Apheresis technology for prevention and regression of atherosclerosis: an overview.

Low density lipoprotein (LDL) apheresis is at present one method of treatment in homozygous cases of familial hypercholesterolemia (FH). It is also effective in the prevention of the development of coronary atherosclerosis in patients with heterozygous FH and other types of mild hypercholesterolemia, leading to the regression of the stenosing lesions. In this paper, an overview is presented on the development of the devices for LDL apheresis and its short- and long-term effects on FH mainly based upon experience with the Liposorber system. LDL apheresis has served to protect the lives of patients from life threatening diseases like myocardial infarction although observations for more than 10 years in some laboratories have shown that the progression of atherosclerosis has taken place in many patients, and more importantly, the involvement of the aortic valve with calcification has developed, especially in patients who had homozygous FH, making this the most obstinate complication of FH. Therefore, more aggressive treatment or the combination of LDL apheresis with other therapies is required in the future. LDL apheresis has also been approved for the treatment of glomerulosclerosis and arteriosclerosis obliterans.     

Low-density lipoprotein apheresis for prevention and regression of atherosclerosis: clinical results.

Hypercholesterolemia can be adequately controlled by appropriate diet and maximum lipid lowering drug therapy in most patients. Nevertheless, there exists a group of patients, including those with familial hypercholesterolemia (FH), who remain at high risk for the development or progression of premature coronary heart disease (CHD). For these patients additional measures such as surgery and low-density lipoprotein (LDL) apheresis have to be considered. The objective of this multicenter trial, which included 30 clinical centers (28 in Germany and one each in Scotland and Luxembourg), was to determine if repeated LDL apheresis using the Liposorber LA-15 system (Kaneka Corporation, Osaka, Japan) could lead to an additional acute and time averaged lowering of total cholesterol (TC) and LDL-cholesterol (LDL-C) in severely hypercholesterolemic patients whose cholesterol levels could not be controlled by appropriate diet and maximum drug therapy. A total of 6,798 treatments were performed on 120 patients, including 8 with homozygous FH, 75 with heterozygous FH, and 37 with unclassified FH or other hyperlipidemias from 1988 through 1994. The mean TC and mean LDL-C levels at baseline were 410.0 mg/dl and 333.9 mg/dl, respectively. LDL apheresis was performed once a week or at least once every 2 weeks in all patients. During treatment with the Liposorber system the mean acute percentage reduction was 52.6% for TC and 63.1% for LDL-C. Very low density lipoprotein cholesterol (VLDL-C) and triglycerides (TG) were also substantially reduced to 60.6% and 47.5%, respectively. Fibrinogen, a potential risk factor for CHD, was reduced by 26.2%. In contrast, the mean acute reduction of high density lipoprotein (HDL) was only 3.4%. During the course of the treatment, the time averaged levels of TC and LDL-C were reduced by approximately 39% and 50%, respectively, compared to baseline levels. The adverse events (AEs) were those generally associated with extracorporeal treatments. The most common AE was hypotension, with 69 episodes corresponding to 1% of all treatments reported in 44 of the 120 patients treated. All other kinds of AEs occurred in less than 0.2% of the treatments. The treatment with the Liposorber LA-15 system was overall well tolerated. It should be noted, however, that a more severe type of hypotensive reaction associated with flush, bradycardia, and dyspnea was reported in patients taking concomitant angiotensin converting enzyme (ACE) inhibitor medication. Except for such anaphylactoid-like reactions associated with the intake of ACE inhibitors, the Liposorber LA-15 system represents a safe and effective therapeutic option for patients suffering from severe hypercholesterolemia that could not be adequately controlled by diet and maximum drug therapy.     

Hemodynamic sequelae of regression of experimental atherosclerosis.

Regression of experimental atherosclerosis is characterized by decreased intimal thickness and luminal enlargement, but intimal fibrosis becomes more dense. We tested the hypothesis that fibrosis of arteries during regression might limit vasodilator capacity and restrict hemodynamic improvement despite luminal improvement. We studied limb, coronary, and cerebral hemodynamics in 11 normal cynomolgus monkeys, 10 monkeys given an atherogenic diet for 20 mo and 8 monkeys given a regression diet for an additional 18 mo. The atherogenic diet induced lesions of moderate severity (50-60% stenosis); owing to characteristic vessel growth during the atherogenic period, luminal size did not decrease correspondingly. Regression monkeys showed typical changes of regression with luminal enlargement but increased fibrosis. The iliac artery was perfused at constant blood flow and maximal vasodilatation was produced with papaverine. Blood flow was measured with microspheres during maximal vasodilatation in the coronary bed (adenosine) and cerebral bed (hypercapnia). In normal monkeys, minimal vascular resistances were 1.95 +/- 0.19 mm Hg/ml/min X 100 g (mean +/- SE) (limb), 0.13 +/- 0.01 (coronary), and 0.44 +/- 0.02 (cerebral). In atherosclerotic monkeys minimal resistance increased (P less than 0.05) 108, 62, and 166% in the limb, coronary, and cerebral beds, respectively. In regression monkeys, minimal resistance increased from values found in atherosclerotic animals in the limb (+22%), decreased inconsistently in the coronary bed (-19%), and decreased significantly in the cerebral bed (-44%, P less than 0.05). Thus morphologic regression was accompanied by significant hemodynamic improvement during maximal dilatation only in cerebral vessels. We conclude that increases in luminal size during regression of atherosclerotic lesions may not be associated with increases in vasodilator capacity, as intimal fibrosis may limit physiologically important hemodynamic improvement.     

Apheresis for renal disease.

Many primary renal diseases are associated with either antibody deposition within the glomerulus or an antibody associated autoimmunity, as may be seen with certain vasculitidies. Examples of these diseases include Goodpasture's syndrome, cryoglobulinemia, antineutrophil cytoplasmic antibody positive syndromes, and other forms of rapidly progressive glomerulonephritis. Immunoglobulins also may be nephrotoxic to the tubules such as is the case with myeloma related light chains. Given the rapid removal of immunoglobulins by therapeutic plasma exchange, this modality has been considered an appealing management option in the treatment of these renal diseases. Although not classically considered as autoimmune diseases, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are related syndromes which often involve the kidneys. Although previously unexplained, it has been long appreciated that therapeutic plasma exchange (PE) can be a useful treatment for these microangiopathic hemolytic anemias, but the most recent insights into their pathogenesis suggest that PE may be beneficial by replacing a missing enzyme or removing pathogenic autoantibodies.     

Exercise therapy for prevention of atherosclerosis

Moderate-intensity physical activities not only reduce the mortality from cardiovascular disease but also all-cause mortality. Mechanism by which moderate-intensity physical activity prevent atherosclerotic cardiovascular disease has become increasingly clear. Atherosclerosis has been confirmed as an inflammatory disease and increased levels of C-reactive protein have been associated with atherosclerosis. This review will examine how physical activities protect from atherosclerosis from the perspective of vascular inflammation.     

Targeting HDL-mediated cellular cholesterol efflux for the treatment and prevention of atherosclerosis.

The hallmark of the atherosclerotic lesion is the overaccumulation of cholesterol in arterial wall cells. As no pathway exists for the degradation of cholesterol in peripheral cells, a mechanism is necessary to prevent its accumulation to toxic levels in these cells and to allow its delivery to the liver for excretion in bile. Promoting this reverse cholesterol transport pathway is believed to be the main cardioprotective action of high density lipoprotein (HDL). The rate-limiting step in this pathway is likely the initial removal of cholesterol from peripheral cells by HDL. The pathway HDL utilizes for inducing efflux of excess cellular cholesterol represents an important and as-yet untapped mechanism to employ for the treatment and prevention of atherosclerotic vascular disease. This review summarizes the potential cardioprotective actions of HDL, the mechanisms of HDL-mediated cellular cholesterol efflux, and evidence that the specific pathway of cholesterol removal by HDL may be enhanced and used as a novel target in the therapy of atherosclerosis.     

New methodologies for studying the prevention of atherosclerosis

To determine if multiple risk factor modification favorably alters the rate of progression of coronary atherosclerosis, 300 patients with established atherosclerosis have been randomized into a clinical trial; 155 to usual care and 145 to special intervention. All patients have medical/risk examinations at baseline and annually for 4 years. The special intervention patients undergo aggressive risk factor management with emphasis on lipoprotein modification, dietary management, smoking abatement, blood pressure control, weight loss and increased physical activity. To measure progression of atherosclerosis, a quantitative, computer-assisted coronary arteriographic system was developed to analyze the baseline and 4-year follow-up arteriograms. This procedure uses a catheter with a metallic calibration cylinder at its tip to determine absolute artery size and automated computer edge detection techniques to define the internal border of the artery. The analysis system detects artery borders using changes in cine film density and measures distances between these borders. For each segment the minimum, maximum and mean diameters are measured and percent stenosis and atheroma area calculated. This system provides precise and reproducible measures of coronary artery segment diameter. Using this technique, we estimate a 33% reduction in the rate of coronary artery progression over 4 years, defined as mean segment diameter, can be detected at a power of 0.80 and an alpha of 0.05 (one tailed test) with a sample size of 120 in each of 2 groups.     

Apheresis technologies and clinical applications: the 2000 International Apheresis Registry.

The developments in apheresis technologies and techniques and their clinical applications worldwide are technologically, sociologically, and economically driven. In the past, apheresis survey statistics have highlighted both the differences by geographical region in clinical practices and in the types of technologies utilized. While a national view of apheresis is critically important, an international view of apheresis may be more representative overall of this therapeutic modality than national results that are highly dependent on the local economics and the available technologies. These regional differences have provided a basis for the scientific and clinical assessments of these apheresis technologies and their clinical outcomes and have impacted the marketing and business developments of new technologies worldwide. The results of the International Apheresis Registry for 2000 reporting on 39 centers on 4 continents are presented. This survey collected data on 1,080 patients for a total of 15,257 treatments. Information gathered included patient demographics, medical history, treatment diagnoses, treatment specifics (type, methodology, access type, anticoagulants, drugs, equipment usage), side effects, clinical response, and payment provider. As in the prior International Apheresis Registry for 1983, the survey results highlighted the regional differences in apheresis usage and treatment specifics, indicating that an international overview of apheresis may be more representative of the impact of this therapeutic modality.     

Influenza and atherosclerosis: vaccination for cardiovascular disease prevention

In both animal and human studies, strong prothrombotic and pro-inflammatory effects have been observed after influenza infection. Influenza is an important trigger for acute coronary syndromes, and it has been shown that in the US it may cause up to 90,000 deaths per year simply by triggering fatal myocardial infarctions. Multiple case-control and cohort studies have shown that the influenza vaccine has a marked protective effect against cardiovascular events, decreasing the incidence of these events by 20 – 70% in the settings of primary and secondary prevention. Although influenza vaccination is an extremely cost-effective method of cardiovascular protection and is recommended for all patients with cardiac diseases, it is largely underused in these patients. Therefore, increased efforts should be directed towards educating physicians and patients about the benefits of influenza vaccination in patients with coronary heart disease.     

Influenza and atherosclerosis: vaccination for cardiovascular disease prevention

In both animal and human studies, strong prothrombotic and pro-inflammatory effects have been observed after influenza infection. Influenza is an important trigger for acute coronary syndromes, and it has been shown that in the US it may cause up to 90,000 deaths per year simply by triggering fatal myocardial infarctions. Multiple case-control and cohort studies have shown that the influenza vaccine has a marked protective effect against cardiovascular events, decreasing the incidence of these events by 20 - 70% in the settings of primary and secondary prevention. Although influenza vaccination is an extremely cost-effective method of cardiovascular protection and is recommended for all patients with cardiac diseases, it is largely underused in these patients. Therefore, increased efforts should be directed towards educating physicians and patients about the benefits of influenza vaccination in patients with coronary heart disease.     

Apheresis techniques and cellular immunomodulation.

Significant advances have been made in the capabilities to remove white blood cells (WBCs) from blood by both centrifugal and filtration techniques. New techniques have applications for both donor products (and their effects upon the recipients) and for selected disease therapeutics. The immunomodulatory effects of donor WBCs may be therapeutic, e.g., granulocytes harvested by apheresis may be used for the treatment of sepsis, or mononuclear cells collected by apheresis for peripheral blood progenitor (stem) cell transplantation or graft versus leukemia effect. In contrast, WBCs are removed from many transfusable components to decrease the immune effects in recipients. This has been accomplished primarily by the use of leukoreduction filters although newer adaptations of centrifugal equipment allow for the reduction of WBCs to target range of <1 x 10(6) WBCs/product. Therapeutic WBC removal by centrifuge has been used for treatment of the effects due to elevated levels of WBCs or platelets. More specific cellular immunotherapy has included lymphocytapheresis for the treatment of autoimmune diseases such as systemic lupus erythematosis (SLE). Various mononuclear cell fractions collected by apheresis have been used for lymphokine activated killer cells (LAK) and tumor infiltrating lymphocytes (TIL) cell therapy or autologous stem cell transplantation. The development of WBC adsorbent filters for therapeutic use has evolved as nonspecific filter materials have been demonstrated to show selective WBC removal, and filter columns permit therapeutic reductions in WBCs using online filtration therapy. Specific adsorption techniques, e.g., CD-34 selection, are in use in vitro and indicate directions for further developments in cellular immunotherapy.     

Apheresis in lupus nephritis.

Systemic lupus erythematosus is a chronic autoimmune disease which commonly involves the kidneys. Despite great improvement in survival over the past years due to immunosuppressive therapy, renal failure remains an important cause of morbidity and mortality. In view of the pathogenesis of lupus nephritis, the use of less toxic and more specific ways of treatment such as the extracorporeal removal of pathogenetically relevant autoantibodies seems rational. On the basis of currently available studies, plasma exchange used alone or as an adjunct to conventional immunosuppressive therapy offers no clear benefit over standard immunosuppression in patients with active lupus nephritis and therefore cannot be recommended. However, although not proven, plasmapheresis might be beneficial in patients with acute life-threatening disease, for which high-dose immunosuppressive therapy may not be possible, or as an adjunct procedure for patients not responding to conventional therapy. Rather than the unselective removal of plasma, adsorption procedures allow the selective or specific removal of immunoglobulins, which seems to be a more reasonable approach in lupus nephritis. The results of the first clinical trials using different adsorption columns seem promising, but their use cannot be recommended until well-designed, case-controlled studies have been performed to prove their usefulness and cost effectiveness in lupus nephritis. So far, clear-cut recommendations regarding type of adsorption column, intensity and duration of treatment, and accompanying immunosuppressive treatment cannot be given.