| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
CARDIOLOGY CASEBOOK |
A 72-year-old retired tailor, an Italian immigrant, living in Los Angeles, Calif, consulted his family physician after persistent urging by his wife following the recent death of a relative with an acute myocardial infarction. The tailor was overweight and a habitual cigar smoker, but felt well. The history, physical examination, and electrocardiogram were normal, however a routine blood lipid analysis revealed an unusually low high-density lipoprotein (HDL) level of 20 mg/dL (0.52 mmol/L). The serum low-density lipoprotein (LDL) level was 100 mg/dL (2.59 mmol/L) and the triglyceride level was 180 mg/dL (2.03 mmol/L). Because the HDL level was unusually low and at a level the family physician had not previously observed, he consulted with the Atherosclerosis Research Center at the Cedar Sinai Medical Center in Los Angeles, California, where extensive lipid research was being carried out. On their recommendation, another blood sample was taken for specialized tests. The subsequent report revealed that the tailor had a rare and unusual finding identified as apolipoprotein A-IMilano (apo A-IM).
QUESTIONS
ANSWERS
1. e. an atheroprotective lipid-free protein introduced 2 centuries ago to the population in a small village near Milan, Italy.
About 20 years ago in Limone sul Garda, a small village near Milan, Italy, about 40 villagers were found to be carriers of a naturally occurring variant of apo A-I now known as apo A-IM. Apo A-I is the major constituent of HDL-I. It appears that a man by the name of Giovanni Pomorolli came to this town in 1780 and procreated with a woman named Rosie Giavenelli. All of their offspring have had low HDL (25–30 mg/dL [0.65–0.78 mmol/L]), but had no cardiovascular disease. All had poor lifestyles, but lived to ages 90 and 100 years.
2. d. all of the above
Atherosclerosis is a systemic endothelial disease and may involve the vasculature throughout the body. Atherosclerosis is the number one cause of death in Western societies and is increasing worldwide. Current management of asymptomatic individuals and those with known coronary artery disease relies on identification of the traditional risk factors, estimating risk, and providing treatment to attenuate risk factors by lifestyle changes and the use of reversing and protective medications. Prevention of coronary artery disease is feasible by controlling or eliminating the major risk factors, however, the challenge remains in identifying those at risk for coronary artery disease. Atherosclerotic disease typically manifests itself in the late decades of life, but also occurs in young adults and in obese teenagers who habitually consume large quantities of fast foods high in saturated fats and simple carbohydrates. Early attention to the etiological factors in atherosclerosis can identify individuals at risk long before the clinical manifestations appear, thus stimulating early preventive measures.
3. e. all of the above
The higher the concentrations of total cholesterol, LDL, very low density lipoprotein (VLDL), and triglycerides, the greater the risks for cardiovascular disease. In contrast, levels of HDL or alpha lipoproteins are inversely related to the risk for cardiovascular disease: the higher the HDL, the lower the risk.1 HDLs are particles in the plasma containing 50% lipid (phospholipids, cholesterol, and triglycerides) and 50% apolipoproteins (apo A-I and apo A-II) by weight.2 Human apo A-I is the major constituent of plasma HDL. Cholesterol is mobilized from peripheral tissues into the circulation by HDL and delivered to the liver, where it is metabolized.3 HDL also has anti-inflammatory properties and selectively removes and destroys pro-inflammatory oxidized lipids from the vessel wall, inhibiting the vicious cycle of LDL oxidation and inflammation. Elevated HDL cholesterol levels correlate with a low incidence of cardiovascular disease. Clinical and epidemiological studies show a correlation between low plasma apo A-I and HDL cholesterol levels and an increased risk of premature cardiovascular disease. The protective role of HDL is due to enhanced cholesterol removal by the high levels of HDL particles and decreased delivery of cholesterol by LDL receptors. The extremes of HDL levels offer striking presentations: markedly elevated HDL levels, are associated with an absence of clinical atherosclerosis, and the appearance of a "longevity syndrome," whereas low HDL levels and elevated triglyceride levels are familial patterns of early myocardial infarction, especially when hypercholesterolemia is present.4 The complete or nearly complete absence of HDL is observed in Tangier disease and is characterized by multiple lipid abnormalities, absence of atherosclerosis, hypertrophied tonsils, and splenomegaly, all related to accumulation of cholesterol in the tissues.4 A structural abnormality of apo A-I has been implicated as the defect in Tangier disease.
4. c. the functional unit of its apo A-I
Clinicians are familiar with LDL, HDL, and total cholesterol; however, a new group of proteins has been identified and found to have a major impact on therapy of atherosclerosis. The human apo A-I is the major protein constituent of plasma HDL. The naturally occurring HDL particles transport cholesterol from peripheral tissues to the liver, where it is excreted in bile. However, it is the functional unit of apo A-I that regulates the ability of HDL to remove cholesterol from the cells. The level of apo A-I is a better identifying marker of angiographically documented coronary artery disease than is HDL.2
The new and naturally occurring molecular variant of human apo A-I, the apo A-IM, was discovered in 1980 in an Italian family living in Limone sul Garda. The father, son, and daughter had diet- and drug-resistant hypertriglyceridemia and severe reduction of plasma HDL and apo A-I levels, but had an altered HDL/apo A-I composition in their blood. LDL levels were within the normal range.4 Remarkably, there was an absence of corneal opacities commonly seen with low HDL and high triglyceride levels ("fish eye disease") and also a notable absence of clinical atherosclerosis that accompanies this biochemical profile. The HDL isolated from this family revealed the presence of an abnormal lipid composition, small dense HDL3-sized particles, in contrast to that in control subjects (noncarriers) who had mixtures of HDL3 and large, less dense HDL2 subpopulations. Immunoelectrophoresis in this family, performed in the same manner as for Tangier disease, showed significant differences. In contrast to the findings in patients with Tangier disease, there was a greater amount of immunoreactive apo A-I present (9 bands compared with 4 in normal subjects) in both serum and HDL. In addition, no apo A-I was detected in the fractionation of centrifuged lipoproteins.4 This molecular variant of human lipoprotein A-I is currently known as apo A-IM.
The apo A-IMgene possesses structural differences that impart a loss in lipid-binding capacity and accelerated catabolism, which is the mechanism underlying a more efficient uptake and removal of tissue lipids.5 In contrast to native apo A-I genes, the apo A-IMgene has a cysteine substituted for arginine at position 173 in the amino acid sequence.5,6 The substitution of arginine for cysteine in the A-IMgene alters the ionic interface on the helix and leads to the disappearance of an ion pair. With an unbalanced ionic structure, the altered apo A-I fragment is not able to maintain its lipid binding capacity as would normal apo A-I.5 Carriers of the apo AMilanogene are characterized by extremely low levels of HDL cholesterol (10–30 mg/dL), significant longevity, and a very low prevalence of atherosclerosis.
5. d. recombinant apo A-IM
Pharmacological therapy development through genetic studies has had a significant impact in clinical medicine. Pharmacogenetics and genetic testing have provided the experimental basis that has shown that the variability in a drug response is a function of an individual’s genetic makeup. Genetic polymorphisms can influence the response to medication through a number of mechanisms.6 Genetic testing can also expose dietary interactions that can either potentiate or attenuate atherogenesis. It is noteworthy that the study of familial hypercholesterolemia and elevations in LDL cholesterol provided the impetus for the development of statins (hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors), agents that are effective in reducing LDL cholesterol levels. Significant beneficial clinical outcome has been achieved with target LDL levels as low as 40 mg/dL (1.03 mmol/L). It is quite possible that lower levels of LDL cholesterol may achieve added benefits in the treatment of atherosclerosis. Clinical trials are in progress. On the other hand, low HDL cholesterol levels are the most common lipid abnormality in patients with CAD and are the primary lipid disorder in half of this population. Raising HDL levels has been difficult, and statins only moderately affect HDL, raising levels approximately 5% to 10%. Nicotinic acid, the most effective drug in raising HDL levels, is fraught with side effects and as a result is employed infrequently.7,8
The identification of a naturally occurring variant of apo A-I (the apo A-IM) led to the finding that this HDL/apolipoprotein variant was antiatherogenic. Its effect is associated with a rapid increase in cholesterol efflux–promoting capacity, mobilization of free cholesterol from tissues, and reduction of lipid and macrophage content within the vascular plaque. The positive effect of apo A-IM on atherosclerosis stimulated the development of a recombinant formulation of apo A-IM, which is administered as a phospholipid complex, ET-216. The newly formed HDL-like particle mobilizes cholesterol from the peripheral tissues to the circulation, which results in regression of atherosclerotic plaques.3 In animal studies, these effects were demonstrated within 48 hours following a single high-dose infusion of recombinant apo A-IM phospholipid complex.3,8 In a randomized controlled trial, groups of patients were given either placebo, a low dose (15 mg/kg) or high dose (45 mg/kg) formulation of an exogenously produced, synthetic HDL, a recombinant apo A-IM phospholipid complex (ETC-216). Pretreatment angiography and intravascular ultrasound (IVUS) were assessed to determine atherosclerotic burden. IVUS is well suited in this study because it provides a 360-degree image of the vessel wall rather than a 2-dimensional projection of the lumen and can measure changes that occur in the vessel wall as well as within the lumen.8 The study drug was administered intravenously at weekly intervals for 5 doses. Within 3 weeks of the final dose, repeat angiography and IVUS demonstrated a decrease in atheroma volume of 1.06% (–14.1 mm) in the group treated with ETC 216 and a volume decrease of only 0.14% (–2.9 mm) in the placebo group. There was no difference between the low-and high-dose treatment group. The recombinant apo A-IM produced results similar to those in the families of Limone sul Garda who have the natural apo A-IM.8
Summary
There is incontrovertible evidence that lowering LDL with statin therapy results in clinical benefit in patients with atherosclerosis. The added significance of HDL cholesterol has surfaced following the identification of apo A-IM, a molecular variant of human apo A-I, initially found in a family living in Limone sul Garda (a small town near Milan, Italy). The carriers of apo A-IM have a markedly low HDL cholesterol level and a very low prevalence of atherosclerosis. An artificial HDLMilano developed by a recombinant formulation has been highly successful in preliminary studies. Although recombinant apo A-IM is very effective treatment for atherosclerosis, preventive measures remain primary in this potentially diffuse arterial disease: for example, diet, exercise, and maintaining a normal blood pressure and weight.
ACKNOWLEDGMENT
Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P.O. Box 016960, Miami, FL 33101.
Bielicki JK, Oda MN. Apolipoprotein A-1 milano and apolipoprotein A-1 paris exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-1. Biochemistry. 2002;41:2089–2096.[Medline]
Kaul S, Coin B, Hedayiti A, et al. Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-1 milano phospholipid complex. J Am Coll Cardiol. 2004;44:1311–1319.
Lusis AJ, Fogelman AM, Fonarrow GC. Genetic basis of atherosclerosis: part I—new genes and pathways. Circulation. 2004;110:1868–1873.
Sitori CR, Calabresi L, Franceschini G, et al. Cardiovascular status of carriers of the apolipoprotein A-1 milano mutant—the Limone sul Garda study. Circulation. 2001;103:1949–1954.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
