In the early days of my medical residency, I met a man whom we’ll call Jason. He arrived to our emergency room on a holiday, nonchalant yet amiable, and complained of mild chest pain. Jason was tall and trim, with a strong South Boston accent and fingertips still faintly stained from his last home-improvement project. He was only 45 years old, but he looked much younger. He didn’t smoke, barely drank alcohol, and his cholesterol levels had always been normal. No one in his family had a history of heart disease. He asked us if we could work quickly—he wanted to be home for dinner with his daughters.
We welcomed a likely false alarm. Maybe Jason was having a bout of acid reflux, or even a panic attack. His heart, surely, was as robust as the rest of him. He was young and without any risk factors for heart disease. And he had been in excellent health all of his life. Our minds wandered to other patients and tasks.
But as the day wore on, Jason’s symptoms persisted. When the results of his blood tests finally blinked on our pagers, we were shocked to find that he was suffering from a massive heart attack. Jason was rushed to the cardiac catheterization lab, where a cardiologist began threading a thin tube through an artery in the leg in an attempt to open up blockages in the arteries feeding the heart.
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As I learned in the ensuing years of training, Jason’s story is not unusual. For too many people, the first clue that they have cardiovascular disease is a heart attack or a stroke—or even death. But we wondered, in Jason’s case, why it had happened—what was the cause?
Traditionally, doctors address common risk factors for developing cardiovascular disease, including high blood cholesterol levels, diabetes, smoking, and family history. But one of the biggest revelations of 21st century medicine is the unveiling of another important cause of heart disease, one that may lurk in the body unseen and unfelt, yet increases the risk of dropping dead from a heart attack or stroke: inflammation.
Inflammation is a primeval force that evolved with benevolent intent, striving to protect the body against pathogens, poisons and traumas—all of which ancient humans routinely succumbed to. It can be grasped by the naked eye. Slam your knee onto the edge of a table with enough force, for example, and redness, heat, pain and swelling—the four cardinal signs of inflammation—inevitably ensue, as blood flow quickens and vessels dilate, allowing fluid and protein to leak out into tissues. Inflammation works to handle and to eventually heal the wound.
But inflammation is not always helpful, or even harmless. In autoimmune diseases like rheumatoid arthritis, lupus, and inflammatory bowel disease, it rages against the body’s own tissues, disrupting essential functions and ultimately leading to disability. Today, we know that inflammation plays an important role not only in autoimmunity but in many other chronic conditions as well, including heart disease, cancer, obesity, diabetes and aging. In fact, low-level, invisible inflammation, simmering quietly in the blood of ostensibly healthy people, may be a common thread running through nearly all diseases.
Research reveals that persistent low-level inflammation, which is twice as common as elevated blood cholesterol levels, plays a part in every stage of heart disease including increasing the risk of plaque rupture which leads to heart attacks. In fact, half of all heart attacks occur in people with normal cholesterol levels. In 2017, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) showed that treating low-level inflammation in people who experienced prior heart attacks—correcting for differences in other factors like blood cholesterol, diabetes and high blood pressure—lowered patients’ risk of heart attacks, stroke and even death from cardiac events. In 2020, another large clinical trial found that colchicine, a medication deployed for centuries by ancient Greeks and Egyptians to treat the glaring, roaring inflammation of gouty arthritis, could also treat the hidden iteration in heart disease, decreasing the risk of cardiac events. Perhaps Jason, seemingly healthy, had been silently inflamed.
Many years after my encounter with Jason, a patient came to my gastroenterology clinic complaining of rectal bleeding. For a couple of years, Rebecca had been noticing small spots of bright blood dotting the toilet paper when she had a bowel movement. This would only happen on occasion, and she insisted her hemorrhoids were responsible for the spotting. She was only 34 years old and had no family history of colon cancer. Busy with three kids to care for and chronically short on time, she had put off visiting a gastroenterologist. But when I performed her colonoscopy, I found more than hemorrhoids: a jagged, motley collection of tissue gripped at the walls of her colon, so hard and unforgiving that I couldn’t advance my scope through its narrow opening. Imaging scans showed that she had cancer which had already spread to the liver. It was the first time I had diagnosed colon cancer in someone so young, but it wouldn’t be the last. Cancer is invading more collective years of human life than ever before.
While inflammation weaves through the arteries feeding the heart, it may fester in tumors as well. The immune system fights tumors as it does germs, attempting to keep cancerous cells in check. But it also betrays the body by helping them to grow and spread. Inflammation fuels cancer in many cases, and cancer—like a cut to the skin—fuels inflammation. Cancer is fed not only by obviously inflamed tissues but by insidious, low-level inflammation as well, which doctors typically do not test for. Whether it shows up before or after the birth of a cancer, inflammation can affect all its life stages, from early genetic influences that transform normal cells into malignant ones to the continued growth and spread of cancerous tissue throughout the body. Cancer, in fact, behaves like a “wound that does not heal,” as scientist Harold Dvorak writes. Of course, cancer may arise in non-inflamed tissues as well, and not all types of tissue inflammation carry an equivalent increase in the risk of cancer.
That inflammation is a common element in humankind’s top killers—heart disease and cancer—is unlikely to be serendipitous. The intricate link between inflammation and modern chronic diseases is rooted in our evolutionary history. In order to survive infections, famine, and other dangers in brutish ancestral times, we developed hyperactive immune systems and insulin-resistant bodies adept at storing fat. But our modern environment has been markedly transformed, from the food we eat to the air we breathe, how we move and more. Our immune system is exceptionally sensitive to the triggers of this new world, portending a higher risk of chronic, hidden inflammation.
Moreover, inflammation is intimately tied to essential, life-sustaining processes occurring throughout the body. Metabolic processes, for example, include those that convert food into energy and remove waste. The metabolic syndrome is a group of risk factors associated with heart disease, diabetes and some cancers: fat around the stomach, high blood pressure, high blood sugar, and unhealthy cholesterol levels. Traditionally, metabolic processes and immune reactions were viewed as distinct entities with disparate functions. But we now know that they are intimately interdependent.
Managing energy and defending the body against infections are both crucial for survival, and coevolved. Fat cells—which are known to play a part in metabolism—and immune cells derive from the same ancestral cell, and share many roles. An excess of fatty tissue, particularly the “visceral fat” that wraps around abdominal organs, acts like immune organ, producing a slew of inflammatory molecules. In fact, in markedly obese individuals, more than half of the cells making up their fat tissue are actually immune cells. Low-level inflammation may help to explain the ties between obesity and a variety of chronic diseases, including heart disease and cancer.
Chronic diseases are complex entities, and a singular, unifying theory of disease may forever be elusive. But mounting evidence suggests that inflammation is an important common thread running through many distinct diseases. Conditions that tend to cluster together include not only heart disease, stroke, cancer, diabetes and obesity but also neurodegenerative conditions like Alzheimer’s. If you are diagnosed with any one of these diseases, you are more likely to develop one or more of the others. And it is no accident that these illnesses tend to emerge during the aging process, which itself is tied to inflammation. In fact, “inflammaging”—the hidden inflammation of old age—is one of several essential factors that drive aging in humans.
The idea that inflammation may be a shared biological mechanism between many of our modern chronic diseases fosters a new understanding of human health. It compels us to consider diagnosing, preventing and treating these diseases in concert rather than only in piecemeal fashion. Doing this means delving into the root causes of hidden inflammation, which are largely lifestyle factors, including our diet. The food we eat can promote, prevent—or, in some cases, even treat–inflammation and chronic diseases. For example, the age-old advice to consume more fiber from whole plant foods takes on new meaning when considered in the context of the immune system and inflammation. One of the most important methods by which fiber exerts its healthful benefits is by manipulating the immune system. A fiber deficiency, present in 95 percent of Americans, is tied to a variety of chronic diseases, including heart disease, cancer, diabetes, obesity and an overall higher risk of death from these and other diseases.
A sedentary lifestyle is also inflammatory. The consequences of moving too little can manifest not only in obvious ways—excess subcutaneous fat, for example, or chronic disease—but in hidden ones as well. Dozens of human clinical trials across age groups point to the power of regular exercise to calm chronic, low-level inflammation. Exercise counters inflammation in many ways. For instance, it shrinks inflammatory visceral fat, which is invisible to the naked eye. Remarkably, even in the absence of weight loss, it lowers the numbers of immune cells that infiltrate fat tissue and churn out inflammatory cytokines.
The ways in which we eat and move are intimately linked to another potential root cause of hidden inflammation: our relationship with the microbes that live inside and around us. The intestinal microbiome, which encompasses trillions of germs—including bacteria, viruses and fungi—functions like an organ. It has a central role in immune function and inflammation. Fostering critical conversations between our microbes and immune cells means changing not only our diet, which can affect inflammation directly or through the microbiome, but other lifestyle factors as well. When we embrace the natural world, for example, we encounter ancestral microbes that swim in water and soil and air. These microbes evolved alongside humans, and some of them became indispensable to immune health and inflammation.
Today, around 15 years since my experience with Jason, we know that inflammation is an independent cause of heart disease, and that lifestyle factors play an important part in combating it. We are also attempting to become more adept at catching this silent killer. Blood levels of a molecule known as C-reactive protein (CRP) are elevated in inflamed bodies. In heart disease, a special test called high-sensitivity CRP can be used to detect low-level inflammation that may be present years or even decades before a heart attack or stroke manifests. But existing isolated blood markers tend to be nonspecific: they do not tell us why the inflammation is there or how long it has been around for.
New research is focusing on the potential of clusters of markers—inflammatory “signatures”—to better define the state of being silently inflamed. Imaging tests like magnetic resonance imaging or computed tomography scans may add invaluable information, picking up inflammation that surrounds blood vessels or pointing to inflammatory findings in atherosclerotic plaques that predict rupture. In the 21st century, as hidden inflammation weaves through our deadliest diseases, unveiling this force—seeing what has long been unseen—is poised to make its mark on medicine.
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Contributor: Shilpa Ravella