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 a significant 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 in 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, its 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 lifespan.
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. A sudden disruption of blood flow causes the 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 of atherosclerotic heart disease and its consequences?
What Is Inflammation?
Inflammation 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 and Heart Disease
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 and 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. Bloodborne 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 the 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 in 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 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 underline 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 to 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 tissue of patients with the metabolic syndrome and obesity produces inflammatory cytokines that may promote vascular inflammation.
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.
Also, some drugs used in the treatment of heart disease, such as aspirin and statins, reduce serum levels of CRP. Reduced inflammation may contribute to the beneficial effects of these drugs.
CRP can be measured using various assays with different testing characteristics. The high sensitivity CRP assay (hs-CRP) 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 hs-CRP, indicating that foods with high GI may be associated with inflammation.
Consumption of trans fats has been associated with markers of systemic inflammation.
Intake 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 on 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 have been associated with low levels of hs-CRP, suggesting that these foods may reduce inflammation. In the ATTICA study adherence to the Mediterranean diet was associated with lower levels of hs-CRP.
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 hs-CRP. 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 underway to address the hypothesis that lowering inflammation will lower event rates and improve prognosis among patients with heart disease.
The CANTOS trial evaluated 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). It is a landmark study because it showed for the first time that blocking an important component of the inflammatory cascade involved in atherosclerotic heart disease is associated with an improved outcome.
The CIRT trial which is funded by the National Heart, Lung, and Blood Institute (NHLBI) will evaluate whether low dose 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.