); total energy intake (kcal/day); and body mass index (kg/m2). Model 3 was additionally adjusted for red and processed meat, fruits and vegetables (excluding avocado), nuts, soda (caloric and noncaloric), whole grains, eggs, tortilla (whole and chips), breads, cheese intakes (in quintiles; tortilla in tertiles in NHS), and trans‐fat.
Results were pooled with the use of the fixed‐effects model. CHD indicates coronary heart disease; CVD, cardiovascular disease; and HR, hazard ratio.
†CVD: fatal and nonfatal myocardial infarction plus fatal and nonfatal stroke.
‡CHD: fatal and nonfatal myocardial infarction.
§Fatal and nonfatal stroke.
We found significant inverse associations in most of the prespecified subgroup analyses (Table 3). No significant interactions were observed for any of the variables analyzed. Prespecified subgroup analyses for CHD and stroke are presented in Table S6. Substituting half a serving/day of avocado for the equivalent amount of margarine was estimated to be associated with 16% lower risk of CVD (HR, 0.84; 95% CI, 0.75–0.95; P=0.004) (Figure). The respective HR estimate for butter was 0.78 (95% CI, 0.63–0.96; P=0.02). For mayonnaise, the HR was 0.92 (95% CI, 0.80–1.07; P=0.29). Substituting half a serving/day of avocado for the equivalent amount of egg and cheese was estimated to be associated with 18% (HR, 0.82; 95% CI, 0.73–0.93; P=0.001) and 13% (HR, 0.87; 95% CI, 0.77 to 0.98; P=0.02) lower risk of CVD. A lower risk of CVD was observed when substituting avocado for processed meats and yogurt, while substituting half a serving/day of avocado for the equivalent amount of olive oil, nuts, and other plant oils was not statistically significant. Replacing half a serving/day of mayonnaise, margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with 19% to 31% lower risk of CHD (Figure). We did not observe significant associations when substituting avocado for any of the prespecified foods and stroke, with the exception of all other plant oils (safflower, corn, soybean, and canola oils). Replacing half a serving/day of all other plant oils with the equivalent amount of avocado was associated with a 45% higher risk of stroke. Cohort‐specific substitution analyses are presented in Figure S1.John Wiley & Sons, Ltd
HRs for half a serving/day (one‐fourth avocado) increase in avocado intake in each subgroup category.
Multivariable model was adjusted for the following: age (y); race (Whitevs other [Black, American Indian or Alaskan Native, Asian, Native Hawaiian or Other Pacific Islander]); ancestry (Southern European/Mediterranean, other Caucasian/Scandinavian, other); alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–14.9, and ≥15.0 g/day); smoking status (never, former, current smoker [1–14 cigarettes per day, 15–24 cigarettes per day; or ≥2 cigarettes per day]); physical activity (<3.0, 3.0–8.9, 9.0–17.9, 18.0–26.9, ≥27.0 metabolic equivalent task–h/week); family history of diabetes (yes, no); family history of myocardial infarction (yes, no); family history of cancer (yes, no); baseline diabetes (yes, no); baseline hypertension or antihypertensive medication use (yes, no); baseline hypercholesterolemia or cholesterol‐lowering medication use (yes, no); multivitamin use (yes, no); aspirin use (yes, no); postmenopausal status and menopausal hormone use (premenopausal, postmenopausal [no, past, or current hormone use], in women only); total energy intake (kcal/day);body mass index (kg/m2, continuous); red and processed meat, fruits and vegetables (excluding avocado), nuts, soda (caloric and low or noncaloric), whole grains, eggs, tortilla (whole and chips), breads, cheese intakes (all in quintiles; tortilla in tertiles in NHS); and trans‐fat, except the stratified factor. AHEI indicates alternative healthy eating index score; and BMI, body mass index.
*1 serving avocado=½ avocado; ½ serving=¼ avocado.
†n= number of cases per subgroup.
Figure 1. Hazard ratios for cardiovascular events associated with substitution of half a serving of avocado for equivalent amounts of other fat‐containing food sources in two large US cohorts.Pooled hazard ratios for cardiovascular disease, coronary heart disease, and stroke associated with substitution of half a serving/day (one‐fourth avocado) of avocado for equivalent amounts of other fat‐containing foods. Multivariate‐adjusted models were adjusted for the following: age (years); race (White) or other [Black, American Indian or Alaskan Native, Asian, Native Hawaiian or Other Pacific Islander]; ancestry (Southern European/Mediterranean, other Caucasian/Scandinavian, all other); alcohol intake (0, 0.1–4.9, 5.0–9.9, 10.0–14.9, and ≥15.0 g/day); smoking status (never, former, current smoker [1–14 cigarettes per day, 15–24 cigarettes per day; or ≥2 cigarettes per day); physical activity (<3.0, 3.0–8.9, 9.0–17.9, 18.0–26.9, ≥27.0 metabolic equivalent task–h/week); family history of diabetes (yes, no); family history of myocardial infarction (yes, no); family history of cancer (yes, no); baseline diabetes (yes, no); baseline hypertension or antihypertensive medication use (yes, no); baseline hypercholesterolemia or cholesterol‐lowering medication use (yes, no); multivitamin use (yes, no); aspirin use (yes, no); postmenopausal status and menopausal hormone use (premenopausal, postmenopausal [no, past, or current hormone use]), only in women; total energy intake (kcal/day); body mass index (kg/m2, continuous), red and processed meat, fruits and vegetables (excluding avocado), nuts, soda (caloric and low or noncaloric), whole grains, eggs, tortilla (whole and chips), breads, cheese intakes (all in quintiles; tortillas in tertiles in Nurses’ Health Study); trans‐fat, and mutually adjusted for other types of fat‐containing foods. Results were pooled with the use of the fixed‐effects model. Horizontal lines represent 95% CIs.
In the sensitivity analysis to test whether the results were affected by selectively stop updating diet, diet was continuously updated until the end of follow‐up. The associations for half a serving/day increase in avocado intake were attenuated (Table S7). The pooled HR for CVD was 0.93 (95% CI, 0.82–1.05; P trend=0.24). However, the CHD results remained consistent (pooled HR, 0.85; 95% CI, 0.73–0.99; P trend=0.03). When using the average intake of the last 2 dietary measurements, the respective HR estimate was 0.75 (95% CI, 0.66–0.86; P trend=<0.0001) (Table S8). Findings persisted after we excluded BMI from the models (Table S3) as well as after we adjusted for socioeconomic status (data not shown). Compared with nonconsumers, those with higher avocado intake (≥2 servings/week) had a 13% lower risk of CVD (pooled HR, 0.87; 95% CI, 0.77–0.98; P trend=0.02) and a 29% lower risk of CHD (pooled HR, 0.81; 95% CI, 0.70–0.94; P trend=0.006). The associations for half a serving/day increase in avocado intake and substitution analysis were also consistent after adjusting for these variables. After adjusting for MUFA intake, results were consistent. The pooled HR for CVD was 0.85 (95% CI, 0.75–0.95; P trend=0.001) (Table S9). The cumulative average method results are shown in Table S10. We did not observe significant associations between avocado intake and incident total CVD, CHD, or stroke.
When we adjusted for multiple testing using the Bonferroni correction, the main results and conclusions did not change, as the P values for the pooled analyses were <0.001. In the substitution analysis, results changed for the replacement of avocado for butter and yogurt (P>0.005).
Discussion
In 2 large prospective cohorts of men and women followed for 30 years, we found inverse associations between avocado consumption and the incidence of CVD and CHD events after adjusting for cardiovascular risk factors and other dietary variables. Compared with nonconsumers, those with higher consumption of avocados had 16% lower risk of CVD and 21% lower risk of CHD, but no association for stroke. Findings were consistent across all subgroups. Additionally, compared with margarine, butter, egg, yogurt, cheese, and processed meats, avocados were associated with lower risk of CVD and CHD, whereas when compared with olive oil, nuts, and other plant oils combined, avocados were not associated with CVD and CHD. To our knowledge, the present study is the first large prospective study to examine and generate evidence on the longitudinal association between avocado consumption and CVD events. Results also suggest that substitution of certain fat‐containing food sources (ie, margarine, cheese, processed meats) with healthy unsaturated fats such as avocado, may lead to lower CVD and CHD risk. On the other hand, the substitution of other healthy dietary fats such as olive oil, nuts, and other plants oils for avocado yielded nonsignificant results, suggesting that they can all be considered as healthy sources of fat for the prevention of CVD. Although we observed a significantly higher risk of stroke when substituting all other plant oils (safflower, corn, soybean, and canola oils) for avocado, this result may be attributable to chance because of the several different replacement foods and outcomes we have examined.
Existing published literature is inconclusive regarding the association between avocado intake and incidence of cardiovascular risk factors and CVD and other chronic diseases.18, 30 While clinical trial evidence on the effects of avocados on the cardiovascular risk profile of adults exist, these intervention studies have reported inconsistent effects on serum lipids in participants with and without cardiometabolic disease.9, 10, 11, 12, 13, 14, 15, 16 This has been further determined by 2, to‐date, thorough systematic reviews and meta‐analyses18, 30 of existing trials examining the effects of avocado intake on heart disease risk factors and plasma lipoproteins. The first review (2016; n=10 studies [8 crossover and 2 parallel trials, 1–12 weeks in duration, 229 participants] in meta‐analysis),30 concluded that avocado‐substituted diets (substitution of SFA with MUFA‐rich avocados versus adding to the free diet) decrease TC, LDL cholesterol, and triglyceride levels, as well as found that HDL cholesterol levels decreased nonsignificantly in healthy adults with a normal BMI. In this review, half of the studies included Hass‐type avocados,9, 10, 12, 14, 17 3 studies replaced MUFA content with avocado and other dietary MUFA sources such as olive oil and almonds,12, 31, 32 and the remaining 7 used avocado as the only source of MUFA.9, 10, 11, 13, 14, 15, 17 All 10 studies examined the substitution of dietary fats for avocados with no particular control diet. However, the most recent review (2018, n=10 studies [8 crossover and 2 parallel trials, 3–24 weeks in duration, 249 participants] in meta‐analysis, 1 not included in the previous analyses and 1 new trial since 2016)18 observed no difference in serum TC, LDL cholesterol, and triglyceride concentrations with avocado intake, but did find an increase in serum HDL cholesterol levels, yet with significant heterogeneity. The quantitative analysis included 7 trials that compared avocado intake with a control diet with no avocado intake.9, 12, 13, 14, 15, 17, 33 It also excluded trials with ❤ weeks of follow‐up, whereas the 2016 review included 2 studies with ❤ weeks of follow‐up10, 14 in their quantitative analysis.
Although the latter systematic review and meta‐analysis seem to provide a more comprehensive assessment of avocado intake and cardiometabolic factors, with a set of abundant sensitivity analyses, it is important to highlight that both reviews showed significant heterogeneity across eligible studies, differed in their inclusion criteria with only 5 shared studies, and were unable to examine risk of CVD events because no studies have reported incident clinical outcomes of CVD, including CHD events or stroke. However, high‐quality randomized controlled trials that have demonstrated a favorable outcome on lipid profiles should be highlighted, as many of the studies included in the meta‐analyses have had a small sample size9, 11, 13, 14, 16 participants had existing cardiometabolic diseases9, 10, 11, 12, 14, 15 and differed in dietary intervention design and feeding period length.10, 13, 16 A high‐grade crossover, controlled feeding trial in adults with overweight/obesity, reported that compared with baseline, the avocado‐containing diet (moderate fat [34% fat] diet with 6%–7% of energy from MUFA from 1 avocado per day in substitution for SFA, ≈136 g with pulp), lowered LDL cholesterol, TC, LDL particle, non‐HDL cholesterol, and TC/HDL cholesterol and LDL/HDL cholesterol ratios significantly more than the moderate‐fat diet (34% fat; 6%–7% of energy from MUFA from high oleic oils to match the fatty acid content of avocado in substitution for SFA).17 This trial also examined circulating oxidized LDL, an independent risk factor for CVD,34 and found that compared with baseline, only the avocado‐containing diet significantly decreased plasma oxidized LDL.35 Furthermore, the reduction in oxidized LDL by this diet was significantly greater than that by the other 2 study diets, moderate‐fat and low‐fat diets.
Despite the conflicting clinical literature among avocado‐enriched trials on cardiometabolic factors and a lack of prospective analyses between avocado intake and risk of CVD for comparison with our results, the current study’s findings provide novel, necessary, and robust evidence that higher intake of avocados is associated with a lower risk of CVD and CHD in healthy US adults. These results are particularly noteworthy since the consumption of avocado has risen steeply in the United States in the past 20 years.36, 37
In lieu of comparable studies, we can evaluate our results against that of olive oil, another MUFA‐rich food that has been extensively studied and shares phytonutrients and the main component, oleic acid, with avocados. Findings from the PREDIMED (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet) trial, determined that a Mediterranean diet supplemented with extra virgin olive oil reduced the risk of cardiovascular events by 31% (95% CI, 0.53–0.91) in a population at high cardiovascular risk.38 Additionally, observational studies have shown that olive oil consumption is inversely associated with cardiovascular events in both Mediterranean39, 40 and US populations.41 In the NHS and HPFS cohorts, compared with nonconsumers, those with higher olive oil intake (>0.5 tablespoon/day or >7 g/day) had a 14% lower risk of CVD (pooled HR, 0.86; 95% CI, 0.79–0.94) and an 18% lower risk of CHD (pooled HR, 0.82; 95% CI, 0.73–0.91). This evidence provides support for our findings. Further replications of our analysis in other cohorts that have collected data on avocado intake and prospectively assessed CVD end points are warranted.
Diet is a key element in improving the cardiometabolic profile, thus decreasing the risk of CVD.4 Favorable bioactive food compounds include MUFAs and polyunsaturated fatty acids, soluble fiber, vegetable proteins, phytosterols, and polyphenols,42 all present in avocados. Moreover, replacement of fats high in SFAs or trans‐fat with unsaturated fatty acids can be beneficial for CVD prevention,4 as indicated by leading medical entities. Thereby, our substitution analysis, estimating the risk of CVD and CHD by substituting specific types of fat‐containing food sources with avocado, is consistent and supported by this evidence. The replacement of fat‐containing foods (some with SFA) with the same amount of avocado was associated with a lower risk of CVD and CHD, while the substitution for olive oil and other plant oils yielded nonsignificant results. This is an important finding for public health recommendations, emphasizing the consumption of avocado and other unsaturated fats to follow a healthy dietary pattern and reduce the risk of CVD.43 Furthermore, 2 current analyses found a lower risk of CHD and CVD mortality when plant‐sourced MUFAs substitute animal‐sourced MUFAs as well as SFAs.44, 45
There are potential biological mechanisms by which avocados offer cardioprotective benefits through modulating cardiovascular risk factors. The primary MUFA present in avocados is oleic acid, and it is suggested that it helps in improving endothelial dysfunction, hypertension, inflammation, and insulin sensitivity.46, 47 Additionally, plant sterols, plant analogs of cholesterol, are moderately high in avocados (136 g fruit without skin and seed=≈104 mg beta‐sitosterol),48 and could have favorable effects on lipid profiles. Moreover, higher fiber intake via avocado consumption can lead to a better lipid profile.49
Interestingly, we found an association between avocado consumption and CHD but not with stroke, including ischemic stroke. Although no evidence exists on the effect of avocados on CHD and stroke prevention, our findings were unexpected since we know that following a healthful diet, such as the Mediterranean dietary pattern, is one of the key lifestyle components that support primordial prevention of cardiovascular events.50 The PREDIMED trial showed that a Mediterranean diet supplemented with extra virgin olive oil significantly reduced the risk of stroke by 35% (HR, 0.65; 95% CI, 0.44–0.95).38 However, PREDIMED investigators did not find a significant reduction in myocardial infarction risk (HR, 0.82; 95% CI, 0.52–1.30) after a median follow‐up of 4.8 years. Similarly, it has been determined that greater adherence to healthy eating patterns, including the Mediterranean diet, was associated with lower risk of total CVD, CHD, and stroke.51 Moreover, a recent study examining the long‐term association between olive oil, another MUFA‐containing food, and CVD risk in the NHS and HPFS cohorts reported no significant associations for total or ischemic stroke.41 Our stroke findings, including the substitution analysis findings, as well as those of olive oil in the NHS and HPFS cohorts, could be explained by chance or the lack of statistical power. It is also possible that the bioactive compound effects of avocado differ by variety and level of ripeness,52 which we did not ask in the biennial questionnaires, affecting their contribution to disease outcomes.
The strengths of this study include a prospective population‐based design, a large sample size, a long follow‐up, repeated and validated measurements of diet and lifestyle data, and a well‐defined clinical event outcome. Limitations need to be considered in our study. First, because dietary information was self‐reported, our assessment of absolute intake of avocado will have some degree of measurement error. However, the use of repeated measurements reduces random measurement error caused by within‐person variation. Misclassification is a possibility, yet because of the study’s prospective design, misclassification and measurement error was most likely nondifferential, attenuating the association towards the null. Third, because of the observational design, a causal association cannot be established and residual confounding cannot be completely ruled out even though the analyses were extensively adjusted for potential confounders. Fourth, our study population consisted of primarily non‐Hispanic White nurses and health professionals, thereby limiting the generalizability of our results to other populations. Still, there is no known reason to expect that the underlying biological mechanisms may be different in other ethnic groups or that socioeconomic status would affect the results since the sensitivity analysis included adjusting the models for socioeconomic status. Finally, because of the large number of statistical tests conducted, it is possible that some were by chance, but the primary outcome results remained unchanged after correcting for multiple testing.
Conclusions
In conclusion, in this large study of US men and women, higher intake of avocados was associated with significantly lower risk of total CVD and CHD. No significant associations were observed for total or ischemic stroke. In substitution analyses, we observed that replacing margarine, butter, egg, total yogurt, total cheese, and processed meats with avocado was associated with a lower incidence of CVD events. Our study provides further evidence that the intake of plant‐sourced unsaturated fats can improve diet quality and is an important component in CVD prevention in the general population. Further studies are needed to assess the impact and effectiveness of avocado intake in reducing incident CVD and CVD risk factors
Menopause is often a turning point for women’s health worldwide. Increasing knowledge from experimental data and clinical studies indicates that cardiometabolic changes can manifest at the menopausal transition, superimposing the effect of ageing onto the risk of cardiovascular disease. The menopausal transition is associated with an increase in fat mass (predominantly in the truncal region), an increase in insulin resistance, dyslipidaemia, and endothelial dysfunction. Exposure to endogenous oestrogen during the reproductive years provides women with protection against cardiovascular disease, which is lost around 10 years after the onset of menopause. In particular, women with vasomotor symptoms during menopause seem to have an unfavourable cardiometabolic profile. Early management of the traditional risk factors of cardiovascular disease (ie, hypertension, obesity, diabetes, dyslipidaemia, and smoking) is essential; however, it is important to recognise in the reproductive history the female-specific conditions (ie, gestational hypertension or diabetes, premature ovarian insufficiency, some gynaecological diseases such as functional hypothalamic amenorrhoea, and probably others) that could enhance the risk of cardiovascular disease during and after the menopausal transition. In this Review, the first of a Series of two papers, we provide an overview of the literature for understanding cardiometabolic changes and the management of women at midlife (40–65 years) who are at higher risk, focusing on the identification of factors that can predict the occurrence of cardiovascular disease. We also summarise evidence about preventive non-hormonal strategies in the context of cardiometabolic health.
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