CASE STUDY

Family History Father: MI and CABG Siblings: Two brothers, one sister have had MI and CABG; one brother died of MI at age 59 years. Physical Exam Height: 68.5 in Weight: 160 lb Body mass index (BMI): 24.3 kg/m2 Waist circumference: 34.5 in Blood pressure: 112/70 mm Hg Pulse: 76 bpm Eyes: No significant abnormality noted Neck: No bruits Chest: Clear Heart: Regular rate without murmur Abdomen: Normal bowel sounds; no hepatomegaly; no bruits Extremities: Normal reflex, sensation, strength, pulse; no edema Medications Diltiazem CD 180 mg qd Ramipril 2.5 mg qd Aspirin 325 mg qd Atorvastatin 80 mg qd Gemfibrozil 600 mg bid Related information on this website: In the Current Literature section: Usefulness of Cardiovascular Family History Data for Population-Based Preventive Medicine and Medical Research (The Health Family Tree Study and the NHLBI Family Heart Study) Williams RR, Hunt SC, Heiss G, et al. Am J Cardiol. 2001;87:129-135. Association of Fibrinogen with Cardiovascular Risk Factors and Cardiovascular Disease in the Framingham Offspring Population Stec JJ, Silbershatz H, Tofler GH, et al. Circulation. 2000;102:1634-1638. In the Newsletter section: An Examination of Novel Risk Factors In the Slide Library section: ATP III: Additional CHD Risk Factors

A Familial Hypercholesterolemic Patient Treated With Heparin-Induced Extracorporeal LDL Precipitation (HELP)   Patrick M. Moriarty, MD   Cheryl Gibson, PhD The following case was provided by NLEC Faculty Member Patrick M. Moriarty, MD, Director of the Lipid, Atherosclerosis, and Apheresis Clinic, University of Kansas Medical Center, and Cheryl Gibson, PhD, a colleague who collaborates on research studies with Dr Moriarty. Drs Moriarty and Gibson are faculty members at the University of Kansas School of Medicine in Kansas City, Kansas. Disclosure Information for Dr Moriarty: Study Grant: B. Braun. Disclosure Information for Dr Gibson: Study Grant: B. Braun. Mr V is a 56-year-old male with a history of familial hypercholesterolemia, hypertension, cardiovascular disease (CVD), four-vessel coronary artery bypass graft (CABG) performed in 1994, and carotid stenosis with left endarterectomy completed in 1997. Family history includes heart disease, with his father, two brothers, and one sister, who have all had myocardial infarctions (MI) and CABG; one brother died of an MI at age 59. Discussion Mr V was referred to the University of Kansas Lipid, Atherosclerosis, and Apheresis Clinic for uncontrolled serum cholesterol levels. When he presented to the clinic, his laboratory values were: TC, 357 mg/dL; TG, 127 mg/dL; HDL-C, 40 mg/dL; and LDL-C, 292 mg/dL—despite diet and combination lipid-lowering therapy (atorvastatin 80 mg qd; gemfibrozil 600 mg bid).     The patient began heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) therapy, a lipid apheresis method that has been shown to be very effective and well tolerated.1,2 LDL apheresis is FDA-approved for patients with CVD and LDL-C levels >200 mg/dL despite maximum lipid-lowering treatment, or LDL-C levels >300 mg/dL without CVD. In the United States, therapy is repeated every 2 weeks. Mr V continues to tolerate the procedure well and has not experienced another cardiovascular event since treatment initiation more than 2 years ago (see Table 1 for lipid levels from his most recent HELP treatment).     The HELP process involves separating red blood cells (RBC) from the plasma, where the latter is then exposed to a buffered (pH 4.8) solution that lowers the plasma pH to 5.2. While adding this buffer, a dose of heparin is mixed with the solution. At a lower pH, the charge state of LDL changes, which attracts heparin and binds the apolipoprotein B. The complex is precipitated from the plasma when passed through a filter. After removal of lipid particles, both the buffer and residual heparin are extracted from the plasma before the addition of RBC. Fewer than 3 L of plasma are treated in one setting and only 300 to 400 mL is ever extracorporeal at any time during the procedure. Albumin, hemoglobin, immunoglobulins, hormones, vitamins, enzymes, and electrolytes are not significantly affected by apheresis. After more than 10 years of long-term treatment, no major complications have been directly associated with LDL apheresis.3     HELP has been found to not only reduce LDL-C acutely and drastically, but also decrease high-sensitivity C-reactive protein (hs-CRP) and fibrinogen by 65%.4 Both of these inflammatory markers have been associated with acute and chronic CVD.5,6 As shown in Table 2, a single apheresis treatment significantly reduced Mr V's hs-CRP and fibrinogen levels. Although the fibrinogen levels rebounded to pre-HELP levels, Mr V's hs-CRP did not return to the pretreatment level.     Blood and plasma viscosity and hemodynamic markers of vascular disease7 can be reduced by more than 15% after one LDL apheresis.8 Assuming a constant hematocrit, the properties responsible for blood viscosity include RBC deformability, RBC aggregation, shear rate, and plasma viscosity.9 Serum cholesterol, particularly LDL-C, can effect RBC deformability10 and RBC aggregation.11 Fibrinogen, due to its asymmetry and size (341,000 daltons), is a major constituent of RBC aggregation and plasma viscosity.12 Improved viscosity is believed to be associated with the 30% increase in coronary vasodilatation capacity found 24 hours after LDL apheresis13 and, more significantly, with the 30% reduction of peripheral vascular resistance that persists 3 weeks after treatment.14     Table 3 lists Mr V's whole-blood viscosity at high and low shear rates before and after HELP therapy. As shown, this patient experienced a greater than 15% reduction in blood viscosity post-HELP therapy. Overall reductions in lipids and other parameters by LDL apheresis may help to explain the immediate improvement in endothelial function, which is important, as dysfunctional endothelial-dependent vasodilatation is an early sign of vascular disease (see Figure 1).15 Conclusion The aggressive reduction of serum lipids and other markers of vascular risk with LDL apheresis can be considered a magnification of what HMG-CoA reductase inhibitors (statins) and other lipid-lowering medications can attain in the prevention and treatment of CVD in patients with dyslipidemia and atherosclerosis. Statins have the ability of reducing both hs-CRP16 and blood viscosity.17 Some statins—but more often fenofibrate and niacin—can significantly reduce serum fibrinogen.18 Statins can also improve endothelial function.19     The effects seen by LDL apheresis further supports the recent changes applied to the guidelines of the National Cholesterol Education Program Adult Treatment Panel III, or ATP III, where aggressive lipid reduction is recommended for patients with CVD, as well as for patients at high risk of developing it. References   1. Lees RS, Holmes NN, Stadler RW, et al. Treatment of hypercholesterolemia with heparin-induced extracorporeal low-density lipoprotein precipitation (HELP). J Clin Apheresis. 1996;11:132-137. 2. Lane DM, McConathy WJ, Laughlin LO, et al. Biweekly treatment of diet/drug-resistant hypercholesterolemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal. Atherosclerosis. 1995;114:203-211. 3. Thiery J, Seidel D. Safety and effectiveness of long-term LDL apheresis in patients at high risk. Curr Opin Lipidol. 1998;9:521-526. 4. Moriarty PM, Gibson CA. C-reactive protein and other markers of inflammation among patients undergoing HELP LDL apheresis. Atherosclerosis. 2001;158:495-498. 5. Lowe GDO. Fibrinogen and cardiovascular disease: historical introduction. Eur Heart J. 1995;16(suppl A):2-5. 6. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143. 7. Rosenson R. Viscosity and ischemic heart disease. Preventive Cardiovascular Medicine. 1993;185:206-212. 8. Schuff-Werner P, Schutz E, Seyde WC, et al. Improved haemorheology associated with a reduction in plasma fibrinogen and LDL in patients being treated by HELP. Eur J Clin Invest. 1989;19:30-37. 9. Lowe GDO. Blood rheology in arterial disease. Clin Sci. 1986;71:137-146. 10. Annapurna V, Puniyani RR, Gupte RV. Red cell deformability and erythrocyte lipids in hypertension. Clin Hemorheol. 1990;10:95-101. 11. Vaya A, Martinez M, Carmena R, Aznar J. Red blood cell aggregation and primary hyperlipoproteinemia. Thrombo Res. 1993;72:119-126. 12. Lane DW, L'Anson S. Viscometric effect of fibrinogen. J Clin Pathol. 1994;47:1004-1005. 13. Mellwig KP, Baller D, Gleichmann U, et al. Improvement of coronary vasodilatation capacity through single LDL apheresis. Atherosclerosis. 1998;139:173-178. 14. Rubba P, Iannuzzi A, Postiglione A, et al. Hemodynamic changes in the peripheral circulation after repeat low density lipoprotein apheresis in familial hypercholesterolemia. Circulation. 1990;81:610-616. 15. Tamai O, Matsuoka H, Itabe H, et al. Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. Circulation. 1997;95:76-82. 16. Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive protein levels. The Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;2861:64-70. 17. Banyai S, Banyai M, Falger J, et al. Atorvastatin improves blood rheology in patients with familial hypercholesterolemia (FH) on long-term LDL apheresis treatment. Atherosclerosis. 2001;159:513-519. 18. Farnier M, Bonnefous F, Debbas N, Irvine A. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med. 1994;154:441-449. 19. Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation. 1994;89:2519-2524.