Stress: The Silent Killer. Chronic Stress and CVD

“Not everything that matters can be measured, and not everything that is measured matters.” – Elliot Eisner

Cardiovascular diseases (CVDs) are the number one cause of death globally. In 2008, more than 17 million people died from them. On a national level, based on the 2004-2005 National Health Survey, 3.7 million Australians are estimated to have existing cardiovascular problems; CVDs were the direct cause of 35% of total mortality in 2005, again the number one cause of death ^1,2. This is despite the billions of dollars spent on medications to reduce the risk and intensity of cardiovascular diseases ³. CVD is no longer considered a disorder of lipid (fat) accumulation, but rather a disease process characterized by low-grade inflammation of the vascular (artery) lining and an inappropriate wound healing of the blood vessels. The answer is to treat the cause of inflammation not cholesterol.

A study in 2004 known as the INTERHEART study found that 90% of all myocardial infarctions (heart attacks) could be attributed to nine potentially modifiable risk factors ^4,5. These factors include tobacco use, atherosclerosis, hypertension, diabetes, abdominal obesity, psychosocial factors, alcohol consumption, physical inactivity and poor diets ^4,6.

Despite convincing evidence linking psychosocial factors such as chronic and acute stress to the risks of cardiovascular disease ^7,8,9, there remains a lack of focus on stress reduction for the prevention and treatment of cardiovascular disease. Risk reduction for stress is low-cost, simple to administer, and “non-pharmaceutical” ¹⁰.

Stress is the failure of an individual to cope with an emotional or physical threat. It results in both psychological and physical effects on individuals by means of two main stress groups: acute stress and chronic stress. Chronic stress occurs from exposure to stressors such as family, society (traffic, population, etc.) and, almost all the time, the workplace. When the body is stressed, a large number of biological and chemical processes can occur that put the body at increased risk of CVD. Chemical mediators are released, which cause the prolonged activation of the sympathetic nervous system ⁷ and increase heart rate and blood pressure, which puts a lot of strain on the heart and cardiovascular system ¹¹. Over time, the strain on the system leads to deterioration of the heart muscle, arteries and vessels ¹¹. Chemical mediators can also result in sleep deprivation, elevated cortisol levels, elevated insulin and blood glucose levels and increases in ghrelin, the hormone that increases appetite ¹¹.

Chronic stress, which is what we are often confronted with in our daily busy lives, plays a huge role in these increases, as it can cause the prolonged activation of the sympathetic nervous system ⁷. This results in an increase in blood pressure and heart rate, which remain elevated, leading to an increased risk of cardiovascular disease. In extreme circumstances this is also linked with endothelial dysfunction (inability of arteries to dilate) and possible necrosis of artery walls ⁷.

Stress increases the release of hormones like cortisol, adrenaline and noradrenaline, which act to increase the heart rate and contractile volume, as well as constricting arteries in the gastrointestinal tract, whilst dilating those in the periphery. Aldosterone and vasopressin, two lesser hormones in the stress response, are also released and act to increase blood volume through increased water retention. One of the functions of cortisol is to increase the concentration of fatty acids carried by lipoproteins and sugars in the bloodstream, leading to more damage to the arterial wall, producing excessive levels of cholesterol that may then bond to the artery walls (and lead to high cholesterol readings by your doctor), a process called atherosclerosis ¹². Atherosclerosis is the process in which a blood vessel wall thickens due to a build-up of fatty substances. The combined effect of these hormones is a marked increase in blood pressure, which may over time result in damage to the vascular tissue in the form of small micro-tears in the vessel walls. These minute tears heal by bonding with molecules floating in the blood (that is, cholesterol acts as a Bandaid). This cholesterol then forms a hard fibrous plaque with calcium, which may build up over time, constricting blood flow in the artery. Stress also causes the blood to become stickier in preparation of potential injury, increasing the likelihood of an artery‑clogging blood clot ¹³. One study found that those who expressed feeling high levels of stress and despair had a 20% greater chance of developing atherosclerosis over a four-year period. This was the same magnitude of increased risk as seen in a pack-a-day smoker.  Studies on animals have shown similar results. A study on hypertensive rats and normal rats found that the hypertensive rats suffering from stress had a higher rate of these events ¹⁴.

There is a large body of evidence demonstrating the relationship between increased stress and increased CVD. A study commenced before the terrorist attacks in the U.S. on September 11, 2001 examined the degree to which acute stress reactions as a result of the terrorist attacks could predict future cardiovascular outcomes through follow-up surveys over three years ¹⁵. In a sample of 2,592 adults, researchers found that the acute stress response was associated with a 53% increased incidence of cardiovascular ailments ¹⁵. Those individuals who had high levels of acute stress following the attacks also reported a two-fold increase in physician-diagnosed hypertension and a three-fold increase in other heart-related problems over the three-year period.

In a study of 11,119 patients found that those patients who had experienced a myocardial infarction reported a higher prevalence of all four stress factors: stress at home, stress at work, financial stress and major life events in the prior year ¹⁶. The study also found that the four stress factors worsened coronary atherosclerosis and endothelial dysfunction and increased inflammation ¹⁶.

The Whitehall II study found a 2.15-fold (215%) increased risk for cardiovascular disease in men who experienced a disparity between effort and reward at work ¹⁷. The study also concluded that high-risk individuals included those who were overcommitted at work, had poor promotion prospects, blocked or stalled careers as well as competitive and hostile work environments. Similarly, in a study of nearly two thousand male workers over a six-year period, researchers found that those who experienced chronic work-related stress were four times more likely to experience cardiovascular ailments ¹⁶. A study at the Beth Israel Deaconess Medical Centre in Boston found evidence that managers who fire someone run twice the usual risk of heart attack in the week following the dismissal; the greatest danger occurred to those who had conducted the firing while working under a high-pressure deadline. Another study found that chronic work stress and divorce increased the risk of cardiovascular mortality ¹⁷.

In a study of 791 patients, researchers reported that high-pressure deadlines increased the risk of heart attacks by 2.3 times within the seven days after the stress of the deadlines. Specific time pressures dramatically increase the risk of heart attack and early death. In a study of 60 women ages 30 to 45, researchers found that those under stress who secreted the highest levels of cortisol were also the ones who turned to high-fat foods in attempts to cope with their stress.

The results are similar for younger populations. In a study of 158 healthy adolescents who undertook self-report measures of chronic stress over 3.3 years, adolescents exposed to chronic, negative stressors that worsened over time demonstrated heightened cardiovascular risk ¹⁸. In a study investigating the responses of university students to stressful situations, researchers found that students exposed to stressful laboratory tasks displayed high levels of cardiovascular responses, which extended into a continued increase in blood pressure during instances of perceived stress in everyday life situations ¹⁹.

Being angry more than doubles the risk of cardiac arrest. In a study of 1,500 people who had suffered heart attacks who were surveyed and asked what their feelings were a few hours prior to the heart attack, it was found that the heightened risk appears to last for about two hours after the episode of anger. 

Psychosocial stress also results in changes in physiological behaviours ^5,7,11, which can put a person at increased risk of CVD. These behaviours include increased smoking and drinking, unhealthy eating and reductions in physical activity ^20,21,22. In addition, chronic stress can lead to constrained appetites or overeating, leading to problems of anorexia or obesity ²³. In extreme cases, anorexia or extreme weight loss can have an effect on heart rhythms and even lead to heart failure ²⁰¹⁰, while overeating may lead to obesity that has significant health risks associated with coronary heart disease, hypertension and type 2 diabetes ²⁵.

Stress is our great silent killer. Despite the growing body of evidence of this, we continue to focus on pharmaceutical treatments to reduce CVD and we continue to fail. The mechanisms behind stress being such a large contributing factor are now understood and numerous major studies have shown that the effects of chronic stress increase the risk from two to nine times. By contrast, medication to reduce cholesterol reduces the risk by 1% or 0.001 times (that is more than 2,000 times less important than stress). The next stage then is to invest in stress management practices. It’s that simple. Or is it?

1.     NHMRC 2009

2.     Bonthuis et al. 2010

3.     Ademi et al. 2009

4.     Yusef et al. 2004

5.     Dimsdale 2008

6.     Begg et al. 2008).

7.     Rozanski et al. 1999

8.     Black and Gabutt 2002

9.     Siegrist 1995

10.  Cade et al. 2010).

11.  McEwen 2008

12.  Brotman et al. 2007

13.  Newton et al. 1990

14.  Hallbäck and Folkow 2008

15.  Holam et al. 2008

16.  Rosengren et al. 2004

17.  Dimsdale 2007

18.  Low et al. 2009

19.  Loft et al. 2007

20.  Sturmer et al. 2006

21.  Logan and Barksdale 2008

22.  Hamer, Bates and Mishra 2011

23.  Rutledge and Linden 1997

24.  Bell 2010

25.  Rapoport, Clark and Wardle 2000

Acknowledgements. Brigitta Curley, Amy Williams

Epigenetics and Disease

Various genetic messages are “turned on” (expressed) or “turned off” (silenced) through epigenetic processes like DNA methylation. When turned off, it is as if a protein glove covers the DNA message so it can no longer be read or acted upon. Although epigenetic modification of our genes is a natural part of our development and well being, these processes can interact with various chemicals in our environment and in foods and drinks we consume, leading to the development of disease. Conversely, epigenetic actions of other compounds in our environment and nutrition are thought to hold the key to providing therapies to fight and prevent disease.

If a genetic mutation for a disease is “turned off” by epigenetic markers, that particular gene—in such an instance—cannot cause disease. For example, an individual may have inherited the genes for a particular disease; if, however, those genes are not expressed, the disease will not develop. However, change to the epigenetic markers (of a mutated gene) could cause the mutated gene to “tune into” and hence develop a specific disease.

Many human diseases have been associated with epigenetic modifications due to environmental exposure. These include cancer, obesity, diabetes, asthma, multiple sclerosis, mental illness and behavioural disorders as well as premature ageing ^1,2,3,4.

Humans are most vulnerable to epigenetic changes during the development of the embryo in the womb, embryogenesis, where epigenetic disruptions can be passed down through multiple generations ⁵. One study on diethylstilbestrol (DES), an environmental oestrogen, found that DES induced a genetic predisposition to a certain cancer and congenital birth defects that was passed down two generations ⁶. Similarly, foetal exposures to plasticizers such as bisphenol A, a chemical found commonly in plastic, contribute to epigenetic changes, which lead to immune abnormalities. Maternal smoking leads to increased pulmonary disease in adulthood including asthma; and certain therapeutic drug exposure leads to vascular defects. These can all be classified as epigenetic changes.

During the past decade, evidence has accumulated showing that apart from genetic alterations (mutations), epigenetic alterations play a major role in the initiation and progression of cancer ⁷. Human cancers arise from a multi- step process characterised by tumour initiation and progression ⁸ but only five percent of cancers can be attributed to heredity. Genetics alone cannot explain all of the properties of cancer. It is now understood that epigenetic abnormalities and the turning off and on of certain genes play a major role in tumour genesis—the development of and proliferation of tumours ^9,10.

Cancer, which is caused by uncontrolled cellular growth, is induced by mutations in the DNA, which can be initiated by errors in the DNA or foreign chemicals called carcinogens. In addition to uncontrolled cellular growth, a characteristic of cancer is inhibition of normal programmed cellular death, called apoptosis. When the body’s DNA makes mistakes in a cell, the mistakes are either fixed by additional DNA repair mechanisms or the cell is destroyed to prevent further damage (apoptosis). Unfortunately, the genes that are responsible for destroying rogue cells can be silenced (turned off) through epigenetics and, as a result, mistakes in the DNA cannot be rectified before they spread. The genes associated with cellular pathways that are prone to cause cancer are called oncogenes. The silencing of tumour‑suppressing genes, activation of oncogenes, and defects in DNA can be caused by epigenetic mechanisms, which can affect several if not many of the steps in a cancer line ¹¹.

We have literally removed the various roadblocks to formation of cancer. Many of the genes that are inactivated by methylation in carcinogenesis have classic tumour‑suppressor functions or play a critical role in cell cycle control (repair of damage to DNA) apoptosis, differentiation, angiogenesis, metastasis, growth factor response, drug resistance and detoxification ¹². An incorrect change in the methylation of the DNA caused by epigenetic carcinogens is the most common activation of cancer cell lines. Although methylation changes occur to different genes depending on the type of cancer, all cancers undergo changes in methylation, suggesting DNA methylation is a major factor in tumour development and can be used as a genetic marker in tumour development ¹³.

To put this in perspective, methylation in some areas of the DNA, called CpG sites, in some tumour suppressor coding regions contributes to as much as 50% of all inactivating mutations in some cancers and 25% of cancers in general.

In contrast to genetic changes in cancer, epigenetic changes are gradual in onset and are progressive. Their effects are dose-dependent and are potentially reversible which increases the scope for the development of epigenetic therapies for disease ¹⁴. These observations present new opportunities in cancer risk modification and prevention using dietary and lifestyle factors as well as treatment as you will see below. In this regard, folate, a water-soluble B vitamin, has been a focus of intense interest because of an inverse association between folate levels and the risk of several malignancies (in particular, colorectal cancer) and because of its potential ability to modulate DNA methylation. Through this process of supplementing with folate, scientists have achieved a certain degree of reprogramming even in adult cell DNA. The use of such inhibitors as folate has been shown to reactivate expression of tumour‑suppressor genes that would otherwise be silenced and a cancer would develop. Treatment for myelodysplastic syndrome, a form of leukaemia, with epigenetic therapies is already approved for use in the U.S. and there are a host of other treatments that continue to show promise ¹⁵.

Even more promising are the roles of diet and lifestyle. In a study of 30 men with low-risk prostate cancer who decided against conventional medical treatment such as surgery, radiation, chemotherapy or hormone therapy, three months of major lifestyle changes significantly lowered the level of prostate cancer. The changes included eating a diet rich in fruits, vegetables, whole grains and legumes and incorporating moderate exercise such as walking each day along with an hour of daily stress management ¹⁶.

Six of the control patients in this study underwent conventional treatment due to an increase in prostate specific antigen (PSA) levels or progression of disease measured by magnetic resonance imaging (MRI) during the 3 months, while none of the lifestyle group did.  PSA levels decreased four percent in the experimental lifestyle group but increased by six percent in the control (no change in lifestyle) group. Other markers such as the growth of prostate cancer cells (LNCaP) were inhibited almost eight times more in blood serum from the experimental group than blood serum from the control group (70% versus nine percent). However, even more definitively, the changes in serum PSA and in prostate cancer cell growth (LNCaP) were positively associated with the degree of change in diet and lifestyle. That is, the more lifestyle changes the men made, the greater the reduction in the prostate cancer markers. The lifestyle group were literally reversing their cancer.

The researchers found even more profound changes when they compared DNA from prostate biopsies taken before and after the lifestyle changes. After only three months, the men had changes in expression of about 500 genes, including 48 that were turned on and 453 genes that were turned off. The activity of disease-preventing genes increased while a number of disease-promoting genes, including those involved in prostate cancer and breast cancer, shut down. The lead researcher, Professor Dean Ornish, noted, “The implications of our study are not limited to men with prostate cancer” ¹⁶. In addition to the benefits in prostate diagnosis the men lost weight, lowered their blood pressure and risk of heart attack and stroke and saw other health improvements while reporting no negative side effects.

There is currently a great deal of interest in the promising chemo-preventive actions of polyphenols, large organic molecules, such as curcumin from curry, resveratrol found in grapes and berries and especially Epigallocatechin-3-Gallate (EGCG) the major polyphenol in green tea ¹⁷. EGCG in green tea has the ability to affect DNA epigenetics to fight cancer beyond just its antioxidant potential. For example, treatment of human oesophageal cancer cells with EGCG caused tumour suppressor genes, the genes that stop cancers from growing, to be “turned on.” The activity of EGCG has also been shown to possibly act to reduce cancer activity in prostate cancer cells ¹⁷.

Other studies link obesity and malnutrition (low nutrient-dense foods) in parents to hypertension in offspring and disease risk in offspring later in life ¹⁸, specifically with regard to obesity and the onset of diabetes later in life ¹⁹. Low-weight newborn babies are biologically different than their bigger counterparts. Smaller infants have fewer kidney nephrons, altered metabolism and are more insulin-resistant. These differences show how dietary habits of the mother during pregnancy can alter the expression of the genes of their offspring in such a way that they will respond differently to the environment that follows after birth. Placental and foetal growth is at its most vulnerable to maternal nutrition status in the first trimester of pregnancy. Promotion of a healthy, nutritionally balanced womb environment will not only ensure optimal foetal development but also reduce the risk of chronic disease in adulthood ²⁰. In support of this, it has been found that folate levels in pregnant women affect DNA methylation in a number of different gene promoter areas associated with infant health.

Some of the most well known studies linking epigenetics and obesity have involved “agouti” mice. Over the past twenty years there have been numerous studies indicating that impaired embryonic, foetal or infant nutrition as a result of out processed western diet and environments can lead to greater risk of obesity and metabolic compromise in later years ²¹. For example, a short‑term dietary intervention in pregnant agouti mice, in the form of supplements of folic acid, vitamin B 12, choline and betaine, have shown long‑lasting beneficial influences on the health and appearance of the offspring for multiple generations ²². By contrast, selectively bred diet‑induced obesity dams (mothers) that were made obese during gestation and lactation had more obese, insulin-resistant children who developed abnormalities of brain neurotransmitter metabolism compared with offspring of lean diet‑induced obesity dams or dams that were diet‑resistant ²³. That is why there is so much emphasis now on pregnant mothers supplementing, particularly with B vitamins. In a study of sheep, metabolic and hormonal signals before birth increased the expression of genes that regulate fat and the conversion of simple sugars into fatty acids in the fat around the kidneys of sheep ²⁴.

In one study, two types of rats were bred: one to develop diet‑induced obesity and the other that was prone to be diet‑resistant. Researchers found that the diet‑induced obesity rats would defend their increased body weight when fed a high-fat diet (31%) whereas the diet‑resistant rats would adjust their (high-fat) diet accordingly to maintain their lean physique. The study also found that the diet‑induced obesity rats, even after long periods of calorie restriction, would return to their higher weight once food was available freely, even when on a five percent fat diet ²⁵.

In other studies, researchers found that in a population with a genetic predisposition toward obesity, the effects of maternal obesity accumulated over successive generations to shift the population distribution toward an increased adult body weight. Perhaps this is something we are heading toward now in the human population…?

It is clear that epigenetic mechanisms may also drive psychiatric and mental disorders. In particular what your mother eats during pregnancy and you eat during childhood not only may influence your adult brain function and its eventual decline as you age, but also may influence your children’s cognitive potential and mental health ²⁶. A foetus that endures poor nutrition during gestation spares the growth of vital organs such as the brain at the expense of tissues such as muscle; the pancreas adapts its metabolism to the limited nutrition ²⁷. Following on from this, increasing evidence indicates that a disturbance in early neurodevelopment may lead to a vulnerability to schizophrenia in adolescence or adulthood ²⁸.

Twin studies have shown that people with schizophrenia and bipolar disorder have changes in genetic activity caused by their respective environments. The findings provide the strongest evidence yet that such gene changes might cause these conditions. A study that scanned the genome of 22 pairs of identical twins (one twin in each pair was diagnosed with schizophrenia or bipolar disorder) found, as expected, that the twins had identical DNA. However, they showed significant differences in epigenetic markings and these changes were on genes that have been linked with bipolar disorder and schizophrenia ²⁹.

Regardless of which condition the twin had, the most significant differences, with variations of up to 20% in the amount of methylation, were in the promoter “switch” for a gene called ST6GALNAC1, which has been linked with schizophrenia. The scans also revealed methylation differences in Gpr24, a gene previously linked to bipolar disorder ²⁹. In support of this, other studies have found differences of up to 25% in methylation of the same gene compared with controls.

Growing evidence suggests how we age is very much epigenetic-related. Some of the strongest, decade-old evidence shows progressive changes in DNA methylation in tissues in the ageing colon, stomach, oesophagus, liver, kidney and bladder adding increased importance to the role of diet and lifestyle in how we age.

Despite the role of our parents’ diet and lifestyles on our future and the future of our own offspring, research shows we can change this outcome by nutrition and lifestyle changes. We are largely in control of our own destiny. From epigenetics, we are learning that it is not all in the genes.

References

1.     Bollatti and Baccarelli 2010;

2.     Dolinoy et al. 2007;

3.     Isles and Wilkinson 2008;

4.     Weidmann et al. 2007

5.     Attig et al. 2010

6.     Newbol 2004

7.     Nystrom and Mutanen 2009

8.     Dworkin, Huang and Toland 2009

9.     Esteller 2008;

10.  Shikhar, Kelly and Jones 2010

11.  Herceg 2007

12.  Kim 2006

13.  Banerjee 2009

14.  Adcock et al. 2006

15.  Issa 2006

16.  Ornish et al. 2008

17.  Link, Balaguer and Goel 2010

18.  Friaz et al. 2011

19.  Ryan 2011

20.  Wu et al. 2004

21.  Gluekman and Hanson 2008

22.  Freeman 2009

23.  Levin et al. 2005

24.  Muhlhausler et al. 2007

25.  Levin 2008

26.  Williams 2008

27.  Jones PB, Rantakallio P, Hartikainen AL, Isohanni M, Sipila P

28.  Brown and Susser 2008

29.  Dempster, Pidsley et al 2011