treating familial hypercholesterolemia

Question: What is the best way to treat familial hypercholesterolemia? I understand that the medication Lipitor can keep some people's cholesterol ratios within normal limits, but my cholesterol is still above 235. What else can be done to reduce my risk of early heart attack? My daughter and I both have it.

Familial hypercholesterolemia is often associated with high LDL cholesterol levels (often above 200) and can lead to premature atherosclerosis. As you've already experienced, lipid-lowering therapy can be helpful but many times does not lower cholesterol to the recommended level for the general population.

It's very important to know that cholesterol levels, although important, only account for about 30% of the variability in CAD (coronary artery disease) incidence. The good news is that other factors like diet, exercise, psychosocial issues and gender are critical, independent of cholesterol levels. So, taking good care of these other factors should reduce your risk, even if you have high LDL cholesterol. Marty Sullivan MD

apolipoproteins in the pathogenesis of atherosclerosis

Recently an international research team described the results of their studies of Lp(a) and apo(a) in the pathogenesis of atherosclerosis. They found that both substances promote vascular smooth muscle cell proliferation and migration, one of the hallmarks of atherosclerosis. Grainger et al. (Cambridge University) and Lawn et al. (Stanford University) cultured smooth muscle cells from healthy human arteries, and then exposed them to Lp(a) and purified apo(A). They found that both Lp(a) and apo(a) -- but not LDL -- caused a dose-dependent acceleration of vascular smooth muscle cell proliferation. They also found that cell-associated plasmin activity was reduced to one seventh the control level by Lp(a) and to one fifth the control level by apo(a) in both human and rat vascular smooth muscle cell cultures. Moreover, Lp(a) and apo(a) both reduced the amount of active TGF-b to 1/100 the level in control (LDL-treated) cultures. Finally, the addition of plasmin to Lp(a)-treated vascular smooth muscle cell cultures overcame the effects of Lp(a) and reduced growth rates to control levels. These results all suggest that the acceleration in smooth muscle cell proliferation is indeed due to the ability of Lp(a) and apo(a) to competitively inhibit the cleavage of plasminogen, reducing plasmin concentrations and TGF-b activation.

Thus, the homology of apo(a) with plasminogen, with subsequent inhibition of plasminogen activation, contributes to atherosclerotic plaque formation by two mechanisms: it prevents the activation of TGF-b, allowing smooth muscle cells to proliferate, and it prevents clot lysis, adding fibrin and other debris to growing atherosclerotic plaque. In addition, Lp(a) binds endothelial and macrophage cells and fibrin, and deposits its cholesterol load and other fatty debris in the vascular endothelium, another hallmark of atherosclerosis. "Both inhibition of clot lysis and enhancement of cell migration could contribute to the process of atherogenesis," concluded the Cambridge and Stanford researchers. "We suggest that Lp(a) may contribute to the growth of the arterial lesions of atherosclerosis by promoting the proliferation of vascular smooth muscle cells."
source:Grainger DJ et al. Science. 1993; 260: 1655- 1658

Eating Rye Bread May Reduce Cholesterol

The ability of dietary fiber, particularly soluble fibers found in cereals, to reduce coronary heart disease risk by improving serum lipid profiles has been demonstrated in several studies. The dietary fiber content of rye is 16.1 g/100 g, but its effects on blood lipids have been studied only in animal models. This study investigated the effects of increasing the amount of rye bread consumed in a daily diet on serum cholesterol levels in men and women in Helsinki, Finland, who had elevated cholesterol. Rye is a commonly used cereal in northern and eastern Europe.

Eighteen men and 22 women participated in the study. They had a baseline serum cholesterol concentration of 6.4 +/- 0.2 mmol/L. Each subject randomly consumed rye or wheat bread as 20% of their total energy intake for 4 weeks at a time, and then crossed over. There was an additional 4-week washout period between bread study periods. During the bread periods, subjects were asked to replace their customarily used breads and baked products with rye bread during the rye period and wheat during the wheat bread period. Test bread portions were 27.5-40.5 g for rye and 22.5-25.0 g for wheat. A minimum of 4-5 portions of the test breads had to be consumed each day. Fasting blood samples were collected at the beginning and the end of the bread periods.

Serum total cholesterol decreased by 8% in men during the rye bread period but did not change significantly in women. Wheat bread did not alter any of the lipid variables studied. Total cholesterol and LDL cholesterol decreased in men in a manner dependent on the amount of rye bread consumed. HDL cholesterol in men increased during the rye bread period, but not significantly. Neither type of bread altered blood levels of glucose and insulin significantly.

The significant reductions in total and LDL cholesterol observed in men were attributed to the fact that men consumed greater quantities of rye bread than women during the study. The greatest change in cholesterol levels occurred in men who ate about 8-10 slices of rye bread per day.

"In conclusion, rye bread is effective in reducing serum total and LDL cholesterol concentrations in men with elevated serum cholesterol," wrote the authors. "Good compliance with consuming a relatively large amount of rye bread in the usual diet indicates that rye bread offers a practical dietary means of reducing serum cholesterol in men."

Journal of Nutrition

activation of plasminogen and apolipoproteins - apo(a)

The major apolipoproteins present in Lp(a) -- the apolipoprotein B or apoB series and the apolipoprotein(a) or apo(a) series -- play different roles in health and disease. ApoB-100 is the portion of the Lp(a) molecule (the ligand) that is recognized by the receptor. Other lipid and apolipoprotein components vary considerably in the LDL complex, but they all interact to maintain the apo B molecule in a specific spatial orientation for receptor binding. The second major Lp(a) apolipoprotein is apo(a), which has been described as a giant mutant of plasminogen. This is because approximately 80% of the amino acid sequence of apo(a) is identical to that of plasminogen. Because of this homology, apo(a) is able to competitively inhibit the surface binding and activation of plasminogen. Blocking plasminogen activation prevents the formation of plasmin, a crucial component in clot lysis. Plasmin is also involved in the activation of a compound referred to as latent transforming growth factor-b (TGF-b), a potent inhibitor of smooth muscle cell growth in the vascular endothelium.
source:Grainger DJ et al. Science

Apolipoproteins and Heart Disease

Lipoprotein(a), or Lp(a), is a lipid-protein complex involved in the transport of cholesterol in the circulation. Scandinavian researchers reported in 1963 that men with high levels of Lp(a) were more susceptible to coronary artery disease (CAD) than men with low levels. Unfortunately, these findings were ignored for more than 20 years because of difficulties in testing for Lp(a). Then 8 years ago, American researchers began reexamining Lp(a). They have since found that a high plasma concentration of Lp(a) is a major risk factor for atherosclerotic and thrombotic vascular disease -- including CAD, myocardial infarction, restenosis of coronary artery grafts, carotid atherosclerosis, and stroke -- and that this risk is independent of age, diet, physical activity, smoking status, ethanol consumption, and sex. Population studies indicate that abnormal plasma levels of Lp(a) may cause up to 25% of premature MIs. Elevated levels of Lp(a) are also associated with significant carotid atherosclerosis, even in the absence of clinical heart disease.
source:Schreiner PJ et al. Arterioscler Thromb.

apolipoprotein studies related to cardiovascular disease

Despite advances in diagnosis, care, and treatment, cardiovascular disease remains the number one killer in the United States and throughout the industrialized world. CAD is particularly common in males, even those less than 50 years old, and in many cases there are no clear risk factors other than a family history of heart disease. Hypercholesterolemia, for example, accounts for less than half of all MIs in the United States. Continuing research on the structure, function, pathophysiology, and heritability of apolipoproteins should lead to improvements in diagnosis, risk assessment, and treatment of cardiovascular and also cerebrovascular diseases.

apolipoprotein E gene polymorphism

Van Bockxmeer and Mamotte studied apolipoprotein E gene polymorphism in 91 Australian men 3--50 years of age with confirmed symptomatic coronary obstructive CAD who had been referred for coronary angioplasty. Each patient had at least one coronary artery with more than 50% luminal diameter obstruction (averaged from multiple views). Patients were compared with 172 healthy men. Five of the 19 CAD patients who were less than 40 years of age were homozygous for the e4 allele, representing a 16-fold increase in prevalence compared with controls. In CAD patients aged 40-50 years, e4 allele frequency was 60% higher than in controls. Moreover, CAD patients homozygous for e4 were 5 years younger, on average, than men with other genotypes (e.g., e3/e4). "Inheritance of e4 seems to confer risk of premature ischemic heart disease in males, homozygotes being especially at risk at a younger age," concluded the investigators.
source:Van Bockxmeer FM, Mamotte CDS. Lancet