EGG CONSUMPTION, CHOLESTEROL INTAKE, AND RISK OF INCIDENT STROKE IN MEN: THE KUOPIO ISCHAEMIC HEART DISEASE RISK FACTOR STUDY
Anna Abdollahi Master’s Thesis Public Health School of Medicine Faculty of Health Sciences University of Eastern Finland
August 2019
University of Eastern Finland, Faculty of Health Sciences Main subject: Public health
ABDOLLAHI, Anna M.: Egg consumption, cholesterol intake, and risk of incident stroke in men: the Kuopio Ischaemic Heart Disease Risk Factor Study
Master's thesis, 64 pages
Supervisors: Jyrki Virtanen, PhD, Heli Virtanen, MSc.
August 2019. ____________________
Key words: eggs, cholesterol, stroke, apolipoprotein e4, prospective study
EGG CONSUMPTION, CHOLESTEROL INTAKE, AND RISK OF INCIDENT STROKE IN MEN: THE KUOPIO ISCHAEMIC HEART DISEASE RISK FACTOR STUDY
The association between egg consumption and cholesterol intake with risk of stroke remains unclear, and largely unexamined for apolipoprotein E4 (ApoE4) carriers who are genetically susceptible to increased intestinal cholesterol absorption. This study utilized data from middle aged and older men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study cohort of Eastern Finland. The aim of this study was to investigate the associations between egg consumption and cholesterol intake with the risk of incident stroke and blood pressure, a major risk factor for stroke, and whether phenotypical ApoE4 modified these associations.
Data on 1950 men from the baseline cohort without prior stroke or cardiovascular disease were examined in the study, of which 1939 had data available on blood pressure and 1015 for ApoE phenotype. During the mean follow-up of 21 years, 217 men were diagnosed with stroke, of which 166 were ischemic and 55 hemorrhagic strokes. Dietary consumption was assessed via four-day food records at baseline. The stroke diagnoses were obtained from the national health registries.
Neither egg nor cholesterol intakes were associated with risk of incident stroke in this study.
While comparing highest egg consumption quartile (up to one egg per day) with the lowest (less than 2 eggs/week), the multivariable-adjusted hazard ratios were 0.81 for total stroke (95% confidence interval (CI): 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI:
0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective hazard ratios for the highest cholesterol intake quartile (>459 mg/day) compared with the lowest (<333 mg/day) were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75).
Regarding blood pressure, subjects from the highest egg consumption quartile had an average of 1.6 mm Hg (P-trend = 0.04) lower diastolic blood pressure than those in the lowest
quartile. No associations were found with systolic blood pressure or cholesterol intake. The ApoE4 phenotype (found in 32% of the men) did not modify the associations with egg or cholesterol intakes and stroke risk or blood pressure.
The findings suggest higher intakes of egg and cholesterol are not associated with higher risk of any stroke type, even in a susceptible population, i.e. those with the ApoE4 phenotype. The study supports evidence that consuming up to one egg per day and cholesterol in moderation is not associated with increased risk of stroke.
ABBREVIATIONS ApoE – Apolipoprotein E CAD – Coronary artery disease CI – Confidence interval CVD – Cardiovascular disease
DASH – Dietary Approaches to Stop Hypertension
KIHD – Kuopio Ischemic Heart Disease Risk Factor Study NNR – Nordic Nutrition Recommendations
TIA – Transient ischemic attack USA – United States of America WHO – World Health Organization
ACKNOWLEDGEMENT
First and foremost, I am infinitely grateful for my supervisor, Dr. Jyrki Virtanen, for the diligent, speedy, and thorough support and guidance: Your professional accomplishments and methods of teaching are a continued inspiration. Especially, I thank you for your patience and confidence in me throughout this past year.
Moreover, I appreciate the time, dedication, and guidance of my second supervisor, Heli Virtanen: Amid a very pivotal and demanding time in your life, you were still available and supportive throughout the manuscript and thesis process. Thank you.
I would like to thank the other contributing authors, in particular Professor Dr. Tomi-Pekka Tuomainen and Dr. Sudhir Kurl who especially assisted me in navigating through the methods used in the KIHD study. Also, the University of Eastern Finland’s Department of Public Heath deserved thanks, especially coordinator Annika Männikkö and KIHD data manager Ari Voutilainen.
Lastly, I would like to thank my peers, who have weathered the many emotions that
accompany the learning process of scripting a thesis alongside me. I am eternally grateful for all the support and friendship.
TABLE OF CONTENTS
1. INTRODUCTION ... 7
2. LITERATURE REVIEW ... 9
2.1 Stroke defined ... 9
2.1.1 Stroke types defined ... 9
2.1.2 International classification of diseases and stroke ... 10
2.2 Stroke epidemiology ... 10
2.2.1 Cost of stroke in Finland ... 11
2.3 Risk factors for stroke ... 11
2.4 Dietary recommendations for stroke prevention ... 13
2.5 Dietary recommendations for egg and cholesterol ... 13
2.5.1 Dietary recommendations for cholesterol ... 14
2.6 Egg nutritional value ... 15
2.6 Egg consumption ... 15
2.9 Cholesterol and risk of stroke ... 17
2.8 Egg consumption and risk of stroke ... 17
2.8.1 Mechanistic pathways related to egg consumption and increased risk of stroke .... 21
2.10 Cholesterol consumption and blood pressure ... 21
2.11 Egg consumption and blood pressure ... 22
2.11.1 Possible mechanisms of egg consumption on reduced blood pressure ... 23
2.13 Impact of ApoE genotype ... 23
2.13.1 Apo-E4 allele and stroke risk ... 24
2.14 Conclusion ... 24
3. AIMS ... 25
4. REFERENCES ... 25
5. APPENDIX 1. Preprint version of the published manuscript ... 36
LIST OF TABLES
Table 1. Risk factors of stroke ... 12 Table 2. Nutrition facts of egg (55g) without shell ... 16 Table 3. Review of descriptive qualities and results of 13 prospective cohort studies with egg intake as exposure and total stroke as an outcome ... 19
1. INTRODUCTION
Stroke is a leading cause of death and disability worldwide (Johnson et al. 2016). The most common form of stroke is ischemic stroke, attributing to over 85% of stroke cases, with hemorrhagic stroke following (Mozaffarian et al. 2016). Major risk factors for stroke are untreatable, such as age, gender, and personal and/or family history of stroke. However, there are many risk factors for stroke that can be influenced by lifestyle modification. Such
modifiable risk factors include limiting smoking and heavy alcohol consumption and treatment of hypertension, dyslipidemia, diabetes, and obesity. (AHA 2019). The latter four are greatly influenced by dietary habits.
There is disagreement about whether specific limitations on dietary cholesterol should be advised for healthy populations and those at higher risk for stroke (Clayton et al. 2017). The previous Dietary Guidelines for Americans recommended limiting cholesterol intake for the general public, with even stricter recommendations for those at higher risk for cardiovascular events (USDA 2010). However, this recommendation was recalled in the current Dietary Guidelines (USDA 2015), as there currently is not enough research to support a significant association with dietary cholesterol and serum cholesterol or adverse effects. Nevertheless, in the past decade, eggs have been villainized due to their high cholesterol content (Spence, Jenkins et al. 2010). Worldwide, there are recommendations that limit egg or cholesterol intake for both healthy population and those at increased risk for CVD still (FAO 2019, Heart Foundation 2019, Heart UK 2019, HSFC 2018, Indian Heart Association 2019), including the many Finnish authorities (Finnish Heart Association 2016, Finnish Medical Society
Duodecim 2017, Fogelholm 2014). However, the Nordic Nutrition Recommendations and the World Health Organization (WHO) do not include a specific upper intake level for cholesterol or a recommendation limiting egg consumption (Nordic Council of Ministers 2014, WHO 2018).
Though slightly varying by size, species, and feed of hen, an average egg contains roughly 200 mg of cholesterol (Aro 2015). Furthermore, eggs are a source of fat, protein, and many micronutrients and antioxidants (Nordic Council of Ministers 2014). The average Finn consumes over four eggs in one week - a trend that has remained fairly stable in the past decades (Niemi & Väre 2017).
Meta-analyses assessing cholesterol intake and stroke risk (Berger et al. 2015, Cheng et al.
2018) have reported mostly null associations, though a recent meta-analysis found an
increased dose response (Zhong et al. 2019). Previous meta-analyses investigating the
association between egg intake and stroke risk have been even more conflicting, with findings reporting increased (Zhong et al. 2019), decreased (Alexander et al. 2016, Xu et al. 2019), and no associations (Rong et al. 2013). A major risk factor for stroke is high blood pressure (AHA 2019). There is little evidence on the effects of egg and cholesterol intakes on blood pressure, with studies reporting mostly beneficial associations from egg consumption (Xu et al. 2019) and potential harm from dietary cholesterol (Sakurai et al. 2011, Stamler et al. 2002). This controversy merits a need to further research egg intake in association with vascular events, such as stroke.
Carriers of apolipoprotein E4 (ApoE4) may be more susceptible to increased intestinal cholesterol absorption (Mahley & Rall 2000) and have shown to have an increased risk of coronary diseases (Mahley & Rall 2000, Song et al. 2004, Xu et al. 2016). ApoE4 carrier status has more than double the prevalence in Finland when compared globally (ALZGENE 2010, Ehnholm et al. 1986). No previous research has been conducted on the associations of egg and cholesterol consumption with stroke risk comparing ApoE4 allele carriers with noncarriers.
This study was conducted to determine the association between egg and cholesterol intake with total, ischemic, and hemorrhagic stroke risk. Additionally, this study investigated the potential modifying effects of the ApoE4 phenotype and the associations of egg and cholesterol intake with both systolic and diastolic blood pressure. The prospective,
population-based Kuopio Ischaemic Heart Disease and Risk Factor (KIHD) study provided a data platform for this research, as it has compiled nutritional, medical, and genetic data from about 2,600 middle-aged men in Eastern Finland. To the best of our knowledge, the
association between egg consumption and cholesterol intake with stroke incidence has not previously been explored in Finland.
2. LITERATURE REVIEW 2.1 Stroke defined
Stroke, in the broadest sense, is the death of cerebral cells due to lack of blood flow. The WHO defines stroke as “a clinical syndrome consisting of a rapidly developing clinical signs of focal (or global in case of coma) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin”
(WHO 1988). It is the third leading cause of death in Finland and second leading cause of death around the world (Johnson et al. 2016, THL 2017). In 2016, the World Health
Organization (WHO) called for global response on stroke prevention and management, due to the growing prevalence of death and disability worldwide (Johnson et al. 2016).
2.1.1 Stroke types defined
The disturbance to the brain’s oxygen supply via blood is most commonly caused by a block in a blood vessel, known as an ischemic stroke, or bleeding of a blood vessel, known as a hemorrhagic stroke. Approximately 87% of strokes are ischemic and 10% hemorrhagic (Mozaffarian et al. 2016). The origin of these strokes are atherosclerosis or embolisms and, respectively, hypertension (Meretoja 2012). These two subtypes are most commonly used in epidemiological studies, as they are the most common forms of stroke.
Due to the ambiguity in definition, there are many subtypes of stroke beyond ischemic (clotted blood vessel in route to brain) and hemorrhagic stroke (ruptured blood vessel within the brain). Subarachnoid hemorrhage is a ruptured blood vessel into the subarachnoid space outside of the brain. However, because of the uncertainty in diagnoses in the absence of brain damage, subarachnoid hemorrhage is often left out of epidemiological studies. Other
diagnoses are sometimes classified under stroke, depending on the coding system or research inclusion criteria, include hypoxic-ischemic encephalopathy, infarct inducing cerebral venous thrombosis, or ill-defined/undefined stroke. The latter encompasses all strokes that are
undefined by imaging or autopsy, yet clinically diagnosed as stroke. (Meretoja 2011).
It is noteworthy to add that if stroke symptoms manifest less than 24 hours, by WHO definition, the diagnosis is given as a transient ischemic attack (TIA) (WHO 1988). Usually lasting less than an hour, TIAs are often deemed as a “warning sign” for stroke, as 10% of TIA patients in Finland have a stroke within one week of diagnosis. In Finland, TIAs that last
over 1-2 hours are often investigated further with imaging to determine if ischemic stroke is the underlying pathology after all. (Atula 2019).
2.1.2 International classification of diseases and stroke
The WHO-based International Classification of Diseases (ICD) is used for diagnosis of diseases worldwide. As disease understanding has increased, the ICD codes are updated to accurately reflect proper diagnosis. (WHO 2019). In regard to epidemiological research, it is important to understand the version and its corresponding diagnoses definitions during time of diagnosis in the study period.
Notable changes between ICD versions nine and ten in stroke include addition of
differentiation in etiology for ischemic stroke and subdivision of intracerebral stroke and subarachnoid hemorrhage (Meretoja 2011, WHO 2019). The code versions ICD-9 were used in Finland from 1987-1995 and ICD-10 since 1996 onward (Meretoja 2011). Long-
established cohort studies, like the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD), will have used both ICD versions nine and ten.
The eleventh version, which was released in 2018 (WHO 2019), has classified stroke, a cerebrovascular disease, under a nervous system disease instead of circulatory, or otherwise known as cardiovascular, disease (Wiseman 2018). This separation of stroke and
cardiovascular diseases (CVDs) has received support of the World Stroke Association, who hypothesize more attention in research and policy to focus on stroke risk and care,
consequently. However, stroke and CVD remain related in practice, research, and literature, as both share common risk factors and etiologies (Wiseman 2018). ICD-11 should be in use by all WHO member states, including Finland, by 2022 (WHO 2019).
2.2 Stroke epidemiology
In 2013, it was estimated the incidence of ischemic and hemorrhagic stroke was 10.3 million (Feigin et al. 2015). It was the second leading cause of death globally, responsible for 12% of all-cause mortality, and third leading cause of disability, responsible for 4.5% of all-cause disability adjusted life years (Feigin et al. 2017). Overall, the incidence of stroke has declined in high income countries, while the burden of stroke has increased three-fold in developing countries (Feigin et al. 2015).
About 1.5% of the Finnish population has suffered from stroke, amounting to over 80,000 persons (Meretoja et al. 2010). In Finland, there are a predicted 11,500 first incident strokes annually, of which 79% of are ischemic and 14% hemorrhagic (Meretoja 2012). The National Institute for Health and Welfare predicted that in 2014, 4428 people died of stroke in Finland.
About nine percent of all deaths in Finland can be contributed to stroke, whereas worldwide stroke as a cause of death amounts to 12%. (THL 2017).
The reported average age of a stroke victim is 75-years old, which is a particularly concerning statistic since the population of elderly Finns has tripled since the seventies (Meretoja 2012).
Even though the incidence of stroke has risen over the last fifty years, the prevalence of stroke has declined in Finland. Likewise, stroke mortality after the first three months of stroke reduced 32% between 1970-2012, which could be attributed to better quality and response of primary and secondary care. (Meretoja 2012). Of the Finnish population over 70 years old, it is estimated that 20% of strokes are undiagnosed (Lindsberg et al. 2016).
2.2.1 Cost of stroke in Finland
An average of 1.1 million euros is spent on stroke patient care annually in Finland, which amounts to about 7% of the total healthcare costs. About 5% of these costs are directly due to stroke, which is comparable to similar western countries (Meretoja 2012). The average lifetime healthcare cost is over 86,000 euros per stroke victim, out of which the first year alone averages over 20,000 euros per ischemic stroke patient and over 24,000 euros per hemorrhagic stroke patient. (Meretoja 2012, Meretoja et al. 2010).
2.3 Risk factors for stroke
Risk factors for stroke are both modifiable and constitutional. The former refers to risk factors that are affected either by lifestyle changes or medical treatment while the latter is hereditary or unaffectable (refer to Table 1). The risk factors for stroke include hypertension, smoking, dyslipidemia, diabetes, presence of CVD or chronic kidney disease, obesity, abdominal obesity, and sedentary lifestyle. (AHA 2019, Lindsberg et al. 2016). Of these, the most prevalent modifiable risk factors influenced by lifestyle changes include hypertension and smoking. Compared to nonsmokers, there is double the risk of stroke for smokers. Likewise,
those with hypertension have a 1.5-times higher risk of suffering from stroke. However, having diabetes may increase risk for stroke four-fold. (AHA 2019).
Constitutional risk factors include age, sex, ethnicity, family history of stroke, prior stroke or TIA, and certain circulatory disorders (AHA 2019, Lindsberg et al. 2016). The National Stroke Association reported that those aged 55-years double their risk of stroke every subsequent decade (AHA 2019). Presumably due to a longer average lifespan, there is a higher prevalence of stroke in females compared to males, as stroke risk increases with age.
Nevertheless, more males suffer from stroke during younger ages. In regard to ethnicity, compared to populations of Caucasian decent, African American, Hispanic, and Asian populations are at increased risk for stroke. Having a previous stroke and TIA can increase risk of stroke up to 17% shortly after the episode. Disorders that effect blood clotting and flow can also increase risk of stroke, including patent foramen ovale and fibromuscular dysplasia. (AHA 2019).
Table 1. Risk factors of stroke
Risk factors for stroke1
Modifiable Constitutional
Lifestyle Medical
Diet
Physical activity Smoking Alcohol use
Psychosocial factors
Obesity/abdominal obesity
Hypertension Atherosclerosis Atrial fibrillation Diabetes
CVD or chronic kidney disease
dyslipidemia
Age Gender
Race and ethnicity Family history Previous stroke /TIA Circulatory disorders
1 Data from American Heart Association and Finnish Ministry of Health and Welfare (AHA 2019, Lindsberg et al. 2016)
Prevention strategies are aimed towards lifestyle changes, such as smoking, hypertension, dyslipidemia, and abdominal obesity (Lindsberg et al. 2016, O’Donnell et al. 2016) and include change in smoking status, use of diuretics (and other medications for hypertension) and statins, weight loss, increased physical activity and modified dietary patterns. Excluding smoking, dietary habits influence most of the modifiable risk factors. (AHA 2019, Lindsberg et al. 2016). For example, the risk of stroke is reduced 40% by treatment of hypertension (Mackay & Mensah 2004), which can be achieved through diet (AHA 2018).
2.4 Dietary recommendations for stroke prevention
The United State National Institute of Health recommends the Dietary Approaches to Stop Hypertension (DASH) diet for reduction of risk for CVD and stroke (AHA 2018). This diet is also promoted by the United States Dietary Guidelines 2015-2020 for the general population (USDA 2015). The DASH diet emphasizes vegetable, fruit, whole grain, low fat dairy and protein sources, as well as limiting sugar-sweetened beverages and foods high in saturated- and trans-fat (Appel et al. 1997). Another promoted diet for general vascular health is the Mediterranean diet (USDA 2015), with focus on mono- and polyunsaturated fats from
vegetable oils, like olive oil, fish, vegetables, fruit, nut and legume consumption coupled with lower intakes of dairy and meat. Guidelines similar to these two dietary patterns are
recommended by stroke prevention organizations, such as the National Stroke Association and American Heart Association (AHA 2015).
The DASH diet has proved to be effective in lowering both systolic and diastolic blood pressure, especially when coupled with reduction of sodium intake (Appel et al. 1997, Juraschek et al. 2017). An experimental trial compared low (1150 mg/d) and high (3450 mg/d) sodium intake for the DASH and control diets on systolic blood pressure. Systolic blood pressure was most reduced when reduced sodium and the DASH diet were combined, with a 21 mm Hg average decrease in systolic blood pressure when compared with the increased sodium control diet. (Juraschek et al. 2017).
As previously mentioned, the Mediterranean diet, which is heavily plant-based with low intake of meat and dairy products traditionally seen in countries in the Mediterranean region, is also recommended for stroke prevention (USDA 2015). A recent meta-analysis found that the risk of stroke was reduced 24% with greater adherence to the Mediterranean diet
compared to those least adherent in five prospective cohorts, with similar findings when pooling two randomized controlled trials (Grosso et al. 2017). Likewise, a previous meta- analysis reported a 29% reduced risk of stroke with high adherence to a Mediterranean diet (Psaltopoulou et al. 2013).
2.5 Dietary recommendations for egg and cholesterol
Globally, there has been much debate on whether cholesterol should be included in dietary recommendations for healthy populations and those at higher risk for vascular diseases (Clayton et al. 2017). Since egg yolks are a significant source of dietary cholesterol, there are
often recommendations limiting consumption also (FAO 2019). However, since dietary cholesterol only moderately affects serum cholesterol concentrations (Hopkins 1992), both egg and cholesterol recommendations vary.
2.5.1 Dietary recommendations for cholesterol
Regarding cholesterol, the WHO has not placed restricting recommendations on cholesterol, but rather focuses on controlling saturated and trans-fat intake, which have shown to be effective in moderation of blood cholesterol concentrations (WHO 2003, 2018). This is congruent with the national dietary guidelines of many developed and developing countries (FAO 2019). The United States Dietary Guidelines 2015-2020 conclude that there is not enough evidence to recommend a limit for cholesterol consumption for the general
population. However, it still states that a healthy eating pattern should contain as little dietary cholesterol as possible (USDA 2015). Prior to 2015, the cholesterol recommendation was restricted to 300 mg per day for healthy individuals and under 200 mg for those concerned with vascular health (USDA 2010). According to the Nordic Nutrition Recommendations, there is no upper intake level for cholesterol (Nordic Council of Ministers 2014).
Finnish nutrition recommendations, which are based on the Nordic Nutrition
Recommendations, have no specific recommendations on cholesterol (Fogelholm 2014). For persons with dyslipidemia, the Finnish Medical Society Duodecim recommends no more than 300 mg per day (Finnish Medical Society Duodecim 2017). Furthermore, the Finnish Heart Association recommends no more than 200 mg of dietary cholesterol a day for those with hypercholesterolemia or CVD (Finnish Heart Association 2016).
2.5.2 Dietary recommendations for egg consumption
The WHO does not place recommendations on egg consumption (WHO 2018).
Internationally and nationally, recommendations vary. Many countries, such as Spain, Greece, the Netherlands, and Germany, include a recommended limit for egg consumption, where many do not, including Japan, Canada, USA, Australia, and England (FAO 2019). However, many heart organizations recommend a strict limit, especially for those suffering from familial or personal hypercholesterolemia, such as India (Indian Heart Association 2019), Australia (Heart Foundation 2019), Canada (HSFC 2018), and England (Heart UK 2019).
Similarly, the Finnish nutrition recommendations state that adults with CVD should limit consumption of egg yolks to 3-4 per week (Fogelholm 2014) and it is also endorsed by the Finnish Heart Association (Finnish Heart Association 2016). Even more strictly, for persons with dyslipidemia the Finnish Medical Society Duodecim recommends no more than 2 egg yolks per week (Schwab 2017).
2.6 Egg nutritional value
Eggs are a low-cost, nutrient-dense food that are rich in protein, fat, and cholesterol. Eggs are a source of micronutrients including vitamin A, B, D, choline, and iron (Table 2). The yolk lipid contains 1% carotenoid pigments carotene and xanthophylls, like lutein and zeaxanthin.
The bioavailability of these carotenoids is higher in egg yolk compared to plant-based sources, due to the high fat content of eggs. Eggs are also rich in antioxidants, including the aforementioned carotenoids, vitamin E, and phospholipids. (Nimalaratne & Wu 2015). Most reservation in egg consumption and justification for limiting recommendations are linked to the high amounts of cholesterol in egg yolk. Like most nutrients, the amount varies between eggs, however, the average is about 200 mg per egg (Aro 2015). In addition, choline, which intestinal flora in turn converts to trimethylamine that is then oxidized to trimethylamine n- oxide (TMAO) in the liver, has fostered reservation in egg consumption, mainly because studies have associated TMAO with increased atherosclerosis and CVD risk (Spence 2018, Tang et al. 2013).
2.6 Egg consumption
Eggs are an affordable source of nutrients that are used in a wide variety of cultures. In the past two decades egg production has risen globally 80%, amounting to an increase of over 30 million tons of egg. Countries leading in egg consumption include Mexico and Japan, with over 300 eggs consumed per capita in 2014. Comparison of national consumption data from 2010 to 2014 found that amount of eggs consumed has risen in countries, including Finland, Sweden, Germany, Netherlands, and USA. (IEA 2015).
Egg consumption in Finland has risen slightly in the past decade, with 11.9 kg (roughly 216 eggs) of eggs per capita consumed in 2016, or about 4.2 eggs weekly per person. However, when comparing over a long period, egg consumption in Finland has remained fairly stable.
For instance, current egg consumption is similar to the amount of eggs consumed in 1980s (11.7 kg) when the KIHD study began. (Kortesmaa 2018, Niemi & Väre 2017).
Table 2. Nutrition facts of egg (55g) without shell
Nutrient1 Amount1
Energy 74 kcal
Macronutrients
Protein 6.9 g
Lipid (fat) 5.1 g
Carbohydrate 0.2 g
Lipids
Cholesterol 198.0 mg
Saturated fat 1.3 g
Trans fat <0.1 g
Monounsaturated fat 2.0 g Polyunsaturated fat 0.7 g Omega-3 polyunsaturated fatty
acid
<0.1 g Omega-6 polyunsaturated fatty
acid
0.6 g
Micronutrients Vitamins
Vitamin A 144.7 mcg
Vitamin B12 1.4 mcg
Vitamin D 1.2 mcg
Folate 32.1 mcg
Minerals
Calcium 31.4 mg
Phosphorus 115.5 mg
Iron 0.9 mg
Sodium 60.7 mg
Selenium 18.1 mg
Other
choline2 147.0 mg
lutein3 700.7 mcg
zeaxanthin3 426.3 mcg
1. Data from Finnish Health and Welfare Ministry unless otherwise specified (THL 2019) 2. Data from the United States National Institute of Health and Schlatter and Breithaupt (National Institute of Health 2018, Schlatterer & Breithaupt 2006)
3. Estimates vary depending on hen feed, reported values are lower estimates of food analysis (Schlatterer & Breithaupt 2006).
2.9 Cholesterol and risk of stroke
The evidence between cholesterol intake and stroke is scarce and controversial. A pooled analysis of six cohorts from USA found that every additional daily intake of 300 mg
cholesterol was associated with a 26% increased risk of stroke (Zhong et al. 2019). However, a recent meta-analysis conducted in 2018 with over 260,000 participants from seven
prospective studies found no association between high cholesterol intake (>300 mg/day) and risk of total stroke, ischemic stroke, or hemorrhagic stroke (Cheng et al. 2018). There remains speculation of the effects of gender, age, and body mass index (Cheng et al. 2018). For
instance, the meta-analysis showed 13% decrease in risk for those studies whose participants were on average under the age of 60, but an 18% increased risk was observed with the studies where average age was over 60 (Cheng et al. 2018). However, it should be noted that in the latter, only two studies were eligible to be assessed and both included only female participants with an average BMI over 24 (Larsson et al. 2012, Yaemsiri et al. 2012). No difference in association was observed in the three studies from USA and three from Japan in a country sub-analysis (Cheng et al. 2018).
Likewise, an earlier meta-analysis of five studies (Berger et al. 2015) found no statistically significant association between cholesterol intake and risk of ischemic stroke. A similar lack of association was reported in a meta-analysis of three studies that included hemorrhagic stroke (Berger et al. 2015). Due to lack of available studies, Berger et al. were unable to report associations between cholesterol intake and total stroke risk. However, likewise, the Nurses’
Health Study (Iso et al. 2001) reported no association with cholesterol intake and total stroke risk. Conversely, the Swedish Mammography Cohort observed an increased risk, though it should be noted that the study population here was only females with average age over 60 and BMI over 24 (Larsson et al. 2012).
2.8 Egg consumption and risk of stroke
Overall, there is little research specific to egg consumption and stroke risk, especially on different stroke subtypes. The majority of the evidence suggests no association between egg consumption and stroke risk (Bernstein et al. 2012, Djousse & Gaziano 2008, Haring et al.
2015, He et al. 2003, Hu et al. 1999, Larsson et al. 2015, Nakamura et al. 2004, Qureshi et al.
2007, Xu et al. 2019, Yaemsiri et al. 2012). However, the evidence that exists remains conflicting, as studies have also found both increased (Zhong et al. 2019) and decreased risk
(Sauvaget et al. 2003, Scrafford et al. 2011). Review and meta-analysis of eight prospective cohort studies reported no association between egg consumption and total stroke risk.
Furthermore, subgroup analysis of four studies showed that higher egg intake was associated with a 25% decreased risk for hemorrhagic stroke. (Rong et al. 2013)
Nevertheless, a recent pooled analysis from six studies in USA found that egg consumption associated with a 10% increased risk of total stroke. However, the analyses did not include associations with ischemic or hemorrhagic stroke in separate. The study suggests that both egg consumption and cholesterol are interdependently associated with stroke risk, as both egg and cholesterol had associations, which were attenuated after adjustment for the other. The increased risk was theorized to be associated with stroke via different metabolic pathways of choline and iron (Zhong et al. 2019), which are described in the succeeding subheading.
However, several observational studies have reported inverse association with egg intake and stroke. Xu et al. performed an updated meta-analysis, which included three (Hu et al. 1999, Larsson et al. 2015, Xu et al. 2019) additional cohort studies for stroke risk analysis when compared to earlier meta-analysis (Rong et al. 2013). A 9% decrease in total stroke risk was observed when comparing higher (over an egg per day) and lower (less than an egg a week) egg consumption, although this was not seen in the sub-analysis with either ischemic or hemorrhagic stroke (Xu et al. 2019)
Similarly, a 2016 meta-analysis of seven studies, which had added data from the Women’s Health Initiative observational study to the meta-analysis conducted in 2013 (Rong et al.
2013), observed a 12% decreased risk in total stroke when comparing those who consumed egg daily with those who had less than two eggs per week. (Alexander et al. 2016).
Interestingly, when isolating studies from USA, egg consumption has been associated with increased risk of type 2 diabetes (Djoussé et al. 2016, Tamez et al. 2016). This association has been attributed to confounding by unfavorable lifestyle, dietary pattern, and cooking methods related to high egg consumption (Tamez et al. 2016). However, regarding stroke risk, a meta- analysis isolating five studies conducted in USA found a 10% reduced risk, with majority of the weight from the National Health Study and Health Professionals Follow-up Study cohort data. (Alexander et al. 2016). Nonetheless, these results were not consistent with the most recent pooled analysis of six studies from USA, which reported egg consumption associated with an increased risk of stroke. (Zhong et al. 2019).
A brief overview of individual studies is summarized in Table 3. In comparing studies, it is important to note the different outcomes; some researchers define outcome as stroke
incidence, while others use only stroke mortality. Moreover, the table excludes results of ischemic and hemorrhagic stroke separately, however, these sub-analyses show similar results, mostly indicating no association (Bernstein et al. 2012, Haring et al. 2015, Hu et al.
1999, Larsson et al. 2015, Qureshi et al. 2007, Xu et al. 2019, Yaemsiri et al. 2012).
Table 3. Review of descriptive qualities and results of 13 prospective cohort studies with egg intake as exposure and total stroke as an outcome
Author (year of article) Country
Outcome
Number of subjects (cases)
Mean follow- up in years
Sex (age)
Results1
(7+ eggs/week v. <1 egg/week)
Zhong et al.
(2019) USA
Total stroke
29 615 (1302)
17.5 Both
(mean 51.6
±13.5)
HR: 1.10 (95%CI: 1.02, 1.19) (for each additional half egg consumed per day)
Xu et al.
(2019) China
Stroke mortality
275 343 (341)
9.8 Both
(50+)
HR: 0.88 (95%CI: 0.57, 1.35)
Haring et al.
(2015) USA
Total stroke
11 600 (699)
6 Both
(45-64)
RR: 1.08 (95%CI: 0.84, 1.39) (0 v. 1 serving /day)
Bernstein et al. (2012) USA
Total stroke
127160 (4030)
22 (male) 26 (female)
Both (30-75)
RR: 0.89 (95%CI: 0.80–1.00) (0.79 v. 0.02 servings /day)
Scafford et al. (2011) USA
Stroke mortality
6833 (63)
8.8 Male
(17+)
RR: 0.27 (95%CI: 0.10, 0.73)
Scafford et al. (2011) USA
Stroke mortality
8113 (74)
8.9 Female
(17+)
RR: 1.03 (95%CI: 0.25, 4.22)
Continued Author (year of article) Country
Outcome
Number of subjects (cases)
Mean follow- up in years
Sex (age)
Results1
(7+ eggs/week v. <1 egg/week)
Djousse et al. (2008) USA
Total stroke
21327 (1342)
20 Male
(40-85)
HR: 0.99 (95%CI: 0.80, 1.23)
Qureshi et al. (2007) USA
Total stroke
9734 (655)
20 Both
(25-74)
RR: 0.90 (95%CI: 0.70, 1.10) (>6 eggs/week v. <1
egg/week) Nakamura*
et al. (2004) Japan
Stroke mortality
5186 (107)
14 Female
(30+)
RR: 1.22 (95%CI: 0.29, 5.17) (>2eggs/day v. <1 egg/week) Nakamura*
et al. (2004) Japan
Stroke mortality
4077 (112)
14 Male
(30+)
RR: 0.25 (95%CI: 0.03, 1.81) (>2eggs/day v. <1 egg/week) Sauvaget et
al. (2003) Japan
Stroke mortality
40 349 (1462)
16 Both
(34-103)
RR: 0.72 (95%CI: 0.54, 0.97) (5+eggs/week v. <1
egg/week) He et al.
(2003)
Total stroke
43 732 (725)
14 Male
(40-75)
HR: 0.73 (95%CI: 0.24, 2.25)
Hu et al.
(1999) USA
Total stroke
80,082 (563)
14 Female
(34-59)
RR: 0.89 (95%CI: 0.60, 1.31)
Hu et al.
(1999) USA
Total stroke
37,851 (258)
8 Male
(40-75)
RR: 1.07 (95%CI: 0.66, 1.75)
1. Results from multivariable adjusted models. Reported hazard ratio or relative risk based on 7+ eggs/week versus <1 egg/week, unless otherwise specified. HR: Hazard Ratio, RR:
Relative Risk, CI: confidence interval.
2.8.1 Mechanistic pathways related to egg consumption and increased risk of stroke As mentioned above, some studies have found an association between egg consumption and stroke risk. The cholesterol in egg yolk has been hypothesized to promote dyslipedimia (Zhong et al. 2019), a risk factor for CVD and stroke, even though dietary cholesterol has little effect on serum cholesterol for the general population (Hopkins 1992, USDA 2015). In addition to the cholesterol in egg yolk, some mechanistic pathways, such as TMAO and iron have been theorized to contribute to this association. (Zhong et al. 2019). Dietary choline, found in egg yolk, can be metabolized to TMAO, which has been associated with CVD events. For example, a study investigating the effects of TMAO found that increased TMAO levels associated with major cardiovascular events, which included stroke. However, stroke risk was not assessed separately in this study (Tang et al. 2013). Two similar observational studies did not find any association with choline intake and stroke risk (Dalmeijer et al. 2008, Millard et al. 2018).
A lesser proposed theory behind egg consumption and increased stroke risk has been
attributed to the increased intake of iron from egg, as increased iron status has been associated with increased risk of stroke by promoting atherosclerosis and blood coagulation. However, low iron status is also associated with increased stroke risk, suggesting a nonlinear curve.
(Gill Dipender et al. 2018). Considering further evidence that observed egg intake to have no effect on iron stores (Rigas et al. 2014), this mechanism at best is poor in explanation.
2.10 Cholesterol consumption and blood pressure
Compared to egg intake, considerably less research has been conducted to explore the associations between cholesterol intake and blood pressure. However, two observational studies have found cholesterol intake to be independently related to increased systolic blood pressure (Sakurai et al. 2011, Stamler et al. 2002), and one trial found cholesterol intake independently related to increased diastolic blood pressure (Stamler et al. 1996).
The Chicago Western Electric Study explored blood pressure change in relation to multiple nutrients in middle aged men over an eight-year period and found an independent positive relationship for cholesterol intake and annual change in average systolic blood pressure, but not diastolic blood pressure. The average amount of dietary cholesterol consumed by study participants was 236 mg per 1000 kilocalories. However, even after adjustment of age,
education, height, weight, dietary factors, and cigarette use, there was only a marginal 0.0018 mm Hg increase per year in systolic blood pressure. (Stamler et al. 2002).
A more recent cross-sectional analysis from the International Study of Macro/Micro-nutrients and Blood Pressure collected data from four countries (Japan, China, United Kingdom, and USA) with 4680 participants to assess the relationship of cholesterol intake and blood pressure. Similar to the previously mentioned observational study, the authors reported that cholesterol intake was related to increased systolic but not diastolic blood pressure. After adjustment for confounders, such as age, gender, physical activity, family history of hypertension, urinary sodium and potassium, and diet, alcohol and supplement intake, the estimated mean difference in systolic blood pressure was 0.9 mm Hg with two standard deviations higher cholesterol intake at 131 mg per 1000 kilocalories. However, after gender- specific sub-analysis, this relationship was only maintained in women. Likewise, the
significant finding was attenuated after further adjustment of height and weight. (Sakurai et al. 2011).
The Multiple Risk Factor Intervention Trial, which investigated associations between various dietary components and blood pressure, found dietary cholesterol to be independently related to diastolic blood pressure, but not systolic blood pressure. For this study of over 11,000 middle-aged men, a statistically significant linear increase in diastolic blood pressure with cholesterol intake was observed. (Stamler et al. 1996).
2.11 Egg consumption and blood pressure
A recent cross-sectional analysis on a Chinese cohort reported inverse associations with both systolic and diastolic blood pressure with higher egg intake (Xu et al. 2019). In a crossover trial with healthy participants aged 18-30 years, three eggs daily for four weeks had no effect on systolic blood pressure, however, there was a statistically significant decrease in diastolic blood pressure with increased egg consumption (DiMarco 2017). Another randomized controlled crossover trial of adults found that daily intake of egg had no effect on blood pressure (Katz et al. 2005).
Observational studies (Golzarand et al. 2016, Lee & Park 2018, Qureshi et al. 2007) support these findings also. According to a 3-year prospective study, higher egg consumption was associated with decreased incidence of hypertension (Golzarand et al. 2016). Furthermore, the
Korean Genome Epidemiology Study reported an inverse association with their highest quintile of egg consumption and incident hypertension, however mean egg intake was considerably low (12.5 g/d) in this population (Lee 2017).
2.11.1 Possible mechanisms of egg consumption on reduced blood pressure The antihypertensive properties of ovotransferrin tripeptide IRW (isoleucine-arginine-
tryptophan) in egg whites has been hypothesized to cause beneficial effects in blood pressure.
Similar to antihypertensive drugs, this protein inhibits angiotensin type 1 receptors, which reduces blood pressure by inhibition of vascular smooth muscle remodeling (Liao et al. 2018).
An alternative explanation for this mechanism could be egg derived phospholipids, which are abundant in the yolk. A randomized, double blinded trial of adults with metabolic syndrome found a diet enriched with egg derived phospholipids improved endothelial vasodilatory function and reduced daytime systolic blood pressure (Skórkowska-Telichowska et al. 2016).
Another possible mechanism may include the antioxidants found in egg, which could inhibit oxidative stress and enhance vascular function, thus reducing blood pressure (Nimalaratne et al. 2011). However, without further research it is unclear to which mechanism the beneficial effect is attributable.
2.13 Impact of ApoE genotype
There are three alleles in apolipoprotein E (ApoE) genes; E2, E3, E4. Phenotypes are exhibited in combination variations: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, and E4/E4. The most common gene allele is E3 (79%) and least common E2 (7%). (ALZGENE 2010). ApoE is fundamental in cholesterol transport, homeostasis, and metabolism. ApoE4 gene has been associated with more efficient intestinal cholesterol absorption, however, whether this is due to dietary cholesterol or remnant metabolism remains unclear (Mahley & Rall 2000). The ApoE4 gene allele has been hypothesized to have originated from ancestral primates (Fullerton et al. 2000) and, in congruence with a meat-rich diet, evolution promoted the presently prevalent E3 allele, whose carriers have a lower risk of chronic disease and their risk factors (Finch & Stanford 2004, Huebbe & Rimbach 2017, Mahley & Rall 2000).
Regardless of the mechanism, there is no disagreement about the increased risk of chronic disease in ApoE4 carriers. Two meta-analyses identified ApoE4 carriers at a 42%-45%
increased risk for coronary heart disease (Song et al. 2004, Xu et al. 2016). ApoE4 carriers
have been found to have increased concentrations of LDL-cholesterol, which is a risk factor for stroke. (Bennet et al. 2007).
Due to enhanced cholesterol metabolism and increased coronary risk, there could be an assumed benefit for ApoE4 carriers to reduce intake of cholesterol-rich foods, including egg.
This genetic variance is of specific concern in Finland, as about one third of the population has the ApoE4 gene allele (Ehnholm et al. 1986), compared to a global prevalence of 14%
(ALZGENE 2010). Though carriers of this gene allele are more likely to absorb intestinal cholesterol more efficiently, analysis of middle aged and older men from Eastern Finland found that egg or cholesterol intakes were not associated with higher risk of coronary heart disease or carotid atherosclerosis in men with the ApoE4 allele (Virtanen et al. 2016).
2.13.1 Apo-E4 allele and stroke risk
The research between ApoE phenotype and stroke risk is controversial and varied by ethnicity. One meta-analysis on 26 case-control studies suggests that the ApoE4 phenotype increases risk for ischemic stroke, but when divided by ethnicities the positive association only existed with Asian populations (Kumar et al. 2016). Alternatively, a dose-response meta- analysis of 16 prospective and 58 case-control studies provided evidence that carriers of ApoE4 of all ethnicities did not have an increased risk of hemorrhagic stroke and had little relation to ischemic stroke risk, although ApoE4-carriers of only European ancestry had a positive associations with the latter (Khan et al. 2013).
The European ancestry dose-response between ApoE4 phenotype and stroke risk is
hypothesized to be caused by the concomitant LDL-cholesterol concentrations, as reduction in serum cholesterol concentrations via statins has been linked to decreased stroke risk,
excluding hemorrhagic stroke (Baigent et al. 2005, CTT 2012). Paradoxically, a meta-analysis of 61 prospective cohorts from North America and Europe found that only middle-aged men exhibited weak positive associations with LDL-cholesterol and ischemic stroke mortality (Prospective Studies Collaboration et al. 2007).
2.14 Conclusion
Even with the limited research on egg and cholesterol intake and stroke risk, there is increasing global evidence suggesting null association, though the topic remains
controversial. Further research is needed to fully elucidate the relationship between cholesterol-rich foods, like eggs, and cerebrovascular events. Moreover, due to the high nutrient density, acceptability, and availability of eggs, it is evidently important to investigate the food as a whole in conjunction with chronic disease. By studying egg consumption with various cerebro- and cardiovascular events, it can be ensured that both cholesterol and egg recommendations are based on scientific evidence.
3. AIMS
Even with increasing evidence worldwide suggesting no positive association between the consumption of eggs and stroke events, the topic remains controversial. The aim of this study was to explore the association between egg consumption and cholesterol intake with incidents of total, ischemic, and hemorrhagic stroke and blood pressure in the middle-aged men who participated in the KIHD study. Additionally, the aim was to investigate whether the ApoE phenotype could have an impact on the associations, since such data was not previously available.
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5. APPENDIX 1. The American Journal of Clinical Nutrition, Volume 110, Issue 1, July 2019, Pages 169–176, doi: https://doi.org/10.1093/ajcn/nqz066 - Final preprint manuscript version.
Egg consumption, cholesterol intake and risk of incident stroke in men: The Kuopio Ischaemic Heart Disease Risk Factor Study
Anna M. Abdollahi, Heli E.K. Virtanen, Sari Voutilainen, Sudhir Kurl, Tomi-Pekka Tuomainen, Jukka T. Salonen, Jyrki K. Virtanen
From the University of Eastern Finland, Institute of Public Health and Clinical Nutrition, P.O.
Box 1627, 70211 Kuopio, Finland (A.M.A., H.E.K.V., S.V., S.K., T.-P.T., J.K.V.) and the Faculty of Medicine, Department of Public Health (J.T.S.), P.O. Box 66, 00014 University of Helsinki, Finland.
Names for PubMed indexing: Abdollahi, Virtanen, Voutilainen, Kurl, Tuomainen, Salonen, Virtanen
Disclaimers: Dr. Virtanen reports that he has received a speaker's fee from the Finnish egg producer company Munax Ltd.
Address correspondence to Jyrki K. Virtanen, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, P.O. Box 1627, 70211 Kuopio, Finland. Phone: +358- 30-355 2957, Fax: +358-17-162 936, E-mail: jyrki.virtanen@uef.fi.
Reprints will not be available.
Source of support: University of Eastern Finland.
Running head: Egg and cholesterol intakes and stroke risk
Data described in this manuscript will not be made available, because it contains sensitive personal data of the subjects, which cannot be completely anonymized.
Abbreviations
Apo-E, apolipoprotein E CHD, coronary heart disease
ICD, international classification of disease
KIHD, Kuopio Ischaemic Heart Disease Risk Factor Study
Clinical trial registration: https://www.clinicaltrials.gov, Identifier: NCT03221127
