ATHEROSCLEROSIS:
Current Pathogenic Concepts

      With an estimated annual priced tag of almost 260 billion dollars, cardiovascular disease is responsible for as many as 40% of all deaths in the United States. Atherosclerosis underlies almost all cardiovascular disease as a contributing factor if not a direct cause, so a great deal of research focuses on not only its treatment, but its prevention.
     Current theories revolve around the widely accepted concept of atherosclerotic pathogenesis as a chronic inflammatory response to tissue injury in the vessel walls. Affecting the elastic arteries (those closer to the heart with more elastic fibers than muscle cells in the tunica medica) to a greater extent than the muscular arteries, the formation of fatty streaks is the initial step in the process. These fatty streaks consist of activated macrophages heavily laden with oxidized lipids and drawn to the subintima of the vessels. Along with the smooth muscle cells, these macrophages secrete enzymes that slowly erode the connective tissue framework of the elastic artery. Activated T-cells produce interferon-gamma, which retards the formation of collagen in the essential connective tissue of these vessels.
     The streaks gradually become atheroma through proliferation and differentiation of smooth muscle cells, causing tissue injury in the vessel walls and ensuing platelet adhesion (implicating a role for the plasminogen activator system) and ultimate thrombosis. This promotes the formation of plaque, which further impairs the elasticity of the arteries, the essential property necessary for the contribution of these vessels to blood pressure regulation. Continued buildup of plaque eventually threatens to occlude the affected vessels to cause ischemia, either by gradual narrowing of the lumen or by thrombi, particles of plaque that break off to occlude smaller vessels.
     Atherosclerosis, then, is a chronic condition that may or may not adversely affect the function of numerous organ systems, but that seems relatively benign in itself because of natural compensatory mechanisms (like development of collateral circulation) that tend to mitigate its affects to some extent in some organ systems. The combination of reduced elasticity, arterial stenosis, and impaired organ function is a frequent contributor to hypertension, which in turn promotes hypertrophy of vessel wall smooth muscle and further arterial rigidity. Acute life-threatening problems arise with the release of thrombi, though; and the risk of plaque disruption (and thrombus release) seems more dependent on composition of the plaque than extent of stenosis, occurring most frequently at biochemical and hemodyanamic stress points.
     Sudden elevations in blood pressure brought on by exposure to cold and/or exercise, smoking, or coronary vasospasm are particularly noted for plaque disruption; while the actual thickness, density, and composition of the plaque’s core and cap as well as the extent of inflammation in the tissues supporting the plaque determine its fragility and the likelihood of thrombus formation with such stimuli.

CONTRIBUTING FACTORS
     Though unquestionably a complex disease process involving many predisposing and contributory factors, attention is now being aimed at such factors that are less obvious than lack of optimal physical condition.     
     Hyperlipidemia is one of the more obvious contributing factors to both atherosclerosis and thrombus formation, not only promoting the formation of plaque, but enhancing the likelihood of unstable ischemic events. It remains a focus of the pharmaceutical industry, as a multi-faceted approach consisting of blood pressure control, regular exercise, limitation of dietary lipid intake, and pharmaceutical reduction of blood lipid levels consistently produces lowered risk of fatal events.
     Likewise, obesity’s contribution to the pathogenic process seems obvious. In the obese patient, the circulatory system must pump through literally miles more capillaries through increased resistance. Any reduction in body fat can bring commensurate improvement in atherosclerotic prognosis in the obese patient.
     Hyperhomocysteinemia has also been shown to consistently accompany higher risk of ischemic injury. First correlated with genetic homocystinuria, an autosomal recessive trait that produces highly elevated levels of homocysteine. Patients are deficient in enzyme systems essential for the metabolism of methionine (as well as folate, Vitamins B12, and Vitamin B6 as integral parts of that enzyme system), a situation that ultimately results in both arteriosclerotic and thromboembolic symptoms of profound proportions; but patients with moderately elevated homocysteine levels in the absence of the autosomal recessive disease also show elevated risk of atherosclerosis and thromboembolism that is completely independent of other risk factors. A partial expression of the recessive traits is suspected as a likely cause of such dose-related risk, and treatment with folate, Vitamin B12, and Vitamin B6 seems to consistently improve prognosis for these patients.
     Chlamydial infection (Chlamydia pneumoniae), noted for causing sinusitis, pharyngitis, bronchitis, and pneumonia, may cause the initial tissue injury mentioned above and precipitate the formation of atherosclerotic plaque or even destabilize existing plaque to trigger an immune response and ensuing arterial inflammation and degeneration.
     Far from mere speculation, the hypothesis is exemplified by the implication of H. pylori in the pathogenesis of peptic ulcer disease and backed by substantial seroepidemiologic, histopathologic, and microbiological evidence. Consistent elevations in IgA and IgG to C. pneumoniae seen in patients with atherosclerosis have indicated that initial colonization occurs in the alveolar macrophages in the lung. These infected macrophages find their way to arterial walls and are acted upon by antibodies specific for c pneumoniae to cause initial tissue injury. A similar scenario is seen with chronic infection of the vessel walls with Herpes viruses as the initial trigger for tissue injury.
     Insulin sensitivity is an important risk factor predisposing to atherosclerosis, but its relation to a variety of other cardiovascular risk factors complicates the determination of whether or not it maintains a distinct role in the process. The results of one recent study indicate that a strong correlation exists between diminished insulin sensitivity and increased atherosclerotic risk in Hispanic and non-Hispanic white populations, but not in black populations.
     Though diabetes itself is considered a significant cardiovascular risk factor, the typical diabetic endures multiple risk factors, such as impaired circulation, dyslipidemia, obesity, hypertension, smoking, lack of exercise, etc. The diabetic patient is therefore at particular risk of serious complications of atherosclerosis and should be managed accordingly.
     Oxidation also seems to play a pivotal role in atherogenesis. LDL, a primary culprit in the formation of plaque and atherosclerotic lesions, is absorbed and retained by macrophages that deposit in the vessel walls as foam cells. Studies have shown, though, that macrophages actually have few receptors for n-LDL, the naturally-occurring form of the molecules, indicating that the LDL must first be oxidized or acetylated in order to be absorbed by scavenging macrophages to cause atherosclerotic deposits.
     In light of the ubiquitous nature of oxidative free radicals, it follows that ensuring the ample intake of dietary or supplemental antioxidants would be of obvious preventive benefit. It is also postulated that such naturally occurring free radicals perpetuate a chain reaction in the LDL to produce abnormally high levels of the oxidative processes, thus further accelerating the uptake of LDL by the macrophages; so the presence of antioxidants is presumed doubly important in slowing the disease process of atherosclerosis. It goes without saying that the more LDL in the system, the more opportunity for oxidation, deposit, and plaque formation.
     Small wonder, then, that proponents of natural remedies laud the benefits of Vitamins A, C, and E. Long-term studies, though, bear out the benefits of Vitamin E in post-surgical coronary patients, while Vitamins A and C appear to have little effect on either plaque or thrombus formation.

White-coat syndrome may not be so benign.
     By measuring arterial plaque formation via ultrasound and monitoring the blood pressure in subjects, researchers have found that those patients with the greatest blood pressure increases under mental stress seem to consistently have the most advanced development of atherosclerosis. Thus it is postulated that one’s response to mental stress is a key factor in cardiovascular risk. Even in the presence of such mental stress, the ability to control blood pressure or even to control one’s emotional response to such stress should substantially reduce the risks associated with atherosclerosis. The correlation increases with age, is more pronounced in males, and is usually seen in patients chronically responding with anger – those with bad tempers. So, chill.
      ASPIRIN was shown in the late 1980’s to be extremely effective at reducing the risk of nonfatal stroke and myocardial infarction in both those with and without a history of cardiovascular disease, effectively reducing the frequency of myocardial infarction in the general population by almost half. Consequent recommendations of the U.S. Preventive Services Task Force (USPSTF) were that all men over the age of forty with increased risk of heart disease should take aspirin in low doses on a regular basis in the absence of contraindications.  
     Current evidence also suggests aspirin not only reduces the frequency of ischemic events, but the severity of such events as well; and higher doses (up to 1,000mg per day) have been shown to reduce both frequency and severity of recurrent strokes. Here’s how a recent study shows we’re complying with that recommendation.

Here’s how a recent study shows we’re complying with that recommendation.

Overall prevalence of aspirin use: 23.3%

IS PRESERVATIVE-FREE REALLY GOOD FOR YOU?    
     Food additives, more frequently suspected as problematic in the eyes of health officials as well as the public, may actually reduce the risks of heart disease instead. Certain additives are “aspirin-like” salicylates that actually inhibit platelet aggregation to short-circuit the process of plaque formation) and prostaglandin synthesis (to reduce inflammation and minimize thrombus formation as well as plaque formation) just like therapeutic salicylates, and they not only show up as food additives, but are also effectively absorbed from cosmetic products through the skin as well. They occur naturally in foods like fresh or canned tomatoes and fruits, fresh oranges and raspberries, certain teas, and numerous spices like cinnamon, curry, dill, oregano, cumin, anise, cayenne, paprika, dry mustard, rosemary, and thyme; and the beneficial impact of these substances in the food supply is actually being touted as producing a significant in the overall health of the population in this country.

MORE INFORMATION FOR YOU AND YOUR PATIENTS
     The American Heart Association maintains an excellent website that offers a wealth of information, both for the layman and the health professional. Look up their Heart and Stroke Guide at http://www.amhrt.org/heartg/aa00.htm. The association’s Heart-Healthy Books and Tapes (http://www.amhrt.org/pubs/cook/books.html) are a ready source of a storehouse of information to help your patients get and stay healthy.

MedWeb (http://www.gen.emory.edu/medweb/medweb.news.html) provides a mountainous compilation of links to health-related sites of all kinds, of particular interest to those needing more information on heart disease, atherosclerosis, stroke, and hypertension.

The National Heart, Lung, and Blood Institute (NHLBI at http://www.nhlbi.nih.gov/nhlbi/nhlbi.htm) provides information, the latest research news, and information for those interested in participating in ongoing research efforts. “Every twenty seconds, a person in the U.S. has a heart attack,” says The Heart Information Network website (http://207.69.209.38/). It, too, provides a plethora of information on the subject for both professional and lay audiences. Medscape (http://www.medscape.com) maintains a very current database of articles, not just on heart disease, but almost any aspect of health care.

MEN VERSUS WOMEN
      Higher estrogen levels seem to protect premenopausal women from the early onset of dyslipidemia and atherosclerosis, with men encountering problems much earlier in life than women. Though early studies recognized significant heart disease only in men and concentrated their research exclusively on populations of men, things have thankfully changed.
     In the early days of cardiovascular research, the critical situation where men were dying off at alarming rates almost demanded such a focussed, if politically misguided, approach that undoubtedly saved countless lives. Unfortunately, though, such research completely ignored the plight of women, encountered later in life after estrogen levels drop to expose them to the same risks men face all their lives.
     Hormone replacement therapy, though having it’s own liabilities, can significantly delay the onset of atherosclerotic problems in women. Administration of oral exogenous estrogens raises HDL, decreases LDL cholesterol, and lowers the increased fibrinogen levels that are common in post-menopausal women; while androgens do the opposite.