By Kilmer McCully, M.D.
Introduction: Vulnerable plaques are a phase in the natural development of atherosclerotic disease when the plaque material is composed primarily of platelets that have aggregated but still lack the stabilizing effect of fibrin connective tissue threads, which take more time to accumulate, so the clotted matter can easily be dislodged.
The term "vulnerable" applies particularly to this unstable phase of development when many different factors can combine to cause fragments of various size to break free of the parent mass and abruptly enter the (arterial) circulation traveling only so far until further progress is impeded by its size, at which point it is stopped, plug-like, to suddenly deprive a segment of cardiac muscle tissue of vital nutrients (infarction).
If this is sustained for more than a short while, muscle damage becomes irreparable causing weakening of the heart as a pump or immediate death by the irritative effect of the injury, often by inducing arrhythmias, ventricular tachycardias (fast heart) or fibrillation (completely irregular heart) incompatible with life.
Infections and Vulnerable Plaques
We have learned that cholesterol plays a minor role in creation of plaques, at least in younger men, and that homocysteine elevation increases the formation of plaques and risk of disease in animals and in human populations, through dietary deficiency of B vitamins, genetic factors, and altered metabolism of methionine.
However, there are many other factors that are known to increase risk of vascular disease. In particular, mental and emotional stress, smoking, aging, male gender, postmenopausal status in women, diabetes, kidney failure, hypothyroidism, and high blood pressure are all important determinants of disease risk.
Surveys, case control studies, and experimental studies have shown that each of these factors increases homocysteine levels in animals and man. How do these diverse factors conspire to produce vulnerable plaques in the arteries that by rupturing cause hemorrhage, thrombosis with occlusion, and death of heart, brain and other tissues in patients with vascular disease?
A century ago the cause of arteriosclerosis was generally considered to originate from "direct irritation of [arterial] tissue by infection or toxins." Bacteria and viruses were considered as the main cause of atherosclerosis, because of increased plaques in patients dying of typhoid fever and other infections.
Sir William Osler, the Canadian pathologist and physician who became the Regius Professor of Medicine at Oxford and a leading physician of his time, described the vulnerable plaque as a pustule. More recently, much evidence has been reported to support the role of infections in vascular disease. In particular, cardiovascular mortality increases during influenza epidemics.
A third of patients with acute myocardial infarction or stroke have had an infectious disease immediately before onset. Bacteriemia and periodontal infections are associated with an increased risk of cardiovascular disease. Serological markers of infection are elevated in patients with cardiovascular disease. And coronary arteries of children are found to be narrowed in children who died of infectious diseases.
Beginning in 1939 and in the next decade, investigators discovered that lipoproteins function as a nonspecific immune system that is capable of inactivating a wide variety of bacteria, viruses, protozoans and their toxins. Lipoproteins form complexes with these organisms that render them inactive, and macrophages in the tissues are capable of phagocytosis of these complexes, leading to formation of foam cells that destroy these organisms.
The lipopolysaccharides and lipoteichoic acids of these organisms bind with lipoproteins, probably because of their lipophilic properties, rendering them inactive. Some examples of organisms that are inactivated this way are Salmonella, the cause of typhoid fever and other gastrointestinal infections, Herpes simplex, Rotavirus and Cytomegalovirus, the cause of ubiquitous viral infections, Chlamydia pneumoniae, a respiratory pathogen, and Staphylococcus aureus, an important cause of boils, carbuncles, and pneumonia.
Beginning in the 1970s investigators found evidence of a wide variety of micro-organisms in human atherosclerotic plaques, as demonstrated by immunohistochemistry, polymerase chain reaction for DNA fragments, and electron microscopy. Only in the case of Chlamydia pneumoniae were investigators able to culture viable organisms directly from plaques.
In most cases, only remnants of micro-organisms are found, and viable organisms cannot be cultured from plaques. Using sophisticated DNA technology, a recent report from Germany demonstrated the presence of 50 different micro-organisms in human plaques, and the average number was 12 per plaque. Arteries without plaques contained no microbial remnants. Many common organisms form complexes with lipoproteins, such as Eschericia coli, Staphylococcus, Streptococcus, Salmonella, and rotavirus. The same organisms are demonstrated in plaques, suggesting an infectious origin of plaques.
Kilmer S. McCully, M.D.
Chief, Pathology and Laboratory Medicine Service
West Roxbury Veterans Affairs Medical Center