chapter four

How Risk Factors
Turn into Disease

Decades of research and evidence have provided insight into the many risk factors for heart disease. When we decrease or modify risk factors, we can see a decrease in atherosclerosis, heart attacks, and death. Based on what we know thus far about disease and risk factors, they are divided into four categories:11

It is important to understand that these categories are based on what we have found easier to focus on. For example, it is easier to measure blood pressure and cholesterol than your psychosocial status. It is also easier to prescribe medications for risk factors than to counsel patients to change their habits that caused them in the first place, resulting in categorizing them in the above manner. It is exceedingly difficult to do large-scale trials of changing behavior and measuring such a change; in comparison, it is much easier to prescribe medicines to one group and a placebo to another and measure blood pressure or cholesterol. The above categories reflect the inherent limitations of evidence-based medicine that we overlook as doctors and patients.

Mark, whom we met in the previous chapter, had high blood pressure, diabetes, and high cholesterol, all of which were being treated with medicines. As he discovered, it is one thing to have risk factors for heart disease and another to have heart disease. The pathway from risk factors to disease involves a complex and intricate interplay of various chemicals and hormones whose function is to maintain homeostasis, or balance, in our blood vessels.

Endothelial Dysfunction and Inflammation

Endothelial Dysfunction

If you are an average-sized adult, you have anywhere between 1 to 1.5 gallons of blood circulating through your heart and blood vessels, which are lined by a single layer of cells called endothelium. Apart from your skin, your endothelium is the largest organ in your body, and it helps maintain balance in all your tissues and organs. Damage to this layer or imbalance in the chemicals it produces is known as endothelial dysfunction, which is the first manifestation of atherosclerosis.12

Your vessels are constantly adjusting to blood flow, plumping up or clamping down in various areas of the body based on what time of day it is, what you’re thinking, how you’re feeling, how high or low your blood pressure and heart rate are, and what the other organs (such as the kidney or liver) are doing. This delicate balance is maintained by the chemicals that the endothelium produces, the most important of which is nitric oxide. As long as your endothelial cells are producing a constant level of nitric oxide, your arteries remain healthy in response to your internal and external environment, plumping up or clamping down to maintain their tone. Moreover, as long as there is a normal level of nitric oxide in your arterial walls, your platelets don’t stick together to cause clots and your white blood cells don’t stick to the walls (see The Magnificent Machine). As soon as the endothelium becomes injured, however, an inflammatory process begins to heal the damage.

Inflammation

Inflammation is a normal protective response of the body to injury or harmful stimuli such as bacteria, viruses, environmental toxins, and irritants. Inflammation is your immune system’s way of repairing and healing itself. Just as your skin heals with a scar when you cut it, inflammation in the endothelium initiates a scarring process when it is damaged by the various risk factors listed above. Quite simplistically, the delicate cells of your arterial walls undergo irreversible changes when exposed to toxins such as cigarette smoke, drugs like cocaine, excess cholesterol, sugar, homocysteine, lipoprotein(a), or triglycerides circulating in your blood or if you have blood flow disturbances because of high blood pressure, like Mark. With the onset of a proinflammatory process, certain genes become activated and produce a variety of chemicals that are meant to stop the injury.

Most of the time, the injury is limited and the endothelium repairs itself. However, certain toxic stimuli such as certain types of cholesterol induce a complex process of permanent activation of certain genes. In this case, your endothelial cells become activated and start producing harmful substances known as chemokines. Chemokines in turn attract macrophages and other cells into the vessel wall. If there are high levels of toxins (such as cholesterol or sugar) circulating in your blood, the vessel wall becomes chronically inflamed, leading to atherosclerosis. We now know that coronary heart disease is indeed a chronic inflammatory process that induces the production of certain substances such as C-reactive protein that can be measured in the blood. Endothelial dysfunction can be measured in the vascular laboratory by a test known as flow-mediated dilation (FMD).

Is High Blood Cholesterol the Sole Culprit?

The role of high cholesterol in heart disease is a hot topic for discussion and controversy. In 2013 the American College of Cardiology and the American Heart Association issued updated guidelines on cholesterol management, where they recommend statin medications to lower cholesterol among many groups of individuals.13 Some recent studies have shown that high cholesterol by itself does not cause coronary artery disease, calling for reevaluation of the guidelines. However, the little-known fact about statins is that they are potent anti-inflammatory agents, which might explain their beneficial effects in atherosclerosis, an inflammatory condition.14

The important thing to remember is this: atherosclerosis does not occur without endothelial dysfunction and inflammation. If you have high cholesterol but no endothelial dysfunction or inflammation, you are unlikely to get coronary artery disease from atherosclerosis. On the other hand, if there is presence of endothelial dysfunction and inflammation, even low levels of bad cholesterol are enough to cause atherosclerosis. Moreover, high cholesterol circulating in the blood can itself be toxic to the lining of the artery resulting in endothelial dysfunction.

While the risk factors listed above are the better known ones that lead to these deleterious processes, there are other lesser-known conditions that lead to atherosclerosis by inducing inflammation.

Hidden Risk Factors

Nearly everyone knows someone who had none of the risk factors presented here and still went on to have a heart attack. This is because there are a growing number of conditions that are being linked to atherosclerosis by their ability to cause endothelial dysfunction and inflammation:

In short, any condition that leads to inflammation is a risk factor for heart disease. As we move into an era of sophisticated research technology and personalized medicine, many more risk factors will be discovered, along with interventions and therapies that are effective.

Heart Disease in Women

Julie came to my office as a last resort. She had seen three other cardiologists for her ongoing symptoms of chest discomfort and palpitations. The discomfort was atypical, as it would come on not only when she was exerting herself but often when she prepared for bed at night. She had symptoms of “pounding” in her chest on occasion, usually associated with the chest discomfort. At fifty-three she was in the throes of menopause with hot flashes and mood swings. One cardiologist had told her it was all hormonal and that heart disease is a “man’s disease.” Two others had performed stress tests, which turned out to be quite normal for her age. They too had dismissed her symptoms, telling her it was all in her head. She confessed that she did not feel well and had an intuition that there was something wrong with her heart. I trusted her and sent her for a CT angiogram since her probability for significant disease was not high. To my surprise, Julie had a severe blockage in one of her arteries, and the other two had mild blockages. She underwent angioplasty and was started on appropriate medicines. All her symptoms went away.

For decades, research trials in heart disease included a disproportionately higher number of men. This led to practices in the field of cardiology that were based on lack of knowledge of disease in women and several misconceptions, including the view that it is a man’s disease. Such practices led to almost exclusive focus on men with respect to preventive strategies and education. Statistical data demonstrates the downstream effects of those misconceptions: currently, more women die of heart disease than men (nearly half a million in the US alone).15 Moreover, women have more complications after a heart attack, including the probability of having another one, death, and heart failure.16

The field of cardiology is in its infancy when it comes to understanding heart disease in women. We now know that heart disease causes more deaths in women than breast cancer. Although there was the erroneous perception that women are “safe” from heart disease until menopause, this has been refuted by data in the last decade. Risk for developing heart disease begins long before menopause. Moreover, treatments in post-menopausal women don’t seem to work as well as in men. As with Julie, women have been shown to have longer time to diagnosis, less intensive resource use, and delays in seeking care. Women tend to have more atypical symptoms of heart disease, with more fatigue, sleep disturbance, shortness of breath, and pain or discomfort that is not in the chest area.17

To complicate things further, traditional tests that focus on identifying blockages are not as accurate in women. Newer tests like calcium scoring and CT angiography seem to be as efficacious in women as in men. However, these tests expose women to X-rays that can be associated with breast and other cancers over their lifetimes. The diagnosis of heart disease in women is also strongly affected by the presence of psychological symptoms. As was the case with Julie, investigators in one study demonstrated that physicians displayed a significant gender bias with respect to diagnosis of heart disease, particularly if a woman presented with added symptoms of stress. On the other hand, men’s symptoms were assumed to be “real” heart disease whether or not they presented with stress or anxiety.18

Risk factors seem to affect women differently than men. For instance, diabetic women have higher rates of death compared to diabetic men.19 Even though some of these differences can be explained by the fact that women present at an older age and have other risk factors, it is not the full story. Psychological factors seem to play a greater role in disease development and management in women. One explanation for the seemingly greater burden of symptoms in women despite having no significant coronary blockage is somatic awareness. Women have been shown to be more sensitive to internal changes, including physical symptoms, emotions, and mental processes.20 This is one explanation for why depression and anxiety are more common in women.

Habits That Kill

Nearly half of all adults have one or more chronic health conditions, and one in four have two or more chronic ailments.21 When we look at risk factors for heart disease and other chronic illnesses, it is striking to note how many are preventable. Studies have shown that four lifestyle habits cause most illness and early death related to all chronic diseases—lack of exercise, poor nutrition, tobacco use, and drinking too much alcohol.

Nearly half of the adults in the US have at least one of the following major risk factors for heart disease or stroke: uncontrolled high blood pressure, uncontrolled high LDL (bad) cholesterol, or current smoking.22 Nine out of ten adults consume too much sodium, increasing the risk for high blood pressure.23 One in five adults smoke cigarettes; cigarette smoking accounts for nearly half a million deaths every year in the US alone. Drinking too much alcohol is responsible for nearly 100,000 deaths each year.

These statistics have serious implications on how a nation spends its resources. In the US, most healthcare costs are related to chronic illnesses and the health-risk behaviors that cause them. For instance, the Centers for Disease Control estimated that in 2010 alone, the total costs of heart disease and stroke (both of which are caused by poor health habits and are largely preventable) were nearly $315 billion!24 Not only do these conditions cost a nation its economic (and other) resources, but they also result in decreased productivity and absence from work. In 2012 the cost of decreased productivity was $69 billion due to diabetes and $47 billion due to arthritis. From 2009–2012 loss of productivity was estimated at $156 billion due to smoking and $224 billion due to excessive alcohol consumption. It is not surprising that our habits have everything to do with our state of health. It is surprising how they enslave us.

Take the example of Jack, who was forty-two when he had his first heart attack. When I met him, he had been treated for the heart attack a month earlier with angioplasty. He worked hard at a job that involved physical labor and long hours, indulging in heavy drinking and chain smoking to keep his stress under control. In the early hours of a chilly fall morning, he experienced chest pain while camping in the woods with his wife. He knew he was having a heart attack because of his familiarity with the disease. His older brother had suffered his first heart attack in his thirties, followed by multiple stents, bypass surgeries, blockages in his legs that required amputations, and, finally, a heart transplant. Jack’s mother had a heart attack in her fifties, requiring several procedures over the next twenty years. Jack was no stranger to heart disease or its risk factors. When we talked, he knew he was drinking too much and that his smoking was a big problem. He knew his diet was poor and that his stress was getting the better of him. In fact, Jack knew more about the detrimental effects of his habits than many doctors, yet he was unable to change his habits. This is where the mind comes in.

While we do not know all the risk factors for heart disease (or for any other condition, for that matter), modern medicine has overlooked the most significant contributing factor of our health and well-being: the mind. In fact, emerging data in the default model is beginning to reveal what the bliss model has maintained all along: that how we process sensory information and how we think and feel have a direct effect on heart health. In the next chapter we will explore the elusive body-mind connection and the brain-hormone pathways that keep us locked in unhealthy habits, as Jack’s example reveals.

Summary

[contents]

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13. N. J. Stone, J. G. Robinson, A. H. Lichtenstein, et al., “2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol 63 (2014): 2889–2934.

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20. C. D. Warner, “Somatic awareness and coronary artery disease in women with chest pain,” Heart Lung 24 (1995): 436–43.

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23. M. E. Cogswell, Z. Zhang, A. L. Carriquiry, et al., “Sodium and potassium intakes among US adults: NHANES 2003–2008,” Am J Clin Nutr 96 (2012): 647–57.

24. A. S. Go, D. Mozaffarian, V. L. Roger, et al., “Heart disease and stroke statistics—2014 update: a report from the American Heart Association,” Circulation 129 (2014): e28–e292.