Two decades ago, many experts predicted that the modification of risk factors, in particular the treatment of high blood pressure and lipid disorders, would eliminate coronary artery disease in 10 – 20 years. Unfortunately this prediction was wrong. Although mortality from cardiovascular disease has decreased in many countries, coronary heart disease remains an important cause of death and disability worldwide. Furthermore, the increased incidence of obesity and type 2 diabetes may ultimately reverse the declining mortality trend from heart disease.

Although there has been some improvement, one has to wonder why we haven´t had more success in reducing the prevalence and mortality from heart disease? Some will claim it´s because we haven´t succeeded with reducing the influence of traditional risk factors, such as high blood cholesterol. They will say that cholesterol lowering drugs (statins) are still underused among individuals at high risk, and that many patients with heart disease are still not treated to target levels of low density lipoprotein (LDL) cholesterol. And they could be right. There are ongoing trials, among them the FOURIER trial, testing the hypothesis that further lowering of LDL cholesterol with PCSK9 inhibitors on top of statin therapy will improve prognosis among patients with cardiovascular disease.

Another reason for the limited success is the possibility that there is a missing link. This link may be inflammation. It has been suggested that inflammation may play a major role in cardiovascular disease. If so, how can inflammation be modified?  To be able to answer this question we will have to start with the basics. What is inflammation? How is inflammation involved in heart disease? Will reducing inflammation lower the risk of heart disease?

When we talk about heart disease in adults we usually mean atherosclerotic coronary artery disease. This disease was first described in the eighteenth century. However, it´s most serious clinical entity, acute myocardial infarction, generally known as acute heart attack was not recognized until the early twentieth century. In the 1950´s acute myocardial infarction was recognized as one of the most common causes of death in the industrialized world. The symptoms were often dramatic and devastating. A previously healthy person was suddenly hit by severe chest pain, often associated with serious disturbances in heart rhythm, frequently resulting in sudden death. The survivors often had to deal with the consequences of damage to large parts of the heart muscle, sometimes resulting in heart failure, severely compromised quality of life and a shortened life span.

Acute myocardial infarction occurs when there is a sudden disruption of blood flow in a coronary artery.  The coronary arteries supply blood to the heart muscle. A sudden blockage is usually caused by a rupture of an atherosclerotic plaque within the vessel wall, with subsequent formation of a blood clot (thrombosis) at the rupture site. Sudden disruption of blood flow causes death of heart muscle cells (infarction), and may impair the function of the heart muscle.

The hunt for conditions that predispose to acute myocardial infarction was well on its way by the mid 1950´s. In 1961 the Framingham team reported that high blood levels of cholesterol and high blood pressure were associated with increased risk of coronary artery disease. The term “coronary risk factors” was defined, and researchers were able to gradually uncover other conditions which predispose to this disease, such as cigarette smoking, the various fractions of cholesterol, insulin resistance, physical inactivity, mental stress, depression and dietary factors. However, although many risk factors have been identified and modified by preventive measures, coronary artery disease remains a common disorder. Despite extensive research, our understanding of the mechanisms behind coronary artery disease and acute clotting of diseased arteries is incomplete.

Today most scientists believe that inflammation plays a key role in atherosclerosis and acute myocardial infarction. As a matter of fact, signs of inflammation at the sites of atherosclerotic plaques have been observed for centuries.  In the nineteenth century there was a fierce controversy between the prominent Austrian pathologist Carl von Rokitansky and his German counterpart, Rudolf Virchow. While the former attributed a secondary role to these inflammatory arterial changes, Virchow considered them to be of primary importance.

Today, almost two centuries later, important issues remain unresolved. How can vascular inflammation be measured and quantified? Which inflammatory mechanisms are most important when it comes to atherosclerosis and coronary artery disease. How can vascular inflammation be reduced or modified? Will measures that reduce inflammation affect the risk for atherosclerotic heart disease and its consequences?

What is inflammation?

Infammation is a protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues. The classical signs of acute inflammation are pain (dolor), heat (calor), redness (rubor), swelling (tumor), and loss of function (functio laesa). A good example of inflammation is when we get a splinter in our finger. The redness is caused by increased blood flow. The swelling is partly caused by white blood cells dispatched by the immune system to destroy the attacker and repair the injury. So, obviously , inflammation is one of the body´s most important defense mechanism. Without it, we would not be able to fight bacterial infections, injuries and destruction of tissues. So, how can inflammation be harmful?

The body´s defenses are controlled by the immune system. The immune system is composed of biological structures and mechanisms that continuously protects us against diseases such as infections and cancer. Immune deficiency is associated with increased risk for these diseases. Autoimmune disorders such as rheumatoid arthritis, Hashimoto´s thyroiditis, systemic lupus erythematosus and type 1 diabetes are all associated with a dysfunction of the immune system.

Inflammation can be both acute and chronic. Acute inflammation is the initial response of the body to harmful stimuli.  Prolonged inflammation, or chronic inflammation is characterized by simultaneous destruction and repair of the tissue from the inflammatory process.

When inflammation is appropriate, it protects us from disease. When inflammation is inappropriate or gets out of hand it can cause disease. Autoimmune disorders are characterized by an inappropriate immune response against cells and tissues in our body. This commonly leads to inflammation of tissues and organs such as joints, endocrine organs like the pancreas and thyroid gland, visceral membranes and internal organs such as the lungs, kidneys and blood vessels. Vasculitis is a term that is commonly applied to autoimmune inflammation of arteries.

Inflammation, atherosclerosis and thrombosis

The wall of most human arteries is composed of three layers. The innermost layer is the endothelium which overlies an intima of extracellular matrix and smooth muscle cells. The next layer, the media contains mainly smooth muscle cells end extracellular matrix. The outermost layer, the adventitia, consists of looser connective tissue, nerve endings, mast cells and the so-called vasa vasorum.

Atherosclerotic lesions (atheromas) are focal thickenings of the innermost layer of the artery, the intima. They consist of cells, connective tissue, lipids and debris. Blood-borne inflammatory and immune cells constitute an important part of an atheroma, the remainder being vascular endothelial and smooth muscle cells. Many of the immune cells exhibit signs of activation and produce inflammatory cytokines. Cytokines are important mediators of the inflammatory response.

Studies have indicated that the infiltration and retention of low density lipoprotein (LDL) in the arterial intima initiate an inflammatory response in the artery wall. Modification of LDL, through oxidation or enzymatic attack in the intima causes release of phospholipids that can activate endothelial cells. Studies in animals and humans also indicate that high blood levels of cholesterol may cause focal activation of vascular endothelium.

Cholesterol crystals are needle like structures that are found within atherosclerotic plaques. The role of these crystals in the atherosclerotic process is unknown. It has been proposed that cholesterol crystals may play a central role in initiating inflammation in atherosclerosis.

Recruitment of white blood cells (leukocytes) to the arterial wall is an early event in the formation of an atherosclerotic plaque. What triggers leukocytes to adhere to the vascular wall is unknown. A widely accepted view suggests that prolonged high levels of low density lipoprotein (LDL) particles in the blood stream may promote an infiltration of these particles to the arterial intima. Indeed, experimental animals begin to recruit inflammatory leucocytes soon after starting a diet enriched in cholesterol and saturated fat.

When inside the vessel wall, some leucocytes (monocytes) change into so-called macrophages. These cells are prominent in the atherosclerotic plaque. Macrophages may ultimately be transformed into foam cells, the prototypical cell in atherosclerosis. The activated macrophages produce inflammatory cytokines and other substances. Many other types of leucocytes are found in atherosclerotic plaques which underlines the important role of the immune system and inflammation in the formation of atherosclerosis.

The ultimate complication of atherosclerosis, the formation of the blood clot or thrombosis, also appears to depend on inflammation. A disruption or rupture of an atherosclerotic plaque is the process that most often triggers thrombosis. The most common form of plaque disruption, rupture of the plaque´s protective fibrous cap, relates closely with inflammatory processes. Plaques that tend to cause fatal coronary thrombi often contain large accumulations of inflammatory cells. They also typically have a thin protective fibrous cap that overlies the lipid core.

Interestingly, many thrombotic occlusions of a coronary artery, resulting in myocardial infarction, do not occur at the sites of critical narrowing of the artery. Rather, lesions that do not cause critical stenosis often underlie clots that cause acute myocardial infarction.

The balance between inflammatory and anti-inflammatory activity controls the progression of atherosclerosis and thrombosis. Metabolic factors also affect this process. Lipid deposition in the artery may initiate inflammation.The adipose tissues of patients with the metabolic syndrome and obesity produces inflammatory cytokines that may promote vascular inflammation.

Inflammatory biomarkers

A biomarker is a substance that can be measured, usually in blood,  and reflects a biological state. Biomarkers reflecting inflammation can help identifying and quantifying inflammation.

C-reactive protein (CRP) is a biomarker of low grade inflammation. Despite a lack of specificity for the cause of inflammation, data from a number of epidemiologic studies have shown a significant association between elevated serum plasma concentration of CRP and the prevalence of underlying atherosclerosis, the risk of recurrent cardiovascular events among patients with established disease, and the incidence of first cardiovascular events among individuals at risk for atherosclerosis. In addition, a number of drugs used in the treatment of heart disease, such as aspirin and statins, reduce serum levels of CRP. Reduced inflammation may possibly contribute to the beneficial effects of these drugs.

CRP can be measured using various assays with different testing characteristics. The high sensitivity CRP assay (hsCRP) is the most used assay to determine cardiovascular risk.

Lipoprotein-associated phospholipase A2 (LP-PLA2) is an emerging inflammatory marker. It is a lipoprotein associated enzyme secreted by macrophages. Elevated Lp-PLA2 has been shown to predict the risk of myocardial infarction and stroke in population studies.

Other examples of inflammatory biomarkers are Interleukin-6 (IL-6) and fibrinogen.

Diet and inflammation

The role of chronic inflammation in heart disease and other chronic diseases has stimulated research into the effects of diet, nutrition and other lifestyle measures on inflammatory markers. Although this research is still in its infancy, some knowledge is available on the relationship between dietary patterns and systemic inflammation.

In one study a relationship was found between glycemic index (GI) and hsCRP, indicating that foods with high GI may be associated with inflammation. Consumption of trans fats has been associated with markers of systemic inflammation. Consumption of omega-3 fatty acids has been associated with low levels of IL-6, suggesting an anti-inflammatory effect of omega-3. Consumption of omega 6 fatty acids shows variable effects on inflammation. Both pro-inflammatory and anti-inflammatory effects have been described. It has been suggested that high levels of dietary omega-6 may increase the amount of omega-3 needed to reduce inflammation. Consumption of carotenoids, flavonoids and magnesium has been associated with lower levels of inflammatory markers. Numerous studies have shown an association between fruit and vegetable consumption and low levels if inflammatory markers.

Much of the research concerning dietary patterns and inflammation has looked at the Mediterranean diet or its components. Adherence to a traditional Mediterranean diet has been associated with a 9% reduction in total and cardiovascular mortality, 6% reduction in cancer, 13% reduction in Parkinson´s and Alzheimer´s disease incidence. All these diseases have been associated with low grade systemic inflammation. High intake of olive oil, vegetables. legumes, fruits and fish has been associated with low levels of hsCRP, suggesting that these foods may reduce inflammation. In the ATTICA study adherence to the Mediterranean diet was associated with lower levels of hsCRP.

Will reducing inflammation help?

Whether inhibition of inflammation will prevent heart disease, or improve prognosis in those with known disease, is currently a major unresolved issue in clinical care. Much of the data evaluating the impact of atherosclerotic therapies on inflammatory biomarkers and clinical events has derived from aspirin or statins, agents that not only reduce inflammation but that either inhibit platelet function (aspirin) or significantly lower LDL cholesterol (statins)

The JUPITER trial demonstrated that potent statin therapy reduces the risk of heart attack and stroke among individuals with low levels of LDL-cholesterol who are at risk due to elevated levels of hsCRP. It is not known whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes.

Two large clinical trials are under way to address the hypothesis that lowering inflammation will lower event rates and improve prognosis among patients with heart disease. The CANTOS trial is evaluating whether interleukin-1ß (IL-1ß) inhibition with the drug canakinumab can reduce the rates of myocardial infarction, stroke, and cardiovascular death among patients with a history of previous myocardial infarction and elevated levels of hsCRP (> 2 mg/L). The CIRT trial which is funded by the National Heart, Lung, and Blood Institute (NHLBI) will evaluate whether low does treatment with methotrexate will reduce major vascular events among patients with a history of myocardial infarction and either diabetes or the metabolic syndrome. Methotrexate is commonly used in the treatment of autoimmune disorders such as rheumatoid arthritis and psoriasis arthritis.

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Today, most specialists acknowledge that emotional or psychologic stress may increase the risk of heart disease. In fact, the negative effects of acute and chronic stress on the cardiovascular system may be much more serious than often thought. Recent research and experience show that emotional stress may increase blood pressure and cholesterol. It may constrict arteries, promote arterial inflammation, blood clotting, and increase the risk for heart attack and sudden death.

There is a huge amount of literature available on psychologic stress and heart disease. In modern healthcare, stress is among the most common patient complaints. However, part of the problem is that the word ‘stress’ is used in so many ways, which may be quite confusing. Stress is not easily defined, it is difficult to quantify, and dealing with it is often time-consuming and complex. This is why the effect of emotional stress on cardiovascular disease has sometimes been downgraded and even ignored. Lately however, we have become more aware of the interactions between the body and the mind. It is now acknowledged that emotions and personality can have a huge impact on the functioning of cells, organs and disease mechanisms.

In order to understand stress we have to differ between the ‘stressor’, which is the external input that causes our body to react, and the ‘response to stressors’, which is the reaction of our body to the external input. The stressor is the external factor that threatens to throw us of balance. It can be an immediate physical threat, like an approaching car when we cross a street. It can be less obvious, like a busy work schedule, a problem in our marriage, or a death of a loved one. Whatever the external input, the body´s reaction is similar. There is increased activity of primitive defense mechanisms involving the autonomic nervous system. Most importantly, the sympathetic nervous system is activated and parasympathetic activity is reduced.

Stress is a normal physical response to events that make us feel threatened or upset our balance in some way. When we sense danger – whether it’s real or imagined – the body’s defenses kick into high gear. This automatic process is known as the ‘fight-or-flight’ response. Let´s say we are walking in the forest on a sunny day and suddenly we realize we are facing a hungry grizzly bear. A grizzly bear is a REAL stressor. Stress hormones, such as cortisol, adrenaline and noradrenaline are released into our blood stream. Heart rate and blood pressure increases. Sugars are poured into our circulation to provide immediate energy. Our breathing becomes faster to meet the increased oxygen demands of muscles and organs. All senses are primed, all muscles are tensed, and we are ready to either fight or flee to save our life.

The stress response is the body’s way of protecting us. When working properly, it helps us stay focused, energetic, and alert. In emergency situations, stress can save our life . The stress response also helps us rise to meet challenges. Stress is what keeps us on our toes during a presentation at work and sharpens our concentration. But beyond a certain point, stress stops being helpful. At that stage it may start causing damage to our health, mood and productivity. It will negatively affect our quality of life and may increase our risk of disease.

What do patients generally mean when they complain of stress? Sometimes they complain about the stressors themselves. There may be unpleasant life circumstances like financial problems, marital problems and job related issues. However, the stressor does not have to be unpleasant in itself to induce stress. Maybe your daughter is getting married, you´re up for a promotion or you´re preparing for a television interview. These are not unpleasant situations, but they are ‘stressors’. You may be sweating a lot, having problems concentrating and you may have sleep problems. Thus, both ‘good and bad’ stressors may cause a stressful experience.

Sometimes patients don´t directly associate their symptoms with the stressors. They may complain of symptoms such as sleep problems and anxiety. In other cases, the symptoms are more physical like heart palpitations, breathing difficulties, stomach pain, nausea or diarrhea.

It is practical to differentiate between acute and chronic stressors. Examples of acute stressors are disasters such as earthquakes, loss of job, business failure or sudden divorce. Examples of chronic ‘stressors’ are job stress, marital unhappiness and financial worries. The effects of a stressor on the health of the individual may differ, depending on the patient´s vulnerabilities. An individual who has a strong familial and emotional support may show better tolerance to the effects of stressors than a person who is socially isolated. A good example of this phenomenon is the story of the people of Roseto.

The Roseto effect

Roseto is an Italian-American town in eastern Pennsylvania. In the early 1960´s a local physician, Dr. Benjamin Falcone, who had been practicing in Roseto for 17 years pointed out that he rarely saw a case of heart attack (acute myocardial infarction) in any of the 1600 inhabitants of Roseto under age of 65. Subsequently it was confirmed that from 1955 to 1965 the mortality rate from heart attack was markedly lower than in nearby communities and the rest of the country. However, the usually accepted risk factors were not less common in Roseto than elsewhere. The men spent their days doing hazardous labor in underground slate mines. Smoking was common. The traditional Italian food had been Americanized, and could not be considered heart healthy. So why weren´t Rosetans dropping dead with heart disease?

Here is how Dr. Stewart Wolf and coworkers describe the social and family structure of the inhabitants of Roseto: “The Roseto that we saw in the early 1960s was sustained by the traditional value of southern Italian villagers. The family, not the individual, was the unit of their society. The community was their base of operations and each inhabitant felt a responsibility for its welfare and quality. Most household contained three generations. Rosetans were proud and happy, generous, hospitable and ready to celebrate any small triumph of their citizens. The elderly were not only cherished but, instead of being retired from family and community responsibilities, they were promoted to the ‘supreme court’. There was no shortage of stress among Rosetans. They experienced many of the same social problems and personal conflicts as their neighbors, but they had a philosophy of cohesion with powerful support from family and neighbor and deep religious convictions to shield them against and counteract the stresses”.

The Roseto effect is interesting because it teaches about how people can be shielded from the effect of stressors, thereby limiting the damaging effects of stress on the cardiovascular system. The important thing is to realize that all the traditional stressors were present among the Rosetans. However the strong emphasis on the family, and not the individual as the unit of their society, appeared to protect the people from the harmful effects of stress on the heart. This is believed to have significantly reduced the incidence of acute heart attack among the Rosetan people.

Emotional stress, heart attack and sudden death

Atherosclerosis is the main underlying cause of heart disease and stroke. Scientific studies have indicated that there may be a link between psychologic stress and atherosclerosis. Five psychosocial domains have been related to the risk of cardiovascular disease, these are depression, anxiety, some character traits, social isolation, and chronic life stress. These domains are sometimes interrelated. The link between psychologic stress and atherosclerosis may be both direct, via damage to the inner layer of the artery, and indirect, via aggravation of traditional risk factors such as smoking, high blood pressure and lipid disorders. As examples, cigarette smokers typically increase their smoking in response to stress. Blood levels of cholesterol have been shown to rise in stressful situations. This has been associated with situations such as preparation of tax returns by accountants, the taking of examination by students, and following job loss or significant life events.

Acute and chronic stress have long been suspected as risk factors for heart attack. Whether there is a causal link has been debated. Myocardial infarction commonly results from acute thrombosis of a coronary artery, following rupture of an atherosclerotic plaque. Interestingly, plaque rupture and thrombosis often occur at sites where narrowing of the artery is minimal. Thus, the transformation of a stable plaque to an unstable one seems to occur acutely.

Acute stressors. The fact that most heart attacks and sudden deaths occur in the morning hours, soon after wakening, suggests that our activities may trigger the acute event. The importance of the morning peak of heart attack and sudden deaths was documented in a meta-analysis of 66.635 patients, showing an increased risk between 6 am and noon compared to the rest of the day. Triggering may occur when ‘external stressors’  lead to increased activity of the sympathetic nervous system and other neuroendocrine mechanisms. This may put an increased load on the cardiovascular system that, in the presence of a vulnerable atherosclerotic plaque cause plaque disruption and thrombosis. A circadian variation in blood clotting mechanisms may also play a role, with highest risk for acute thrombosis occurring in the morning hours. These mechanisms also appear to be influenced by the sympathetic nervous system.

The INTERHEART study was a large study of risk factors for a first heart attack among 11.000 patients worldwide who were compared with 13.000 matched controls. Stressful life events occurred more frequently within the prior year among patients than among controls. These life events included marital separation or divorce, loss of job or retirement, loss of crop or business failure, violence, major intrafamily conflict, major personal injury or illness, death or a major illness of a close family member, death of a spouse, or other major stress. The authors of the study concluded that the “presence of psychosocial stressors is associated with increased risk of acute myocardial infarction, suggesting that approaches aimed at modifying these factors should be developed”.

A recent Swedish study assessed the effects of being diagnosed with cancer. Patients with a recent diagnosis of cancer were six times more likely than their controls to die of cardiovascular disease, within one week of receiving the diagnosis. The risk of suicide was also significantly increased among those diagnosed with cancer.

A number of studies have showed an association between disasters and acute cardiovascular events. There was a statistically significant 49 percent increase in patients admitted with acute heart attack through 16 emergency departments within a 50 mile radius of the World Trade Center in the 60 days after September 11, 2001, compared with the 60 days before.

An increased risk of heart attack was observed after the 1994 Los Angeles earthquake, compared to the week before the disaster. The 1994 earthquake occurred at 4:31 in the morning when circadian vulnerability is high. The authors did not find a similar increase in the incidence of heart attack following the 1989 Loma Prieta earthquake that struck the San Francisco Bay Area. This earthquake occurred at 5:04 in the afternoon, during a period of relatively reduced circadian vulnerability. Thus, circadian vulnerability may affect the cardiovascular consequences of ‘external stressors’ such as natural disasters.

Anger in response to stress may be of particular importance. This issue was addressed in a study of 1055 male medical students that documented anger reactions to stress by self-reporting on a questionnaire administered in medical school. After a median follow-up of 36 years, those with the highest level of anger, compared to those with the lowest level, had a significantly increased risk of premature cardiovascular disease developing before the age of 55.

Chronic stressors. The INTERHEART study also studied chronic stress. Sources of chronic stress were divided into work stress, home stress and financial stress. Patients with a first heart attack reported significantly more stress in each of these categories than controls. Interestingly, the proportion of patients experiencing moderate or severe home stress varied widely among regions, from 43.8 percent in North America to 15.6 percent in China and Hong Kong.

The Whitehall II study assessed the effects of chronic stress at the work place. There was a 2.15-fold increased risk for new coronary heart disease in men who experienced a mismatch between effort and reward at work. The high-risk subjects were those who were competitive, hostile, and overcommitted at work, in the face of poor promotion prospects and blocked careers.

Sigmund Freud more than once implied that what is fundamental to happiness is the ability to love and work; that is, to be able to invest in something other than yourself. In a study of the impact of work stress and marital stress on the incidence of coronary heart disease in a cohort of Stockholm women followed for 5 years, marital stress was associated with a 2.9 fold increased risk of recurrent events, whereas work stress did not predict the risk of coronary events. Similar data are available for men from the MRFIT trial (Multiple Risk Factor Intervention Trial). That trial showed that chronic work stress and marital dissolution increased the risk of cardiovascular mortality in men who were followed for nine years. In his great review of psychological stress and heart disease from 2008 Dr. Joel E. Dimsdale recapitulates the words of the late Dutch internist Johannes Groen who used to say: “What´s a man to do, where can he go if he is unhappy at work and home?” The implied, if somewhat flamboyant, answer was always: “… to an early grave”.

Pathophysiological considerations 

The human body is equipped with regulatory mechanisms that are designed to maintain stability and survival. These mechanisms are in large part maintained by the endocrine and the nervous systems. The nervous system transmits electrochemical signals as two-way traffic between tissues in reflex circuits, and the endocrine systems releases chemical mediators termed hormones into the circulation for action far away from their site of origin. In fact, these two systems operate very closely with each other, and there are no sharp boundaries between them. Furthermore, there is an intimate link between the nervous and endocrine systems at the level of the hypothalamus.

There are several possible mechanisms by which psychological stress may trigger an acute heart attack or sudden death. The effects of acute or chronic stress involve an increase in blood pressure, heart rate, vascular tone and platelet activity. This is thought to be largely mediated by the autonomic nervous system, particularly an increase in the activity of the sympathetic nervous system and a reduced parasympathetic tone. This autonomic imbalance may also increase the risk for life threatening disturbances in heart rhythm.

Interestingly, activation of neuroendocrine mechanisms, such as the sympathetic nervous system, is associated with worse prognosis in patients with heart disease. Although life saving under acute circumstances, long-term neuroendocrine activation appears to be harmful. Such an activation puts a strain on the cardiovascular system, elevates blood pressure and heart rate, increases the oxygen demands of the heart muscle, and increases the risk for thrombosis and life threatening arrhythmias.

Increased heart rate and blood pressure, brought on by emotional stress may lead to increased myocardial oxygen demand and plaque disruption. Mental stress has been shown to enhance platelet aggregation following sympathetic nervous system activation. Rupture of an atherosclerotic plaque in a coronary artery with subsequent thrombosis and coronary artery occlusion is the key pathophysiologic mechanism leading to heart attack which in some cases may cause sudden death.

Treatment considerations

Although emotional stress may have an adverse effect on the heart and increase the risk of cardiovascular disease, it would be wrong to say that stress causes heart disease. That would be an oversimplification, similar to saying that cholesterol causes heart disease. Cardiovascular disease is much more complicated than that. It involves a number of different pathologic and causative mechanisms. However, considering that emotional stress is a risk factor for heart disease, and may sometimes trigger an acute event, modifying stress might reduce risk. It remains to be proven though, that reducing stress will influence risk and improve prognosis.

How can we modify the damaging effects of stress on our hearts and wellbeing? Firstly, we could limit the stressors. This may be hard to do in modern society. We will all be exposed to different types of stressors through our life. We can try to avoid them as much as possible, but sooner or later most of us will have to face our stressors. Acute stressors such as a disasters, accidents, business failure, loss of job or divorce will hit us. Chronic stressors such as marital problems, job stress and caregiving of an ill family member can´t be avoided. Extended work hours, multitasking, long commutes, single-parent households – these are just some of the issues many of us have to deal with. So, maybe the secret is not to avoid stress, but to manage and control it.

Secondly, we could shield ourselves from the effects of the stressors like the Rosetans. This could be done by strengthening our social network and family relations. Most specialists also believe that taking time out to relax is important. Anything you can do to relax your mind and body will increase your chances of managing the effects of stress on your life. Physical exercise, walking, jogging, reading a book, listening to music, meditation and practicing yoga are all methods we can use.

Thirdly, the effects of stress on the cardiovascular system could be modulated, for example by drugs. Beta blockers may reduce the response of the sympathetic nervous system to stressful situations. This may to some degree explain why beta blockers improve prognosis and reduce the risk of sudden death after a heart attack. Treatment with antidepressants has not been shown to be better than placebo among patients with depression following a heart attack.

In order to be able to cope with stress we have to recognize the problem and the factors that contribute to it. Try to identify the main stressors in your life. Analyze them and check if they can be modified. Discuss them with your family and friends. These people may offer you a different perspective which is often beneficial. Managing stress is about taking charge. Taking control of your thoughts, emotions, your schedule and environment is very important. Remember that sleep is important and regular exercise is most often beneficial. Eat well. Healthy food choices are very important. Avoid refined sugars and processed foods. Instead, choose fruit, vegetables, whole grains and high quality proteins from fresh fish and unprocessed meat. Last, but not least, don´t hesitate to seek professional help.

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Measurements of lipids in blood/plasma are frequently used to assess the risk of future coronary heart disease or stroke, commonly termed cardiovascular disease (CVD). Plasma levels of total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) are frequently measured. These numbers are then used to calculate levels of low density lipoprotein cholesterol (LDL-C) which has been found to be strongly correlated with the risk of CVD. Recently measurements of atherogenic lipoprotein particles, such as LDL-P, apolipoprotein B and lipoprotein(a) have been found to be very useful to assess risk.

Lipoprotein(a) or Lp(a) is a risk factor for CVD. However, the lack of clinical trial data have resulted in Lp(a) being largely ignored by clinical guidelines assessing the prevention of CVD. In 2010, the European Atherosclerosis Society (EAS) consensus panel recommended screening for elevated Lp(a), in people at moderate to high risk of cardiovascular disease. Desirable Lp(a) levels < 50 mg/dL were considered a treatment priority, after therapeutic management of LDL-C. According to a statement from the EAS, ‘‘The evidence clearly supports Lp(a) as a priority for reducing cardiovascular risk, beyond that associated with LDL-C. Clinicians should consider screening statin-treated patients with recurrent heart disease, in addition to those considered at moderate to high risk of heart disease”. 

What is Lp(a)?

Lipoproteins are the particles that transport cholesterol and triglycerides in the blood stream.  Lipoproteins are composed of proteins (apolipoproteins), phospholipids, triglycerides and cholesterol. The lipoproteins vary in the major lipoprotein present, and the relative contents of the different lipid components. Lp(a) is a lipoprotein rich in cholesterol. It differs from LDL as it contains an additional protein, apolipoprotein (a). Similar to LDL, an Lp(a) particle also contains one molecule of apolipoprotein B.

What are normal plasma levels of Lp(a)?

It as assumed that Lp(a) is produced by liver cells. The pathways for the clearance of this substance are not clearly understood. Plasma levels of Lp(a) rise shortly after birth and the levels appear to become consistent within a few months. In adults, plasma levels of Lp(a) vary widely, ranging from 0.2 – 250 mg/dL. The levels are similar in men and women. Studies indicate that about one in five individuals have plasma levels above 50 mg/dL (80th percentile), and about one in four individuals have plasma levels above 32 mg/dL (75th percentile). Lp(a) levels less than 30 mg/dL are considered normal.

The EAS Consensus panel recommends that Lp(a) should be measured in high risk individuals such as those with premature CVD, familial hypercholesterolemia, family history of premature CVD and/or elevated Lp(a), and individuals with recurrent CVD despite statin therapy.

Lp(a) and risk for heart disease

A number of epidemiological evidence indicates that Lp(a) is associated with the risk of CVD. The Copenhagen City Heart Study found that individuals with plasma Lp(a) levels above 50 mg/L had 2 to 3 – fold increase risk for heart attack (myocardial infarction). A series of meta-analyses has provided evidence of a link between Lp(a) and CVD. Furthermore, studies on patients with familial hypercholesterolemia have provided additional evidence. Studies have indicated that the association is without a threshold, and does not depend on high levels of LDL or non-HDL cholesterol, or the presence of other cardiovascular risk factors. However, some authors have suggested that the risk of elevated Lp(a)is small, if LDL-cholesterol is not elevated.

How is Lp(a) involved in atherosclerosis and heart disease?

Lp(a) and LDL penetrate the inner layer of the arterial wall and accumulate together at sites for atherosclerotic plaque formation. Evidence suggests that Lp(a) may be more strongly retained in the arterial wall than LDL. Furthermore, Lp(a) transports oxidized phospholipids whose plasma levels are strongly correlated with the severity of coronary artery disease. Interestingly, these Lp(a) associated oxidized phospholipids possess pro-inflammatory activity. This might be one of the links between lipids and inflammation in atherosclerosis. There is also some experimental data suggesting that Lp(a) may promote clot formation in arteries burdened by atherosclerotic plaque. This may be one of the mechanisms behind the involvement of Lp(a) in heart attack and stroke.

How can Lp(a) be modulated?

Lp(a) is mainly genetically determined and therefore refractory to lifestyle intervention. Dietary changes, exercise and weight loss have not been shown to lower Lp (a). The data on the effects of statins on Lp(a) are conflicting and the same is true for fibrates. Oestrogen replacement therapy in women has been shown to lower Lp(a), although by less than 10 percent. Other agents that have been reported to slightly lower Lp(a) are aspirin, l-carnitine, ascorbic acid/L-lysine, angiotensin converting enzyme inhibitors, calcium antagonists, androgens and anti-oestrogens.

Niacin lowers Lp(a) by approximately 30 percent. Therefore, the EAS Consensus Panel has recommended niacin as the primary treatment for lowering elevated Lp(a) levels. Consistent with treatment guidelines, reduction of elevated Lp(a) levels should be a secondary treatment priority, after maximal lowering of LDL-C. However, these recommendations may have to be reevaluated in light of th results from the recent AIM-HIGH and HPS2-THRIVE trials.

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I find it extraordinary how carbohydrate restriction is repeatedly rejected by the medical community as an alternative approach for obesity, the metabolic syndrome and type 2 diabetes. Obesity has reached epidemic proportions in many countries around the world. Diabetes and other obesity related disorders have become increasingly common. Public health organizations and medical societies usually advocate a low-fat, high-carbohydrate, energy-deficient diet to manage weight. Nonetheless, clinical experience and scientific studies indicate that other approaches may be more effective.

The main argument against carbohydrate-restricted, high-fat diets are concerns regarding their long-term safety. Most such diets encourage increased consumption of animal products and therefore they often contain high amounts of saturated fat and cholesterol. It has been suggested that this may cause unfavorable changes in blood lipids and thereby increase the risk of heart disease. Therefore, several professional organizations have cautioned against the use of low-carbohydrate, high-fat diets.

According to a statement from the American Heart Association AHA, updated january 2012, “eating large amounts of high-fat foods for a sustained period raises the risk of coronary heart disease, diabetes, stroke and several types of cancer”. An older statement from the Heart and Stroke Foundation of Canada claims that ” low carbohydrate diets often lack vitamins and are low in fibre. A low fibre diet can result in constipation and can increase your risk of colon cancer. Low carbohydrate diets tend to replace carbohydrate with fat and protein. High intake of protein can result in large amounts of calcium in the urine, and loss of bone mass. High intake of fat, particularly saturated and trans fat, can lead to atherosclerosis, heart disease or stroke”.

These statements are based on observational data at best. Randomized clinical trials generally don´t support these conclusions. Indeed, low carbohydrate diets have demonstrated their therapeutic value in numerous studies, and often outperform other diets when comparisons are made. Nonetheless, they are still ignored by governments and medical societies. Keep in mind though, that carbohydrate restriction is a matter of definition. Some diabetic associations have accepted moderate carbohydrate restriction as an alternative approach for weight loss in type 2 diabetes.

Doctors, cardiologists included, commonly recommend low-fat, high-carbohydrate diets to patients with heart disease, as well as for cardiovascular prevention. Limitation of saturated fats and cholesterol is advocated. This is what doctors are urged to do by clinical guidelines. The guidelines are written by specially selected experts and published by professional organizations. Interestingly, there is often no mention of individual differences between patients. The low-fat, low saturated fat, low cholesterol, high-carbohydrate approach is recommended for all. It doesn´t matter whether you have high blood pressure, whether  you are obese or overweight, have the metabolic syndrome, or whether you have diabetes.

I have nothing against low fat diets. Look at the DASH diet for example. Extensive research indicates that this diet lowers blood pressure and cholesterol, and is associated with lower risk of several diseases, including heart disease. Furthermore, it was recently suggested that the DASH diet may be used for weight loss as well. I would be very satisfied if may patients would stick to the DASH diet. I usually urge them to do so. I am sure it benefits their health. The same thing can be said about a vegetarian diet. I consider such a diet to be a very heart healthy diet. Furthermore, I very often recommend a Mediterranean type diet to my patients. There is a lot of scientific date supporting the use of this diet for cardiovascular prevention as well as for patients with heart disease.

The role of diets takes on a different perspective when it comes to obese patients, and those with the metabolic syndrome, where weight loss is a priority. For years I have struggled with the low-fat, high-carbohydrate, energy-deficient dietary approach to manage these conditions. Simply put, the results have been disappointing. Often weight loss is limited and not sustained, and there are very limited improvements in metabolic function. However, I might admit the lack of result is more often due to lack of compliance than something else. Maybe we provide instructions and recommendations that patients are unable to comply with, no matter how hard they try.

I have found that people suffering from obesity or the metabolic syndrome are much more likely to lose weight and improve their metabolic function on a low-carb, high-fat diet. My clinical experience is that the effects of such a dietary approach on blood lipids is a bit hard to predict. Commonly there is an elevation of total cholesterol and LDL-cholesterol (“bad cholesterol”) which may be considered harmful. However, at the same time there is most often an elevation of HDL-cholesterol (“good cholesterol) and triglycerides are lowered. So the question is; Should I not recommend a dietary approach that works in terms of weight loss and metabolic control, because there may be a slight elevation of LDL-cholesterol? According to the medical associations and the clinical guidelines, I should not.

Low carb diets and heart disease – The scientific studies

My purpose is not to go through all available scientific data on the issue of carbohydrate restriction and heart disease. However, I will try to convince you that the available data does not support the conclusion that low-carbohydrate diets are less safe than other dietary approaches for people who are obese, overweight or suffer from the metabolic syndrome.

The initial recommendations to avoid saturated fat and cholesterol were based on observations from epidemiological research. Some of this research was led by the famous American scientist, Ancel Keys. In a personal reflection from 1995 Keys wrote: “These observations led to our subsequent research in the Seven Countries Study, in which we demonstrated that saturated fat is the major dietary villain.” Keys observed that death rates were related positively to the average percentage of dietary energy from saturated fatty acids, but negatively to dietary energy percentage from monounsaturated fatty acids. In short; saturated fats seemed to increase risk, while monounsaturated fats appeared to lower risk.  Since then, an independent association of saturated fats with the risk of heart disease has not been consistently found in epidemiologic studies. Replacing saturated fats with carbohydrates has not been shown to be beneficial. Indeed, replacement of saturated fats with refined carbohydrate can worsen blood lipids when insulin resistance is present, by increasing triglycerides, the number of small LDL particles, and by decreasing HDL-cholesterol. Some studies have indicated that replacing saturated fat with monounsaturated or polyunsaturated fat may be beneficial, although the latter was not supported by the recently published Sidney Diet Heart Study.

The relationship between the consumption of fat, saturated fat in particular was studied in the Swedish Malmö Diet and Cancer Study published in 2007. In this large prospective observational study, no trend towards higher cardiovascular event risk for women or men with higher total or saturated fat intakes, was observed. This study was later included in the much cited Siri-Tariono meta-analysis published 2010, showing no significant evidence for concluding that dietary saturated fat is associated with an increased risk of heart disease.

A number of randomized clinical trials have compared low-carbohydrate diets with other dietary approaches. In many of these studies, low carb diets have resulted in more short-term weigh loss in healthy women, individuals with severe obesity with high prevalence of the metabolic syndrome and type 2 diabetes, overweight adolescents, overweight individuals with hyperlipidemia, and  premenopausal women, compared with low-fat diets. Furthermore, negative effects on blood lipids with low-carbohydrate diets were not observed in these studies and markers of the metabolic syndrome were generally improved.

Most of these randomized trials are short term studies. Thus, the long-term effect of low-carbohydrate diets still remains to be clarified. Recently, it has been suggested that such diets may be harmful. In a systematic review and meta-analysis of observational studies, published November last year, Noto and coworkers found that low-carbohydrate diets were associated with a significantly higher risk of all-cause mortality. However, they did not find an association between low-carb diets and the incidence of, and mortality from cardiovascular disease. The authors acknowledge that their analysis is based on limited observational studies, and that large-scale trials on the complex interactions between low-carbohydrate diets and long-term outcomes are needed. It is also necessary to point out that there was a substantial difference between studies, concerning both study design and definitions. Such heterogeneity may make meta-analysis problematic.

Few final words

There are many different versions of low-carbohydrate, high-fat diets. Some promote the consumption of saturated fat, while others don´t. For a patient with heart disease or someone with elevated cholesterol, I usually recommend monounsaturated fat and polyunsaturated fats rich in omega-3. I find that using the Mediterranean approach, when selecting which fats to eat may be very helpful.

Although it does not comply with guidelines, I commonly recommend individuals who are obese or suffer from the metabolic syndrome to cut down on carbohydrates and increase fats. In most instances, I find these recommendations very useful. I don´t recommend my patients to stay in ketosis for long periods of time. However, if they choose to do so, if they feel well, and if their health is improving, I find no reason to tell them not to.

If an obese person with metabolic dysfunction manages to achieve weight loss and improve his or her metabolic function on a low carbohydrate diet, it is hard to understand how such an achievement may be harmful.

I look forward to the day when low-carb, high-fat diets are accepted by public health representatives and medical associations for the treatment of obesity, metabolic syndrome and type 2 diabetes. The medical community, which I am a part of, accepts that drugs that lower cholesterol, and slightly reduce the risk of heart disease (although having considerable side effects, among them increased risk of diabetes) are given to 25 percent of adults in many countries around the world. I find it a bit hard to accept that the same medical community does not accept and recommend a dietary approach for obesity and the metabolic syndrome, that causes weight loss, increases wellbeing and improves metabolic function, and indeed appears to outperform other diets in this respect.

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An interesting scientific paper on the efficacy of different dietary approaches in type 2 diabetes recently caught my eye. The study has not received much media coverage although it certainly addresses a question of importance to millions of people worldwide. More than 20 million people in the US have type 2 diabetes. According to the International Diabetes Foundation (IDF), the number of people diagnosed with diabetes in the last twenty years has risen from 30 million to over 246 million, or about 7.3% of the world population. Approximately 90% of those have type 2 diabetes. Diet and nutrition play a central role for the wellbeing of all those people. 

The study, which is a systematic review, was published in a recent issue of the American Journal of Clinical Nutrition. A systematic review is an unbiased survey of all the scientific evidence available on a given question. In this case, Ajala and coworkers from Plymouth UK addressed the efficacy of different diets to induce weight loss and improve glycemic control and lipid profile among people with type 2 diabetes.

Before we go further, let me touch on few basic issues, just for the sake of clarification. Type 2 diabetes is a chronic condition that affects the way our body metabolizes sugar (glucose). Glucose is the body’s main source of fuel. With type 2 diabetes, the body either resists the effects of insulin — a hormone that regulates the movement of sugar into our cells — or doesn’t produce enough insulin to maintain a normal glucose level.

Glucose comes from two major sources, food and the liver. Our liver produces and stores glucose. When glucose enters the blood stream, insulin is released from the pancreas. Insulin enables sugar to enter the cells of the body where it is used for energy production. Without insulin, or when insulin resistance is present, glucose builds up in the blood stream. This is what happens in diabetes. Elevated levels of blood glucose may cause a number of symptoms, and increase the risk of developing heart disease and stroke.

It is not fully understood why people develop type 2 diabetes, but certain factors increase the risk. Overweight is a risk factor. However, many overweight and obese individuals never have diabetes, and many people with type 2 diabetes are not overweight or obese. If our body stores fat primarily in the abdomen, the risk of diabetes is higher than if the body stores fat elsewhere such as on our hips and thighs. Family history and physical inactivity also increases the risk of diabetes. The risk of type 2 diabetes increases with age. Lately, type 2 diabetes has become increasingly common in children, adolescents and young adults. The main goals of therapy are to improve glucose metabolism and thereby reduce blood sugar levels, and to reduce the risk factors for the main complications of diabetes, heart disease and stroke. Overweight often contributes significantly to the development of type 2 diabetes, therefore weight loss often plays a large role for the treatment of the disorder.

Prediabetes is a condition in which blood sugar level is higher than normal, but not high enough to be classified as diabetes. Left untreated, prediabetes often progresses to type 2 diabetes. There is good evidence showing that dietary modification can prevent the progression from prediabetes to type 2 diabetes. Howvever, the optimal dietary approach to type 2 diabetes is  less clear. Before I discuss the recent study by Ajala and coworkers, let´s have a look at the background stage.

For some years, experts and scientists have debated what dietary approach is best to control and treat type 2 diabetes. Most regulatory authorities, like the British Diabetic Association, European Association for the Study of Diabetes (EASD), American Diabetes Association (ADA), Canadian Diabetes Association and many more usually recommend a carbohydrate intake of 50-60% of total energy intake, total fat intake less than 30% of energy, with restriction of saturated and trans fat intake. Some experts believe there is insufficient evidence to justify these recommendations.

Almost five years ago, an international group of scientists and experts on diabetes, nutrition and carbohydrate metabolism published an overview paper suggesting a critical appraisal of  the role of carbohydrate restriction in type 2 diabetes mellitus and the metabolic syndrome.The authors pointed out that current nutritional approaches often emphasized a reduction in dietary fat. They believed that such approaches often were ineffective, leading to more reliance on drug therapy. They argued that carbohydrate restricted diets were at least as effective for weight-loss as low-fat diets, and that the substitution of fat for carbohydrate was generally beneficial for the risk of cardiovascular disease. Furthermore, they provided evidence suggesting that carbohydrate restriction improved control of blood glucose and reduced insulin fluctuations. They believed the recommendation to reduce the intake of saturated fat in type 2 diabetes lacked scientific evidence. The authors concluded: “Finally, while no systematic study of clinical practice has been done, anecdotal evidence suggests that carbohydrate restriction is a common clinical recommendation for diabetes. We believe that there is a need to codify these recommendations in light of current evidence.”

In the recent systematic review by Ajala and coworkers, data was collected from all studies published up to July 2011 that compared low carbohydrate, vegetarian, vegan, low glycemic index (GI), high fiber, Mediterranean, and high protein diets with control diets including low-fat, high-GI, ADA diet, EASD diet, and low-protein diets. Only randomized controlled trials with an intervention lasting longer than six months were selected. A total of 20 studies including 3073 individuals fulfilled the defined criteria, and were selected for the metaanalysis. Measured outcomes were HbA1c (which reflects glucose control), difference in weight loss, and changes in HDL-cholesterol (“good cholesterol”), LDL-cholesterol (“bad cholesterol”) and triglycerides.

The low carbohydrate, low-GI, Mediterranean, and high protein diets all led to a greater improvement in blood glucose control (HbA1c) compared with their respective control diets, with the largest effect seen with the Mediterranean diet. Low-carbohydrate and Mediterranean diets led to a greater weight loss compared with their control diets. Low carbohydrate, low-GI, and Mediterranean diets all led to an elevation of HDL-cholesterol. Only the Mediterranean diet led to a significant reduction in triglycerides. High protein diets had no effects on markers of lipid profile. One study from their review compared the effects of a vegan diet to the low fat ADA diet. The vegan arm had a significantly lower levels of total cholesterol, LDL-cholesterol and HbA1c, indicating better glycemic control by the vegan diet. Similar results were obtained in one study that compared the effect of a vegan diet with the EASD diet, with more weight loss on the vegan diet.

Ajala and coworkers conclude that their review provides evidence that modifying the amount of macronutrients can improve glycemic control, weight and lipids in type 2 diabetes. In their analysis, low carbohydrate diets appeared to provide superior weight loss, better control of blood glucose, and better lipid profile, compared with low fat diets. The authors also conclude that vegan and vegetarian diet may improve glucose control and promote weight loss in type 2 diabetes.

The Mediterranean diet is rich in olive oil, legumes, unrefined cereals, fruit and vegetables, low in meat and meat products, and with moderate contents of dairy products (mostly cheese and yogurt), fish and wine. The total fat in this diet is typically 25-35% of calories, with saturated fat less than 8% of calories. The metaanalysis indicates that a Mediterranean diet provides better control of blood glucose, greater weight loss and a more favorable lipid profile compared with a conventional diet and ADA diet.

A metaanalysis of such widely different studies may be problematic. For example the control diets differed significantly between studies and the duration of the studies ranged between six months and four years. The definition of a low carbohydrate diet varies between studies. While the authors acknowledge the limitations of their study, they believe that low carbohydrate, low-GI, Mediterranean and high-protein diets should be considered in the overall strategy of diabetes management.

What is the best diet for type 2 diabetes?  Although, there is probably not a simple answer, the question reflects one of the main challenges of modern medicine. It is likely that our dietary recommendations will have to be tailored to the needs of the individual. A one-size-fits-all approach is unrealistic. Although not providing any definitive answers, the study by Ajala and coworkers is an important contribution to our understanding of this highly important issue.

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The risk of heart disease has been associated with countless different things. Smoking, diabetes, high blood pressure, overweight, obesity, sitting and watching TV, eating too much fat, eating too much sugar, not eating certain fats, eating meat, not eating fish, eating too much animal fat, eating cholesterol, eating saturated fat, eating trans fats, high blood cholesterol, high LDL-cholesterol, inflammation, family history of heart disease…. The list is long. Is it really possible to avoid being hit by this dreadful disease, the most common cause of death and disability worldwide?

The risk of heart disease increases with age. So, if we become old enough, we will probably have heart disease sooner or later, and most likely die from it. But that is not necessarily a bad thing. We all have to die from something. Dying from something else is not a goal by itself. So maybe we would be more accurate if, instead of aiming at prevention, our goal was to delay the onset of heart disease. However, defining our goal is probably less important than defining the methods to achieve it.

A huge number of healthy adults will have heart disease in the next ten years. Many will be treated with drugs, some will have angioplasty  and stents, and some will have open heart surgery. Many will die from the disease. A substantial number will be left with severe disability.  Many will not be able to work, and many will not enjoy the quality of life they had before the disease hit them.  So, I presume we all agree that delaying the onset of heart disease is a worthwhile target.

Who should worry about getting heart disease? Probably everybody. But, who should worry the most? Who is most likely to be struck by heart disease in the next few years? This is where it comes to the so-called risk factors. If you have many risk factors, the risk of having a heart attack or stroke becomes higher. The strongest risk factors are smoking, diabetes, high blood pressure, high levels of LDL-cholesterol, low levels of HDL-cholesterol, overweight or obesity, and family history of premature coronary artery disease. If you don´t have any risk factors, your aim should be to avoid them at all costs. But, if you have some of these risk factors, what can you do?

Let´s assume you are a responsible person (you probably are by the way, because you are reading my blog), and you want to do everything you can to delay the onset of heart disease. Maybe your father had a heart attack in his fifties. Maybe you have gained a bit of weight and maybe your cholesterol level is a bit to high. So, you decide it´s time to have a chat with your general practitioner Dr. Oxenhaler, the family doctor. Last year he put you on a drug to lower your blood pressure. This time, you are better prepared for your visit because you have been reading my blog.

You are sitting in front of Dr. Oxenhaler in his office. He just finished measuring your blood pressure and now he is watching your blood work on his computer screen. This is how the conversation might evolve.

‘Is there a specific reason you decided to come to see me. Have you been having chest pain or discomfort of any kind?’
‘No Doctor Oxenhaler. I was just worried. I´ve been reading lots of stuff about heart disease on the internet. I was wondering what I should do to avoid having a heart attack.’
‘Well, I guess you should be a little bit worried, but I´m glad you care. That´s the first step. Your blood pressure is fine, thanks to the medication I prescribed for you last year. However, your cholesterol is 277 mg/dl (6.9 mmol/L), that´s way to high.’
‘How about my LDL cholesterol?’

Doctor Oxenhaler watches you closely, his glasses gliding down on his nose. He takes a deep breath.
‘I see you´ve been reading. That´s good. Education is the key to a better health. Your LDL cholesterol is 182 mg/dL (4.7 mmol/L), that´s also way to high. HDL-C, the good cholesterol is 40 mg/dL (1.0 mmol/L) which is to low. Considering your family history and your history of high blood pressure, the risk of having coronary heart disease is quite high. By using the Framingham risk calculator I can see that your risk of having a heart attack in the next ten years is about 17 percent.’

You feel a little numb, like the blood is draining from your face. Doctor Oxenhaler notices your paleness and becomes a bit more sympathetic.
‘Don´t be scared though. We can take care of this. Treatment is available. By putting you on a cholesterol lowering drug, we can lower your risk substantially. Your cholesterol will go down and so will LDL-cholesterol. Your risk of heart attack will be much less’.
‘But I read that the effects of statin drugs is very small when they´re used for prevention in people who don’t have heart disease’.
‘No. that´s a misinterpretation. The risk reduction in the clinical trials is about 30 percent among high risk individuals, which in my mind is quite substantial.’
‘You´re talking about relative reduction then Dr. Oxenhaler, aren´t you?´

There is a momentary pause. You catch a glimpse of surprise in his eyes. He looks at his watch and then back at you, a faint smile on his lips.
‘Yes, relative reduction, that´s correct’, he says.
‘I´ve read that statins have lots of side effects as well.’
‘Side effects are very uncommon. A small number of of people have muscle pain, but it´s rare. Most people do not have any problems with cholesterol lowering drugs.’
‘I read that some people have memory loss.’ 
He looks surprised.
‘I don´t recall any of my patients complaining of memory loss from statins.’
Now you can´t help wondering whether Doctor Oxenhaler is taking statins. You dismiss the thought immediately. You have to keep focus.
‘I´ve heard there is more risk of diabetes if you take statins.’
He loosens his tie a bit, he has stopped smiling. You´re aware that you´re using up a lot of his time. There are more patients waiting for him.
‘Let me just tell you that the benefits of statins definitively outweigh the risks’, says Doctor Oxenhaler

But you´re not giving up.
‘Isn´t there something I can do by my self, change may diet or exercise more?, you ask.
‘Diet and exercise is fine. Cut down on fats, especially saturated fat and don´t eat too much cholesterol. That´s helpful. But it won´t replace statin treatment when it comes to reducing your risk.’
‘I heard about a study published last week in The New England Journal of Medicine showing that a Mediterranean diet could lower the risk of heart attack and stroke if you have risk factors like me’
‘You´re right indeed, but the effect is very small. Besides, diets are usually hard to stick with.’
‘I read that the relative risk reduction was about 30 percent on the Mediterranean diet compared to a low fat diet. Isn´t that about the same effect that statins have in a similar population?’ Could a Mediterranean diet be an alternative to statin therapy?

Doctor Oxenhaler does not answer right away. He stares at the computer screen.
‘Very well, why don´t you try the Mediterranean diet for six months and then come visit me again. We´ll measure your cholesterol and decide what to do. If it´s still high I definitively recommend statin treatment to cut your risk´, he says eventually, still watching the computer screen.
‘Isn´t it possible that the diet is helpful, although my cholesterol stays the same?’
Now he is looking at you again, more seriously than before. You can´t really tell whether he is annoyed or not.
‘If we are to succeed in lowering your risk of heart disease, we must lower your LDL-cholesterol. That´s a fact.’
‘But, I just read about the Women´s Health Initiative  where reducing the intake of fat lowered cholesterol, but did not cut the risk of heart disease’.
Now he is up on his feet and offering his hand. He shakes his head in disbelief, but he is smiling again.
‘Please come back to see me in six months. Good luck with the Mediterranean diet. Go easy on the wine though. And for God´s sake don´t believe everything you read on the internet…..‘

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“I would only argue that Senators don´t have the luxury that the research scientist does, of waiting until every last shred of evidence is in.” These words were spoken by Senator George McGovern 35 years ago when confronted by Dr. Robert Olson from St. Louis University. Senator McGovern´s Select Committee on Nutrition and Human Needs went ahead and published their famous report, “Dietary goals for the United States” in 1977. Doctor Olson, however had pleaded for “more research on the problem before making announcements to the American public”. The main message from the McGovern report was to reduce overall fat consumption, reduce the consumption of saturated fat and cholesterol, and to substitute polyunsaturated fatty acids (PUFA) for saturated fat. Decreased consumption of meat, butterfat, eggs and other high cholesterol sources was recommended. McGovern´s words reflect the fact that the report was not based on strong scientific data.

The committee´s members acknowledged that their recommendations relied on epidemiological and observational data at best. There were no prospective randomized studies available to support their recommendations. Dr. D.M. Hegsted, professor of nutrition at Harvard School of Public Health, who assisted in the preparation of the report wrote: “The question to be asked, therefore, is not why should we change our diet but why not. What are the risks associated with eating less meat, less fat, less saturated fat, less cholesterol, less sugar, less salt and more fruits, vegetables, unsaturated fat and cereal products – especially whole grain cereals. There are none that can be identified and important benefits can be expected”. What the committee´s members probably did not realize however, was that their report laid the foundation for worldwide dietary guidelines for the next 35 years. Ever since , “eat less saturated fat and cholesterol…” , has been the cornerstone recommendation from medical professionals, for patients with heart disease or those who want to reduce their risk of heart attack.

Although the McGovern committee´s report turned out to be influential, several other important expert panels had already provided similar recommendations. The advise to limit saturated fats was already alive in the 1950s. In 1957 the American Heart Association suggested that a decreased consumption of saturated fats might reduce the risk of heart disease. The Inter-Society Commission for Heart Disease Resources and The American Heart Association had already in the early 1970s suggested a reduction in dietary cholesterol to less than 300 mg a day. However, the experts did not agree. In October 1977, the Canadian Department of National Health and Welfare concluded that: “Evidence is mounting that dietary cholesterol may not be important to the great majority of people… Thus a diet restricted in cholesterol would not be necessary for the general population”. However, the wheels were turning fast and food manufacturers were already adopting new strategies. Low fat food varieties of all possible kinds spread throughout the world. Butter consumption decreased and vegetable oils became popular. Cholesterol and saturated fat were to be eliminated from our dishes. The villains had been exposed and had to be taken care of.

Trans fat joins the villains

The French scientist Paul Sabatier developed the hydrogenation process in the 1890s. In 1902, Wilhelm Normann found that liquid oils could be hydrogenated to form trans fatty acids. This turned out to be the first man made fat. During the second world war the use of trans fats rose because of the increased use of margarine. In the early 1980s there was a strong campaign by consumer advocacy groups against using saturated fat for frying in fast-food restaurants. In response, most fast-food companies began using partially hydrogenated oils containing trans fat instead of beef tallow and tropical oils high in saturated fats.

A lot of evidence indicates that the fear of saturated fats during the 1950s through the 1980s, lead to an increased use of trans fats. In the 1990s it became clear however that trans fats might be harmful. Numerous research studies during the 1990s revealed correlations between trans fatty acids and increased LDL-cholesterol and a higher incidence of heart disease. In 1993 health advocacy groups started calling for fast-food restaurants to stop using partially hydrogenated oils in their deep fryers. Trans fat was the new villain. In 2003, Denmark was the first country in the world to limit the use of trans fats by law. Trans fat labeling became mandatory in the United States in 2006. The same year, The American Heart Association became the first major health organization to specify a daily limit:  less than 1 percent of calories from trans fat. Later in the year, New York became the first U.S. city to pass a regulation limiting trans fat in restaurants.  Multiple cities and states have since proposed similar regulations.

Is polyunsaturated fat (PUFA) a healthier option than saturated fat?

The recommendation to substitute PUFA for saturated fat was one of the main goals of the McGovern report in 1977. This probably originated from the research of the influential Minnesota epidemiologist, Ancel Keys. Keys is often acknowledged as the father of the diet-heart hypothesis. He published many studies in the 1960s and ´70s demonstrating higher cholesterol levels among patients with heart disease. His studies also showed higher cholesterol levels among people who consumed food rich in saturated fat and cholesterol. From his famous “Seven Countries Study” he concluded that dietary fat was the single most important cause of heart disease because it elevates blood cholesterol. However, the study has been criticized for the method in which populations were selected for the study, and the way that the population (ecologic) correlations were carried out. Keys believed, like so many others, that a Mediterranean-style diet low in animal fat and rich in PUFA protected against heart disease.

Advice to replace animal fats rich in saturated fats by vegetable oils rich in PUFA has been a cornerstone of worldwide dietary guidelines for half a century. However, when the advice originated fifty years ago, PUFAs were regarded as single molecular category with one highly relevant biological effect – to reduce blood levels of cholesterol. At that time, omega-6 (linoleic acid) was the best known PUFA. Since then, it has been recognized that PUFAs comprise multiple species of omega-3 and omega 6, each with unique biochemical properties, and perhaps different cardiovascular effects.

What was the evidence behind recommending decreased consumption of saturated fat and increased consumption of PUFA? Interestingly, there were three prospective studies performed during the 1960s and 70s comparing the effects of these two types of fats. The studies involving a total of 1300 men with heart disease in England, Norway and Australia used diets with high ratios of PUFAs to saturated fats, limited dietary cholesterol, and low levels of monounsaturated fat. The trials lasted five years, and despite achieving lower cholesterol levels, people on the experimental diet did not do any better than their counterparts did on the control diet. Therefore, these studies did not support the hypothesis that substituting PUFA for saturated fat was beneficial. Somehow, the medical community did not seem to take notice. Interestingly, one of these studies, The Sydney Diet Heart Study was recently recovered, reevaluated and published in the British Medical Journal. The results have received huge attention.

Linoleic acid (omega – 6) –  The new villain

The Sidney Diet Heart Study was a randomized trial conducted from 1966 – 1973. It tested the effect of replacing saturated fat with linoleic acid (omega-6) from safflower oil. Safflower oil is a concentrated source of linoleic acid, containing no other PUFAs. The study population consisted of 458 men aged 30-59 years with a recent history of heart attack (acute myocardial infarction or acute coronary insufficiency).The men were randomized to an intervention group (n=221) and a control group (n=237).

The intervention group received instruction to increase their PUFA intake to about 15% of food energy, and to reduce their intake of saturated fat and dietary cholesterol to less than 10% of food energy and 300 mg per day, respectively. To achieve these targets, intervention participants were provided with liquid safflower oil and safflower oil polyunsaturated margarine (“Miracle” brand, Marrickville Margarine).  Liquid safflower oil was substituted for animal fats, common margarines, and shortenings in cooking oils, salad dressings, baked goods, and other products, and was also taken as a supplement. Safflower oil polyunsaturated margarine was used in place of butter and common margarine.The control group received no specific dietary instruction. However, some participants began substituting polyunsaturated margarine for butter after their coronary event.

The results of the study were quite striking. Compared with the control group, the intervention group had an increased risk of all cause mortality (17.6% vs. 11.8%),  cardiovascular mortality (17.2% vs. 11.0%) and mortality from coronary heart disease (15.3% vs. 10.1%). This difference existed despite the fact that serum total cholesterol decreased more in the intervention group than in the control group (13.3% vs 5.5%). These unfavorable effects of omega-6 are consistent with two other randomized controlled trials, in which saturated fats were replaced with omega-6 and common margarines were replaced with corn oil. By reanalyzing the original Sidney Diet Heart Study data, the authors were able to include the study into their previous metaanalysis. The metaanalysis covers secondary prevention studies where saturated fats were replaced, either by omega-6 selective PUFA interventions or a combination of omega-6 and omega-3. In short; replacing saturated fats with PUFAs containing mainly omega-6 fatty acids appears to increase coronary heart disease mortality, while replacing saturated fats with a combination of omega-3 and omega-6 decreases coronary heart disease mortality. This may explain why a diet rich in omega-3, such as the Mediterranean diet appears to positively affect the risk of heart disease.

Omega-6 is the most abundant fatty acid in low density lipoprotein (LDL) particles. Oxidized linoleic acid metabolites (OXLAMs) are the most abundant oxidized fatty acids in oxidized LDL. The authors of the British Medical Journal paper suggest that a diet induced increase in the production of bioactive OXLAMs may contribute to atherosclerosis and cardiovascular disease pathogenesis. This hypothesis supports the possibility that atherosclerosis may occur through mechanisms that are very distantly related to plasma cholesterol.

Is it all due to the trans fats?

Australia´s National Heart Foundation has claimed the recent Sidney Diet Heart Study is misguided. Dr Robert Grenfell who is National Health Director at the Heart Foundation points out that “in the 60s and 70s margarine still contained trans fats which we now know are extremely harmful to heart health. Replacing saturated fat with a product that was high in trans fat would never be recommended now”. Bill Shrapnel, the Deputy Chairman of the Sidney University Nutrition research Foundation agrees that “the study was not objective because margarine no longer contains the trans fatty acids it did at the time of the trials”. He adds: When the study began, Miracle margarine contained approximately 15 per cent trans fatty acids which have the worst effect on heart disease risk of any fat. The adverse effects of the intervention in this study was almost certainly due to the increase in trans fatty acids in the diet.”

The authors of the recent British Medical Journal article have a completely different view on the trans fat issue. In their discussion of the results they point out that the trans fatty acid content of the participant´s diets was not recorded. On the other hand they argue that the restriction of common margarines and shortenings (major sources of trans fatty acids) in the intervention group would be expected to substantially reduce consumption of trans fatty acids compared with the control group. Thus, the consumption of trans fatty acids may indeed have been higher among the control patients than the intervention patients. Trans fatty acids are known to raise cholesterol levels. The fact that cholesterol levels decreased more in the intervention group than in the control group does not indicate that the intervention group had more trans fatty acids in their diet.

Dietary fat and heart disease – Exposing the villain

I have always been a fan of Agatha Christie´s famous crime novels. Agatha was the master of twists and turns. You never knew until the last page who was the villain. In one chapter you were lead to believe it was the gardener or the butler. In the next chapter you definitively suspected the beautiful widow. The two things you could be certain of was that there were always going to be more twists and turns, and the end would take you by surprise. I somehow have a similar feeling about fat and heart disease. There will be  more twists and turns before we know the truth. For the time being though, it appears that the doomed outlaw, saturated fat may not be the worst villain. Indeed, the evidence against it is fairly weak. At least, saturated fat appears more innocent than trans fat and omega-6.  I wonder, could Ancel Keys have been studying an effect of trans fat instead of saturated fat in his epidemiological research. Since he never separated these two we will probably never know.

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I have a strong interest the prevention of heart disease. I believe healthy nutrition and lifestyle are the key to our health and well being. In my early career as a cardiologist, working in the hospital setting, I was fascinated by the diagnosis and treatment of heart disease. Don´t misunderstand me, I still am. However, as the years have passed I have become more and more interested in disease prevention. Helping people stay healthy and avoid disease is very different from diagnosing and treating. However, although prevention is important, it is not always easy to practice and the results are hard to measure. It´s time consuming, you don´t see the results immediately and it deserves both patience and persistence. Therefore, it´s not surprising that doctors are often less interested in prevention than treating and curing. As Dr. Bernard Lown recently put it so elegantly on his blog, The Lown Conversation: “Diligent prevention unfortunately plays second fiddle to heroic cures.”

The most powerful tool to cut the burden of heart disease in our community is education. Let me quote the remarkable Maya Angelou: “When you know better you do better”. One of the most important roles for doctors and other medical professionals is educating people about healthy lifestyle, nutrition, exercise and other measures to prevent disease. However, to educate is not always a simple task. Furthermore, bad education is often worse than no education. There are so many books written today on lifestyle, exercise, diet and nutrition, and there is an overflow of information on the internet. Obviously, some of it is good and some of it is bad. In many cases, education and information is driven by a product line designed to enrich the bank account of the author. Obviously, such information may be misleading.

Many books and articles have been written on the role of cholesterol in heart disease. Elevated cholesterol has traditionally been considered a risk factor for cardiovascular disease. Lowering cholesterol, low density lipoprotein (LDL) cholesterol in particular, is generally considered important. Recently however, the role of cholesterol in heart disease has been debated. A few weeks ago a ran into a new book on the subject, called “The Great Cholesterol Myth written by nutritionist Jonny Bowden, PhD, and cardiologist Stephen Sinatra, MD. At first sight I wasn´t interested in the book. There are so many similar books I thought: The Cholesterol Myths by Uffe Ravnskog, The Great Cholesterol Con by Malcolm Kendrick, The Great Cholesterol Con by Antonio Colpo and The Great Cholesterol Lie by Dwight Lundell. Sounds pretty boring. However I decided to give Bowden´s and Sinatra´s book a chance. Although, I thought I already knew what their hypothesis was about, I was quite curious to find out how they present their data and how they argument their theories.

In the field of cardiology, the role of cholesterol in atherosclerosis and cardiovascular disease is often debated. In my opinion, the so-called lipid hypothesis is an oversimplification of  a complex disorder. Sometimes we debate because we disagree on how to simplify complex mechanisms. Cholesterol is just one of many players in the atherosclerotic process. The main reason it has become such a popular player is that it is easy to measure, not because it plays the main role. However, medical debates are often quite interesting, and they may actually have some positives. They often provoke lively discussions, and they may stimulate scientific research. The downside is that if you have already chosen a side, you run the risk of neglecting, or not choosing to accept scientific results or arguments that don´t support your own opinion.

There are different ways for authors to present a hypothesis they believe is true. You can choose to present all available data, and then make an argument for the  data you believe support your hypothesis. Such a balanced, informative approach is honest, and it gives the reader a chance to make up his own mind. However, it doesn´t necessarily catch the attention of the news media or make the headlines.

If you are absolutely convinced that you have a lock on the truth, you may prefer to predominantly present data that reinforce your own beliefs. In my opinion, the recent book by Bowden and Sinatra is an example of this approach. Their book is a perfect example of how to convince you have the truth at your proposal. You may have the feeling while reading, that somehow the authors have managed to unlock the hidden truth, and you may admire how fearlessly they expose, what they call the misinformation fed by the scientific community. Let me quote the first sentence of the first chapter: “The two of us came together to write this book because we believe that you have been completely misled, misinformed, and in some cases directly lied to about cholesterol”. Certainly an interesting book, quite fun to read and provoking. Because of the controversy, such a book is likely to get media attention, I presume that´s a part of the procedure. Strangely, people often like to read about how they have been cheated and mislead. If you manage to convince them they have been cheated, they are also more likely to believe your own theories and arguments.

While reading “The Great Cholesterol Myth”, I had this strong urge that I had to play the devil´s advocate. It´s not necessarily because I dislike the book or disagree with everything the authors write. On the contrary, I think they have some great tips on healthy lifestyle and diet. It´s just because I believe people have the right to hear both sides of the story, and then make up their own mind. I´m not a book critique, so whether I liked the book or not is irrelevant. However, taking on the role of the devil´s advocate I want to bring forward some of my thoughts while reading the book.

In the first two chapters the role of cholesterol in heart disease is discussed. The authors believe that cholesterol numbers are a poor predictor of heart disease. They point out that more than half of the people hospitalized with heart attacks have what they call “perfectly normal cholesterol levels”.  The importance of cholesterol for different bodily functions is underlined. The message is; because cholesterol is essential for life it can´t be bad. Let me quote the book: “Both of us became skeptical of the cholesterol theory at different points in our careers, traveling different pathways to arrive at the same conclusion: Cholesterol does not cause heart disease.”

The second chapter bears the name “Cholesterol is harmless“. The people who write the special reports and guidelines, meant to help doctors make treatment decisions, get a fierce amount of critique. A quote from the book: “When the National Cholesterol Education Program lowered the optimal cholesterol levels in 2004, eight of the nine people on the panel had financial ties to the pharmaceutical industry, most of them to the manufacturers of cholesterol-lowering drugs who would subsequently reap immediate benefits from these same recommendations”.

Atherosclerosis is the underlying cause of cardiovascular disease. It leads to the building of plaques within the walls of our arteries. These plaques are composed of several substances, among them is cholesterol. Atherosclerosis typically affects the coronary arteries, the vessels supplying blood to the heart muscle. In medical school I was taught that the exact cause of atherosclerosis was unknown. However, there were certain risk factors, which if present increased the likelihood of developing atherosclerosis and coronary artery disease. The main risk factors were family history, smoking, high blood cholesterol, high blood pressure, diabetes and obesity. None of these risk factors was considered to be the cause of heart disease. However, by modifying the risk factors, the likelihood of developing heart disease could be reduced.

I have never believed that cholesterol is the cause of heart disease. However, it is certainly involved, and it is quite clear that cardiovascular disease as we know it would not exist if cholesterol was not present. Is a tsunami caused by water? No, but it won´t happen without it. Is heart disease caused by cholesterol? No, but it won´t happen without it.

The fact that cholesterol is a very important biologic substance and essential to life, does not prove that high levels may not promote a disease process. There are many examples of this phenomenon. Iron for example has important biologic functions. However high levels of iron in the body can cause a disease called haemochromatosis. Insulin is essential for our metabolism, however research indicates that high levels are undesirable and may promote obesity. A certain level of blood glucose is essential for life. If we don´t get glucose through our diet, the body produces it. However, high blood levels of glucose are undesirable and associated with the disease we call diabetes. So, although cholesterol is an important biologic substance, high levels could certainly be associated with disease.

In animal models, atherosclerosis does not occur in the absence of greatly elevated blood cholesterol. Furthermore, heart attacks have been shown to be uncommon in humans with very low plasma levels of LDL cholesterol due to a sequence variation in the PCSK9 gene. In cell cultures, according to Nobel prize winners Brown and Goldstein, cellular needs for cholesterol can be met with an LDL cholesterol level of 25 mg/dl (0.65 mmol/L). Human newborns have an LDL cholesterol in the range of 40-50 mg/dl (1.1-1.3 mmol/L). Healthy adult levels are 3-4 times higher. The normal LDL cholesterol range is 50 to 70 mg/dl (1.3-1.5 mmol/L) for native hunter-gatherers, healthy human newborns, free-living primates, and other wild mammals, all of whom do not develop atherosclerosis. Randomized trial data suggest atherosclerosis progression and coronary heart disease events are minimized when LDL is lowered to <70 mg/dl (1.8 mmol/L). No major safety concerns have surfaced in studies that lowered LDL to the range of 50 to 70 mg/dl.

Familial hypercholesterolemia (FH) is a disorder characterized by high cholesterol levels, specifically levels of LDL-cholesterol. Many individuals with this disorder die prematurely of atherosclerotic cardiovascular disease. I have found no mention of this disorder in Bowden´s and Sinatra´s book. The most common problem in FH is the development of coronary artery disease at a much younger age than would be expected in the general population. So, try telling a thirty year old woman with FH, and an acute heart attack, that cholesterol is harmless. Statin drugs have improved prognosis and quality of life in patients with FH.

It is important to emphasize, that it is lipoproteins that interact with the arterial wall and initiate the cascade of events that leads to atherosclerosis. Cholesterol is only one of many components of lipoproteins. LDL, the major carrier of cholesterol in the circulation, is the most atherogenic lipoprotein. High levels of LDL in the blood may lead to increased transport of this substance into the vessel wall. When inside the arterial wall, LDL can undergo a variety of modifications including oxidation, uptake by white blood cells called macrophages, formation of so-called foam cells and the initiation of inflammation. This cascade of events may ultimately result in an atherosclerotic plaque within the vessel wall. Obviously, cholesterol is not the cause of all this, but it is always involved. So, could it be that atherosclerosis is more likely to occur if plasma concentration of LDL-cholesterol is high than if it is low. The answer is yes. A number of scientific studies indicate that this is definitively the case. However, this does not mean that cholesterol causes heart disease. That is an oversimplification.

The authors claim that inflammation is the true cause of heart disease. Let me quote the book: “So if cholesterol isn´t the cause of heart disease, what is? The primary cause of heart disease is inflammation”. The authors point out that chronic inflammation is a significant component of virtually every single degenerative condition, including heart sisease, Alzheimer´s, diabetes, obesity, arthritis, cancer, and many other diseases. They believe oxidation is an important contributor to inflammation and atherosclerosis.

Bowden and Sinatra consider the size of the atherogenic LDL particles to be important. Thus, the more of the large fluffy particles, the better. The more of the small dense particles, the higher your risk. They even suggest these parameters may be considered the “new good and bad” cholesterol, instead of the traditional HDL cholesterol and LDL cholesterol.

Nature is complex and so are biological mechanisms that control bodily functions. A disease often occurs during specific conditions that involve many different biological mechanisms. Of course environmental and genetic factors play a role as well. So, why should there be a one simple cause of heart disease such as chronic inflammation or cholesterol? Isn´t it more likely that lipoproteins, cholesterol, oxidation, inflammation and many other factors are all involved at the same time? So, again, we may disagree because our methods of simplifying complex mechanisms are different.

An association between LDL particle size and cardiovascular risk has been found in some studies. However, measurements reflecting the number of LDL particles appear to be a stronger predictor of risk than particle size in itself. LDL-P and apolipoprotein B reflect the number of LDL-particles. Interestingly, patients with FH usually have large LDL-particles, but their risk of heart disease is very high, and so is their LDL-particle number. It is likely that the association between small LDL and heart disease reflects an increased number of LDL particles in patients with small particles. Therefore, particle size in itself may be unimportant.

Bowden and Sinatra consider the benefits of statin drugs to have been widely exaggerated. Furthermore, they believe the side effects of these drugs to be much more common than previously thought. They point out that statin therapy may be associated with cancer and diabetes. Other common side effects may be memory problems, lack of energy and sexual dysfunction. They believe that much of the side effects of statin therapy may be traced to depletion of coenzyme Q-10. Dr. Sinatra only uses statin drugs for high risk middle aged men.

I share many of the authors thoughts on statin therapy. I think side effects are underreported and doctors should be much more alert on the possible effects on muscle, diabetes risk, energy, memory and cognitive function. However, in my opinion most people tolerate statin therapy quite well. Furthermore, I believe these drugs certainly reduce cardiovascular risk  in patients with documented cardiovascular disease and in many high risk individuals without disease. However, in my opinion statins are used to often in low risk patients. We, doctors should take time to inform these low risk individuals about possible alternatives to statin therapy, such as diet, exercise and healthy lifestyle. Interestingly, the chapter on statin therapy ends with a final cautionary note, let me quote: “Look, there´s not much doubt that statin therapy can significantly reduce the incidence of coronary morbidity and mortality for those who are at great risks of developing coronary artery disease“. Here I definitively agree with Dr. Bowden and Dr. Sinatra, but I have to wonder whether they disagree with themselves.

The seventh chapter of the book bears the name “Help your heart with these supplements”, and deals, as the name suggests, with different nutritional supplements. There are a number of supplements the authors believe improve the health of our hearts.  Among these are coenzyme Q10, which the authors call the spark of life, D-ribose, L-carnitine, magnesium, niacin, vitamin E, fish oils and Omega-3.  Interesting list, but somehow I could not help thinking that, if the authors owned companies that were selling these products on-line, it would seriously affect the credibility of the book and reduce its educative value. However, keeping in mind the they believe that the lipid hypothesis is kept alive by medical professionals, getting paid by pharmaceutical companies, I will have to assume that Dr. Bowden and Dr. Sinatra have no conflict of interest.

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Last year I wrote a couple of articles about statin therapy, so maybe you think I should give it a rest. However, I think it is such a hugely important issue, and I have this strong feeling that the truth really has not emerged yet. There are two reasons for the issue resurfacing on my blog now. Firstly, two recent scientific papers touching on the effects of statins on cognitive function, glucose tolerance, skeletal muscle function and coenzyme Q10 really had me thinking a lot about how much we still don´t know about the long-term use of statins. Secondly, last month I happened to read a fantastic book about “the other side” of statin therapy written by an American cardiologist. A well written, thought-provoking, easy to read book that everyone interested in modern-day health care should read, not least doctors. I´ll get back to the book later.

Statins are used by about 25 percent of Americans 45 years and older. Between six and seven million people in the UK take statin drugs every day. But what are they used for? What disease or disorder in our society motivates drug therapy for such a large proportion of the population? In short, statins are prescribed by doctors to help protect healthy but high-risk people from heart disease and to prevent heart attacks and strokes in people who have already been diagnosed with cardiovascular disease.

One has to wonder what gives medical professionals the right to prescribe therapy to such a huge number of people? Firstly, prove of efficacy must be substantial and there is really no room for any doubt. You would expect such therapy to significantly lessen the burden of disease and to prolong life. Secondly, it has to be absolutely proven that such treatment does not cause harm. If we trust regulatory authorities, we will have to assume this is true for statin drugs.

Statins were approved to lower cholesterol in the United States in 1987. Lovastatin (Mevacor) was the first statin approved by the FDA. At that time there was evidence that this drug lowered LDL-cholesterol but it had not been proven that doing so would reduce the risk of heart disease or improve survival. During the next 20 years a number of large clinical trials adressed the clinical efficacy of statin therapy in healthy people with increased risk of heart disease (primary prevention) and in patients with documented cardiovascular disease (secondary prevention).

Approximately 65 thousand patients were included in the primary prevention trials, 65 percent were men and 35 percent were women. Taken together, all-cause mortality rate was 11.4 per one thousand person years among people on placebo and 10.7 per one thousand patient years on people on statins. This difference is not statistically significant. Furthermore, there was no relationship between the amount of reduction of LDL-cholesterol and all-cause mortality. So, shockingly some might say, the evidence that statin drugs prolong life among healthy people with increased risk of cardiovascular disease is nonexistent.

Several studies have addressed the efficacy of statin drugs compared with placebo among patients with documented cardiovascular disease. The three largest trials, 4S (Scandinavian Simvastatin Survival Study), LIPID (Long-Term Intervention with Pravastatin in Ischemic heart Disease study) and HPS (Heart Protection Study) showed that all-cause mortality was significantly lower among patients receiving statin therapy compared with placebo. The absolute reduction in all-cause mortality was 4 percent, 3.1 percent and 1.8 precent in the three trials respectively.

So, if we focus on all cause mortality, the conclusion is twofold. Firstly, statin therapy is effective and saves lives among patients with documented cardiovascular disease such as prior heart attack or stroke. Some might say the effect is small, but it is consistent and cannot be ignored. Therefore, not giving statins to patients with documented atherosclerotic cardiovascular disease is bad clinical practice and goes against evidence based medicine. Many will say it is malpractice. Secondly, however, it has not been proven that statin drugs reduce mortality among healthy people with increased risk of heart disease, except for individuals with diabetes and those with the relatively rare disorder of familial hypercholesterolemia.

Thus, it is absolutely clear that we are treating a substantial proportion of the adult population with statin drugs, despite the fact that treatment has not been proven to reduce the risk of death. However, treatment is commonly motivated by study results showing that treatment will reduce the risk of cardiovascular events such as heart attacks and stroke.

Among relatively low risk individuals, it has been estimated that for every 1 mmol/L reduction in LDL-cholesterol there is an absolute reduction in major vascular events of about 11 per 1000 over 5 years. What does this really mean? Let´s say that I am a low risk patient and my LDL-cholesterol is 143 mg/dl ( 3.7 mmol/L ). My doctor prescribes a statin and I decide that I will take it every day for the next five years. My LDL-C goes down to 104 mg/dl (2.7 mmol/L) while I´m taking the drug.  This treatment is going to make it one percent less likely for me to have a coronary event or a stroke during those five years, compared to if I do not take the drug. Not very impressive indeed.  One has to wonder whether this proposed benefit outweighs the risk of treatment. If there is doubt, we should not treat. Primum non nocere; first do no harm.

The other side of statin therapy?

The clinical studies comparing statins with placebo indicate that statins are remarkably safe drugs with few side effects, muscle ache being the most common. However, it is well-known that side effects ar less common among patients participating in clinical trials compared to “real life” patients. In most clinical trials involving statins, less than one percent of subjects are reported to develop muscle pain or myopathy. In clinical practice, however, far more will experience myopathy. The much lower rate reported in clinical trials may be because eligibility criteria usually exclude patients with significant potential for drug interactions or concurrent health problems, whereas healthcare providers obviously cannot exclude such patients in clinical practice. Some studies have suggested that a quarter or even up to a third of patients who take statins will sooner or later develop a clinically significant myopathy. Cases of rhabdomyolysis have been reported. This happens when muscle fibers die and release a protein called myoglobin into the blood stream. High blood levels of this protein can lead to kidney failure. Although this is a rare disorder, it can be fatal.

In october last year a study addressing the possible negative effects of statin therapy on cognitive function was published in the American Journal of Geriatric Pharmacotherapy. Statin therapy was withdrawn in eighteen older subjects with Alzheimer´s disease. After six weeks the patients were put back on statin therapy. MMSE (mini mental state examination) was used to assess cognitive function. This is a standardized mental status examination reflecting memory and simple thought processes. In short, cognitive function improved when the patients were taken off statins and worsened again when statin therapy was restarted. The authors conclude that statins may adversely affect cognitive function in patients with dementia. This is a small study and the results will have to be confirmed by more research. However, it is not the first study to show negative effects of statins on cognitive function. The next most common adverse effect reported by people taking statins, next to the muscle side effects, involve cognitive impairment. These are interference with inability to think, concentrate, remember and solve mental problems. It has been suggested that this may have to to with the lowering effects of statins on CoQ10 levels. CoQ10 is important for mitochondrial function and mitochondrial density is high in brain tissue.

An interesting study by Danish researchers was published in the very recent first issue of the 2013 Journal of the American College of Cardiology. The  study addresses the effects of statin therapy on glucose metabolism, muscle function and CoQ10. Twenty male subjects were recruited for the study. Ten were on treatment with the statin drug simvastatin due to high blood cholesterol and ten were healthy control subjects. The groups were matched for age, weight, body mass index, fat percent (total and abdominal) and maximal oxygen uptake. Fasting glucose and insulin measurements were done and a standard glucose tolerance test was performed. Muscle biopsies were taken for analyses of mitochondrial respiratory capacity of muscle cells. Insulin levels were similar in the groups under the glucose tolerance test, but glucose concentrations were higher in subjects on simvastatin, indicating impaired insulin sensitivity compared with the healthy controls. Q10 protein content in muscle was reduced in patients on simvastatin compared with controls. There were signs of impaired mitochondrial respiratory capacity in patients on simvastatin compared to controls.

According to the authors of the study, impaired glucose tolerance found in simvastatin treated patients is in agreement with earlier findings of impaired insulin sensitivity with statin treatment, although a deleterious effect on glucose tolerance by simvastatin has not been reported before. Remember that last year, regulatory authorities warned against an increased risk of diabetes with statin therapy.

The Danish scientists suggest that there may be a relationship between the decrease in Q10 protein content and reduced mitochondrial respiratory capacity among patients on long-term treatment with simvastatin. Possibly, muscle pain, impaired exercise tolerance and fatigue seen among some patients on statins may be traced to these mechanisms.

Statins inhibit an enzyme called HMG-CoA reductase which is involved early in the pathway leading to cholesterol synthesis. Statins therfore also affect other products of this pathway, including production of CoQ10. Statins have been shown to reduce blood levels of CoQ10. CoQ10 is important for cellular function and the generation of cellular energy by so-called mitochondria which are cellular organs that play a key role for many cells in the body. Nerve cells, heart muscle cells and skeletal muscle cells are rich in mitochondria. Several diseases are caused by abnormal mitochondrial function. There is some evidence that statin myopathy may, at least partly be related to low levels of Q10. However, it has not been proven yet that statin induced myopathy may be successfully treated with Q10.

The truth about statins

Doctor Barbara H. Roberts has written a book called “The Truth About Statins” that was released in April last year. Dr. Roberts is a cardiologist, associate clinical professor at the Alpert Medical School of Brown University as well as director of the Women´s Cardiac Center at the Miriam Hospital in Rhode Island. In her book Dr. Roberts discusses the benefits and health risks of statin therapy in a very professional way. She discusses the role of cholesterol in the body and explains the role of cardiovascular risk factors. She explains the “cholesterol hypothesis” and the evidence supporting it. She cites clinical trials and explains in laymen terms how they are interpreted, underlining for example the difference between absolute and relative risk reduction. She thoroughly goes through the Yin and Yang of statin therapy. She also mentions the possibility that LDL-cholesterol may be less important as a risk factor among women than men, and that data showing that statins reduce risk appears less convincing for women. Her discussion is objective, evidence based, and she does not jump to any conclusions. Although she has a point to make, her writing is careful and unbiased. She finally presents a possible healthy lifestyle alternative to statin therapy, based on the Mediterranean diet concept. This is an honestly written book. Unlike so many medical authors today, Dr. Roberts does not to my knowledge have any product line designed to enrich her bank account.

I recommend everyone interested in cardiovascular disease and modern-day health care to read Dr Roberts´s book. It is a strong reminder of our real lack of knowledge of the long-term effects of drugs that are being prescribed to millions of people worldwide.

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Diabetes is an increasing health problem worldwide. Approximately 11.3 precent of US adults have type-2 diabetes. Keeping in mind that diabetes is such a strong risk factor for cardiovascular disease, it is likely that the burden of heart disease and stroke in our community will increase in the near future. Therefore, in order to imply preventive measures, an understanding of the underlying causes of the diabetes epidemic is hugely important. Several epidemiological studies have shown that habitual caffeine consumption, in the form of tea and coffee is associated with less risk of diabetes. However, this has been confounded by some short term metabolic studies showing that caffeine may elevate blood sugar levels and decrease insulin sensitivity. Both these effects might in theory increase the risk of diabetes. An analysis of huge epidemiological data, published in the most recent issue of the American Journal of Clinical Nutrition has highlighted the association of caffeinated and decaffeinated coffee and tea consumption on the risk of type-2 diabetes. Furthermore, the researchers investigated the joint effects of caffeine and sugar-sweetened beverages and caffeine and coffee on the risk of type-2 diabetes.

Bhupathiraju and colleagues at The Harvard Public School of Health used data from the Nurses Health Study (NHS) and the The Health Professionals Follow-up Study (HPFS) to study the effects of caffeinated and caffeine free beverages on the risk of developing type-2 diabetes among women and men. The consumption was based on repeated food frequency questionnaire (FFQ). Participants were asked how often on average during the previous year they had consumed caffeinated and decaffeinated coffee, and different types of sugar-sweetened and artificially sweetened carbonated beverages. Carbonated beverages included caffeinated and caffeine-free colas and carbonated soft drinks. The caffeine content was estimated to be 137 mg per cup of coffee, 47 mg per cup of tea, and 46 mg per bottle or can of cola beverage. Follow-up was for 24 years, between 1984 and 2008.

These were the main findings of the study

• There were about 10 thousand cases of diabetes registered among more than 172 thousand participants.
• After major lifestyle and dietary risk factors were controlled for, intake of caffeinated and caffeine-free sugar-sweetened beverages was significantly associated with a higher risk of type-2 diabetes
• Caffeine-free artificially sweetened beverages were associated with increased risk of type-2 diabetes among the women but not men
• The consumption of caffeinated and decaffeinated coffee was associated with a lower risk of type-2 diabetes
• Caffeinated tea was associated with a lower risk of type-2 diabetes among women
• Substitution of caffeinated carbonated beverages with other caffeinated beverages such as coffee and tea was associated with lower risk of type-2 diabetes

What can we learn from the study?

Not surprisingly, the consumption of sugar sweetened beverages, irrespective of the caffein content, appears to increase the risk of diabetes. Other studies have indicated that sugar-sweetened beverages are associated with weight gain, the metabolic syndrome and type-2 diabetes. The study also indicates that drinking artificially sweetened beverages may increase the risk of diabetes in some groups, although the association appears weaker than for sugar-sweetened beverages. The latter are sweetened with sucrose or high-fructose corn syrup, both of which rapidly increase blood sugar and insulin concentration.

Drinking coffee, both caffeinated and decaffeinated was associated with lower risk of diabetes. According to the study results, a risk reduction of 4 to 8 percent in incident type-2 diabetes may be expected for every 1-cup increment in coffee consumption. The authors propose several possible mechanisms to explain the protective effects of tea and coffee on the risk of developing diabetes. Tea contains flavonoids, an antioxidant that may inhibit oxidative stress associated with the risk of diabetes. Coffee is rich in chlorgenic acid, an antioxidant which may improve glucose metabolism.

The main conclusion is that while the consumption of soft drinks, in particular those that are sugar-sweetened, appear to increase the risk of developing diabetes, drinking coffee and tea seems to lessen the risk. However, whether the coffee contains caffeine or not appears unimportant in this respect.

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